occurring several hours before the medication would be expected to wear

off. Patients may report seeing the “ghost” of slow-release tablets in their
stool. Most patients who have a low colostomy (in the left lower quadrant
on abdominal exam) only uncommonly malabsorb slow-release opioids,
whereas patients with a right-sided colostomy or ileostomy are at much
higher risk. These patients should be considered for transdermal opioids or
some other route of opioid administration.
Patients who have upper GI malignancy and pain are also at risk to
develop concurrent nausea, obstruction, or other GI symptoms. At an early
stage in their disease, they should be considered for another route of
administration of analgesic medication.

MANAGING CANCER PAIN IN THE ADDICT

The overall strategy for pain management in the patient who carries an
addiction diagnosis should be tempered according to whether the history is
that of remote addiction, recent addiction, or active addiction. It must be
stated that use of controlled substances for any legitimate medical purpose
requires vigilance and a risk management approach that considers
diversion and abuse, irrespective of the patient’s diagnosis or history.
However, medical judgment must be used to determine the extent of such
programs relative to the patient’s individual circumstances. In all
situations, the clinician will want to understand if the patient is in active
recovery and/or maintenance therapy, communicate with the patient’s
addiction counselor/therapist, and look carefully for evidence of aberrant
or problematic drug-taking behavior. The patient with a remote history of
substance abuse and who currently has a stable social situation and a
spouse or other close family member should be managed as any other
cancer pain patient. However, these patients and their family members are
oftentimes very concerned about rekindling addiction and may be highly
opioid phobic. Long-acting oral opioids, transdermal opioids, or opioid
preparations with abuse-deterrent technologies are the preference. The
dose should be titrated upward to effect, with a structured management
program (e.g., frequent follow-up visits, small or modest supplies of
medicine dispensed at any given time, urine drug screens) to provide
sufficient support for the patient and family. There should in most

2001
circumstances be only one prescribing physician, and once stable analgesia
is achieved, there should be sufficient confidence and evidence of
compliance and increasingly longer periods of time between prescribing
visits. To the patient who is a recent user and in recovery, the discussion
needs to be more frank and the plan of care more structured. The clinician
should not only outline the goals of care (improved comfort and improved
function) but also inquire the patient about his or her level of concern
regarding opioids. The physician should warn the patient to not take the
opioids for any reason other than relief of pain. Together, they should
agree as to how often the medication prescriptions should be refilled and
by whom. Comanagement with an addiction specialist is advised if the
prescribing clinician is not well versed in addiction medicine.
Unsanctioned dose escalation is not allowed, and if necessary, the
medications may need to be controlled by the spouse or other family
member.
Cancer patients who are actively abusing pose particular challenges. The
patient and the clinician hope that the patient can achieve relief of pain, but
the prescribing physician will be particularly wary of causing harm. Harm
includes the risk of drug diversion or overdosing because the patient is
accustomed to a less potent source of drug. Also, there is the risk that the
pain medication may be stolen by those around the patient because of the
social circumstances that often accompany addiction. There needs to be a
firm, concrete framework to support clinical care. In these situations, daily
dispensing of pain medication is often required, along with observed
ingestion. If transdermal fentanyl patches are prescribed, which may be
useful in these circumstances, the patch should be replaced under
observation and then either disposed of properly or the used patch may be
brought to the next prescribing visit and disposed under observation of
clinicians. Liquid methadone may also be preferable over other analgesics
or formulations in this circumstance.
A written agreement delineates expected behavior and the consequences
of nonadherence. The agreement (sometimes referred to as an opioid
contract) should include periodic unscheduled drug screening if the patient
has committed to not use other drugs. In certain jurisdictions, the
prescribing physician can benefit from a state or provincial computerized

2002
prescription network whereby it can be determined if the patient is
obtaining prescription medications from another legitimate source. One
should avoid high doses of opioids and should also consider
nonpharmacologic interventions at an earlier stage (such as palliative
radiotherapy or neural blockage).

SAFE PRESCRIBING PRACTICES: UNIVERSAL

PRECAUTIONS
Beyond strategies applicable for the situation of cancer pain in a patient
with a history of addiction is an emerging approach to safe prescribing
opioid practice which is designed to guide care for all patients who are
potentially candidates for opioids, whether or not there is a history of
substance abuse. Recent years have seen heightened awareness of risk of
misuse of opioids acquired through the health care system—awareness by
the health care community, by patients and their families, by the public,
and by regulatory bodies. Extensive guidance is available regarding safe
prescribing practices44 and universal precautions.45 Although much
attention has been paid to safe practices in noncancer pain management,
increasingly, there is awareness that cancer pain, palliative care, and end-
of-life care are situations which warrant similar high levels of caution.
Accurate use of words helps to delineate the landscape of substance
abuse and the clinician’s role in risk reduction. As described elsewhere in
this book (see Chapter 32), addiction is on the far end of a spectrum of
substance use disorders. Addiction is characterized by continued substance
use despite demonstrable harm, craving, loss of control, and compulsive
drug use such as gorging. Drug abuse is defined as drug use in a manner
different than social norms. Evidence of drug abuse in the clinical setting
can include aberrant drug behavior or nonadherence behavior.
A universal precautions strategy to prescribe opioids for cancer pain
should be applied to all pain patients; it should include a specific focus on
clinical assessment to stratify for risk, and a focus on elements of ongoing
care:
Clinical assessment to stratify for risk
• Personal history of alcohol consumption
• Personal history of drug abuse

2003
 • Current heavy smoking/chronic unemployment
• Poor psychosocial support
• Family history of alcohol or drug abuse
• Establish treatment goals such as targets for pain reduction or
improved function
Ongoing care
• Only one physician prescribes scheduled medications.
• Regularly review a patient’s scheduled prescriptions using a state,
provincial, or national prescription drug monitoring program.
• Monitor for and respond to aberrant behavior such as unsanctioned
dose escalation, lost prescriptions, seeking medications from other
physicians, or other aberrant activity.
• Continue opioid therapy only if meaningful benefits are present that
outweigh the risks to patients.
Clinicians working in a cancer pain practice are often surprised at
advice that they should consider instituting safe prescribing practices
which are more commonly encountered in the chronic noncancer
population. However, drug abuse touches almost all parts of society.
Having a prospective, structured approach to safe prescribing equips the
clinician to continue to have a prescribing relationship with a patient who
subsequently develops what appears to be aberrant behavior.
Commensurate with risk, the clinician should consider a range of
approaches to respond to problematic behavior. These can include weekly,
semiweekly, or daily carries of prescription refills for scheduled
medications; random urine drug screens; blood levels of analgesics or of
acetaminophen if it is present in breakthrough medications (record
carefully when the last dose was taken in relation to timing of
phlebotomy); home visits by physician or nurse, including medication
reconciliation and direct interview of family members to explore their
perspectives; or switch to opioid preparations considered to have a lower
risk of diversion or abuse.
If drug diversion has occurred, stop prescribing or switch to a highly
structured regimen such as witnessed ingestion of methadone.

SYMPTOM CLUSTERS

2004
Cancer patients commonly have more than one symptom. A large survey
of medical oncology inpatients and outpatients from a US Veterans Affairs
medical center revealed that most had several symptoms, including low
energy (62%), pain (59%), dry mouth (54%), shortness of breath (50%),
and sleeping difficulty (45%).46 Patients with “moderate” intensity pain
had a median number of 11 symptoms, and as the performance status fell,
the number of intense symptoms increased. Other studies have confirmed
that cancer patients commonly have many distressing symptoms, and as
the severity of disease increases, so does the number and severity of
symptoms.47
The concept of symptom clusters has emerged as an area of intense
research. Symptom clusters have been defined as three or more concurrent
symptoms that are related to each other but do not necessarily share the
same etiology.48 There is evidence that the coexistence of several
symptoms in the same patient is associated with worse quality of life and
potentially will benefit from specific, targeted therapeutic approaches. For
example, it has been suggested that release of cytokines may result in a
range of symptoms related to cancer and its treatment.49 A wide array of
specific clusters has been reported. Examples posited to date include
fatigue-anorexia-cachexia cluster (easy fatigue, weakness, anorexia, lack
of energy, dry mouth, early satiety, weight loss, and taste changes), upper
GI cluster (dizzy spells, dyspepsia, belching, bloating), neuropsychological
cluster (sleep problems, depression, and anxiety), and others.50 Further
research is needed to confirm their existence as discrete nosologic entities,
to delineate their underlying pathogenesis and connectedness, and to
explore mechanism-based approaches to their management.51,52 Cancer
pain can be difficult to manage in the presence of other cancer-related
symptoms, in part because opioids, nonopioids, and nondrug analgesic
interventions can be more difficult for the patient to tolerate. Furthermore,
even if pain is effectively managed, the patient may continue to have other
severe symptoms and poor quality of life.

PAIN AT THE END OF LIFE

In the final hours of life, it may not be appropriate or there may not be
sufficient time to obtain a detailed history, physical examination, and

2005
diagnostic studies in order to quickly obtain relief of distressing
symptoms. The actual mechanism of pain becomes increasingly less
relevant as death approaches. In the instance of severe pain, one would
consider subcutaneous or intravenous opioids with rapid titration to effect.
Severe regional pain such as abdominal, pelvic, or lower extremity pain
can be managed with neuraxial (epidural, intrathecal) local anesthetics or
opioids. In a pain crisis at the end of life, the patient may be a candidate
for palliative sedation.53 Palliative sedation is appropriate when the patient
is aware that they are at the end of life, other interventions are not
expected to relieve pain quickly enough, and the patient or family has
requested this approach and given their informed consent. Assessment
tools have been developed to guide the depth of sedation and must be
used.54 These issues are discussed further in Chapter 109.

CANCER PAIN EMERGENCIES

Occasionally, patients will present to their physician with persistent,
horrible cancer pain. A cancer pain emergency has been defined as pain
that is severe or excruciating (8 out of 10 on a 0 to 10 scale), for more than
6 hours.55 Such patients typically come to an emergency room in great
distress. The patient may already be on large doses of opioids and may be
dehydrated due to limited oral intake during the previous days. Often, the
patient will not have slept at all during that time. In such cases, the patient
assessment is greatly truncated. The physician examines the patient
quickly to determine whether there is evidence of a ruptured viscous,
subarachnoid hemorrhage, ischemic crisis, pathologic fracture, spinal cord
compression, or other catastrophe. Vital signs and cognitive status are
monitored, and an intravenous access is secured. Opioid is administered
with rapid upward titration using a mini-bolus technique until there is
relief of pain. Intravenous protocols for cancer pain emergencies have
been described for morphine55 and fentanyl56; oral transmucosal and other
routes of administration of opioids have also been described.57 Unlike
conscious sedation, rapid upward titration of opioid in the setting of
unrelieved cancer pain almost never results in serious toxicity. After relief
of pain is obtained, the physician reassesses the patient in detail for the
underlying cause of the pain crisis. Some patients appear to be able to

2006
leave the emergency room an hour or few hours after obtaining relief of
pain. Only uncommonly will the cause of the cancer pain emergency be
apparent, such as a pathologic fracture. Typically, the flare of pain arises
in a place of known metastatic disease, and the pain goes away as
mysteriously as it came. Pain crises can occur in the palliative setting, and
interventional approaches may be needed to obtain control of pain in a
timely manner.58

OPIOID DIVERSION AT THE END OF LIFE

Cancer pain often increases as disease progresses and death approaches.
As a result, opioid dose often also increases. Clinicians who have
undertaken home visits in patients with advanced cancer have seen literally
stacks of pill containers which have accumulated over time, covering
bedroom furniture, filling bathroom cabinets, and overflowing onto the
floor or stuffed into suit cases. After death, families often have custody of
very large amounts of analgesic pills, injectable medications, and other
drug preparations. What happens to these prescription medications?
Little is actually known. It is suspected, however, that some of this
medication is diverted by family or friends and much of this may happen
without it ever being discovered.
To prevent drug diversion at this most vulnerable of times, safe
prescribing practice in end-of-life care should include identification of a
medication custodian at an early time in this journey, usually the spouse or
main caregiver. That individual should be asked to create an ongoing
medication inventory and assure that scheduled medications are always
secure. There should be a discussion about a formal plan for drug disposal
after death, such as agreement with the dispensing pharmacy to dispose of
this medication.

Conclusion
Cancer pain is common and, when present, is often severe. Fortunately, a
great deal is known about its epidemiology, assessment, and management.
An individualized approach to each patient offers the best opportunity to
provide relief of pain and improve the quality of life at all stages of

2007
oncologic disease.

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2010
CHAPTER 42
Assessment and Diagnosis of the
Cancer Patient with Pain
DERMOT FITZGIBBON

Cancer is a major health problem in the United States and other countries
and is the second leading cause of death in the United States and the most
prominent cause of death in terms of years of potential life lost (Fig.
42.1).1,2 In the United States, there was a total of 1,688,780 new cancer
cases (or 4,600 new cancer diagnoses per day) and 600,920 deaths for
cancers in 2017.3 For all sites combined, the cancer incidence rate is 20%
higher in men than in women, whereas the cancer death rate is 40% higher
in men. From 1991 to 2014, the overall cancer death rate dropped 25%.
Prostate, lung and bronchus, and colorectum account for 42% of cases in
men, whereas in women, breast, lung and bronchus, and colorectum
account for 50% (Fig. 42.2). Prostate cancer accounts for 1:5 new
diagnoses in men, and breast cancer almost 1:3 of new diagnoses in
women. Lung and bronchus cancers present approximately 1:4 cancer-
related deaths in men and women (see Fig. 42.1). Cancer incidence
patterns reflect trends in behaviors associated with cancer risk and changes
in medical practice, such as the introduction of screening. Over the past
decade of data, the overall cancer incidence rate in men declined by about
2% per year overall, whereas the incidence rate in women has remained
generally stable since 1987 (Fig. 42.3).

2011
FIGURE 42.1 Number of deaths from 10 leading causes by sex—National Vital Statistics System,
United States, 2015.

Over the past three decades, the 5-year relative survival rate for all
cancers combined has increased 20 percentage points among whites and 24
percentage points among blacks. The decline in cancer mortality over the
past two decades is the result of steady reductions in smoking and
advances in early detection and treatment, reflected in considerable
decreases for the four major cancers (lung, breast, prostate, and
colorectum) (Fig. 42.4). In contrast to declining trends for the four major
cancers, death rates rose from 2010 to 2014 by almost 3% per year for
liver cancer and by about 2% per year for uterine cancer. Cancer survival,
particularly for advanced-stage diseases, will likely improve because of
advances in precision medicine and immunotherapy for late-stage cancers
(e.g., melanoma, lung cancer).4,5 Cancer incidence and death rates vary
considerably between racial and ethnic groups, with rates generally highest
among blacks and lowest among Asian/Pacific Islanders.3 The major
behavioral determinants of cancer, such as smoking, diet, alcohol use,
obesity, physical inactivity, reproductive behavior, occupational and
environmental exposures, and cancer screening, are substantially
influenced by individual and area-level socioeconomic factors.6 Health
care inequalities have also risen in both absolute and relative terms and
socioeconomic and racial/ethnic disparities in stage at diagnosis and
survival from major cancers have persisted.1
Figures 42.2, 42.3, and 42.4 show estimated new cancer cases and

2012
deaths, trends in cancer incidence (1975 to 2013) and death rates (1975 to
2014) by sex and trends in death rates by sex overall and for select
cancers, United States (1930 to 2014).

FIGURE 42.2 Estimated new cancer cases and deaths. (From Siegel RL, Miller KD, Jemal A.
Cancer statistics, 2017. CA Cancer J Clin 2017;67[1]:7–30. Copyright © 2017 American Cancer
Society. Reprinted by permission of John Wiley & Sons, Inc.)

2013
FIGURE 42.3 Trends in cancer incidence (1975 to 2013) and death rates (1975 to 2014) by sex.
Rates are age adjusted to 2000 US standard population. (From Siegel RL, Miller KD, Jemal A.
Cancer statistics, 2017. CA Cancer J Clin 2017;67[1]:7–30. Copyright © 2017 American Cancer
Society. Reprinted by permission of John Wiley & Sons, Inc.)

2014
FIGURE 42.4 Trends in death rates by sex overall and for select cancers, United States, 1930 to
2014. (From Siegel RL, Miller KD, Jemal A. Cancer statistics, 2017. CA Cancer J Clin
2017;67[1]:7–30. Copyright © 2017 American Cancer Society. Reprinted by permission of John
Wiley & Sons, Inc.)

The number of cancer survivors has steadily increased since the 1970s
with an estimated 13.7 million people in the United States in 2012 who
had been diagnosed with cancer representing approximately a threefold

2015
increase compared to 1975 (Fig. 42.5). The number of cancer survivors is
projected to increase by 31% to almost 18 million in 2018, which indicates
an increase of more than 4 million survivors in 10 years7 or more than 20
million in 20268 with 60% of cancer survivors aged 65 years or older by
the year 2020.9 Improvements in survival for the most common cancers
have been similar by sex but are much more pronounced among patients
aged 50 to 64 years than among those aged older than 65 years likely
reflecting lower efficacy or use of new therapies in the elderly
population.10 Progress has been more rapid for the hematopoietic and
lymphoid malignancies and less so for lung and pancreatic cancers for
which the 5-year relative survival is 18% and 8%, respectively.3 As the
number of cancer survivors continue to grow, the need to address the
effect of symptoms of cancer, including pain, on individuals’ lives will
become increasingly critical to efforts to reduce the burden of cancer and
its treatment.

FIGURE 42.5 Estimated and projected number of cancer survivors in the United States from 1977
to 2022 by years since diagnosis. (Data from Parry C, Kent EE, Mariotto AB, et al. Cancer
survivors: a booming population. Cancer Epidemiol Biomarkers Prev 2011;20[10]:1996–2005.)

Despite advances in early detection and effective treatments, cancer is

one of the medical conditions patients fear most.11 The diagnosis often

2016
results in complex decisions at a time when patients may feel particularly
vulnerable and distressed. Although clinical decisions previously followed
one standard, many guidelines now outline several options and include
explicit recognition of the need to incorporate patients’ preferences to
determine the most appropriate treatment.12–14 Consequently, the demands
and stresses imposed on patients during treatment may be considerable.15
In addition to anxiety about cancer as a potentially lethal disease, patient
and family expectations that pain is an inevitable and untreatable
consequence are additional major sources of distress.16 Cancer pain
elevates psychological distress,17,18 alters social life,19 disturbs sleep,20
affects enjoyment of life,21 and potentially compromises survival.22
Fatigue, insomnia, neuropathy, and pain are among the most common
troublesome symptoms experienced by cancer survivors23 suggesting that
pain rarely occurs in isolation. Furthermore, survivorship from cancer
imposes its own issues including physical, psychosocial, and financial
burdens with its associated impact on quality of life (QOL).
Differences exist between cancer pain patients and those that experience
acute pain and/or chronic nonmalignant pain. The possibility of multiple
complex and potentially painful oncology treatments (surgery, radiation
therapy, chemotherapy, bone marrow transplantation, or other new
treatments such as endocrine therapy for breast cancer) may result in a
constant changing environment resulting in new pain complaints separate
from the original tumor-related pain. For example, breast cancer is a major
health burden and endocrine therapy with aromatase inhibitors (AIs) may
be prescribed for up to 10 years in patients with hormone receptor-positive
tumors. Unfortunately, AI-associated arthralgia is an adverse event
associated with low compliance with treatment.24 Cancer patients also tend
to have a higher symptom burden (especially psychological) compared to
noncancer patients.25 Patients may experience moderate-to-severe
symptom distress (particularly pain, fatigue, and insomnia) after cancer
treatment initiation.15 End-of-life considerations and palliative care are
rarely major issues for acute and chronic nonmalignant pain conditions,
but these concerns become extremely important for the cancer pain patient
with advanced disease (see Chapter 109). The complexities that emerge
from the medical and psychosocial aspects of the situation necessitate a

2017
multi- and/or interdisciplinary approach for care. The changing nature of
cancer pain, either in response to treatments directed at the tumor and/or
progression of the tumor, mandates vigilance and potential frequent
alteration of treatment strategies for pain. In addition, cancer survivors
face ongoing surveillance for the possibility of disease recurrence, and
new pain complaints in these patients require careful assessment. As
cancer treatments continue to improve survival, many oncology patients
face long-term pain management issues from aggressive treatment of their
disease. As such, different treatment strategies may need to be considered.
The effects of cancer diagnosis and subsequent treatment represent a
continuum with an initial focus in early disease on health in survivorship
and with advanced disease on QOL.26 Comprehensive cancer care usually
requires that many health care professionals become involved with the
cancer pain patient at any one time. Successful pain management requires
that the person or persons responsible for pain management adopt, or at
least become familiar, an interdisciplinary approach. In addition, the
humanitarian nature of cancer pain management, the focus on suffering
and comfort, and the associated effects on patients’ relatives all contribute
to the uniqueness of this form of pain control.

Issues in Assessment and Diagnosis of Cancer Pain

Controlling pain associated with cancer is a major health care problem.
Multiple studies from the 1990s documented inadequate treatment of pain
in patients with cancer.27–30 Despite the subsequent availability of
effective pain treatments and various pain management guidelines, these
deficiencies continued both in the United States and in other countries into
the new millennium.31–35 In 2008, approximately 1:2 patients with cancer
pain was considered undertreated with geographic and economic trends in
favor of the wealthiest countries.36 A 2009 study suggested that 1:4
patients were untreated.37 In a follow-up 2014 study from the 2008 study
using similar methodology, 25% of patients were still considered
untreated.38 Ineffective pain management can have significant
consequences. QOL for cancer patients and their families is profoundly
affected by the presence of severe pain and other symptoms.39 Health-

2018
related QOL parameters (physical functioning, appetite loss, and pain)
provide significant prognostic value in addition to the sociodemographic
variables (age and sex) and clinical variables (World Health Organization
[WHO] performance status and distant metastases) and increase the
predictive accuracy of the survival prognoses in patients with cancer.40
Individual studies or those focusing on a particular cancer site generally
reported a higher hazard ratio for pain,41,42 appetite loss,43 and physical
functioning,44 suggesting that the prognostic value of health-related QOL
parameters scales might vary between different cancer sites.
Barriers to adequate pain management in cancer patients differ in low-
versus high-resource environments.45 Trainee physicians in the high
resource group identified inadequate knowledge of cancer pain,
assessment of pain etiology, concerns about opioid dependence, and drug-
seeking behaviors as well as physicians’ reluctance to prescribe opioids, as
the major barriers. Trainee physicians in the low resource group reported
less competence in cancer pain management despite having more cancer
patients with advanced disease were less inclined to think that patients
benefited from cancer pain management and less likely to consult another
physician for cancer pain management and felt that patients poorly
characterized their pain. Experienced physicians have also recognized a
need for significant improvement in cancer pain assessment and treatment
in their practice.46,47 Lack of expertise by clinicians in assessing and
managing cancer pain is an important cause of poor pain control.30,48,49
Pain management requires a variety of assessment skills and the
integration of knowledge about pharmacology, pharmacokinetics and
pharmacodynamics, patient characteristics like individual variability and
compliance with medications, side effects and QOL determinants, and
disease specifics. These skills must contribute to clinical judgment and
decision making, often requiring substantial individual experience. Most
studies concerning pain education of undergraduate medical students focus
on knowledge, but relatively little is known about the interviewing skills
and pain evaluation. Leila et al.50 suggested that formative assessment of
both knowledge and communication skills is essential for the development
of a functional pain curriculum for training medical students in pain
management of chronic pain patients. Core competencies in pain

2019
management include domains that define the multidimensional nature of
pain, pain assessment and measurement, management of pain, and the
context of pain management.51 These serve as a foundation for developing,
defining, and revising curricula and as a resource for the creation of
learning activities across health care professions. Introducing pain
education early in the training of health professionals offers the
opportunity to reverse the disparity between what students are taught and
what they confront in practice. Continuing education is needed across
many disciplines but, in order to ensure the provision of quality pain
management care, it is especially important to reach the following
providers: oncologists, hematologists, urologists, surgeons, and radiation
therapists who initially treat cancer patients; primary care physicians;
nurses; and social workers and other providers of psychosocial services.

Pain and the Cancer Patient

Pain is an unpleasant sensory and emotional experience associated with
actual or potential tissue damage or described in terms of such damage.52
The sensory features and subjective qualities of pain vary, depending on its
origin. Activity induced in the nociceptor and nociceptive pathways by a
noxious stimulus is not pain, which is always a psychological state, even
though one may well appreciate that pain most often has a proximate
physical cause. Its emotional features depend in part on the social and
physical context in which pain occurs, associated cognition, and the
meaning of tissue trauma for the individual, but they are almost always
negative.
It is important to recognize that the source of pain in the cancer patient
is usually not a single entity but often has multiple sources that are
dependent on different issues such as tumor staging, treatment phase,
preexisting conditions that may cause chronic pain, and posttreatment
complications.53 As such, it is more accurate to use the term pain in the
cancer patient than the more confusing term cancer pain. Many clinical
trials in cancer pain do not differentiate the two and tend to use the latter
descriptor resulting in difficulty in interpreting results.54–59
Tumor-related pain may be classified as nociceptive or neuropathic.

2020
Patients may present with different sources of tumor pain. Figure 42.6
shows a patient with extensive locally recurrent sacral chordoma
presenting with tumor infiltration of somatic (sacrum, left sacroiliac [SI]
joint, left iliac wing, left gluteal muscles) and neuropathic sources of pain
(left S1 foramen with nerve root involvement, encasement of the left
lumbosacral plexus). Pain is labeled nociceptive if the noxious stimulus is
related to ongoing tissue injury and is subdivided into somatic and visceral
types. Pain is neuropathic if there is evidence that the pain is associated
with injury to neural tissues and is sustained by aberrant somatosensory
processing in the peripheral or in the central nervous system (CNS). The
International Association for the Study of Pain (IASP) defines neuropathic
pain as pain caused by a lesion or disease of the somatosensory nervous
system.60 The restriction to the somatosensory nervous system is important
because conditions such as musculoskeletal pain (e.g., due to spasticity)
arising indirectly from disorders of the motor system should not be
confused with neuropathic pain. Caraceni and Portenoy53 defined tumor
pain characteristics and syndromes and was nociceptive due to somatic
injury in 71.6% of patients, nociceptive visceral in 34.7%, and neuropathic
in 39.7%. Prevalence rates for tumor-related neuropathic pain are difficult
to determine. Often, studies reporting on neuropathic pain in cancer
patients tend to have mixed sources (Table 42.1).

FIGURE 42.6 Magnetic resonance imaging image (axial T1 gadolinium-enhanced) of pelvis.

Patient has extensive locally recurrent chordoma. A: A mass within the left sacrum and iliac wing
spanning the left sacroiliac joint with large extraosseous soft tissue component extending into the
left gluteal muscles (green arrow heads) and left iliopsoas muscle in addition to the left piriformis.
The sacroiliac mass approaches the left S1 neural foramen (red arrow). B: The anterior margin of
the left sacroiliac mass abuts and partly encases the left lumbosacral plexus at the level of S1 (red
arrow heads).

2021
 TABLE 42.1 Etiology of Neuropathic Pain in Cancer Patients
Predominant Cause of Pain with Neuropathic Mechanism
Number of
Pains with Associated
Neuropathic Cancer with Unrelated
Study Mechanism Cancer Treatment Cancer to Cancer Unknown
Chua et al. 18 38.9% 27.8% 0% 11.1% 22.2%
1999503
García de 477 52.8% 32.9% 0% 14.3% 0%
Paredes et
al. 2011504
Grond et al. 254 72% 12% 4% 9% 3%
1999505
Grond et al. 925 68% 16% 5.3% 8.3% 2.4%
199661
Total 1674 64% 20.3% 3.5% 10.2% 2%
Modified from Bennett MI, Rayment C, Hjermstad M, et al. Prevalence and aetiology of
neuropathic pain in cancer patients: a systematic review. Pain 2012;153:359–365.

The major pain syndromes comprised bone or joint lesions in 41.7% of

patients, visceral lesions in 28.1%, soft tissue infiltration in 28.3%, and
peripheral nerve injuries in 27.8%. Somatic nociceptive pain may be
grouped into superficial (cutaneous) and deep. Most cutaneous pain is well
localized, sharp, pricking, or burning. Deep tissue pain usually seems
diffuse and dull or aching in quality. Visceral pain is very diffuse, often
referred to the body surface, perseverating, and frequently associated with
a queasy quality that patients describe as “sickening.”
The mechanisms of tumor involvement of the nervous system are
heterogeneous and include lesions within the cerebrospinal fluid (CSF)
space, local invasion, compression, direct infiltration, perineural spread,
and rarely intraneural metastasis.62 Tumor involvement of the CNS occurs
intracranially or within the spinal cord. Direct mechanisms for tumor
involvement of the spinal cord occur in one of three anatomic
compartments: parenchymal (intradural intramedullary), subarachnoid or
CSF (intradural extramedullary), or epidural (extradural).63 Parenchymal
(intradural intramedullary) spinal cord disease may be metastatic
(intramedullary metastases from systemic cancer) or the consequence of a
primary spinal cord tumor. Direct spinal cord disease may also result from

2022
disease of the subarachnoid/CSF compartment as in leptomeningeal
metastasis (LM) or by extramedullary intradural primary spinal cord
tumors. Direct spinal cord disease may also occur due to epidural
metastases resulting in epidural spinal cord compression. Peripheral nerves
consist of all the spinal nerves as well as the cranial nerves, with the
exception of the optic nerve (cranial nerve II), which is a tract of the
diencephalon rather than a peripheral nerve. Lymphoma, as well as breast,
lung, prostate, colorectal, gynecologic, skin, and head and neck cancers,
invade peripheral nerves through direct extrinsic involvement or perineural
spread. Once the dense connective tissue of the epineurium is disrupted,
malignant cells can travel both proximally and distally along the perineural
and endoneural planes while remaining encased by the epineurium.64
Compression and invasion of nerves by tumor results in the destruction of
myelinated and unmyelinated fibers and of supporting tissue. Because
peripheral nerves can usually evade pressure from a tumor on one side,
infiltration by tumor tissue is the quintessential tissue trauma stimulus. In
addition, indirect damage of unknown pathogenesis might also occur to
peripheral nerves in the context of tumor conditions (e.g., paraneoplastic
syndromes). Infiltration of tumor tissue into the perineural cleft is seen
relatively often, and perineural tumor spread is more frequently associated
with carcinoma arising in head and neck tumors with sources from minor
or major salivary glands (more often adenoid cystic carcinoma), mucosal
or cutaneous squamous cell carcinoma, basal cell carcinoma, melanoma,
lymphoma, and sarcoma.65 Neurolymphoma is a rare extranodal
manifestation of lymphoma that reflects intraneural infiltration of
malignant lymphocytes. Neurolymphoma has been encountered with both
B-cell and T-cell lymphoma, yet it appears to occur most frequently in the
context of large B-cell non-Hodgkin lymphoma (NHL).66 A massive and
subsequent painful entrapment of a nerve plexus or individual nerves may
occur, especially in extensive breast carcinomas and their recurrences or in
chest wall metastases of lung tumors.

MOLECULAR MECHANISM OF TUMOR PAIN

In addition to cancer cells, tumors consist of different cell types including
inflammatory cells and blood vessels that are often adjacent to primary

2023
afferent nociceptors. These cells include immune system cells such as
macrophages, neutrophils, and T cells. These secrete various factors that
sensitize or directly excite primary afferent neurons and include
prostaglandins (PGs), tumor necrosis factor (TNF), endothelin, interleukin
(IL)-1 and IL-6, epidermal growth factor, transforming growth factor
(TGF), and platelet-derived growth factor (PDGF). Receptors for many of
these factors are expressed by primary afferent neurons. Endothelin
(endothelin-1, endothelin-2, and endothelin-3) is a family of vasoactive
peptides that are expressed at high levels by several types of tumor,
including prostate cancer. Endothelin could contribute to cancer pain by
directly sensitizing or exciting nociceptors, as a subset of small,
unmyelinated primary afferent neurons expresses endothelin-A
receptors.67 Like PGs, endothelins that are produced by cancer cells are
also thought to be involved in regulating angiogenesis and tumor
growth.68,69 Consequently, these factors and others from cancer and
inflammatory cells, such as adenosine triphosphate (ATP), bradykinin
(BK), H+, nerve growth factor (NGF), PGs, and vascular endothelial
growth factor (VEGF) excite or sensitize adjacent nociceptors.70 Tumor
growth, spreading, and metastasis require the development of a local
vasculature. One of the key signaling processes in the development of the
tumor vasculature is the hypoxia-induced stimulation of VEGFs
production, and the development of anti-VEGF therapy (e.g.,
bevacizumab) provides options for limiting tumor growth by targeting
angiogenesis.71 Adjacent nociceptors such as vanilloid receptor-1 (VR1)
detect extracellular H+ and endothelin-A receptors detect endothelins
released by cancer cells. NGF increases angiogenesis through its
tropomyosin receptor kinase A (TrkA) on endothelial cells and by
indirectly inducing VEGF expression.72 Nociceptor activation results in
the release of neurotransmitters, such as calcitonin gene-related peptide
(CGRP), endothelin, histamine, glutamate, and substance P (SP).
Nociceptor activation also causes the release of PGs from the peripheral
terminals of sensory fibers, which can induce plasma extravasation,
recruitment and activation of immune cells, and vasodilatation.
Other mechanisms, particularly tissue acidosis, may be involved in
tumor-related pain. Tumors could cause a decrease in pH by several

2024
mechanisms. As inflammatory cells invade neoplastic tissue, they release
protons that generate local acidosis. The large amount of apoptosis that
occurs in the tumor environment also contributes to acidosis, as apoptotic
cells release intracellular ions to create an acidic environment. This
decrease in pH can activate signaling by acid-sensing channels (including
VR1) that are expressed by nociceptors. Tumor-induced release of protons
and acidosis might be particularly important in the generation of bone
cancer pain.73 Finally, tumor-induced distention of sensory fibers may also
be involved in tumor-associated nociceptive processes.

SOMATIC PAIN
Somatic cancer pain can be caused by tumor invasion of bone, joint,
muscle, or connective tissue. Somatic pain is the most common type of
tumor pain with the most prevalent being tumor bone involvement.
Nociceptive afferents are most concentrated in the periosteum. Some of
the mechanisms contributing to neoplastic bone pain include stretching of
the periosteum by tumor expansion, local microfractures that cause bony
distortion, nerve compression due to either collapsed vertebrae or direct
tumor encroachment, and local release of algesic substances from the bone
marrow. Because inactivity and deconditioning predisposes to muscle
pain, the debilitated cancer patient may experience muscle pain that is
likely to contribute to complaints of localized or generalized pain. Skeletal
muscle accounts for approximately 50% of body weight and is a major
cause of morbidity. Myofascial pain is often underdiagnosed and
inappropriately treated. Myofascial pain should be considered separately
from fibromyalgia. In 2010, the American College of Rheumatology
abandoned the use of a tender point count in the diagnostic criteria of
fibromyalgia with the definition now based on the number of painful body
regions and the presence and severity of fatigue, unrefreshed sleep,
cognitive difficulty, and the extent of somatic symptoms.74 Myofascial
pain syndrome (MPS) is a local or regional pain problem with tender areas
that reproduce symptoms on palpation and may be primary or secondary to
another condition.75 There may be associated muscle stiffness and
decreased range of motion with palpable taut bands or nodules. Trigger
points may be defined as the presence of defined “exquisitely” painful

2025
trigger in a taut band of muscle that produce characteristic patterns of
referred pain on palpation and a local twitch response to mechanical
stimulation or needling. Proposed criteria for diagnosis of MPS are listed
in Table 42.2. Sustained contractile activity leading to increased metabolic
stress and reduced blood flow likely contributes to the persistence of a
myofascial trigger point. In addition to the sustained contractile activity,
metabolic alterations and cell stress trigger release of myokines,
inflammatory cytokines, and neurotransmitters that contribute to
myofascial trigger points and MPS.76,77 Muscle pain is generally described
as aching and cramp-like. It can be difficult to localize and may be referred
to other deep somatic structures.

TABLE 42.2 Proposed Criteria for Diagnosis of Myofascial Pain

Syndrome
A tender spot is found with palpation, with or without referral of pain (“trigger point”).
Recognition of symptoms by patient during palpation of tender spot and at least three of the
following:
Muscle stiffness or spasm
Limited range of motion of an associated joint
Pain worsens with stress.
Palpation of taut band and/or nodule associated with tender spot
From Rivers WE, Garrigues D, Graciosa J, et al. Signs and symptoms of myofascial pain: an
international survey of pain management providers and proposed preliminary set of diagnostic
criteria. Pain Med 2015;16(9):1794–1805. Reproduced by permission of American Academy of
Pain Medicine.

Muscle nociceptors are free nerve endings connected to the CNS by thin
myelinated (group III) or unmyelinated (group IV) afferent fibers.78
Muscle nociceptors can be sensitized to chemical and mechanical stimuli.
Muscle nociceptors can be activated by BK, prostaglandin E2 (PGE2),
serotonin (5-HT), and other endogenous substances.79 SP, CGRP, and
somatostatin are neuropeptides present in primary afferent fibers from
muscle.80 In muscle-free nerve endings, SP, CGRP, vasoactive intestinal
polypeptide, NGF, and growth-associated protein 43 are present.81 These
neuropeptides are synthesized in the soma of the primary afferent neuron
in the dorsal root ganglion and transported via axonal transport to the
receptive ending in muscle and to the central terminals in the spinal cord.

2026
Molecular receptors for many algesic substances (BK, 5-HT, PGE2, and
ATP) are present in muscle tissue and are released during painful
stimulation or pathologic conditions. Some of these receptors control ion
channels that cause an ion flux across the membrane that can depolarize
the ending. Purinergic receptors may be of particular importance for
muscle pain because ATP, which is present in large amounts in muscle
tissue and is released during muscle damage, could excite the nociceptor
directly. Muscle nociceptors do not respond to everyday stimuli, such as
normal contractions or weak deformation of muscle tissue.82 Two
chemical stimuli are particularly relevant as causes of muscle pain. The
first is a drop in tissue pH, and a large number of painful alterations of
muscle tissue are associated with an acidic interstitial pH. The second
important cause of muscle pain is a release of ATP.78,83

VISCERAL PAIN
Visceral pain refers to pain resulting from noxious stimuli such as painful
swelling, ischemia, and inflammation that act on visceral organs via
peripheral and central pathways. Visceral pain is typically correlated with
the excitation of spinal (thoracolumbar, sacral) visceral afferents. Spinal
visceral afferents are polymodal and activated by adequate mechanical and
chemical stimuli.84 All groups of spinal visceral afferents can be sensitized
(e.g., by inflammation). Spinal visceral afferent neurons project into the
laminae I, II (outer part IIo), and V of the spinal dorsal horn over several
segments; mediolateral over the whole width of the dorsal horn; and
contralateral. Typically, patients complain of a vague sensation with an
unclear location that may be referred to other nonvisceral somatic areas
and associated with autonomic changes. The majority of thoracic and
abdominal visceral organs, except the pancreas, are dually innervated by
parasympathetic (craniosacral) and sympathetic (thoracolumbar) outflows.
Thoracic viscera and upper abdominal viscera are primarily innervated by
the vagus (cranial nerve X) and spinal thoracolumbar outflows. The lower
abdominal viscera, including the small and the large intestine and the
urogenital organs, are innervated by thoracolumbar (i.e., lumbar
splanchnic nerve and hypogastric nerve) and sacral (i.e., pelvic nerve)
outflows. Sensory afferents innervating the visceral organs are not just a

2027
homogeneous group of afferents signaling visceral pain to the CNS. Pain is
primarily signaled by spinal afferents, whereas vagal afferents signal
nonpainful sensations such as hunger, satiety, fullness, and nausea.85
Transient receptor potential (TRP) channels are predominantly distributed
in both somatic and visceral sensory nervous systems and play a crucial
role in sensory transduction.86 The majority of spinal afferents projecting
to the gastrointestinal tract or pelvic organs are TRPV1, TRPA1, and/or
TRPM8 positive and respond to mechanical stimulation87–89 and are also
sensitive to noxious stimuli from pungent compounds, temperature, acid,
and inflammation.90 Visceral nociceptive messages are conveyed to the
spinal cord by relatively few visceral afferent fibers that activate many
central neurons by extensive functional divergence through polysynaptic
pathways.84
Pancreatic pain is perceived as a severe discomfort in the upper
abdomen frequently radiating through to the back. Malignant pancreatic
tumors, acute and chronic inflammation of the pancreas, and obstruction of
the pancreatic duct can produce severe pain. Hepatic, biliary, and
pancreatic pain appear to be mediated by afferent fibers in sympathetic
nerves, and vagal innervation does not appear to contribute to nociceptive
transmission.91 Pain related to pancreatic cancer may occur in 50% to 70%
of patients,92 but only 30% of patients with early stage pancreatic cancer
complain of abdominal pain, compared to 60% of patients with limited and
80% of patients with advanced pancreatic cancer.93,94 Abdominal pain
tends to occur regardless of tumor location, although it was reported by
more patients with cancer in the body and tail of the pancreas (90%)
compared with those with cancer in the head of the pancreas (70%).95
Histopathologic and molecular changes have been observed in pancreatic
cancer specimens which are associated with pain which include increased
nerve density and nerve hypertrophy, peri- and endo-neural cancer cell
invasion, altered expression of nociceptors, parenchymal immune cell
infiltration in the pancreas, and release of neurotrophic growth factors
which are undetectable in the normal pancreas.96 Others have proposed
perineural spread or invasion by the tumor, capsular stretching, and
pancreatic cancer ductal obstruction as mechanisms of pain.97 Afferent
signaling of pancreatic nociceptive processes is likely via the celiac plexus

2028
and thoracic splanchnic nerves as suggested by the efficacy of celiac
plexus block in managing associated pain.92

NEUROPATHIC PAIN
Pain usually results from activation of nociceptive afferents by actual or
potential tissue-damaging stimuli. Pain may also arise by activity
generated within the nervous system without adequate stimulation of its
peripheral sensory endings. Neuropathic pain arises as a direct
consequence of a lesion or disease affecting the somatosensory system.
The presence of symptoms or signs (e.g., touch-evoked pain) alone does
not justify the use of the term neuropathic and as such neuropathic pain is
a clinical description (and not a diagnosis) which requires a demonstrable
lesion or a disease that satisfies established neurologic diagnostic criteria.
As such, neuropathic pain should not be diagnosed by pain descriptors
only. The process of tumor compression and invasion of nerves entails
several degenerative, regenerative, and other pathophysiologic processes.98
The whole afferent neuron is affected and goes through reactive,
presumably reparative, biochemical changes. The neuron loses its
neuropeptides,99 atrophies, and may finally degenerate. Animal models
indicate that axonal degeneration following peripheral nerve injury causes
neuropathic pain,100 and these effects are related to the production of
proinflammatory cytokines such as TNF-α with upregulation in
endoneurial macrophages and Schwann cells101 with other cytokines such
as IL-1β and IL-6 and of the anti-inflammatory cytokine IL-10 both in the
peripheral (sciatic nerve, dorsal root ganglia [DRG]) and the central
(spinal cord) nervous system.102 Nerve injuries both proximal and distal to
the DRG induce mechanical allodynia, which are likely related to DRG
TNF-α expression and apoptosis.103 Microglia and astrocytes within the
CNS play a pivotal role in the development and maintenance of
neuropathic pain. Microglia propagate neuroinflammation by recruiting
other microglia and eventually activating nearby astrocytes, thus
prolonging the inflammatory state and leading to chronic neuropathic
pain.104

AFFECTIVE PROCESSING AND SUFFERING

2029
Fear of pain in patients has cognitive and emotional variables in the
experience of pain in patients with advanced cancer.105 The aversive
nature of pain elicits a powerful emotional reaction that feeds back to
modulate pain perception. Negative emotions are associated with increased
activation in the amygdala, anterior cingulate cortex, and anterior
insula,106 brain structures that not only mediate the processing of emotions
but also are important nodes of the pain neuromatrix that tune attention
toward pain, intensify pain unpleasantness, and amplify interoception.107
Anger, sadness, and fear may result from pain and affect biobehavioral
processes that influence pain perception to exacerbate anguish and
suffering. The emotional mechanisms of cancer pain are the reasons that it
generates suffering. Brain processing of pain in humans is based on
multiple ascending pathways and brain regions that are involved in several
pain components, such as sensory, immediate affective, and secondary
affective dimensions.108 Brain mechanisms supporting discrimination of
sensory features of pain extend far beyond the somatosensory cortices and
involve frontal regions traditionally associated with affective processing
and the medial pain system. The level of psychological and emotional
distress associated with a cancer diagnosis contributes to increased rates of
comorbidities and mortality while reducing QOL and compliance to
care.109,110 Transient mood disturbances occur frequently among cancer
patients during the disease trajectory, and depression often persists in these
patients.111 Lower QOL scores may be associated with variables related to
a patient’s premorbid psychological characteristics and with coping skills
for the cancer than to cancer-related variables (e.g., treatment types and
cancer severity).112 Of course, most cancer patients suffer from a complex
array of problems and not only pain. Nonetheless, sustained nociception in
and of itself can produce suffering because of its ability to create negative
emotional arousal and elicit associated stress responses.
Suffering is a complex, negative emotional and cognitive state
characterized by perceived threat to the integrity of the self, perceived
helplessness in the face of that threat, and exhaustion of psychosocial and
personal resources for coping with that threat.113 The perceived threat to
the self may encompass the body, the psychosocial self, or both. Suffering
related to cancer is inherently emotional, unpleasant, complex, and

2030
enduring. The clinician should recognize that, although suffering may be a
consequence of pain, it is separate from pain and not a synonym for it. It
differs from pain in that it entails additional cognitive affective states. For
example, perceived helplessness (inability to cope; bankruptcy of physical,
psychological, or social resources) is a key element in the suffering of
most patients with incurable disease. Similarly, grief can ensue when a
cancer patient perceives the loss of a psychological or social resource, a
body part or desired personal appearance, a prized employment status, or a
physical capability for a treasured activity. Loss often equates with
perceived threat to self. In addition, suffering in the cancer patient
sometimes involves a sense of separation from social support or alienation.
These factors, combined with the emotional distress, fatigue, and stress
associated with prolonged pain produce a complex state that differs from
pain itself. Wilson et al.114 in a study of 381 patients with advanced cancer
found that 25% of patients were suffering at a moderate to extreme level
and that suffering is a multidimensional experience related most strongly
to physical symptoms but with contributions from psychological distress,
existential concerns, and social-relational worries.

PSYCHOLOGICAL FACTORS AND THE

COMPLEXITIES OF CANCER PAIN
Somatic symptoms are a feature of anxiety, depressive, somatoform, and
other psychiatric disorders. Somatization refers to patients who transform
distress and global suffering into pain and symptom expression, and health
care providers frequently view pain reported by cancer patients as
primarily somatogenic, whereas chronic nonmalignant pain in patients
who lack adequate objective physical pathology is viewed as
psychogenic.115 Consequently, providers tend to treat cancer pain with
pharmacologic, medical, or surgical modalities. Psychological factors tend
to be considered of secondary importance.116 Pain is a complex experience
entailing physiologic, sensory, affective, cognitive, and behavioral
components. The final individual perception of pain is dependent on
nociceptive input and psychological modifiers such as fear, anxiety, anger,
and depression (Fig. 42.7).

2031
FIGURE 42.7 Individual perception of pain. Noxious stimuli are modified at supraspinal level by
emotions such as anxiety, fear, and anger.

Turk et al.115 classified the multidimensional nature of cancer pain and

compared the adaptation of cancer patients and chronic noncancer patients
to persisting pain. The majority of the cancer patients, both with (81%) and
without (84%) metastatic disease as well as the noncancer chronic pain
patients (85%) fit one of three psychosocial subgroups: dysfunctional
(high levels of pain, perceived interference, affective distress, and low
levels of perceived control and activity), interpersonally distressed (high
levels of affective distress, negative responses from significant others, and
low levels of perceived support), and adaptive copers (low levels of
interference and affective distress, high levels of perceived control and
activity).
Substantial evidence suggests that psychological factors play an
important role in exacerbating pain with clear origins of disease (see
Chapters 29 to 33). For example, the belief that pain signifies disease, a
commonly held belief among cancer patients,117 is associated with
elevated pain intensity.118,119 Although pain is frequently associated with
metastatic disease, it is by no means universal.120,121 Spiegel and
Bloom119 reported on the affective states of cancer patients and the belief
that pain is an indicator for disease progression and that medication use
predicts pain severity. Patients who attribute their pain to a warning of
underlying disease report greater pain intensity than patients with more
non–tumor-associated interpretations, despite comparable levels of disease

2032
progression. In this study, the predictors of pain were use of analgesics,
emotional distress, and pain beliefs, and that treatment of metastatic pain
should include attention to the patient’s mood and adjustment to illness.
Because of psychological factors, the relationship between pain severity
and the extent of disease is rarely as linear as one might assume,122 and
there is a nonlinear relationship between cancer pain severity and
interference with function.123 Research investigating the relationships
between physical pathology and pain in cancer has shown conflicting
results. First, not all patients with advanced cancer report pain. Twycross
and Fairfield124 reported that only 41 of 100 terminal-stage cancer patients
reported pain due to disease. Front et al.120 demonstrated that for many
cancer patients, pain reports did not correspond to the presence or location
of bone metastases. Turk et al.115 found that patients with cancer-related
pain reported a significantly higher level of perceived disability and
inactivity due to pain than did those with pain of nonmalignant origin.
Because the level of pain severity was comparable for the two patient
groups, elevated disability may have been a consequence of the meanings
patients attributed to their pain. The progression of disease means further
deterioration of health and impending death. Indeed, the patients with
cancer-related pain appeared to be more fearful of pain and reported
significantly higher levels of cognitive and behavioral fear responses than
did the patients with chronic pain not associated with cancer. These
patients appeared to think and worry more about pain, avoid activities in
order to prevent initiation of pain, and they generally felt more hopeless
than the patients with non–cancer-related pain.

Depression in Cancer Patients

The prevalence of major depressive episodes is increased with most
chronic conditions but especially those characterized by inflammation and
pain.125 The prevalence of depression among cancer patients increases
with disease severity and symptoms such as pain and fatigue.126
Adjustment disorder, major depression, delirium, and anxiety disorders
occur between 10% and 34% of cancer patients.127–129 Major depression
has been found to occur in approximately 16% of patients with cancer,

2033
with minor depression and dysthymia combined reported in almost 22% of
patients.130,131 Mood disturbance, sleep disturbance, fatigue, and pain
either alone or in combination is also highly prevalent in patients receiving
cancer therapy.132 The overlap of physical illness and symptoms of major
depression is widely recognized in physically healthy adults based on the
presence of neurovegetative complaints, including insomnia, anorexia,
fatigue, and weight loss in addition to depressed mood, hopelessness, guilt
or worthlessness, and suicidal ideation. Major depressive disorder is a
debilitating disease that is characterized by depressed mood, diminished
interests, impaired cognitive function, and vegetative symptoms, such as
disturbed sleep or appetite.133,134 Similarly, vegetative symptoms such as
appetite loss, insomnia, and fatigue are not uncommon in the cancer
patient particularly with advanced disease or cancer treatment, and the
diagnosis of depression in cancer patients can be difficult because of this
overlap.20,135 Levels of physical impairment, age (particularly younger
patients), advanced stages of illness, inadequately controlled pain, prior
history of depression, and the presence of other significant life stresses or
losses are associated with a higher prevalence of depression in cancer
patients. In addition, patients with certain cancer types such as pancreatic,
head and neck, gastric, and lung cancers have higher rates of
depression,136,137 with the highest rates in lung, gynecologic, breast,
colorectal, and genitourinary patients.138 Within these disease states, a
diagnosis of major depression was more likely in patients who were
younger, had worse social deprivation scores, and, for lung cancer and
colorectal cancer (CRC), female patients. Seventy three percent of 1,538
patients with depression were not receiving potentially effective
treatment.138 Various chemotherapy agents including alkylating agents
(procarbazine, carmustine, busulfan), vinca alkaloids (vincristine,
vinblastine), antimetabolites (pemetrexed, fludarabine), medications that
interfere with DNA and RNA synthesis (doxorubicin, daunorubicin, L-
asparaginase), and mitotic inhibitors (taxanes including paclitaxel,
docetaxel) may cause depression. Biologic agents including IL-2,
corticosteroids, tyrosine kinase inhibitors (imatinib, dasatinib, cetuximab,
sorafenib, sunitinib), and hormonal agents (tamoxifen, anastrozole,
gonadotropin-releasing hormone [GnRH] agonists) are associated with

2034
depression.139
Broadly speaking, depressed persons complain of a pervasive dysphoric
mood, anhedonia, apathy and disinterest in normal activities, sleep
problems, low energy, and in severe cases suicidal ideation.
Approximately 20% to 30% of cancer patients meet the criteria for a
psychiatric diagnosis, mainly depressive disorders, anxiety, and adjustment
and stress-related disorders, across the trajectory of their disease,130,140,141
whereas the prevalence of depression in primary care patients
approximates 6% to 10% for outpatients and 10% to 14% for
inpatients.142–144 Depression is one of the strongest predictors of
subsequent development of regular opioid use for treatment of chronic
pain,145 and multifocal pain is especially likely to be associated with
depression and with opioid use.146

DETECTING AND ASSESSING DEPRESSION IN THE

CANCER PATIENT
It is important for the physician treating cancer pain to recognize and
address depression. Untreated depression has a significant impact on
patient QOL, health care utilization, disease outcome, and influences care
and participation in treatment.147 Depression may go unnoticed or
unaddressed in the cancer patient.148–151 Few oncologists or supporting
consultants feel qualified to address depression, and for those who do, time
limits on patient contact time make it difficult to engage in extensive
questioning about psychological well-being. Patients and family members
may add to the problem by assuming that care providers concern
themselves solely with controlling the disease and wish to avoid the
distractions that psychological management entails.
Depressive disorders include disruptive mood dysregulation disorder,
major depressive disorder (including major depressive episode), persistent
depressive disorder (dysthymia), premenstrual dysphoric disorder,
substance/medication-induced depressive disorder, and depressive disorder
due to another medical condition. The common feature of all of these
disorders is the presence of sad, empty, or irritable mood accompanied by
somatic and cognitive changes that significantly affect the individual’s
capacity to function. Depression may have two components: the

2035
psychological or “cognitive” component (e.g., mood) and the physical or
“somatic” component (e.g., loss of appetite). Diagnostic and Statistical
Manual of Mental Disorders (5th edition; DSM-5) criteria requires either
depressed mood or loss of interest or pleasure with four other depressive
symptoms (changes in sleep, appetite or weight, activity,
guilt/worthlessness, death/suicide, fatigue/loss of energy, decreased focus
or concentration) for at least 2 weeks. Diagnosing depression in the cancer
patient is not straightforward because there is symptom overlap between
the psychiatric disorder, the toxicities of treatment, and the effects of the
primary disease. Anxiety and depression may also mimic physical
symptoms of cancer or treatments, and consequently, emotional distress
may not be detected. Many clinicians tend to focus on somatic rather than
psychological problems in patients with life-threatening illness, and some
erroneously regard reactive depression in a patient who has received a
diagnosis of cancer to be a normal response. Mitchell et al.152 analyzed the
diagnostic significance of somatic and nonsomatic symptoms indicative of
depression in 279 patients within 9 months of first presentation with a
diagnosis of cancer. No single symptom was a good proxy for depression.
Emphasis on the presence of somatic symptoms (appetite loss, weight loss,
insomnia, fatigue, loss of energy, and diminished ability to think or
concentrate), feelings of worthlessness, and suicidal ideation may not be
useful, among the DSM (4th ed.; DSM-IV) criteria, for diagnosing and/or
judging the severity of depression among cancer patients.153 Many of the
traditional physical symptoms of depression such as fatigue, diminished
appetite, and weight loss also occur in emotionally healthy cancer
patients.154
The prevalence of depression in oncology varies widely by study and is
often attributable to differences in assessment procedures.155 Common
assessment methods for depressive spectrum disorders in cancer settings
are listed in Table 42.3. In practice, the diagnosis of depression is too
complex for any screening tool, used in isolation, to be of diagnostic
certainty. Structured clinical interviews have traditionally been considered
the standard for identifying the prevalence, clinical significance, and
potential treatment of depression because of their rigorous criteria.
Common interview tools include the Structured Clinical Interview for

2036
DSM disorders (SCID) and Research Diagnostic Criteria. A disadvantage
of such tools includes the lack of validation in a population without
significant comorbid physical illness such as cancer. A variety of written
self-report measures have been used to identify symptoms of depression in
cancer patients. These include the Hospital Anxiety and Depression Scale
(HADS), the Rotterdam Symptom Checklist (RSCL), the Beck Depression
Inventory (BDI) (regular and short forms), the Brief Symptom Inventory-
Depression scale, Center for Epidemiologic Studies Depression Scale
(CES-D), and the Zung Self-Rating Depression Scale (both full and brief
forms). The majority of research on depression in cancer patients has used
the HADS, with much of this research focused on identifying the optimal
cutoff scores for depressed patients with cancer.111 The Patient Health
Questionnaire-9 (PHQ-9) and briefer versions, the PHQ-2 and PHQ-8, are
easily administered, commonly used depression screening tools. In a study
of 463 patients from 35 community-based radiation oncology sites and 2
academic radiation oncology sites, the PHQ-2 demonstrated good
psychometric properties for screening for mood disorders, which were
equivalent to the PHQ-9.156 Some authors suggest that the CES-D and
BDI-II may be most feasible given their time efficiency, administrative
simplicity, and strong psychometric properties.157 Others have suggested
that the PHQ-9 with a cutoff score ≥8 is a good screening tool in cancer
outpatients.158,159

TABLE 42.3 Common Assessment Methods for Depressive

Spectrum Disorders in Cancer Settings
Tools Characteristics Clinical Use Comments
Interviews
Structured Clinical Clinician version and Designed to be Assessment of current
Interview for DSM standard research administered by a psychiatric patients,
disorders (SCID) version to be used clinician or trained lifetime psychiatric
in research and mental health diagnoses in
clinical settings professional medical patients,
family members,
community samples
World Health Comprehensive, fully Designed to be used Assessment of mental
Organization structured by trained lay disorders according
World Mental interview interviewers to the definitions
Health Composite and criteria of ICD-

2037
 International 10 and DSM-IV in
Diagnostic epidemiologic and
Interview (WHO cross-cultural
WMH-CIDI) studies and for
clinical and
research purposes
Diagnostic Criteria Clinical interview Set of 12 psychosocial Research evidence
for Psychosomatic syndromes accumulated in
Research (DCPR) demoralization, several clinical
disease phobia, settings
health anxiety (cardiology,
thanatophobia, oncology,
illness denial, gastroenterology,
persistent endocrinology,
somatization, primary care,
functional somatic consultation
symptoms psychiatry,
secondary to a nutrition, and
psychiatric community)
disorder,
conversion
symptoms,
anniversary
reaction, irritable
mood, type A
behavior, and
alexithymia
Short Psychometric Questionnaires
Hospital Anxiety 14 items (7 for Score HADS-D: 0–7 In oncology, best
Depression Scale anxiety; 7 for = normal; 8–10 = thresholds for
(HADS) depression) plus borderline case; screening = 15 for
total score 11–21 = case; the HADS total
HADS total ≥15 (sensitivity 0.87;
adjustment specificity 0.88), 7
disorders; ≥19 for the HADS-D
MDD subscale
(sensitivity 0.86;
specificity 0.81
disorders)
Center for 20 items 0–3 Likert Scores ≥16: risk for CESD-R (revised
Epidemiologic scale clinical depression; version) also
Studies Depression ≥22: clinically available, reflecting
Scale (CES-D) relevant depression; DSM-5 diagnosis
≥25: MDD of MDD
Beck Depression 21 questions, each Score 14–19: mild
Inventory II (BDI- answer being depression; 20–28:
II) scored on a scale moderate
value of 0–3 depression; 29–63:

2038
 severe depression
Sensitivity: 81%;
specificity: 92%
Profile of Mood 65 adjectives (5-point 6 factors (Anger- Short version
States (POMS) scale) Hostility; available for cancer
Confusion- settings
Bewilderment;
Depression-
Dejection; Fatigue-
Inertia; Tension-
Anxiety; Vigor-
Activity)
Patient Health 9 items (scored 0–3, Score 5–9: mild Score ≥8: sensitivity
Questionnaire range 0–27) depression; 10–14: 93%, specificity
(PHQ-9) covering DSM moderate 81%, PPV 25%,
criteria for MDD depression; 15–19: NPV 99% in cancer
moderately severe settings
depression; 20–27:
severe depression
Demoralization Scale 24 items on a 5-point Scores ≥30: high DS and DS-II
(DS) Likert scale 16 demoralization validation studies
Demoralization Scale items on a 3-point Scores 0–3: low in progress in
II (DS-II) Likert scale demoralization; 4– cancer settings
10: middle
demoralization;
≥11: high
demoralization
Subjective 12 items on a 0–3 Studies on threshold SI validation studies
Incompetence Likert scale scores in progress in progress in
Scale (SI) cancer settings
DSM, Diagnostic and Statistical Manual of Mental Disorders; DSM-IV, DSM 4th edition; DSM-5,
DSM 5th edition; ICD-10, International Statistical Classification of Diseases and Related Health
Problems, 10th revision; MDD, major depressive disorder; NPV, negative predictive value; PPV,
positive predictive value.
Modified from Caruso R, GiuliaNanni M, Riba MB, et al. Depressive spectrum disorders in cancer:
diagnostic issues and intervention. A critical review. Curr Psychiatry Rep 2017;19:33.

Screening for depression should focus primarily on the

cognitive/affective features of depression because these are not
confounded with treatment-associated toxicities. In palliative care patients,
several studies have found that the single question “Are you depressed?”
was used as a screening tool with the high sensitivity, specificity, and
positive predictive value.160,161

2039
Cancer-Related Fatigue
Cancer-related fatigue (CRF) may be defined as a common, persistent, and
subjective sense of tiredness related to cancer or to treatment for cancer
that interferes with usual functioning.162 It may be perceived as a feeling
of extraordinary exhaustion associated with a high level of distress,
disproportionate to activity, and is not relieved by sleep or rest. Patients
may describe fatigue as feeling tired, weak, worn-out, heavy, slow, or that
they have no energy or get-up-and-go. CRF and sleep disturbances may
occur as distinct symptoms but are often comorbid.163 Fatigue is also a
nonspecific symptom that may be found in association with most mental
and physical disorders. It is prevalent among all types of cancer, but
breast, lung, and pancreatic are among the most frequently associated with
persistent fatigue.164 Abrahams et al.165 estimated that 1:4 breast cancer
survivors suffer from severe fatigue and identified higher disease stages,
chemotherapy and receiving the combination of surgery, radiotherapy, and
chemotherapy, both with and without hormone therapy, as risk factors.
Fatigue may be an issue during all phases of treatment and into
survivorship for extended periods of time.166 It is estimated that fatigue is
present at the time of diagnosis in approximately 40% of cancer
patients.167 It occurs in up to 75% of patients if bone metastases already
are present.168 An estimated 60% to 96% of cancer patients in treatment
experience fatigue, including 90% of patients on radiation treatment and
80% of patients on chemotherapy. Except for chemotherapy-induced
anemia, the pathogenesis of fatigue in patients with cancer is understood
poorly, but proposed mechanisms include the direct effects of cancer and
the various modes of cancer treatment plus a wide variety of concomitant
diseases (such as anemia, infections, dehydration, and electrolyte
disorders), sleep disorders, chronic pain, immobility and lack of exercise,
and a variety of psychosocial disorders. Because of the high prevalence of
anemia in oncology patients, the association of anemia with fatigue has
been extensively studied. Sobrero et al.169 indicated that general scores for
QOL, fatigue, and sensations of physical and functional well-being are
significantly higher among patients with hemoglobin (Hb) levels >12
g/dL, but Bremberg et al.170 found that physical and functional aspects

2040
may be more important to consider than increasing the Hb level to reduce
the fatigue.
Screening for fatigue is an important issue in the overall care of the
oncology patient.171 Various tools for assessing CFR have been used
(Table 42.4). The most widely used of these scales are the Functional
Assessment of Cancer Therapy: Fatigue (FACT-F) and the European
Organisation for Research and Treatment of Cancer Quality of Life Care
Questionnaire (EORTC QLQ-C30) fatigue subscale which have data from
over 10,000 patients between them and have been widely used in
intervention studies to treat CRF. The FACT-F has the advantage of
having a validated clinically significant score change—it also covers the
social impact of CRF but takes longer to administer than the 3-item
EORTC QLQ-C30 fatigue subscale.172

TABLE 42.4 Fatigue Scales Used to Evaluate Cancer-Related

Fatigue
Instrument Dimensions of Measurement
Fatigue Symptom Inventory 13-item, physical, cognitive,
Scale and psychosocial fatigue
Fatigue Severity Scale 9 questions, no clear
dimensional separate
Brief Fatigue Inventory One dimension, 9-item VAS,
cutoff scores for mild,
medium, severe fatigue
Visual Analogue Scale for 18-item, originally used in
Fatigue patients with sleep disorder
Multidimensional Fatigue 16-item, originally validated
Inventory in rheumatoid arthritis,
multidimensional
EORTC Likert, 30-item, physical and
mental fatigue, full tool
used extensively as quality
of life instrument
FACT-F Numerical, 13-item, physical
functioning
Cancer Fatigue Scale 15-item, 3 factors (physical,
affective, cognitive)
multidimensional
Usefulness in Oncology
Used in patients undergoing
active treatment and
survivors
Not validated; limited use
Useful for screening purposes
Very limited use in cancer
patients
Relatively poorly validated
Ceiling effect in advanced
cancer patients; not
recommended as single
measure in this group; used
in cancer chemotherapy
trials
Used in intervention studies to
treat CRF
Designed for oncology use

2041
CRF, cancer-related fatigue; EORTC, European Organisation for Research and Treatment of
Cancer; FACT-F, Functional Assessment of Cancer Therapy: Fatigue; VAS, Visual Analogue
Scale.
Modified from Gerber LH. Cancer-related fatigue: persistent, pervasive, and problematic. Phys Med
Rehabil Clin N Am 2017;28(1):65–88. Copyright © 2016 Elsevier. With permission.

Once fatigue is identified, a detailed clinical evaluation should be

performed. Components of the evaluation should include details of the
cancer including the type and duration of the treatment and its capacity to
induce fatigue. Other components include documenting the characteristics
of the fatigue such as when it started, what factors aggravate it, etc.
Emotional and psychological components should be identified, and the
effect of the fatigue on the performance of normal, daily life activities
should be determined. Then, various clinical organic conditions that can
cause fatigue should be evaluated. If a specific cause of CRF is identified
(anemia, insomnia, depression, metabolic disorders, etc.), then this should
be treated first. Antidepressants and analgesics should be prescribed for
patients with depression and pain. After common causes of anemia have
been excluded, patients with low levels of Hb should receive treatment
with erythropoietic agents. Patients with sleep disorders should receive
appropriate instructions for improving sleep quality or carefully prescribed
drugs. Educating patients about fatigue is extremely useful.173 Moderate
exercise can be more effective than continuous rest.174–176 Aerobic
exercises can increase overall muscle tone, and it may be wiser to advise
such exercise than rest.

Sleep Disturbance in Cancer

Sleep disturbances include reduced nocturnal sleep time, sleep
fragmentation, nocturnal wandering, and daytime sleepiness. Acute
insomnia is characterized as lasting up to a month and insomnia syndrome
is defined as insomnia occurring more than three nights per week,
difficulty falling asleep or nighttime awakenings (>30 minutes), ratio of
sleep time to time spent in bed <85% (sleep efficiency), impaired daytime
functioning, and marked distress. Insomnia syndrome is also called
chronic insomnia, as it usually persists nightly for >4 weeks. A history of
cancer increases the likelihood of having sleep disturbance.177 Insomnia is

2042
a prominent problem for patients with cancer and 25% to 60% of patients
may be affected178–180 and a prevalence rate almost twice that of the
general population.181 The prevalence of sleep disturbance varies
depending on the cancer type, cancer stage, treatment received, and time
since completion of treatment. Compared with other types of cancer, breast
cancer is associated with an exceptionally high rate of reduced sleep
quality.182,183 Insomnia in patients with lung cancer undergoing
chemotherapy may be as high as 52%.184 Sleep disturbance is one of the
five most common symptoms reported as moderate to severe by primary
brain tumor patients and occurs anywhere between 17% and 54% of
patients.185 Despite its prevalence and importance, insomnia is often
unrecognized and poorly managed. Insomnia refers to difficulty falling or
staying asleep, whereas sleep impairment refers to sleepiness, tiredness,
and perceived functional impairments during wakefulness associated with
sleep problems or impaired alertness. Insomnia typically occurs as a
transient inability to initiate or maintain sleep or as hyperarousal, often in
response to a situation or event. Daytime consequences of fatigue and
insomnia are similar and include dysphoric states, such as irritability,
impaired cognition (poor concentration and memory), and interference
with usual activities.
Identification of sleep disturbance typically involves screening for the
problem followed by a comprehensive assessment for those who screen
positive. The National Institutes of Health recommends that screening may
include asking two questions: (1) Do you have problems with your sleep or
sleep disturbance on average for three or more nights a week? If yes, (2)
does the problem with your sleep negatively affect your daytime
functioning? If the answer is yes to both questions, a more focused
assessment of sleep disturbance is indicated.186 Use of the Insomnia
Severity Index (7-item, self-report questionnaire) was also recommended
to screen for cases of insomnia in cancer patients and for assessing the
effects of treatment (Table 42.5).187 Once identified, the Pittsburgh Sleep
Quality Index (PSQI) can be administered for a more detailed assessment.
The PSQI is a 19-item questionnaire evaluating sleep quality and
disturbances over the past month.188 The first 4 items are open questions,
whereas items 5 to 19 are rated on a 4-point Likert scale. Individual items

2043
scores yield 7 components (subjective sleep quality, sleep latency, sleep
duration, habitual sleep efficiency, sleep disturbances, use of sleeping
medication, and daytime dysfunction). A total score (global PSQI),
ranging from 0 to 21, is obtained by adding the 7 component scores. A
score >5 suggests poor sleep quality.

TABLE 42.5 Insomnia Severity Index

For each question, please CIRCLE the number that best describes your answer.
Please rate the CURRENT (i.e., LAST 2 WEEKS) SEVERITY of your insomnia problem(s).
Insomnia Problem None Mild Moderate Severe Very
Severe
1. Difficulty falling asleep 0 1 2 3 4
2. Difficulty staying asleep 0 1 2 3 4
3. Problem waking up too early 0 1 2 3 4
4. How SATISFIED/DISSATISFIED are you with your CURRENT sleep pattern?
Very Moderately Very
Satisfied Satisfied Satisfied Dissatisfied Dissatisfied
0 1 2 3 4
5. How NOTICEABLE to others do you think your sleep problem is in terms of impairing the
quality of your life?
Not at all Very Much
Noticeable A Little Somewhat Much Noticeable
0 1 2 3 4
6. How WORRIED/DISTRESSED are you about your current sleep problem?
Not at all Very Much
Worried A Little Somewhat Much Worried
0 1 2 3 4
7. To what extent do you consider your sleep problem to INTERFERE with your daily
functioning (e.g., daytime fatigue, mood, ability to function at work/daily chores,
concentration, memory, mood, etc.) CURRENTLY?
Not at all Very Much
Interfering A Little Somewhat Much Interfering
0 1 2 3 4
Guidelines for Scoring/Interpretation:
Add the scores for all seven items (questions 1 + 2 + 3 + 4 + 5 + 6 + 7) = ________ your total
score
Total score categories:
0–7 = No clinically significant insomnia
8–14 = Subthreshold insomnia
15–21 = Clinical insomnia (moderate severity)
22–28 = Clinical insomnia (severe)
From Charles M. Morin, PhD, Université Laval.

2044
 Treatment of insomnia favors the use of pharmacologic aids. The
common hypnotics including barbiturates, benzodiazepines, the “Z” drugs
(eszopiclone, zaleplon, zolpidem, zopiclone), and other benzodiazepine-
receptor agonists bind to γ-aminobutyric acid (GABA) receptors.
However, a European study demonstrated that publication bias exists for
insomnia trials and that the positive trials are two times more likely to be
published than the negative ones.189 There is little controlled evidence that
long-term uses of hypnotics produce benefits of any sort.190 A study of
almost 2,000 cancer patients found that 22.6% were taking hypnotic
medication for sleep problems, and half of those were taking medication
every night for periods longer than 6 months.191 Use of hypnotic drugs is
associated with a greatly increased risk of all-cause mortality. Some of this
mortality has been documented as deaths caused by hypnotics by medical
examiners, attributed to respiratory arrests resulting from “overdose.”
However, it is likely that many deaths from respiratory depression occur
among patients never seen by coroners, especially when the death is
caused by a combination of hypnotics with other contributing factors, so
that the lethal hypnotic dosage may by itself have been within customary
dosage ranges.192 In addition to respiratory depression, hypnotics appear to
be causally related to serious illnesses and premature deaths from cancer,
serious infections, mood disorders, accidental injuries, suicides, and
homicides.193 Cognitive-behavior therapy for insomnia (CBT-I) includes
components of sleep restriction (limiting time in bed), stimulus control
(conditioning the bed for sleep by restricting behaviors incompatible with
sleep in the bedroom), and cognitive restructuring (addressing maladaptive
thoughts and beliefs about sleep) to reestablish a regular sleep pattern.
CBT-I was superior to zopiclone both in short- and long-term management
of insomnia in older adults.194

Sources of Pain in the Cancer Patient

Pain in the oncology patient can arise from different sources (Table 42.6):
• Direct or indirect tumor involvement
• Cancer-directed therapy
• Mechanisms unrelated to cancer or its treatment

2045
 • A combination of the above

TABLE 42.6 Causes of Pain in Patients with Cancer

Cause
As a direct consequence of tumor
As an indirect consequence of tumors
As a consequence of tumor therapy
Without relation to cancer
A combination of the above
Example
Involvement of bones
Obstruction of hollow organs
Compression of nerves
By infections
By metabolic imbalances
By venous/lymphatic occlusion
By paraneoplastic syndromes
Following surgical intervention
Following chemotherapy
Following radiation therapy
Migraine
Diabetic neuropathy
Myofascial pain problems
Metastatic lung cancer to bone with hypertrophic
osteoarthropathy affecting tubular bones in a
patient with painful peripheral diabetic neuropathy
and chemotherapy-induced peripheral neuropathy

Patients may present with complex patterns of pain that result from
combinations of these categories, thus complicating the diagnosis. Factors
influencing the pain complaint include the primary tumor type, stage of
disease, tumor site, and mood factors (anxiety and depression). Although
estimates vary, the prevalence of pain in cancer survivors has been
reported to be as high as 40%195–198 with variable durations of painful
symptoms199 and with disparities in race and sex.200 The prevalence of
pain in patients with cancer varies with tumor type, treatment phase, and
stage of disease. Van den Beuken-van Everdingen et al.196 estimated the
pain prevalence rates were 39.3% after curative treatment; 55% during
anticancer treatment; and 66.4% in advanced, metastatic, or terminal
disease with 50.7% in all cancer stages. Moderate to severe intensity pain
(numerical rating scale score ≥5) was reported by 38.0% of all patients. Of
note, lower pain prevalence rates occurred in prostate cancer patient
compared to head and neck, lung, and breast cancer patients. In 2007, the
authors previously reported prevalence rates of 33% after curative
treatment; 59% during treatment; 64% in advanced, metastatic, or terminal
disease; and 64% in all cancer stages with approximately 33% grading

2046
pain intensity as moderate to severe and the highest prevalence in
head/neck cancer patients.201 High prevalence of pain has also been
documented in hematologic tumor patients initially at diagnosis, during
treatment, and in the last month of life.202,203
Many patients with advanced disease frequently have multiple pain
complaints at different sites and were more common in patients with
breast, lung, and prostate cancer compared with gastrointestinal cancers.204
In a prospective study of 2,266 cancer patients, Grond et al.61 assessed
localization, etiology, and pathophysiologic mechanisms of pain
syndromes associated with cancer. Thirty percent of the patients presented
with one, 39% with two, and 31% with three or more distinct pain
syndromes. The majority of patients had pain caused by cancer (85%) or
antineoplastic treatment (17%); 9% had pain related to cancer disease and
9% due to etiologies unrelated to cancer. These investigations classified
pain as originating from nociceptors in bone (35%), soft tissue (45%) or
visceral structures (33%), or of neuropathic origin (34%). Patients had
localized pain syndromes in the lower back (36%), abdominal region
(27%), thoracic region (23%), lower limbs (21%), head (17%), and pelvic
region (15%). Regions and systems affected by the main pain syndrome
varied widely depending on the site of cancer origin, whereas the cancer
site did not markedly influence the pain’s temporal characteristics,
intensity, or etiology.
Many metastatic bone lesions cause few or no symptoms and are
diagnosed incidentally during an initial staging workup or at follow-up
restaging evaluations.205 Bone cancer pain is the most common pain in
patients with advanced cancer, and approximately two-thirds of patients
with metastatic bone disease experience severe pain.206 Many of the most
common tumors (breast, prostate, thyroid, kidney, and lung) have a strong
predilection for bone metastasis, and an estimated 70% of patients with
breast and prostate cancers develop bone metastases compared with 20%
to 30% of patients with lung or gastrointestinal cancers.207 Although pain
is frequently associated with the presence of metastases, certain tumor
types are exceptions, notably breast and prostate cancers. Neither the
prevalence nor the severity of pain among breast cancer patients varied
directly as a function of metastatic sites of disease.118,119 Palmer et al.208

2047
evaluated the sensitivity of pain as an indicator of bone metastases in
patients with breast or prostate cancer. Pain was a common finding,
whether or not metastatic disease was present, and it occurred in over half
of the patients. Although most patients with bone metastases reported bone
pain, some (21% of breast and 22% of prostate patients) were
asymptomatic.
The majority of neoplasms are responsible for symptoms caused by
mass effects to surrounding tissues and/or through the development of
metastases. Paraneoplastic syndromes arise from tumor secretion of
hormones, peptides, or cytokines or from immune cross-reactivity between
malignant and normal tissues and may affect different organ systems, most
notably the endocrine, neurologic, dermatologic, rheumatologic, and
hematologic systems. The most commonly associated malignancies
include small-cell lung cancer (SCLC), breast, gynecologic, and
hematologic malignancies. Hypertrophic pulmonary osteoarthropathy
(HPO) is characterized by periostosis and subperiosteal new bone
formation along the shaft of long bones and the phalanges (“digital
clubbing”), joint swelling, and pain and may be present in 1% to 10% of
patients with lung tumors209,210 and may also been seen in patients with
mesothelioma and lymphoma. Classically, HPO is diagnosed based on
clinical symptoms (severe pain, edema, and erythema in the extremities)
and radiologic findings. Periostitis is the hallmark of HPO, and imaging
shows periosteal membrane thickening and periosteal new bone formation
particularly in the distal long bones (especially the tibia). Bone scan is also
useful for the detection of HPO. Peripheral nerves are a common target in
paraneoplastic syndromes.211 Antibodies directed against neural antigens
expressed by the tumor (onconeural antibodies) may occur in most of
those affected by classical paraneoplastic syndromes, suggesting that an
autoimmune process underlies these disorders. Subacute sensory
neuronopathy (SSN) is a classical paraneoplastic syndrome.212 The
neuropathy generally develops subacutely accompanied by pain and
rapidly progressive paresthesia. Involvement of the upper extremities may
occur with asymmetric sensory deficit or multifocal with facial, thoracic,
and abdominal involvement. Many patients with SSN also have signs and
symptoms suggestive of multifocal involvement including areas of the

2048
CNS. Paraneoplastic vasculitis of the peripheral nervous system usually
precedes the tumor diagnosis and presents as multineuritis or asymmetric
distal sensory-motor neuropathy with pain as a commonly reported
symptom. This form is generally associated with lymphoma or cancer at
various sites (lung, prostate, uterus, kidney, or gastric).213
Cancer-directed therapy pain syndromes may result from chemotherapy,
radiation therapy, or surgery. Chemotherapy-induced peripheral
neuropathy (CIPN) is well described with a variety of agents.214 Sensory
symptoms tend to be greater than motor or autonomic, and the majority of
signs and symptoms due to CIPN arise from damage to dorsal root
ganglion neurons or their axons, leading to acral pain, sensory loss, and
sometimes sensory ataxia. With platinum compounds, as many as 30% of
patients experience worsening of neuropathy for a few months following
completion of therapy, and a sizable cohort report persistent symptoms
lasting years. Paclitaxel-associated CIPN usually improves in the months
following treatment cessation but still has been associated with long-term
persistence of some degree of neuropathy in up to 80% of patients, with
roughly a third of these patients reporting severe symptoms.215 Table 42.7
lists the National Cancer Institute Common Terminology Criteria for
Adverse Events for neurotoxicity.

TABLE 42.7 NCI CTCAE v4.0 Neurotoxicity: National Cancer

Institute Common Terminology Criteria for Adverse Events
Adverse Grade
Event Grade 1 Grade 2 Grade 3 Grade 4 5
Peripheral Asymptomatic, Moderate Severe Life-threatening Death
motor clinical or symptoms; symptoms; consequences;
neuropathy diagnostic limiting limiting urgent
observations instrumental self-care intervention
only; ADLa ADLa; indicated
intervention assistive
not indicated device
indicated
Peripheral Asymptomatic; Moderate Severe Life-threatening Death
sensory loss of deep symptoms; symptoms; consequences;
neuropathy tendon reflexes limiting limiting urgent
or paresthesia instrumental self-care intervention
ADLa ADLa indicated
Paresthesia Mild symptoms Moderate Severe

2049
 symptoms; symptoms;
limiting limiting
instrumental self-care
ADLa ADLa
aInstrumental
ADL include preparing meals, shopping, using the telephone, managing money. Self-
care ADLs include bathing, dressing, using the toilet, and taking medications. Paresthesia is
characterized by functional disturbances of sensory neurons resulting in abnormal cutaneous
sensations of tingling, numbness, pressure, cold, and warmth that are experienced in the absence
of a stimulus. Peripheral motor neuropathy is characterized by inflammation or degeneration of
the peripheral motor nerves. Peripheral sensory neuropathy is characterized by inflammation or
degeneration of the peripheral sensory nerves.
ADL, activities of daily living.

Chemotherapeutic toxicity may be attributable to steroids, which are

coadministered in many chemotherapeutic protocols. In particular,
avascular necrosis is a well-described complication of steroid use.
Morbidity is related to progressive joint damage often leading to decreased
range of motion, pain with movement, and arthritis. Weight-bearing joints
are most commonly involved. The shoulder, elbow, wrist, hand, and
vertebral bodies can also be involved. The total cumulative dose and daily
dose of glucocorticoids, and likely the underlying condition, affect the risk
of developing avascular necrosis.216 Short-term, low-dose protocols are
occasionally associated with necrosis.217 It most commonly occurs in the
femoral and humeral heads. Pain is usually the first symptom, but the
clinical presentation is variable and depends on the site and size of the
infarct. Persistent hip or shoulder pain, especially with joint movement,
tenderness, or reduced range of motion, warrants magnetic resonance
imaging (MRI) which can visualize aspects of the necrotic lesion
(necrosis, reactive zone/granulation tissue, sclerotic changes, edema).
Bone marrow signal abnormality, the double-line sign, and subchondral
fracture are characteristic MRI findings of avascular necrosis.218
Combined medical and radiation therapies, both sequential and
concurrent, are improving clinical outcomes for locoregional tumor
control, with enhanced patient survival and delay of recurrence.219 During
the course of external radiation therapy, treatment generally influences
normal tissue function in tissues that have more rapid self-renewing
proliferative index (e.g., mucosal surfaces such as skin, head/neck, and
esophagus) and other surface tissues that have more limited potential for

2050
self-renewal (e.g., hair, nails, and surface glands). Injuries to these tissues
are often self-limited and heal without specific intervention secondary to
stem cell renewal. Acute effects from radiation therapy do not uniformly
predict for late effects from treatment. Late effects generally affect tissues
that have limited potential for self-renewal, and injury is often more
permanent, requiring surgical débridement and possibly resulting in
functional damage.
Radiation-induced neural damage and pain may become apparent
sometime after completion of radiation therapy confounding the diagnosis
in some cases.220–222 Postsurgical pain syndromes come in many varieties,
including postmastectomy, postamputation, postthoracotomy, and other
chronic pain states. Treatments for head and neck cancer have the potential
to cause persistent pain and discomfort. Radical surgery, such as resection
of portions of the tongue, palate, and mandible, and radical neck dissection
(RND) cause major structural changes. Radiation therapy, which
frequently is the primary therapy, may cause mucositis, xerostomia, loss of
taste, and decreased QOL. Subsequent late fibrosis of skin and soft tissues
may lead to temporomandibular joint dysfunction and MPSs. Eating
difficulties and persistent pain are frequent issues in head and neck cancer
survivors.223,224
Cancer patients and, in particular, cancer survivors may experience
chronic non–tumor-related pain. The challenge for the treating clinician is
to distinguish between tumor-associated and non–tumor-associated pain.
Many of the same interdisciplinary treatment paradigms apply to cancer
survivors as apply to all chronic pain patients, but an appreciation for the
disabilities associated with treatments of cancer is essential. Long-term
management of pain associated with cancer and its treatment poses a
substantial challenge for the clinician. Pain complaints frequently change
over time, involve multiple sites, stem from several origins including
chronic disabilities, involve several causes simultaneously, and may relate
loosely or not at all to the tumor.

Classification of Cancer Pain by Feature

Several schemata exist for classifying pain in the cancer patient and are

2051
potentially useful for diagnosis and management. One such scheme is
presented in Table 42.8.

TABLE 42.8 Methods Used for Classifying Pain in the Cancer

Patient
Chronicity
Intensity/severity
Pathophysiology/mechanism
Individual type and stage of disease
Pattern of pain
Syndrome

CHRONICITY
Acute pain is the normal, predicted physiologic response to a noxious
stimulus and typically is associated with invasive procedures, trauma, and
disease. Various anticancer therapies, particularly postoperative pain
following surgical intervention and radiation therapy, can cause acute pain
(Table 42.9). The course of acute pain is usually predictable and self-
limiting, and the pain does not represent a difficult diagnostic problem. In
contrast, assessment of patients with chronic pain tends to be much more
difficult and complex. Chronic pain is best considered as persistent pain
beyond the expected healing time. As healing times vary for different
stimuli and trauma, conventional definitions of chronic pain based on
arbitrary intervals between 3 months and 6 months are less useful. One
exception to this is the development of postherpetic neuralgia (PHN) after
the development of herpes zoster. Several cancers including oral,
esophageal, stomach, colorectal, lung, breast, ovarian, prostate, kidney,
bladder, and CNS cancers as well as lymphoma, myeloma, and leukemia
were associated with an increased risk of zoster, particularly within the
first 2 years after diagnosis and among younger individuals.225 Some have
proposed that only clinically relevant pain be defined as PHN to avoid
overestimation of the problem and as pain ≥3 on a 10-point scale persisting
120 days after rash healing.226–229

2052
 TABLE 42.9 Acute Pain Associated with Cancer Management
Procedure Problem
Diagnostic Blood samples
procedures Lumbar puncture
Biopsy
Chemotherapy Mucositis
GI distress including typhlitis, colitis, pancreatitis
Cardiomyopathy
Extravasation of drug into tissues
Radiation Skin burns
treatment Mucositis
Pharyngitis
Esophagitis
Proctitis
Itching
Interventional Yttrium-90 radioembolization
radiology Chemoembolization
procedures Radiofrequency ablation
Surgical therapy Postoperative pain
GI, gastrointestinal.

INTENSITY/SEVERITY
Health care providers underestimate the severity of a patient’s pain,
particularly when relying on their own observations.230–232 This tendency
is problematic because pain is often undertreated when patients and
physicians differ in their judgment of the pain’s severity.233 Patient self-
report is always the primary source of information for the measurement of
symptoms, and subjective reporting of pain is considered a key component
of pain assessment.234 Observer ratings of symptom severity correlate
poorly with patient ratings and are generally inadequate substitutes for
patient reporting. The discrepancies were most pronounced in those
patients reporting severe pain.233 Although clinicians can monitor some
objective signs to clarify the manifestations and impact of certain
symptoms, these signs only complement subjective assessment and self-
reporting. An assessment of pain intensity should include an evaluation of
not only the present or average pain intensity but also pain at its least and
worst over a defined time period.
The three most commonly used instruments for assessing cancer pain

2053
intensity are the following:235
• Visual Analogue Scale (VAS): A slash mark corresponding to
intensity of pain is placed on a 100 mm line ranging at one end from
“No Pain,” to the other end, “Pain as bad as it could possibly be.”
• Numeric Rating Scale (NRS): A number is assigned to the intensity of
pain on a scale of 0 to 10; 0 reflecting “No Pain” and 10 reflecting the
“Worst Pain Possible.”
• Verbal Rating Scale (VRS): The patient chooses one of the following
words that best describes pain: “No Pain,” “Mild Pain,” “Moderate
Pain,” “Severe Pain,” “Worst Possible Pain.”
All three measures correlate highly with one another. For pain
assessment in clinical settings, the VAS, VRS, and NRS approach
equivalency236 so that clarity, ease of administration, and simplicity of
scoring become justifiable criteria in response scale selection. On the basis
of relatively few studies in cancer, results or recommendations did not
differ conclusively from those in other populations.235 In clinical
scenarios, the NRS or VRS has proven more popular than the VAS and
scales has high correlations, especially with less educated patients.237,238
Numerical scales as measures of QOL end points work well as cancer
clinical trial instruments because they are easier to understand and easier
to score.239
Several studies have shown that differences between categorical pain
severity items are not linear.240,241 For instance, when pain severity is
rated at the midpoint or higher on numeric rating scales, patients report
disproportionately more interference with daily function.122 Many patients,
both with and without cancer, function quite effectively with a background
level of mild pain that does not seriously impair or distract them. As pain
severity increases to moderate intensity, pain passes a threshold beyond
which it is hard for the patient to ignore the pain. At this point, it disrupts
many aspects of the patient’s life. When pain is severe, it becomes a
primary focus of attention and prohibits most activities. Pain severity and
the degree to which the patient’s function is impaired are highly
associated. As a way of delineating different levels of cancer pain severity,
Serlin et al.122 explored the relationship between numerical ratings of pain
severity and ratings of pain’s interference with such functions as activity,

2054
mood, and sleep. Based on the degree of interference with function, ratings
of 1 to 4 correspond to mild pain, 5 to 6 to moderate pain, and 7 to 10 to
severe pain. In a follow-up study in categorizing the severity of cancer
pain, Paul et al.123 confirmed a nonlinear relationship between cancer pain
severity and interference with function and that the boundary between a
mild and a moderate level of cancer pain was at 4. However, they failed to
confirm the boundary between moderate and severe cancer pain and
reported that a rating of 7 was in the moderate category and ratings >7
being in the severe category.

PATHOPHYSIOLOGY/MECHANISMS
A general classification by pathophysiology distinguishes nociceptive
(somatic and visceral) from neuropathic pain (see “Pain and the Cancer
Patient” section). This distinction is fundamental in assessment because it
may determine and guide therapy. In principle, pain results from
stimulation of nociceptors or by lesions of afferent nerve fibers. Pain is
nociceptive if the sustaining mechanisms are related to ongoing tissue
pathology. Pain is neuropathic when there is evidence that the pain stems
from injury to neural tissues and aberrant somatosensory processing in the
periphery or in the CNS. Physical influences such as pressure, traction,
compression, and tumor infiltration as well as metabolic or chemical
disturbances produce pain. Obviously, classification by physiologic
mechanism would be an improvement, but sufficient information to do this
is not available.

Tumor Involvement of Encapsulated Organs

Primary or secondary tumors of the liver are the most frequent examples of
tumors of encapsulated organs. These can enlarge the organ to several
times the normal size. Because the organ capsule of connective tissue
grows less rapidly than the tumor, the intracapsular pressure rises as
capsular distention develops. In addition, tumor infiltrates the capsule
locally, producing dull, and rarely also stabbing, pains. The massive
growth of the organ not only stimulates intracapsular nociceptors, but it
also irritates larger nerves by pressure or traction on the tissue suspending
the organ. Similar organ-enlarging processes in the spleen and kidneys do

2055
not lead to pain to the same extent as in the liver, perhaps because of the
more stable suspension or embedding of these organs, which are farther
away from the midline with its abundant nerve pathways. The initial
presentation of renal tumors can include pain, weight loss, and hematuria
but typically occurs in only 9% of patients and is often indicative of
advanced disease with approximately 30% of patients with renal
carcinoma present with metastatic disease, 25% with locally advanced
renal carcinoma, and 45% with localized disease.242 The detection of
kidney pain relies on input from sympathetic, parasympathetic, and
sensory nerves. The sympathetic nerves supplying the kidneys originate in
spinal cord segments T10–L1 and travel via white rami to the
paravertebral ganglia. The sympathetic nerves travel via the lesser
splanchnic nerves from the T10–T11 thoracic paravertebral ganglia to the
synapse at the ipsilateral aorticorenal and celiac ganglia. From the 12th
thoracic paravertebral ganglion, nerves travel via the least splanchnic
nerve to the synapse either in the aorticorenal ganglion or in the renal
plexus. The first lumbar splanchnic nerve and the postganglionic
sympathetic nerves from the aorticorenal and celiac plexus synapse in the
renal plexus. The parasympathetic innervation originates from the vagus
nerve. These parasympathetic nerves traverse through the celiac plexus or
pass directly to the renal plexus. Sensory renal nerves travel via the renal
plexus, splanchnic nerves, thoracic sympathetic ganglia, T10–T12 spinal
nerves, and spinal cord dorsal horn neurons. Patients may complain of
abdominal, back, and flank pain in addition to the sensation of flank
heaviness.
Pain-sensitive structures in the head include extracranial structures such
as the skin, muscles, and blood vessels in the head and neck; mucosa of the
sinuses and dental structures; and intracranial structures including the
regions of the large arteries near the circle of Willis, the great intracranial
venous sinuses, parts of the dura and dural arteries, and cranial nerves
(particularly glossopharyngeal, vagus, and trigeminal). The cranium
(except the periosteum), brain parenchyma, ependymal lining of the
ventricles, and choroid plexus are all pain insensitive. The brain is also an
encapsulated organ. Its special feature is that the bony skull capsule
prevents any enlargement. Pain arises here, not by destruction of

2056
parenchyma, but by the increase of intracranial pressure with stimulation
of the meningeal nociceptors. Such an increase of intracranial pressure
occurs in space-occupying tumor growth or in focal or generalized brain
edema. Focally, edema can develop around isolated tumors. Generalized
edema develops in diffuse metastatic invasion of the meninges due to
disturbance of the circulation of CSF. Such a tumor invasion of the
leptomeninges is frequent in malignant lymphomas. However, metastatic
invasion of the leptomeninges occurs in patients with solid tumors (e.g.,
bronchial carcinoma and malignant melanoma), with the predominant
symptom being headache. In such cases, tumor infiltration of cranial
nerves may also occur.

Tumor Infiltration of Peripheral Nerves

Because peripheral nerves can usually evade pressure from a tumor on one
side, infiltration by tumor tissue is the quintessential tissue trauma
stimulus. In addition, indirect damage of unknown pathogenesis might also
occur to peripheral nerves in the context of tumor conditions such as occur
with paraneoplastic syndromes. Paraneoplastic syndromes may affect
diverse organ systems, most notably the endocrine, neurologic,
dermatologic, rheumatologic, and hematologic systems. The best described
paraneoplastic syndromes are attributed to tumor secretion of functional
peptides and hormones (endocrine paraneoplastic syndromes) or immune
cross-reactivity between tumor and normal host tissues (neurologic
paraneoplastic syndromes) and may affect up to 8% of cancer patients.243
In paraneoplastic neurologic syndromes, tumor-directed onconeural
antibodies are produced and may result in permanent damage to neural
tissue.
Tumor tissue often infiltrates the perineural cleft; however, this does not
regularly cause pain. A massive and then painful entrapment of the nerve
plexus or individual nerves sometimes occurs, especially in extensive
breast carcinomas and their recurrences or in chest wall metastases of
bronchial carcinomas. The perineural cleft widens tumor infiltration, and
infiltration of the tumor into the nerve itself is common. Degenerative
changes of the axis cylinders are sometimes visible with conventional
screening methods. Primary tumors of the peripheral nerves themselves

2057
lead to painful destruction. Tumor compression regularly elicits pain when
the affected nerve cannot give way (e.g., a spinal nerve).

Tumor Infiltration of Soft Tissues

Tumor infiltration of soft tissues causes pain via the mechanisms described
in the earlier discussion, as with massive infiltrations of the
retroperitoneum. Infiltration and destruction of mobile structures (e.g., of
the skeletal musculature) can lead to pain via disturbance of function.
Here, the tumor spreads in the interstitium and destroys blood vessels,
lymphatics, and nerves.

Tumor Infiltration of Bone

The most frequent cause of pain in tumor patients is infiltration of bone.
This applies to primary and secondary neoplasias originating from the
bone marrow as well as to neoplasias of the bone itself. Such tumors
always cause pain when they lead to an elevation of the intraosseous
pressure, to loss of stability, or to a lesion of the periosteum resulting in
periosteal elevation, or with the release of chemical mediators of
nociception. The neural structures that generate nociception reside in the
bone marrow, in the bone, and in the periosteum.
In metastatic processes, the degree of bone destruction is often
extensive. Vertebral spread of tumor may involve intervertebral foramina,
where it can compress nerve roots. Further spread posteriorly leads to
encroachment of the spinal cord and the spinal nerves. In the bone,
metastases localized to the bone marrow result in osteolysis or
osteosclerosis. Necroses and hemorrhages occur frequently in bone
metastases and doubtless play a role in the etiology of pain. The
hemorrhages probably result from microfractures. Metastatic bone disease
is discussed in detail later.

Tumor Infiltration of Abdominal Hollow Organs

Tumor involvement in abdominal hollow organs causes pain. This applies
to all primary and secondary intestinal tumors. However, their pain-
eliciting potency differs widely from individual to individual. The pain
results from ulcerations, motility disorders, dilatations, and disorders of

2058
blood flow. In accordance with the extent of the lymphatic tissue, large
tumors with extensive ulceration and hemorrhage occur in malignant
lymphomas of the gastrointestinal tract. Perineural tumor infiltration,
arteritis, or perineural inflammatory reactions are common in tumors of the
abdominal and urogenital hollow organs. Tumor infiltration of the urinary
bladder can vary from a sense of uneasiness felt in the suprapubic region
or a severe, constant agonizing deep pelvic pain. The pain may also radiate
and extend into the thighs. Intolerable cystitis may occur with tumor
infiltration of the bladder wall.

Tumor Infiltration and Inflammation of Serous Mucosa

The parietal pleura lines the inner chest wall, whereas the visceral pleura
covers the lung surface including interlobar fissures. The peripheral part of
the diaphragm and costal portion of the parietal pleura are innervated by
somatic intercostal nerves with the central portion of the diaphragm
innervated by the phrenic nerve. The visceral pleura are extensively
innervated by pulmonary branches of the vagus nerve and the sympathetic
trunk. Pleural carcinomatosis with infiltration of both parietal and visceral
surfaces can be extremely painful and difficult to manage.244 Somatic
nerves innervate the parietal peritoneum. These nerves also supply the
muscles and skin of the overlying body wall. Afferent nerves that travel
with the autonomic supply of the underlying viscera innervate the visceral
peritoneum. Nociceptive information from diseases that affect the parietal
or visceral peritoneum reflects these different patterns of innervation.
Animals with peritoneal carcinomatosis exhibit hypersensitivity to
mechanical stimulation and visceral pain-like behavior.245

TUMOR TYPE AND STAGE OF DISEASE

Factors influencing the pain complaint include the primary tumor type,
stage of disease, and tumor site. When metastatic disease appears, about
one in three patients report significant pain. Vainio and Auvinen246
reported that moderate to severe pain was present in 51% of patients with
advanced cancer with severe pain more commonly seen in patients with
prostate, esophageal, gynecologic, colorectal, head/neck, breast, and lung
cancers. At least half of lung and breast cancer patients had at least

2059
moderate intensity pain. Although pain tends to reflect the presence of
metastases, this may not always be the case for certain tumor types,
particularly for patients with breast or prostate cancers. Although many
patients with bone metastases report bone pain, a significant fraction (21%
of breast and 22% of prostate patients) was asymptomatic.208 Levren et
al.247 examined the relationship between pain and bone metastases in
patients with prostate or breast cancer referred for bone scintigraphy. In
patients with prostate cancer, metastases were found in 47% of the patients
with pain but only in 12% of the patients without pain (P = .01). In patients
with breast cancer, metastases were more common in patients without pain
(71%) than in patients with pain (34%; P = .02).
Pain caused by tumor may occur at the onset of disease or at an
advanced stage. Although rarely one of the early indicators of the onset of
disease, pain is not a significant problem for the majority of patients in the
early stages of disease, with 5% to 10% of patients with solid tumors
reporting pain at a level that interferes with mood and activity. However,
pain is obviously a major concern that often prompts the patient to seek
medical consultation. Vuorinen248 found that 28% of newly diagnosed
unselected cancer patients reported pain. Cleeland249 reported that the
majority of patients with end-stage disease have pain of a severity that
interferes with several aspects of the patient’s QOL. Daut and Cleeland118
found that pain was an early symptom of cancer in 40% to 50% of patients
with cancer of the breast, ovary, prostate, colon, and rectum, and in about
20% of patients with cancer of the uterus and cervix.
Knowing the natural history of the disease facilitates an understanding
of the pain process and is important in determining the nature and timing
of treatment. Examples of the more common disease processes follow.

Pancreatic Cancer
Most pancreatic tumors are exocrine tumors, including ductal
adenocarcinoma, acinar cell carcinoma, cystadenocarcinoma,
adenosquamous carcinoma, signet ring cell carcinoma, hepatoid
carcinoma, colloid carcinoma, undifferentiated carcinoma,
pancreatoblastoma, and pancreatic mucinous cystic neoplasm. The most
common form is ductal adenocarcinoma characterized by moderately to

2060
poorly differentiated glandular structures, comprising 80% to 90% of all
pancreatic tumors. Endocrine pancreatic tumors are rare and account for
only 1% to 2% of all pancreatic tumors. Pancreatic ductal adenocarcinoma
is the fourth leading cause of cancer-related death in the United States.3
Surgical resection is the only potentially curative treatment, but because of
the late presentation, only 15% to 20% of patients are candidates for
surgical intervention. Even after complete resection, prognosis is poor with
only 6% of patients (ranges from 2% to 9%) surviving 5 years after
diagnosis.250,251 The highest incidence and mortality rates of pancreatic
cancer are found in developed countries. Resectable cancers typically have
no vascular or regional spread. Borderline cancers have regional spread
into vessels (i.e., portal vein) or other organs (i.e., stomach), which would
make surgery difficult, and locally invasive cancers have invasion into
structures (e.g., celiac artery), which make curative surgery impossible. Up
to 90% of patients with pancreatic cancer experience significant abdominal
pain during the course of their illness.250
Incidence rates for pancreatic cancer in 2012 were highest in Northern
America (7.4 per 100,000) and Western Europe (7.3 per 100,000),
followed by other regions in Europe and Australia/New Zealand (equally
about 6.5 per 100,000).251 In the United States, whites and blacks
experienced opposite trends in pancreatic cancer death rates between 1975
and 2013 with white men death rates decreased by 0.7% per year from
1970 to 1995 and then increased by 0.4% per year through 2009. Among
white women, rates increased slightly from 1970 to 1984, stabilized until
the late 1990s, then increased by 0.5% per year through 2009. In contrast,
the rates among blacks increased between 1970 and the late 1980s
(women) or early 1990s (men) and then decreased thereafter.252 Pancreatic
cancer is difficult to diagnose. The appearance of symptoms usually
indicates an advanced stage and the most frequent presentations are
progressive weight loss, anorexia, abdominal pain, and jaundice. These
symptoms are nonspecific and varied in different regions of pancreas.
Tumor in the head of the pancreas (75%) produces weight loss, painless
jaundice, nausea, and vomiting. If cancer is located at the body/tail of the
pancreas, patients usually present with abdominal pain that radiates to the
sides or through to the back. Local tumor extension almost invariably

2061
involves the peripancreatic fat tissue through direct invasion of lymphatic
channels and perineural spaces. Duodenum, stomach, gallbladder, and
peritoneum are infiltrated by tumors located in the pancreatic head; body
and tail tumors can invade liver, spleen, and left adrenal gland. Lymphatic
spread to adjacent and distant lymph nodes seems to precede
hematogenous spread, which affects, in descending order, liver,
peritoneum, lungs, adrenals, kidneys, bones, and brain. At diagnosis, 30%
to 40% of patients report abdominal pain, 80% develop pain with disease
progression, and 44% of these describe the pain as severe. The presence of
pain in newly diagnosed patients with potentially operable pancreatic
cancer is an ominous predictor of resectability and of survival.253
A number of factors contribute to the generation and maintenance of
pancreatic cancer pain. One of the most striking neural alterations in
pancreatic cancer is neural invasion, which occurs in up to 100% of
patients.254,255 Pancreatic cancer is characterized by invasion of nerves by
cancer cells (neural invasion), pancreatic nerve damage, pancreatic
neuroinflammation (neuritis), and noticeable hypertrophy with sprouting
of intrapancreatic nerves.256 Cancer cells that invade nerves express a
large set of neurotrophic factors such as NGF, artemin, neurturin that are
similarly released by mast cells or other inflammatory cells and can
strongly sensitize nociceptive nerve endings. Intrapancreatic nerves
increase in size (neural hypertrophy) and number (increased neural
density). The proportion of autonomic and sensory fibers (neural
remodeling) is switched and is invaded by pancreatic cancer cells (neural
invasion).257 These neuropathic alterations also correlate with neuropathic
pain.
Pain due to pancreatic cancer is usually abdominal, typically referred to
the epigastric region or the upper abdominal quadrants, but it can also
involve the lower quadrants or be diffuse.258 Back pain is associated with
abdominal pain in 50% to 65% of cases, but only 5% to 10% of patients
report it as their only complaint. In one series, 67% of patients could not
describe their pain location better than as over the “diffuse abdomen.”259
Eating often aggravates the pain. Tumors of the head of the pancreas may
cause epigastric pain with right flank radiation more often, whereas pain
from tumors in the tail has left-sided radiation. Lying flat typically

2062
exacerbates it and sitting relieves it. This pain probably comes from
retroperitoneal tumor involvement, and it may not respond to celiac plexus
block. It often merges with similar syndromes caused by nodal or other
soft-tissue tumor involvement in the retroperitoneal region (Table 42.10).
The impact of pancreatic pain can be profound. It is commonly associated
with depressed mood and contributes to the rapid decline in function that
characterizes this disease.259,260 In addition, severe pain can influence
survival.261–263

TABLE 42.10 Pancreatic Cancer Pain Syndromes

Pain due to Tumor Involvement Pain due to Cancer Therapies
Visceral pain: Postoperative pain syndromes:
Pancreatic gland infiltration Delayed gastric emptying
Gastric infiltration Wound dehiscence or non-healing
Duodenal infiltration
Liver metastases: capsule distention,
diaphragmatic irritation
Biliary tree distention
Bowel obstruction (duodenal, peritoneal
carcinomatosis)
Ischemic abdominal pain due to mesenteric
vessel involvement
Somatic pain: Biliary prosthesis complications
Retroperitoneal involvement (direct, nodal)
Parietal peritoneum and abdominal wall
involvement
Abdominal distention due to ascites
Bone metastases
Neuropathic pain: Post-chemotherapy pain syndromes:
Radiculopathy from retroperitoneal spread or Liver chemoembolization
bone metastatic involvement Mucositis
Lumbosacral plexopathy Post-radiation pain syndromes:
Epidural spinal cord compression Radiation enteritis
From Caraceni A, Portenoy RK. Pain management in patients with pancreatic carcinoma. Cancer
1996;78(3):639–653. Copyright © 1996 American Cancer Society. Reprinted by permission of
John Wiley & Sons, Inc.

Ovarian Cancer
Ovarian cancer may be subdivided into different histologic subtypes,
which include epithelial cancer serous, endometrioid, clear-cell, and
mucinous carcinomas. Of these types, high-grade serous carcinoma is the

2063
most commonly diagnosed. Histologically and clinically, low-grade
endometrioid carcinoma and low-grade serous carcinoma are different
compared with their high-grade counterparts. Other more rare pathology
includes small-cell carcinoma (predominantly occurs in younger women)
and carcinosarcoma. Nonepithelial ovarian cancers include germ cell
tumors and sex cord stromal tumors, which account for approximately
10% of ovarian cancers. Estimated new cancer cases in the United States
for 2017 were 22,440 with 14,080 deaths (fifth most common cause of
death from cancer in women).3 Overall survival varies greatly based on
stage at initial diagnosis with a 92% survival for stage I and 25% for stage
IV.264 Epithelial ovarian cancer can spread by intraperitoneal,
lymphogenous, and hematogenous mechanisms.
The lifetime risk of ovarian cancer in women by the age 70 years is
approximately 40% for BRCA1 and 18% for BRCA2.265 Most of these
cancers are high-grade serous cancers. Other inherited disorders, such as
Lynch syndrome, can increase the risk of ovarian cancer. Lynch syndrome
is associated with colorectal, endometrial, and ovarian cancers but is also
associated with cancers of the urinary tract, stomach, small intestine, and
biliary tract. The symptoms of ovarian cancer are relatively nonspecific
and often occur when the disease has spread throughout the abdominal
cavity or with the presence of ascites. Abdominal discomfort or vague
pain, abdominal fullness, bowel habit changes, early satiety, dyspepsia,
and bloating are frequent presenting symptoms. Occasionally, patients may
present with bowel obstruction due to intra-abdominal masses or shortness
of breath due to pleural effusion. Early-stage disease is usually
asymptomatic, and the diagnosis is often incidental, although such patients
may occasionally present with dyspareunia or pelvic pain due to ovarian
torsion. Serum CA-125 level has been widely used as a marker for a
possible epithelial ovarian cancer in the primary assessment of a pelvic
mass. Although CA-125 is the best known serum ovarian cancer
biomarker, it is not the only one: Carcinoembryonic antigen (CEA)
(mucinous), lactate dehydrogenase (LDH) (dysgerminoma, mixed germ
cell tumors), β-human chorionic gonadotropin (β-hCG) (choriocarcinoma,
mixed germ cell tumors), inhibin B (granulosa cell tumors), α-fetoprotein
(yolk sac tumors, embryonal cell tumors), and HE4 are also available.266

2064
 The prevalence of pain associated with ovarian cancer resembles the
prevalence rates in populations with other solid tumors.267 Ovarian cancer
spreads by intraperitoneal, lymphatic, and locally invasive pathways.
Lymphatic pathways may extend from the abdominal retroperitoneum to
the groin via the inguinal/femoral canals or across the diaphragm to the
pleural space. Intraperitoneal spread of tumor begins with extension of
tumor through the ovarian capsule, allowing implantation of tumor
throughout the abdomen. Intraperitoneal metastases show a predilection
for the omentum and diaphragm, but no organ is spared, and concomitant
ascites is frequent. Portenoy et al.267 noted that pain, fatigue, and
psychological distress were the most prevalent symptoms in patients with
advanced (stage III or IV) ovarian cancer. Patients generally describe pain
as occurring in the abdominopelvic or lower back region, as being frequent
or almost constant and moderate to severe in intensity. Patients with
advanced disease may experience pain in the lower extremities either from
invasion of the lumbosacral plexus by tumor or by lymphedema secondary
to iliac vessel occlusion.

Cervical Cancer
Cervical cancer is the fourth most common malignancy diagnosed in
women worldwide. Nearly all cases result from infection with the human
papillomavirus (HPV), and prevention includes screening and vaccination.
Rates have declined in the United States with an estimated 12,820 new
cases in 2017 and 4,210 deaths.3 Disparities in incidence and mortality still
occur, with black and Hispanic women continuing to have higher rates of
cervical cancer than white women.268 There are several histologic
subtypes of cervical carcinoma, but the majority of cases tend to be HPV-
associated malignancies including adenocarcinoma, squamous cell
carcinoma, or adenosquamous carcinoma. Neuroendocrine (small-cell or
large-cell) carcinomas are not associated with HPV exposure and clear cell
carcinoma and are rare. Computed tomography (CT) or MRI is often used
to define lymph node status and to assess extent of local disease.
Combined positron emission tomography (PET) and CT imaging may be
useful for detecting smaller nodal disease.269 Cervical cancer usually
spreads to regional lymph nodes, and parametrial invasion is common. The

2065
common sites of distant spread include the aortic (para-aortic, periaortic),
lateral aortic and mediastinal nodes, lungs, and skeleton. Recurrent
cervical cancer is almost always incurable.

Prostate Cancer
Prostate cancer is one of the most prevalent cancers in men worldwide.
Estimated new cancer cases in the United States for 2017 were 161,360
with 26,730 deaths.3 The majority of prostate cancer survivors (64%) tend
to be older (aged 70 years or older) with less than 1% under the age of 50
years.8 Prostate cancer varies widely in its intrinsic development, ranging
from indolent to aggressive. Once clinically significant disease is
established, surgery, radiation, and androgen deprivation therapy (ADT),
which all carry substantial morbidities, are considered standard treatment
options for localized disease. It is often insidious and asymptomatic even
when advanced and for detection, MRI is currently the best imaging
modality.270 Prostate cancer is a heterogeneous group of malignant tumors
and 95% are adenocarcinoma originating from the glands and ducts in the
prostate. Most adenocarcinomas are of the acinar type, typically referred to
as prostate carcinomas. More than 1% consist of other variants that often
have a poor prognosis such as ductal carcinoma, mucinous carcinoma,
signet ring cell carcinoma, and small cell carcinoma. Five percent of
prostate cancer cases are of other types originating from transitional
epithelial cells in the urethra or pars prostatic urethra (urothelial
carcinoma), support tissue (sarcomas), or lymphoid tissue (lymphomas).
Prostate adenocarcinoma may spread locally, by direct invasion of seminal
vesicles, urinary bladder, or surrounding tissues or distantly. Distant
metastases can derive from an initial lymphatic spread or from a direct
hematogenous spreading, mainly to the bones. The Gleason system is the
most widely used grading system for prostate cancer (adenocarcinoma
only). Prostate cancers are stratified into five grades (1 to 5) on the basis of
the glandular pattern and degree of differentiation. The Gleason score is
derived from the sum of the most represented grade (primary grade) with
the second most represented grade (secondary grade) (e.g., 3 + 4 = 7); this
correlates better with prognosis than the single Gleason grade. The
Gleason system can be applied to biopsy and surgical specimens, but not

2066
to fine needle biopsy (FNB), which lack architectural data. Most prostate
cancers in the United States are diagnosed by prostate-specific antigen
(PSA) testing, although many expert groups, including the American
Cancer Society, have concluded that data on the efficacy of PSA screening
are insufficient to recommend routine use of this test and recommend that
for the average risk asymptomatic male over 50 years, a PSA with or
without a digital rectal examination after receiving information about the
benefits, risks, and uncertainties associated with prostate cancer screening
is appropriate.271 Digital rectal examination is recommended along with
PSA for men with hypogonadism because of reduced sensitivity of PSA.
Men at higher risk, including African American men and men with a
family member (father or brother) diagnosed with prostate cancer before
age 65 years, should receive this information beginning at age 45 years.
The clinical behavior of prostate cancer ranges from indolent, localized
disease to aggressive, disseminated disease associated with significant
morbidity and mortality. Although the majority of prostate cancer cases
present while the disease is localized to the prostate, some patients have
evidence of metastatic disease at diagnosis. Typically, metastases are
found in the axial skeleton, pelvic lymph nodes, and the lungs. Because of
the predilection of prostate cancer to spread to bony sites, a significant
proportion of patients with metastatic disease will have bone pain.
Metastases from prostate cancer, most of which are adenocarcinomas,
nearly always form osteoblastic lesions in bone; in contrast, bone
metastases from kidney, lung, or breast cancers more often are osteolytic.
However, metastases from the relatively uncommon neuroendocrine
tumors of the prostate also produce osteolytic lesions. Approximately 90%
of patients who die from prostate cancer have evidence of bone
metastases.272 Radiographically, bone metastases are detected on
technetium-99m (99mTc) bone scintigraphy scans. Newer modalities for
detection include 18sodium fluoride PET and 18fluorodeoxyglucose PET
(FDG-PET). Five-year relative survival varies with stage at diagnosis from
80% or more when malignancy is confined to the prostate to about 25%
where bone metastases are present. Radium-223 (223Ra) is an α emitter
with a half-life of 11.4 days. It is a calcium mimetic and forms complexes
with bone mineral hydroxyapatite in areas of active bone remodeling. The

2067
α particles cause double-strand DNA break of cells. With a range of
penetration of <0.1 mm, 223Ra is able to achieve localized killing of cancer
cells with less collateral damage to the nearby bone marrow273 and is the
first radiopharmaceutical agent demonstrated to improve survival among
patients with symptomatic bone-metastatic castrate-resistant prostate
cancer with no known visceral disease.
Prostate cancer rarely spreads to vital organs, and the disease tends to
progress slowly. Exceptions are spinal cord compression or ureteral
obstruction secondary to retroperitoneal lymph node metastases. Tumors
of the prostate gland may produce local rectal, urethral, suprapubic, and
penile pain as a result of expansion and inflammation of the prostate, pain
referred to the back, lower extremities, and abdominal area resulting from
tumor growth within the pelvis, and distant bone pain with associated
neurologic dysfunction associated with long bone, vertebral, and skull
metastases (Table 42.11). The regional lymph nodes of the prostate are the
nodes of the true pelvis, which are the pelvic nodes below the bifurcation
of the common iliac arteries. Distant lymph nodes are outside the confines
of the true pelvis. They are the aortic (para-aortic, periaortic, lumbar),
common iliac, inguinal, superficial inguinal (femoral), supraclavicular,
cervical, scalene, and retroperitoneal nodes.

TABLE 42.11 Causes of Pain in Prostate Cancer

Causes of Pain Examples/Clinical Syndromes
Bone metastasis Single metastasis of pelvis or long bone
Vertebral body metastasis, spinal cord compression
Base-of-skull metastasis, cranial nerve palsies
Perineal pain syndromes
Soft tissue metastasis Lumbosacral plexopathy
Pelvic tension “myalgia”
Pelvic visceral pain “Prostatitis” pain
From Payne R. Pain management in the patient with prostate cancer. Cancer 1993;71(suppl
3):1131–1137. Copyright © 1993 American Cancer Society. Reprinted by permission of John
Wiley & Sons, Inc.

Clinical syndromes may be identified by the site of bony involvement,

the coexistence of mechanical instability secondary to fractures, and the
neurologic dysfunction caused by tumor infiltration of contiguous
neurologic structures. Bone metastases to the hip and pelvis often produce

2068
local pain that is exacerbated by movement, especially during weight
bearing. Local invasion of tumor from the pelvis into the sacrum may
produce the syndrome of perineal pain. Patients with this syndrome
complain of local and perirectal pain that is accentuated by pressure on the
perineal region, such as that caused by sitting or lying prone. In its most
extreme form, the patient cannot sit or lie flat. Dysfunction of the
parasympathetic sacral innervation to bladder and bowel impairs
continence early in the course of this syndrome. Local spread of tumor
from the prostate into other pelvic and abdominal structures often produces
visceral and neuropathic pain. Tumor invasion of the lumbosacral plexus
may occur.

Breast Cancer
Breast cancer is the most commonly diagnosed cancer and the second
leading cause of cancer-related mortality among North American women.
Estimated new cancer cases for women in the United States for 2017 were
252,170 with 40,610 deaths.3 Seventy-five percent of breast cancer
survivors (more than 2.6 million women) are 60 years or older, whereas
7% are younger than 50 years.8 Breast cancer tends to be diagnosed at a
younger age than other common cancers, with a median age at diagnosis of
61 years with 19% of breast cancers are diagnosed in women ages 30 to 49
years, and 44% occur among women who are age 65 years or older.
Lymphedema of the upper extremity occurs in 20% of women who
undergo axillary lymph node dissection and in about 6% of women after
sentinel lymph node biopsy.274 Gene expression profiling of human
tumors has provided a new paradigm for classifying breast carcinomas,
predicting response to treatment, and risk of recurrence. Women diagnosed
with breast cancer undergo receptor testing for estrogen (ER), human
epidermal growth factor 2 (HER2) receptor tests, and progesterone (PR)
status. Approximately 75% of breast cancers are hormone receptor positive
and 15% to 25% are HER2 positive.275 Approximately 15% to 20% of all
breast cancers do not have hormone or HER2 receptors (triple negative)
and are typically more aggressive and difficult to treat. Breast MRI has
become a widely used second-line imaging modality with well-defined
roles in assessing multifocal tumor and planning surgery and in monitoring

2069
local tumor response to neoadjuvant chemotherapy. MRI screening is used
in high-risk young women such as those with a BRCA gene mutation or
with previous mantle irradiation for lymphoma. PET scanning can be used
to evaluate primary lesions, regionally metastatic and systemic metastases
of breast cancer.
All breast cancers are adenocarcinomas arising from the terminal duct
lobular units. Breast cancers are divided into two main categories,
noninvasive and invasive. Infiltrating ductal carcinoma is the most
common breast cancer histology, accounting for approximately 80% of all
breast cancers. Lobular carcinoma constitutes 10% of the breast cancers.
Ductal carcinoma in situ (DCIS) is the most common type of noninvasive
breast cancer, accounting for about 15% of all newly diagnosed breast
cancer cases. DCIS is classified into five histologic subtypes associated
with varying prognostic implications. These include solid, papillary,
cribriform, micropapillary, and comedo. Most lesions represent a
combination of at least two of these subtypes. Comedocarcinoma is
considered high grade and predictive of recurrence. Lobular carcinoma in
situ (LCIS) is characterized as a benign-appearing proliferation of terminal
ducts and ductules that is often multifocal and bilateral. LCIS is much less
common and is associated with less risk of the development of invasive
cancer than DCIS. Invasive ductal carcinoma (IDC) is the most common
type of breast cancer. About 80% of invasive breast cancers are classified
as IDC. Tubular carcinoma is a highly differentiated invasive carcinoma
with limited metastatic potential and better than average prognosis.
Medullary carcinoma is a relatively uncommon type of invasive
carcinoma, accounting for less than 5% to 7% of all invasive breast
cancers. Mucinous carcinoma is an invasive form of breast cancer
characterized by large amounts of extracellular mucin production and is
associated with a relatively favorable prognosis. Invasive cribriform
carcinoma is a well-differentiated cancer that shares some features with
tubular carcinoma and is also associated with better than average
prognosis. Adenoid cystic carcinomas similarly rarely spread to the lymph
nodes or distant areas and have a very good prognosis.
Breast cancer can metastasize to any organ in the body: Bone, lung,
liver, and brain are frequent sites. Metastases usually appear within a few

2070
years but recurrence may occur, particularly in bone, many years later.
Approximately, 5% of women present with metastatic disease during
breast cancer diagnosis,276 and bone is the most frequent site of metastatic
lesions.206 In population-based cohort studies of patients with newly
diagnosed breast cancer, 1% to 2% have bone metastases at diagnosis and
another 5% to 6% are diagnosed to have bone metastases within the next 5
years.277,278 In a Danish study of women with metastatic bone disease
secondary to breast cancer, 1-year survival was just over 52%.
Approximately, 13% survived 5 years after diagnosis of bone metastases,
and shorter bone metastases free interval was independently associated
with decreased survival among patients with breast cancer who were
diagnosed with bone metastases ≥1 year following their breast cancer
diagnosis. Survival among patients with metastatic breast cancer may vary
according to the site of metastasis and receptor status. Risk of death within
1 year was highest for brain-only (62 %) and liver-only (43 %)
involvement and nearly the same for patients with lung-only (32 %), bone-
only (32 %) involvement, and other/combination of sites (34 %). Positive
hormonal receptor status on the primary tumor was a favorable prognostic
factor for all metastatic sites.279
Bone metastases are predominantly osteolytic (50%) or mixed osteolytic
and osteoblastic (40%), with only a small proportion (about 10%) being
osteoblastic alone.280 Although metastatic disease may be asymptomatic,
the most common site of metastases, bone, typically are painful. Between
40% and 60% of patients with metastatic breast cancer will have bony
disease, and in many of these patients, the involved bones (vertebrae,
femoral and humoral shafts, the acetabular area) are those that are involved
with motion. Metastatic breast cancer is currently an incurable yet
treatable disease. Although median survival is of the order of 18 to 24
months, survival ranges from a few weeks to several years.281 This
biologic variability means that for many women, metastatic breast cancer
can be viewed as a chronic relapsing and remitting disease that may
respond for a time to an array of cytotoxic and endocrine therapies.
The clinician will most likely have a long relationship with the patient
with metastatic breast cancer and will have the opportunity to follow the
course and progression of disease. The course of disease in patients with

2071
metastatic breast cancer fits one of two patterns: an indolent course or
disease not immediately life threatening and that which is rapidly
progressing or with extensive vital organ disease. Knowledge of the
natural history of the disease is important in determining the nature and
timing of treatment. Table 42.12 lists some of the common causes of pain
in patients with breast cancer.

TABLE 42.12 Causes of Pain in Patients with Breast Cancer

Etiology Example Example
Tumor related Bone metastases —
Neural metastases Brachial plexopathy
Spinal cord compression
Meningeal carcinomatosis
Peripheral neuropathy secondary to
tumor infiltration
Visceral metastases Pleural
Liver
Bowel
Peritoneum
Anticancer therapy Procedure-related pain in breast —
Postmastectomy syndrome
Lymphedema related
Postradiation treatment
Peripheral neuropathy
Phlebitis
Mucositis
Chemical cystitis (e.g., secondary to
cyclophosphamide)
Osteoporosis or avascular necrosis
Preexisting Chronic nonmalignant pain —
conditions

Lung Cancer
The two major forms of lung cancer are non–small-cell lung cancer
(NSCLC) (85% of all lung cancers) and SCLC (15%). NSCLC can be
divided into three major histologic subtypes: squamous cell carcinoma,
adenocarcinoma, and large-cell lung cancer. Smoking causes all types of
lung cancer but is most strongly linked with SCLC and squamous-cell
carcinoma; adenocarcinoma is the most common type in patients who have
never smoked. NSCLC is the leading cause of cancer death in the United

2072
States. Nearly 60% of NSCLC cases are metastatic at diagnosis, and the 5-
year relative survival rate for metastatic disease is 4.2%.282 SCLC is a very
aggressive malignancy characterized by high cellular proliferation and
early metastatic spread. Most patients with SCLC receive chemotherapy.
Unfortunately, SCLC initially exhibits a good response to chemotherapy
and radiation therapy, but inevitably, relapses decrease patients’ chance of
survival. Metastases initially occur in the lymph nodes and thereafter in
other organs such as the lung itself, liver, adrenal glands, brain, bone, and
bone marrow. Histologically, SCLCs include small cell anaplastic
carcinoma, which includes the oat cell type. Small cell anaplastic
carcinoma is an aggressive and rapidly growing neoplasm and is limited to
the thorax at presentation in only 25% of patients.
NSCLCs are a morphologically diverse group that includes squamous
cell carcinoma, adenocarcinoma, and large cell anaplastic carcinoma. For
stage I and II NSCLC, the majority of patients (69%) undergo surgery, and
about 25% of surgical cases also receiving chemotherapy and/or radiation
therapy. Most patients with stage III and IV NSCLC receive chemotherapy
with or without radiation (53%). Squamous cell carcinoma is less likely to
metastasize early. Adenocarcinoma metastasizes widely and frequently to
the other lung, liver, bone, kidney, and the CNS. Large cell anaplastic
carcinoma metastasizes in a pattern quite similar to adenocarcinoma with a
predilection for mediastinal lymph nodes, pleura, adrenals, CNS, and bone.
Lung cancers, particularly SCLC, often entail clinical paraneoplastic
syndromes. Malignancy-associated hyponatremia is commonly associated
with excessive production of arginine vasopressin (AVP) by tumor cells,
and a large fraction of new cases of syndrome of inappropriate antidiuretic
hormone secretion (SIADH) in elderly smokers are due to SCLC.
Approximately, 10% of all lung cancer patients have hypercalcemia, and
of these patients, 10% to 15% do not have evident bone metastases.
Humoral hypercalcemia of malignancy is more common in NSCLC
especially squamous cell carcinoma. The neurologic syndromes associated
with lung cancer are rare disorders such as subacute cerebellar
degeneration, optic neuritis and retinopathy, subacute necrotizing
myelopathy, and peripheral neuropathy. The 1-year relative survival for
lung cancer increased from 34% during 1975 through 1977 to 45% during

2073
2008 through 2011, largely because of improvements in surgical
techniques and chemoradiation. The majority of lung cancers (57%) are
diagnosed at a distant stage because early disease is typically
asymptomatic; only 16% of cases are diagnosed at a local stage. The 5-
year survival rate is 55% for cases detected when the disease is still
localized, 27% for regional disease, and 4% for distant stage disease. The
5-year survival for SCLC (7%) is lower than NSCLC (21%).8
Pleural involvement by tumor can be a source of intractable severe pain.
Diagnosis of pleural disease can be challenging and involve a variety of
imaging modalities including CT, PET, MRI, and ultrasound. CT is widely
used as the primary imaging modality with the most common CT findings
being pleural thickening with or without pleural effusion, involvement of
the interlobar fissures and/or mediastinal pleural involvement, volume
reduction of the chest, mediastinal shift, and mediastinal lymph node
invasion.
Pain is a major symptom in patients with all types of advanced lung
cancer. Chest pain is the most common site of pain in patients with small
cell cancer. The pain complaint is often poorly localized, dull in character,
may radiate to the neck or back, and exacerbates with coughing.
Mercadante et al.283 reported that patients with advanced lung cancer
commonly reported chest wall (including ribs and shoulder blade) pain,
followed by lower extremities and lumbar regions, then abdomen and
upper extremities, and the head area.

Renal Cell Cancers

Renal cell carcinoma (RCC) encompasses a heterogeneous group of
cancers derived from renal tubular epithelial cells with the major subtypes
being clear cell RCC (ccRCC), papillary RCC (pRCC), and chromophobe
RCC (chRCC). The remaining subtypes are very rare (each with ≤1% total
incidence), and in cases in which a tumor does not fit any subtype in the
diagnostic criteria, it is designated as unclassified RCC. ccRCC is the most
common subtype (75%) and accounts for the majority of deaths from
kidney cancer. The majority of diagnoses result from incidental findings.
Paraneoplastic syndromes—symptoms caused by hormones or cytokines
excreted by tumor cells or by an immune response against the tumor—are

2074
not uncommon in RCC and symptoms include hypercalcemia, fever, and
erythrocytosis. CT imaging with contrast enhancement of the chest,
abdominal cavity, and pelvis is required for optimal staging.
Approximately 30% of people with RCC have already developed
metastatic RCC at presentation,284 and another 20% of people with
clinically localized RCC eventually develop metastases during the course
of the disease despite treatment.285,286 Frequent sites include the lung
(50% to 60%), bone (30% to 40%), liver (30% to 40%), and brain (5%).
Unusual sites of metastases characterize renal cancer, however, and may
involve virtually any organ site, including the thyroid, pancreas, skeletal
muscle, and skin or underlying soft tissue. Regional and distant lymph
nodes may also be involved. The regional lymph nodes of the kidney are
renal hilar, paracaval, aortic (para-aortic, periaortic, lateral aortic), and
retroperitoneal. Metastatic bone disease is often highly osteolytic and
particularly destructive causing substantial morbidity, including pain,
pathologic fracture, spinal cord compression, and hypercalcemia. The
presence of bone metastasis in RCC is associated with a poor prognosis.287

Colorectal Cancer
CRC is one of the most common malignancies in the Western world and is
the third most commonly diagnosed cancer among men and women in the
United States.288 Incidence and mortality rates have been declining for
several decades because of historical changes in risk factors (e.g.,
decreased smoking/red meat consumption, increased use of aspirin), the
introduction and dissemination of screening tests, and improvements in
treatment. The 5-year relative survival rate for patients diagnosed from
2006 to 2012 (all followed through 2013) was 65% declining to 58% at 10
years after diagnosis.288 The median age at diagnosis for CRC is 66 years
for males and 70 years for females. Patients with rectal cancer tend to be
younger at diagnosis than those with colon cancer (median age, 63 years).
CRC often develops over more than 10 years, and dysplastic adenomas
are the most common form of premalignant precursor lesions. The two
most common forms of hereditary CRCs are hereditary nonpolyposis
colon cancer (Lynch syndrome) and familial adenomatous polyposis coli.
The vast majority of these tumors are adenocarcinoma (>90%) and, to a

2075
lesser degree, carcinoid tumors, leiomyosarcomas, and lymphoma. Spread
to regional lymph nodes generally correlates to depth of invasion by the
primary tumor and the grade of differentiation. Nodal spread occurs in
10% to 20% of tumors confined to the bowel wall. Hematogenous spread
is usually to the liver via portal venous transmission.
The liver is the prime organ for metastatic spread (65%); extra-
abdominal metastases in lung (25%) and brain and bone (10%) are much
less common. Approximately, 15% to 20% of patients with CRC will
present with metastatic liver disease, and half of all patient with CRC will
develop liver metastases, with a median survival of 8 to 12 months in
untreated patients.289 Liver imaging should be done for all patients with
CRC. MRI had a significantly higher sensitivity than did CT for lesions
less than 10 mm. Surgical resection represents the only chance of long-
term survival, but only 20% to 25% of patients may be eligible for
resection.290 Systemic chemotherapy and/or intra-arterial locoregional
techniques may be options for patients not eligible for surgery. These
techniques include hepatic arterial infusion, transarterial
chemoembolization (TACE), embolization with drug-eluting beads
(DEBTACE), selective internal radiation therapy with 90Y (SIRT), and
percutaneous ablation with radiofrequency or microwave ablation.
The majority of patients with stage I and II colon cancer undergo partial
or total colectomy alone (84%), whereas about two-thirds of those with
stage III disease (as well as some with stage II disease) receive
chemotherapy in addition to colectomy to lower their risk of recurrence.
For patients with rectal cancer, proctectomy or proctocolectomy is the
most common treatment (61%) for stage I disease, and about one-half also
receive radiation and/or chemotherapy. Stage II and III rectal cancers are
often treated with neoadjuvant chemoradiation therapy.

Leukemias and Lymphomas

The majority of patients with leukemia (92%) are diagnosed aged 20 years
or older. Acute myeloid leukemia (AML) and chronic lymphocytic
leukemia (CLL) are the most common types in adults. Chemotherapy with
or without stem cell transplantation (SCT) is the standard treatment for
AML. Approximately 60% to 85% of adults aged 60 years and younger

2076
with AML can expect to attain complete remission status after the first
phase of treatment, and 35% to 40% of patients in this age group will be
cured. In contrast, 40% to 60% of patients aged older than 60 years will
achieve complete remission, but only 5% to 15% will be cured.
The two types of lymphoma are Hodgkin lymphoma (HL) and NHL.
NHLs may be indolent or aggressive and each include subtypes that
progress and respond to treatment differently. Prognosis and treatment
depend on the stage and type of lymphoma. The two major types of HL are
classical HL (CHL) and nodular lymphocyte-predominant HL (NLPHL).
CHL is the most common and is characterized by the presence of Reed-
Sternberg cells. NLPHL comprises only about 5% of cases and is a more
indolent disease with a generally favorable prognosis. The 5-year and 10-
year survival rates for HL are 86% and 80%, respectively. The 5-year
survival rate is 94% for NLPHL and 85% for CHL. The most common
types of NHL are diffuse large B-cell lymphoma (DLBCL), representing
37% of cases, and follicular lymphoma, representing 20% of cases.
DLBCLs grow quickly, but most patients with localized disease and about
50% of those with advanced-stage disease are cured. In contrast, follicular
lymphomas tend to grow slowly and often do not require treatment until
symptoms develop, but many are not curable. Some cases of follicular
lymphoma transform into DLBCL. The 5-year survival rate is 86% for
follicular lymphoma and 61% for DLBCL; 10-year survival declines to
77% and 53%, respectively.

Multiple Myeloma
Multiple myeloma (MM) is a clonal plasma cell malignancy that accounts
for 10% of all hematologic malignancies. MM usually progresses from
asymptomatic precursor stages, namely monoclonal gammopathy of
undetermined significance (MGUS) and smoldering multiple myeloma
(SMM) with possible progression to MM. Some patients experience rapid
progression from MGUS/SMM to MM, whereas others may remain
indolent with minimal progression during their lifetimes. The median age
of diagnosis is 69 years. The 5-year survival rate of patients with MM is
48.5%, and despite the introduction of immunomodulatory drugs and
proteasome inhibitors, many patients with high-risk features still have low

2077
progression-free survival rates and poor overall survival. CT imaging is
useful for detecting early bone destruction but not for detecting myeloma
activity in areas of prior destruction. MRI can detect early marrow
infiltration. The first biomarker for MM was the Bence Jones protein.
Other markers included M protein, plasmacytosis of the bone marrow, and
β2 microglobulin. Serum free light chain (FLC) assays were developed to
aid the diagnosis of MM and to monitor treatment response and disease
progression. Treatment plans are guided by serially measuring serum FLC
levels and the FLC ratio to define a complete response or progressive
disease in oligosecretory myeloma.

Tumor Markers
A biomarker is a characteristic that is objectively measured and evaluated
as an indicator of normal biologic processes, pathogenic processes, or
pharmacologic responses to a therapeutic intervention and are important
tools for diagnosis, prognosis, and management of malignancies.291 Most
tumor markers are produced by normal cells (tumor-associated) as well as
by cancer cells (tumor-derived); however, they are produced at much
higher levels in cancerous conditions. Markers include a variety of
substances like cell surface antigens, cytoplasmic proteins, enzymes,
hormones, oncofetal antigens, receptors, oncogenes, and their products.
These substances can be found in the blood, urine, stool, tumor tissue, or
other tissues or bodily fluids of some patients with cancer. Most tumor
markers are proteins, but patterns of gene expression and changes to DNA
are also used as tumor markers. Predictive biomarkers, which include
somatic mutations in BRAF and EGFR genes where the presence of
certain molecular targets helps identify the appropriate, targeted therapy
and thus predict the response to these agents. They can also be beneficial
to identify patients with high susceptibility to certain cancers through
detection of germline mutations, such as BRCA or somatic mutations.
DNA sequencing and gene expression studies have shown that at a
molecular level, almost every case of breast cancer is unique and different
from other breast cancers.292 For optimal management, patients should
receive treatment that is guided by the molecular composition of their
tumor. Mandatory biomarkers for every newly diagnosed case of breast

2078
cancer are ER receptors and PR receptors in selecting patients for
endocrine treatment and HER2 for identifying patients likely to benefit
from anti-HER2 therapy.293 Examples of tumor markers in malignancy are
shown in Table 42.13.

TABLE 42.13 Tumor Markers in Malignancy

Marker Tissue Analyzed Cancer Type
α-Fetoprotein Blood Liver cancer, germ cell tumors
β-2-microglobulin Blood, urine, CSF MM, CLL, some lymphomas
β-human chorionic gonadotropin Urine, blood Choriocarcinoma, germ cell tumors
(β-hCG)
BRCA1 and BRCA2 gene Blood Ovarian cancer
mutations
BRAF V600 mutations Tumor Melanoma, colorectal cancer
CA15-3/CA27.29 Blood Breast cancer
CA19-9 Blood Pancreatic cancer, gallbladder
cancer, bile duct cancer, gastric
cancer
CA-125 Blood Ovarian cancer
Calcitonin Blood Medullary thyroid cancer
Carcinoembryonic antigen (CEA) Blood Colorectal cancer
Chromogranin A Blood Neuroendocrine tumors
EGFR gene mutation Tumor Non–small-cell lung cancer
Estrogen receptor Tumor Breast cancer
(ER)/progesterone receptor (PR)
HER2/neu gene amplification or Tumor Breast cancer, gastric cancer, and
protein overexpression gastroesophageal junction
adenocarcinoma
Immunoglobulins Blood, urine Multiple myeloma and
Waldenström macroglobulinemia
KRAS gene mutation analysis Tumor Colorectal cancer and non–small-
cell lung cancer
Prostate-specific antigen (PSA) Blood Prostate cancer
Thyroglobulin Blood Thyroid cancer
NOTE: Neu is derived from a rodent glioblastoma cell line.
BRAF, gene that encodes protein B-Raf; BRCA1 and BRCA2, breast cancer gene and protein
product; CA, cancer antigen; CLL, chronic lymphocytic leukemia; CSF, cerebrospinal fluid;
EGRF, epidermal growth receptor factor; HER2/neu, human epidermal growth factor receptor;
KRAS, proto-oncogene for Kirsten rat sarcoma viral oncogene; MM, multiple myeloma.

PATTERNS OF CANCER PAIN

Cancer patients may have constant or intermittent pain. The term

2079
breakthrough pain (BTP) was popularized by Portenoy and Hagen294 in
1990 and refers to sudden increases in the base level of pain or different
but recurring pains. BTP was originally defined as “a transitory
exacerbation of pain that occurs in addition to otherwise stable persistent
pain or one that interrupts a tolerable background level of pain” or as “a
transitory exacerbation of pain that occurs on a background of otherwise
stable pain in a patient receiving chronic opioid therapy.”295 However,
most definitions consider BTP only after the background pain is
adequately controlled. BTP should be distinguished from crescendo pain,
which largely results from poorly controlled baseline pain.296 The
estimated prevalence of BTP in cancer patients may be more than 50%,297
but the prevalence is difficult to estimate because of difference between
studies in the definitions and diagnostic criteria and the inclusion of
patients with poorly controlled background pain.298 Different terms for
BTP have been used in some studies including incident pain, incidental
pain, episodic pain, and transitory pain.295
The cause and anatomical site of BTP is often, but not always, the same
as that of the baseline persistent pain.299 Typical features of BTP include
rapid onset (the time from onset of BTP to peak severity is usually within
3 to 5 minutes), short duration (approximately 30 minutes), and of variable
intensity.300 There are three types of BTP:
1. Incident pain: pain that is precipitated, stimulus dependent, or
triggered such as turning in bed, weight bearing, a bowel movement,
coughing, swallowing meals, etc. Often, incident pain is well defined
and predictable, so that clinicians can anticipate and treat the
problem prophylactically. Incident pain may be volitional or
nonvolitional.
2. End of dose failure: pain that emerges because of too much time
between doses of medication. This pattern is predictable for the
individual patient and readily preventable by using time-contingent
dosing at an appropriate interval. The key is monitoring symptoms in
relation to the dosing schedule.
3. Spontaneous pain: pain that occurs spontaneously without
relationship to particular events or procedures. These pains are more
difficult because of their unpredictable nature and often fleeting

2080
 character.
Cancer-related BTP has high interference with activity, mood, ability to
walk and work, social relations, sleep, and enjoyment of life.300–302
Uncontrolled or poorly controlled pain of any etiology is strongly
associated with impairment of sleep, walking, daily activities, enjoyment
of life, and relationships with others. It also is correlated with worsening of
anxiety and depression, dissatisfaction with opioid therapy, and poor
medical outcomes.303 In addition, patients with cancer-related BTP or
uncontrolled pain are likely to use more health care resources, have more
pain-related hospitalizations and emergency department visits, and have
greater direct and indirect treatment costs than those without BTP.304

CANCER PAIN SYNDROMES

Tables 42.14 to 42.17 list the common pain syndromes in the patient with
cancer.

TABLE 42.14 Pain Syndromes due to Tumor Involvement

Characteristics of Other Symptoms and
Primary Etiology Pathophysiology Pain Signs
Tumor Invasion of Bone
Vertebral body metastases
Subluxation of Metastasis of Severe neck pain Progressive sensory,
atlas odontoid process radiating to back somatomotor, and
of axis → fracture and top of skull, autonomic
of atlas → aggravated by dysfunction beginning
compression of flexion and other in upper extremity
spinal cord or movements
brainstem
C7–T1 metastases Cancer of breast and Constant, dull, Tenderness on
lung → aching pain in percussion of spinous
hematogenous paraspinal area process; paresthesia
spread or more radiating to both and numbness in ulnar
frequently tumor shoulders; distribution of limb;
originating in unilateral, progressive weakness
brachial plexus or radicular pain with of triceps and hand;
paravertebral radiation to Horner syndrome
space → spread to shoulder and indicating
adjacent vertebra medial (ulnar) sympathetic
and epidural space aspect of limb involvement
L1 metastases Frequent site of Dull, aching pain in Possible numbness and
metastasis from midback with weakness in the back;

2081
 breast, prostate, or reference to pain exacerbated by
other tumors regions of one or lying or sitting and
both sacroiliac relieved by standing
joints and superior
iliac crest;
radicular pain with
girdle-like
distribution
anteriorly or to
both paraspinal
areas in the
sacroiliac region
Sacral metastases Another frequent site Dull, aching pain in Perianal sensory loss
of metastasis from the low back and bowel and
breast, prostate, or and/or coccygeal bladder dysfunction
other tumors region exacerbated and impotence
by lying or sitting
and relieved by
walking
Base of the skull metastases
Jugular foramen Metastasis to jugular Occipital pain with Tenderness of occipital
foramen with reference to the condyle and often
involvement of vertex and one or ptosis, hoarseness,
cranial nerves IX– both shoulders and dysarthria, dysphagia,
XII arms, exacerbated and neck and shoulder
by head movement weakness
Clivus syndrome Metastasis to clivus Progressively severe Dysfunction of lower
of sphenoid bone vertex headache cranial nerves (VII–
and basilar portion exacerbated by XII), which begins
of occipital bone neck flexion unilaterally but
extends bilaterally
Sphenoid sinus Metastasis to the Severe bifrontal Nasal stuffiness or sense
sphenoid sinus on headache radiating of fullness in the head
one or both sides to both temples associated with
with intermittent diplopia
retro-orbital pain
Cavernous sinus Metastasis to Unilateral frontal Dysfunction of cranial
cavernous sinus headache and dull nerves III–VI,
syndrome from aching pain in diplopia,
breast, prostate, supraorbital and ophthalmoplegia,
and lung facial region papilledema
Occipital condyle Metastasis from Severe localized Cranial nerve XII
breast, lung, continuous, paralysis → paralysis
prostate unilateral occipital of tongue; weakness
pain aggravated by of
neck flexion sternocleidomastoid,
stiff neck
Other bone involvement

2082
 Pelvis Metastasis from Dull, aching pain in Extension to sacral
breast, prostate, or sacrum, hips, or plexus with
other tumors pubis consequent motor,
sensory, and/or
autonomic changes
Long bones Metastasis from Dull, aching, severe
breast, prostate, or pain localized to
other tumors site of tumor that
may be referred
(e.g., reference to
knee from hip
metastasis);
pathologic fracture
produces severe
pain on movement
Tumor Involvement of Nerves, Plexus, or Spinal Cord
Peripheral, cranial, Infiltration, Dull, aching, burning Hypesthesia,
or spinal compression, or pain associated dysesthesia, motor,
neuropathy damage to nerve with bouts of and/or autonomic
lancinating pain in dysfunction and reflex
distribution of changes
affected nerve or
nerves;
hyperpathia
Brachial plexus Compression, Progressively more Paresthesia, dysesthesia,
infiltration, or severe, dull, hypesthesia;
damage of aching pain which subjective numbness
brachial plexus by is first located in and progressive
metastatic tumor the shoulder and muscle weakness in
or lower cervical arm and vertebral C7, C8, and T1
and upper thoracic border of scapula distribution, often
vertebra or and later extends Horner syndrome and
Pancoast tumor to medial part of anhidrosis of the
arm, elbow, ipsilateral face
forearm, and hand
Lumbosacral Compression, Radicular pain either Paresthesia followed by
plexus infiltration, or in groin and numbness and
damage of lumbar anterior thigh (L1, dysesthesia and
and sacral plexus L2, and L3 nerve progressive motor and
by cancer of the involvement) or sensory loss in the
prostate, bladder, down the posterior areas supplied by the
uterus, cervix, or aspect of leg to the involved nerves
colon from heel (L5, S1, and
extension of tumor S2 distribution) or
into adjacent dull, aching
lymph nodes and midline pain in the
bone perianal area (S2,
S3, S4

2083
 distribution)
Reflex Compression, Severe burning pain Hyperalgesia,
sympathetic infiltration, or not limited to a vasomotor, and
dystrophy damage of major segmental or sudomotor
nerve or plexuses peripheral nerve disturbances and other
distribution; symptomatology of
aggravated by causalgia
touch and
emotional stress
Leptomeningeal Tumor infiltration of Pain in 40% of Malignant cells in
carcinomatosis the cerebrospinal patients of two cerebrospinal fluid,
leptomeninges types: headache, elevated protein and
with or without with or without low glucose levels
invasion of the neck stiffness and
meninges of the pain in the low
brain back and buttock
regions
Epidural spinal Tumor compression Local dull, aching Depends on site of
cord compression of cervical, pain, and epidural compression,
thoracic, or tenderness in the includes motor
lumbosacral parts region of involved weakness progressing
of spinal cord and vertebral body or to paraplegia, sensory
involvement of radicular pain, loss, and loss of
vertebra or roots which is unilateral bowel and bladder
of spinal nerves with cervical or function
lumbosacral
compression and
bilateral with
thoracic cord
compression
Tumor Involvement of Viscera
Obstruction of Contraction of Diffuse, poorly Dyspnea and cough with
hollow viscus or of smooth muscle localized, dull, thoracic viscera;
ductal system of under isometric aching, or colicky abdominal distention,
solid viscus conditions → pain referred to nausea, vomiting with
intense distention abdominal wall or abdominal visceral
of smooth muscles chest wall pathology
Rapid tumor Rapid growth of Dull, aching, poorly Symptomatology of
growth in solid hepatic, splenic, or localized pain visceral dysfunction
viscus kidney tumors → referred to midline
rapid distention (liver) or in one
and stretching of side in lower
investing fascia → thoracic and upper
stimulation of lumbar segments
mechanical
nociceptors
Other Types of Tumor Involvement
Tumor involvement

2084
of blood vessels
Infiltration Perivascular Burning pain in the Signs of
lymphangitis and areas supplied by vasoconstriction or
vasospasm the affected ischemia
vessels
Obstruction of Venous engorgement Severe headache Edema and cyanosis of
large vein → progressive with obstruction of affected part
edema → veins to head; pain
distention of in limbs with
fascial obstruction in
compartments and axilla or pelvis
soft tissue
Obstruction of Ischemia in tissues Progressively severe, Paresthesia, pallor of
large artery with liberation of burning pain affected part
algesic substances
Necrosis or Necrosis, infection, Excruciating local or Signs of infection or
ulceration of and inflammation referred pain inflammation
mucous membrane of mucous depending on site
membrane → of lesion
algesic substances
→ lowering of
nociceptors’
threshold

TABLE 42.15 Pain Syndromes Associated with Cancer Therapy

Characteristics of Other Symptoms
Primary Etiology Pathophysiology Pain and Signs
Postsurgical Syndromes
Postthoracotomy, Partial injury or Continuous, burning Dysesthesia,
postradical neck complete severance or dull, aching hyperesthesia in
resection, of nerves during pain with the scar area with
postmastectomy operation → occasional bout of hypesthesia in the
damage to nerve lancinating pains surrounding zone
membrane or in the areas
neuroma formation, supplied by
which becomes affected nerves,
hypersensitive to aggravated by
pressure and touch, movement,
norepinephrine → or emotional stress
abnormal sensory with
input to central catecholamine
nervous system release
(peripheral-central
mechanisms)
Postamputation pain Persistent nociception Constant aching or Sudomotor and
in stump and loss of burning pain in vasomotor changes
sensory input to stump or in in stump

2085
 neuraxis → phantom limb or
deafferentation cramping
(peripheral-central “proprioceptive”
mechanism) pain characterized
by abnormal
position of missing
part of limb; also
lancinating pain
Postchemotherapy Pain
Peripheral Symmetrical Constant burning Dysesthesia and
neuropathy polyneuropathy pain in the hand paresthesia
caused by vinca and/or feet
alkaloids (peripheral
mechanism)
Steroid Diffuse myalgias and Diffuse pain and Fatigue and general
pseudorheumatism tenderness in malaise; these and
arthralgias caused affected muscles the pain disappear
by withdrawal of and joints with reinstitution
steroid medication of steroid
(peripheral medication
mechanism)
Aseptic necrosis of Aseptic necrosis of Dull, aching pain in Limitation of joint
bone humoral head or the shoulder or movement with
femoral head as knee inability to use
complication of arm or hip joint →
chronic steroid frozen shoulder or
therapy (peripheral impaired hip
mechanism)
Mucositis Drug produces Severe, excruciating Difficulty or inability
biochemical pain in mouth, to eat, drink, or
changes in mucous throat, nasal even talk
membranes and passages, and
other structures gastrointestinal
(peripheral tract
mechanisms).
Postradiation Therapy Pain
Radiation fibrosis of Radiation-induced Progressively Numbness,
brachial or fibrosis of increasing, severe, paresthesia,
lumbosacral plexus connective tissue diffuse, burning dysesthesia, and
surrounding plexus pain in a part or motor weakness in
and consequent the entire limb, distribution of C5
injury to nerve which occurs after and C6 in the
structures develops other upper limb or in
6 mo to 20 y symptomatology lower limb
following therapy
→ deafferentation
(peripheral-central
mechanisms)

2086
 Radiation Damage to spinal cord Pain that is localized Dysesthesia and
myelopathy → Brown-Séquard or referred to other
syndrome peripheral symptomatology
progresses to structures of myelopathy
complete transverse
myelopathy (central
pain)
Painful peripheral Radiation induces Progressively severe, Progressive
nerve tumors nerve sheath tumors burning, aching neurologic deficit
4–20 y after therapy pain in distribution
of involved nerves
Postherpetic Induced by radiation Continuous burning Dysesthesia,
neuralgia or after herpes pain associated hypesthesia, and
zoster in the area of with intermittent hyperpathia
tumor pathology lancinating pain

TABLE 42.16 Pain Syndromes Caused by Cancer-Induced

Pathophysiologic Changes
Characteristics of Other Symptoms
Primary Etiology Pathophysiology Pain and Signs
Paraneoplastic syndromes — — —
Myofascial pain syndromes — — —
Debility, constipation, bed Related to specific Local or referred Related to specific
sores, rectal or bladder lesions pain pathophysiology
spasm, gastric distention depending on
involved site

TABLE 42.17 Pain Syndromes Unrelated to Cancer

Characteristics of Other Symptoms
Primary Etiology Pathophysiology Pain and Signs
Examples: arthritis, Pathology of Local or referred Related to specific
migraines, osteoporosis affected part pain pathophysiology

Table 42.18 lists the prevalence of painful manifestations of cancer and

their common etiologies. Bone, viscera, and nerve are the most common
sites of metastases associated with chronic cancer pain. Each of these sites
will be dealt with separately.

TABLE 42.18 Prevalence of Painful Manifestations of Cancer and

Common Etiologies
Approximate
Primary Site of Incidence of Pain

2087
 Cancer (%) Common Pain Syndromes
Oropharynx 55–80 Post-radical neck dissection syndrome
Infection
Colon–rectum 45–95 Bone metastasis
Perineal pain syndrome
Lumbosacral plexopathy
Epidural spinal cord compression
Pancreas 70–100 Abdominal visceral pain
Liver/biliary tract 65–100 Abdominal visceral pain
Lung 55–90 Bone metastasis
Epidural spinal cord compression
Brachial plexopathy
Postthoracotomy syndrome
Breast 55–100 Brachial plexopathy
Postmastectomy syndrome
Bone metastasis
Epidural spinal cord compression
Leptomeningeal carcinomatous
Uterus–cervix and 40–100 Lumbosacral plexopathy
ovary
Prostate 55–100 Bone metastasis
Base of skull syndromes
Vertebral body syndromes
Epidural spinal cord compression
Urinary tract 60–100 Lumbosacral plexopathy
Epidural spinal cord compression
Lymphoma and 5–75 Leptomeningeal carcinomatosis
leukemia Bone pain
Mucositis
Sarcoma and 75–90 Postamputation pain (stump, phantom limb)
primary bone Epidural spinal cord compression
tumors

Bone Metastases
Common locations for metastasis are the lung, liver, brain, and bone. Bone
is the third most common site for tumor cells to spread305 and is most
prevalent in advanced breast (70% to 80%), prostate (70% to 80%),
thyroid (60%), lung (10% to 50%), and renal cancers (30%).306 Prostate,
lung, breast, kidney, and thyroid cancer account for 80% of skeletal
metastases and MM favors involvement of the bone marrow. The most
common sites of bone metastases are the spine, ribs, pelvis, proximal
femur, and skull. Breast cancer preferentially metastasizes to the lungs and

2088
bones, whereas prostate cancer almost exclusively metastasizes to the
bones.307 Bone metastases may be classified according to the primary
mechanism of interference with bone remodeling as osteolytic,
osteoblastic, or mixed.308 In osteolytic lesions, bone destruction is
primarily mediated by osteoclasts and not a direct effect of tumor cells,
whereas osteoblastic (or osteosclerotic) lesions are characterized by the
deposition of new bone. Osteolytic bone metastases are presumed to be
caused by the release of osteoclastogenic agents by tumor cells in the bone
microenvironment, whereas osteoblastic metastases are the result of the
release of factors that stimulate osteoblast proliferation, differentiation,
and uncontrolled bone formation by metastatic cancer cells. Accordingly,
bone metastases are typically characterized as “lytic,” “sclerotic,” or
“mixed,” according to radiographic appearances. Metastasis to the bones is
facilitated by the fenestrated structure of the bone marrow sinusoid
capillaries, high blood flow in the areas of red marrow, and adhesive
molecules on tumor cells that bind to the bone marrow stromal cells such
as osteoblasts and osteoclasts as well as the bone matrix. Bone
homeostasis is maintained by balanced production of osteoblasts and
osteoclasts. Tumor cells influence bone cells in two predominant ways.
Most often, cancer cells stimulate the osteoclast lineage to increase
osteoclast differentiation and activity while simultaneously inhibiting
osteoblasts. Osteoclastic bone resorption then exceeds osteoblastic bone
formation resulting in bone degradation and the formation of osteolytic
lesions (as may be seen in breast, lung, and MM). In some cases, instead of
inhibiting osteoblasts, tumor cells release substances to stimulate the
osteoblast lineage to increase osteoblast differentiation and new bone
deposition causing osteoblastic lesions. Mechanistically, osteoclasts and
osteoblasts play significant roles in the formation of both lesion types.
In osteolytic bone metastases, tumor cells secrete factors that stimulate
osteoclast activity through the activation of the receptor activator of
nuclear factor–κB ligand (RANKL)/RANK pathway, a primary mediator
of osteoclast-mediated bone resorption.309 Osteoblasts secrete receptor
activator of RANKL which interacts with osteoclast precursors displaying
RANK receptor on their surface, resulting in their activation and finally
maturation into functional osteoclasts. Osteoblasts also produce

2089
osteoprotegerin (OPG), a soluble decoy receptor which can block
RANK/RANKL signaling by scavenging of RANKL. The activation of
osteoclasts is triggered by the balance between RANKL and OPG.
RANKL also can induce factors involved in migration, invasion, and
angiogenesis such as matrix metalloproteinases 1 and matrix
metalloproteinases 9 (MMP1, MMP9), matrix metalloproteinase inducer
EMMPRIN/CD147, intercellular adhesion molecule-1 (ICAM-1), IL-6 and
IL-8, and VEGF and decrease the expression of metastasis suppressor
serpin 5b/maspin. RANKL can also promote the function of regulatory T
cells (Tregs) and macrophages. Osteolysis is based on a self-perpetuating
signaling system (vicious cycle) that is maintained by mitogenic factors for
tumor cells such as TGF-β, insulin-like growth factor-1 (IGF-1), fibroblast
growth factors (FGFs), PDGFs, and Ca-ions released from demineralized
bone as well as parathyroid hormone-related peptide (PTHrP) derived
from tumor cells. PTHrP acts as a promotor of osteolysis by osteoclasts
(Fig. 42.8).

FIGURE 42.8 Mechanism of osteolytic bone metastases. Metastatic cancer cells are attracted to
spindle-shaped N-cadherin positive osteoblasts (SNO) and remain dormant. Quiescent cells can
become activated and grow giving rise to an overt metastasis. The metastatic cells produce factors,
which include parathyroid hormone-related peptide (PTHrP), interleukins (ILs), PGEs, and CXCR4
that mediate their interaction with osteoblastic cells of the metastatic microenvironment.
Osteoblasts, in turn, communicate with preosteoclasts, primarily via the receptor activator for

2090
nuclear factor κB (RANK)–receptor activator for nuclear factor κB ligand (RANKL) axis and
promote osteoclastic morphologic and functional maturation. PTHrP can also induce osteoclastic
maturation via non-RANK/RANKL-dependent pathways. Fully activated osteoclasts resorb bone
causing osteolytic bone disease. Hypoxic conditions and factors that are released during the
degradation of the bone extracellular matrix further stimulate cancer cells, feeding the “vicious
circle” of lytic bone metastasis. β2AR, β2 adrenergic receptor; ECM, extracellular matrix; IGF,
insulin-like growth factor; IKK, inhibitor of NF- κB kinase; MAPK, mitogen-activated protein
kinase; OBL, osteoblast; OCL, osteoclast; OPG, osteoprotegerin; PGE, prostaglandin E; PLC,
phospholipase C; SC, stromal cell; SNS, sympathetic nervous system; TGF-β, transforming growth
factor-β; TNF-α, tumor necrosis factor-α. (From Papachristou DJ, Basdra EK, Papavassiliou AG.
Bone metastases: molecular mechanisms and novel therapeutic interventions. Med Res Rev
2012;32[3]:611–636. Copyright © 2010 Wiley Periodicals, Inc. Reprinted by permission of John
Wiley & Sons, Inc.)

Osteoblastic bone metastases are preferentially associated with prostate

cancer but may also occur with breast, lung, carcinoid, and
medulloblastoma tumors and produce sclerotic lesions. Endothelin-1 has
been implicated in osteoblastic metastasis from breast cancer. It stimulates
the formation of bone and the proliferation of osteoblasts in bone organ
cultures, and serum endothelin-1 levels are increased in patients with
osteoblastic metastasis from prostate cancer.310 Furthermore, in an animal
model of osteoblastic metastasis, treatment with a selective endothelin-
1A–receptor antagonist decreased both osteoblastic metastasis and the
tumor burden. A vicious circle may also be involved in osteoblastic
metastasis in which tumors induce osteoblast activity and thus the
subsequent release from the osteoblasts of growth factors that increase
tumor growth. In addition to endothelin-1, PDGF, a polypeptide produced
by osteoblasts in the bone microenvironment, urokinase, and PSA may
also be involved. Overproduction of urokinase-type plasminogen activator
(u-PA) by prostate-cancer cells increases bone metastasis. Human PC3
prostate-cancer cells produce a factor that is homologous to u-PA.
Prostate-cancer cells also release PSA, a kallikrein serine protease. PSA
can cleave parathyroid hormone–related peptide at the N-terminal, which
could block tumor-induced bone resorption. It may also activate
osteoblastic growth factors released in the bone microenvironment during
the development of bone metastases, such as IGF-I and IGF-II or TGF-β
(Fig. 42.9).310

2091
FIGURE 42.9 Mechanisms of osteoblastic bone metastases. Cancer cells secrete a series of factors
that augment osteoblast activation and bone formation at the site of metastasis. Two of the major
signaling cascades involved in this process are the endothelin-1A/endothelin-1A receptor and the
Wnt/β-catenin, which target osteoblast-specific genes such as c-jun, runx2, osterix, and c-myc. In
addition, cancer cells produce urokinase plasminogen activator (uPA) that activates proteases such
as prostate-specific antigen, further enhancing the osteosclerotic process either via activation of the
quiescent forms of TGF-β and IGF-1 or via degradation of parathyroid hormone-related peptide
(PTHrP). ET-1, endothelin-1A; ETAR, endothelin-1A receptor; IGF, insulin-like growth factor;
LRP-F, low-density lipoprotein receptor–related proteins-Frizzled complex; MAPK, mitogen-
activated protein kinase; PLC, phospholipase C; TGF-β, transforming growth factor-β. (From
Papachristou DJ, Basdra EK, Papavassiliou AG. Bone metastases: molecular mechanisms and novel
therapeutic interventions. Med Res Rev 2012;32[3]:611–636. Copyright © 2010 Wiley Periodicals,
Inc. Reprinted by permission of John Wiley & Sons, Inc.)

Imaging modalities available for diagnosing bone metastases are CT,

MRI, bone scintigraphy, and PET imaging with tumor-specific or bone-
specific tracers. Bone scintigraphy with 99mTc-labeled diphosphonates
has limited sensitivity and poor specificity for identifying bone metastases
particularly in the early stages of the disease when tumor is confined to the
marrow. This is improved by the addition of single-photon emission
computed tomography (SPECT), which has the advantage of providing
anatomic localization of abnormal tracer uptake with better contrast
resolution. An alternative strategy is PET-based radionuclide imaging. The
commonly used radiopharmaceuticals are 18F-fluoro-2-deoxyglucose

2092
(FDG) and 18F/11C-choline as tumor-specific agents or sodium fluoride
as a bone-specific tracer (NaF).

CHARACTERISTICS OF METASTATIC BONE PAIN

Adult bone receives a restricted and unique innervation as it is only
innervated largely by thinly myelinated, TrkA+ sensory nerve fibers (Aδ)
and TrkA+ C fibers, and receive little, if any, innervation by the larger
more rapidly conducting Aβ fibers or the TrkA-negative, unmyelinated
peptide poor C fibers. Most of the sensory nerves that innervate the bone
appear to only be activated by injury or damage to the bone (i.e., silent
nociceptors).311 The initial sharp pain experienced from a fracture of any
bone is probably detected by mechanotransducers expressed by the Aδ and
C-sensory fibers. The dull aching pain following injury, bruising, or
stabilization of the fractured bone is likely associated with activation of
unmyelinated C fibers present in the periosteum. Cortical bone and bone
marrow are also innervated by the same population of Aδ and C-sensory
nerve fibers that innervate the periosteum, although the relative density of
sensory nerve fibers per unit area is markedly lower.311 Osteoclasts resorb
bone by forming a highly acidic resorption area between the osteoclast and
bone that stimulates the TRPV1 or ASIC3 channels expressed by a
significant population of nerve fibers that drive bone cancer pain.312
Tumor-associated bone pain is usually first described as dull in character
and constant in nature with the pain gradually intensifying over time.
Nociception from bony metastases can produce a variety of symptoms
such as muscle spasms or paroxysms of stabbing pain. Hematologic
malignancies (especially acute leukemias) may produce a syndrome of
generalized and migrating bone pain as a result of marrow infiltration.313
Limb pain is the most common presentation, and local bone tenderness
(especially on long bone diaphyses) is a frequent finding. The vertebrae
are the most common sites of bone metastases. The thoracic spine is
affected in more than 66% of cases, the lumbosacral spine in 20%, and the
cervical spine in 10%. Multiple vertebral lesions are common. Pain from
metastases involving T12 and L1 often is referred to the iliac crest or SI
joint unilaterally or bilaterally. Patients with tumor invasion of the upper
cervical vertebrae may present with pain in the neck that is referred to the

2093
occipital region and skull vertex. Neck flexion typically exacerbates the
pain.
Osteolytic bone metastases often present with bone pain, pathologic
fractures, hypercalcemia, and, more rarely, swelling or neurologic
complaints. The vertebrae, pelvis, ribs, femur, and skull are the sites most
frequently involved.314 Pain gradually develops during a period of weeks
or months, becoming progressively more severe. The pain is usually well
localized in a particular area and is often strongest at night or on weight
bearing. Patients describe the pain as dull in character, constant in
presentation, and gradually progressive in intensity. Pain increases with
pressure on the involved area. Continuous pain may be moderate on
resting and then increase with different movements or positions, such as
standing, walking, or sitting. BTP can result from weight bearing or
instability due to incipient or actual pathologic fractures. Although the
locus of bone pain usually corresponds to the site of the underlying lesion,
characteristic patterns of referral to noncontiguous cutaneous areas occurs.
By way of example, hip pain due to a hip lesion may refer to the knee.
Fractures are common through lytic lesions in weight-bearing bones.
Damage to both cortical and trabecular bone is structurally important.
Radiologic features that may predict imminent fracture include large,
predominantly lytic lesion that erode the cortex. The main complications
of vertebral metastases are vertebral collapse, radiculopathy, and
metastatic epidural spinal cord compression (MESCC). Collapse of
vertebral bodies is particularly frequent in the thoracic spine metastases.
Back pain is a frequent symptom in patients with advanced cancer and in
10% of cases is due to spinal instability. The pain, which can be severe, is
mechanical in origin, and frequently, the patient is only comfortable when
lying still. Radiculopathies can occur at any level; patients feel the pain in
the spine, deep in the muscles innervated by the affected nerve root, and in
the corresponding dermatome. Metastatic spinal cord compression is a
serious complication of vertebral metastases (see section in the following
text).

PROGNOSIS
A real estimate of the impact of bone metastases is difficult to assess

2094
because incidence is influenced by factors including the sensitivity of
diagnostic tools and by the length of survival of the patients. In general,
the prognosis for patients presenting with bone metastases is poor (Table
42.19).

2095
 TABLE 42.19 Incidence and Prognosis of Bone Metastases
Incidence of Bone Metastases in
Patients with Advanced Disease Median Survival from Diagnosis
(%) of Bone Metastases (mo)
Breast 65–75 19–25
Prostate 65–75 12–53
Lung 30–40 6–7
Bladder 40 6–9
Renal cell 20–25 12
Thyroid 60 48
Melanoma 14–45 6
Reprinted from Selvaggi G, Scagliotti GV. Management of bone metastases in cancer: a review.
Crit Rev Oncol Hematol 2005;56(3):365–378. Copyright © 2005 Elsevier Ireland Ltd. With
permission.

Patients with fewer metastases or solitary lesions appear to have a better

outlook than those with multiple metastatic deposits. Once tumor cells
spread to the skeleton, the disease is usually incurable. Issues related to
bone metastases include reduced survival, morbidity, and pain that
negatively affect the patient’s QOL as well as skeletal-related events
(SREs). In prostate cancer, skeletal metastases are associated with overall
survival ranging from 12 to 53 months.315 In a Danish study of
approximately 36,000 breast cancer patients, the 5-year survival was
75.8% for patients without bone metastases, 8.3% for patients with bone
metastases, and 2.5% for those with both bone metastases and SREs. The
adjusted mortality rate ratio (MRR) was 10.5 (95% confidence interval
[CI] 9.5, 11.6) for breast cancer patients with bone metastases and 14.4
(95% CI 13.1, 15.8) for those with bone metastases and SREs, compared
with breast cancer patients with no bone metastases but possibly other sites
of metastases.316 Bone metastases can be a major cause for morbidity,
characterized by pain, impaired mobility, pathologic fractures, spinal cord
compression, myelosuppression, and hypercalcemia with the most
disability caused by long bone fracture or epidural extension of tumor into
the spine. Both osteolytic and osteoblastic bone metastases are prone to
fracture either because of increased bone resorption or because newly
deposited bone is mostly immature is less mechanically competent than
mature, lamellar bone.317

2096
 Factors that influence prognosis in patients with metastatic disease
include the interval between primary diagnosis and the development of
metastases and the Karnofsky performance status (Table 42.20). The
Karnofsky score after palliative irradiation reliably predicts
survival.318–320 Other factors that predict survival include the site of the
primary disease and whether single or multiple bone metastases are
present.321,322 The distribution of metastases on bone scans also has
prognostic significance. Bone involvement offers specific measurability
criteria for tumor response assessment.323 Patients with metastatic prostate
carcinoma survive significantly longer if their metastases respond to
therapy and do not spread beyond the pelvis or lumbar spine.324 The use of
223Ra dichloride for metastatic castration-resistant prostate cancer reduced

symptomatic skeletal events325 and significantly improved survival.326

TABLE 42.20 Karnofsky Performance Status

Grade Performance Level
100 Normal, no complaints, no evidence of disease
90 Able to carry on normal activity; minor signs or symptoms of disease
80 Normal activity with effort; some signs or symptoms of disease
70 Cares for self; unable to carry on normal activity or to do active work
60 Requires occasional assistance, but is able to care for most of his or her needs
50 Requires considerable assistance and frequent medical care
40 Disabled, requires special care and assistance
30 Severely disabled, hospitalization indicated; death not imminent
20 Very sick, hospitalization necessary, active supportive treatment necessary
10 Moribund, fatal processes, progressing rapidly
0 Dead

SACRAL INSUFFICIENCY FRACTURES

Insufficiency fractures represent a special category of stress fractures that
occur in bones with reduced mineral content and elastic resistance. They
are often observed in osteoporosis, rheumatoid arthritis, prolonged
glucocorticoid treatment, pelvic radiation therapy, and metabolic bone
diseases. Pelvic radiation therapy has a reported prevalence of 21% to
34%327–329 and may occur because of a direct effect on bone and an
indirect effect associated with vascular changes.330 Following radiation
therapy, the reduction of the number of osteoblasts induces a reduction of

2097
collagen production and decreased alkaline phosphatase activity, key
mechanisms involved in bone mineralization. Radiation-induced occlusion
of bone microvascularization also results in ischemia, which contributes to
the formation of insufficiency fractures.331 Osteoporosis is also a major
risk factor because of a greater susceptibility to injury with normal
repetitive activities and minor trauma. Trabecular bone is more affected by
osteoporosis than cortical bone, but cortical bone is also significantly
attenuated; hence, the vertebral bodies, pelvis, and sacrum are particularly
susceptible to fractures as the ratio of trabecular to cortical bone is highest
in the sacral alae and lower in the central portion of the sacrum.332
Common areas for insufficiency fractures include weight-bearing areas
such as the sacral ala, sacral body, and pubic limb. Typically, patients
present with acute onset severe diffuse sacral pain and tenderness,
frequently with radiation to the hips/buttocks and groin, and classically
worsen with axial loading. Many patients have pain intense enough to
render the patient nonambulatory. Physical examination may reveal low
back or groin tenderness with restricted hip movement. Physical
examination may reveal tenderness to palpation in the region of the sacral
ala, but diagnosis is usually made radiologically in patients with a prior
history of pelvic radiation treatment (Fig. 42.10). CT images should
include coronal and sagittal reconstruction views. Patients with sacral
insufficiency fractures may be misdiagnosed as having pathologic
fractures from metastatic disease.333,334 Biopsy of the lesion is not
recommended because of low diagnostic yield. On MRI, stress fractures
present an easily recognizable edema signal in contrast to metastases that
disorganize the bone and form a real replacement tissue.331 The most
commonly used classification system for sacral fractures is the Denis
classification and subclassification system (Fig. 42.11).335 Zone I and II
fractures can cause injury to the L5 nerve root in the lumbosacral tunnel
(space between the lumbosacral ligament and the S1 ala). Zone II and III
fractures can cause injury to the S1 nerve root or pudendal nerve. S1 nerve
injury in this setting is usually not isolated and tends to be associated with
a lumbosacral plexus injury. Zone III fractures have the highest rate of
neurologic deficit including bowel, bladder, and sexual dysfunction.

2098
FIGURE 42.10 Magnetic resonance imaging (MRI) and computed tomography (CT) images of
pelvis showing sacral insufficiency fracture. A: MRI axial T1 imaging shows H-shaped sacral
fracture (type 1 transverse zone 3). Green arrows indicate fractures bilaterally. B: CT images of
same fracture. Minimally displaced zone 1 sacral ala fractures. The fracture on the left is intra-
articular and extends into the sacroiliac joint (red arrow heads). The fracture on the right is barely
visible on this view with evidence of disruption of the cortex (green arrow head).

FIGURE 42.11 Denis classification and subclassification system of sacral fractures. The
classification is based on the direction, location, and level of sacral fractures. The fractures are
based on the sacrum’s division into three anatomic zones: zone I (alar region), zone II (foraminal
region), and zone III (region of the central sacral canal). A zone II fracture can involve zone I but
cannot extend into zone III, whereas a zone III fracture can involve zones I and II. Zone 3 fractures
morphologically include “H”-, “U”-, “A”-, and “T”-shaped fractures.

2099
GRANULOCYTE COLONY-STIMULATING FACTORS–
ASSOCIATED BONE PAIN
Granulocyte colony-stimulating factor (G-CSF) agents act on the
hematopoietic system to stimulate the proliferation and differentiation of
neutrophil precursors and produce mature functional neutrophils. Agents
such as filgrastim and pegfilgrastim are used as primary or secondary
prophylaxis to reduce the risk of febrile neutropenia and allow the dose
maintenance in patients receiving myelosuppressive chemotherapy.
Pegfilgrastim is a long-acting, pegylated formulation of filgrastim that is
given as a 6-mg dose subcutaneously on a once-per-cycle administration
24 to 72 hours after the administration of cytotoxic chemotherapy.
Filgrastim is administered subcutaneously once daily. Pegfilgrastim causes
proliferation of immature progenitor and mature myeloid cells within the
bone marrow. Bone pain is the most commonly reported adverse event
associated with pegfilgrastim occurring in approximately 26% of
patients336 with severe bone pain reported in 3% to 7% of patients with the
highest incidence in the first cycle.337 Although the exact mechanism of
associated bone pain is unknown, inflammatory processes within the bone
marrow, stimulation of osteoclasts and osteoblasts, and expansion of the
bone marrow are potential sources of pain.338 The incidence of bone pain
between filgrastim and pegfilgrastim was similar between patients
receiving either formulation of G-CSF when used as support with
chemotherapy in breast cancer.339

Visceral Pain
Visceral infiltration is a common cause of pain in cancer patients. Table
42.21 lists the common pain syndromes associated with tumor infiltration.

TABLE 42.21 Pain Syndromes Related to Tumor Infiltration of

Viscera
Esophageal mediastinal pain
Shoulder pain from diaphragmatic infiltration
Epigastric pain from pancreatic or other upper abdominal tumor
Right upper quadrant pain from hepatic capsule distention
Left upper quadrant pain from splenomegaly

2100
 Diffuse abdominal pain from abdominal or peritoneal disease with or without obstruction
Pleural infiltration
Gastrointestinal perforation
Biliary obstruction
Ureteric obstruction
Suprapubic/pelvic pain from bladder infiltration
Perineal pain from infiltration of rectum or perirectal tissue

MECHANISM
Visceral pain is defined as pain emanating from organs in the thorax,
abdomen, or pelvis. The main factors capable of inducing pain in visceral
structures include abnormal distention and contraction of hollow visceral
walls, rapid stretching of the capsules of solid visceral organs, ischemia of
visceral musculature, formation and accumulation of algogenic substances,
direct action of chemical stimuli on compromised mucosa, and traction or
compression of ligaments, vessels, or mesentery.340–342 Gastric acid is a
noxious stimulus that contributes to pain arising from the esophagus,
stomach, and upper small intestine. Mechanical trauma to normal mucosa
causes no pain, implying that preceding inflammation is necessary.
There are two distinct classes of nociceptive sensory receptors in
viscera.91 One population of afferents can code nonnoxious, as well as
noxious stimuli, and a second population is not activated unless more
intense and potentially damaging stimuli are encountered. These relatively
insensitive fibers are normally silent and only become active following
injury or in disease.343 The first class is composed of “high-threshold”
receptors that respond to mechanical stimuli within the noxious range.
These have been identified within many viscera, including the heart, lungs,
gastrointestinal tract, ureters, and urinary bladder. The second class is
composed of receptors that have a low threshold to natural stimuli and
encode the stimulus intensity in the magnitude of their discharges, the so-
called “intensity-encoding” receptors. Both receptor types are mainly
concerned with mechanical stimuli such as stretch and are involved in the
peripheral encoding of noxious stimuli in viscera. In the presence of local
inflammation or tissue injury, these afferents become sensitized and
respond to previously innocuous natural stimuli. High-threshold afferents
signal acute visceral pain. Local ischemia, hypoxia, and inflammation
cause pain by sensitizing high-threshold receptors and these previously

2101
“silent” or unresponsive receptors. Pain in visceral structures is not
necessarily linked to tissue injury but is more dependent on the nature of
the provoking stimulus. Adequate stimuli that induce pain are distention,
ischemia, and inflammation. Hollow organs such as the colon are very
sensitive to luminal distention or inflammation but are totally insensitive to
cutting or burning stimuli. Visceral structures from the esophagus to the
transverse colon are innervated not only by DRG located in the cervical,
thoracic, and upper lumbar regions but also by sensory neurons arising
from the superior and inferior vagal ganglia.343 Visceral structures located
distal to the transverse colon, particularly the distal colon, rectum, and
bladder, are also innervated by two populations of afferents; however,
these are both of spinal origin arising from two different levels of the
spinal cord (thoracolumbar and lumbosacral). Sensory neurons arising
from these two spinal locations appear to convey different aspects of the
complex sensation that humans identify as visceral pain.343 Poorly
localized visceral pain may be explained by the low density of visceral
nociceptors, the functional divergence of visceral input with the CNS, and
viscerovisceral convergence in the spinal cord.
Localization of visceral pain is difficult. Afferent nerves from viscera to
the spinal cord are relatively few in number and comprise only 2% to 15%
of all afferents to the spinal cord.344,345 These visceral nociceptive
afferents can excite many second-order neurons in the spinal cord which in
turn generate extensive divergence within the CNS, sometimes involving
supraspinal loops. Such a divergent input activates several systems—
sensory, motor, and autonomic—and thus triggers the general reactions
that are characteristic of visceral nociception: a diffuse and referred pain
and prolonged autonomic and motor activity.340 The dorsal column in the
spinal cord contains an ascending excitatory pathway that plays a crucial
role in the perception of visceral pain, especially under the conditions of
peripheral inflammation.346 Activation of thalamic neurons by the dorsal
column pathway, through a relay in the dorsal column nuclei, may be an
important element in this mechanism. The dorsal column pathway may
contain an ascending part of an amplification loop that enhances the
responsiveness of spinal cord neurons through a descending facilitatory
pathway, possibly originating in the rostroventral medulla.347 This

2102
amplification circuit could lead to potentiation of the responses of different
projection neurons, including spinothalamic and postsynaptic dorsal
column neurons. The effectiveness of the midline myelotomy in visceral
pain patients could thus be explained by a direct reduction in the activation
of thalamic neurons mediated by postsynaptic dorsal column neurons as
well as by an interruption of the amplification loop, thereby preventing the
potentiation of the visceral responses of other projection neurons such as
spinothalamic tract cells.
The origin of nociceptive impulses determines the site and type of pain.
Visceral pain is either true, referred, nonreferred parietal, or referred
parietal. True parietal abdominal pain is dull and poorly localized; it
occurs in the region of the epigastric, periumbilical, or lower mid-
abdominal region. Patients may describe the pain as gnawing or cramping,
and often, it is associated with nausea, sweating, pallor, and, occasionally,
vomiting. Referred visceral pain is more precisely localized, usually in the
dermatomal or myosomal regions of the same segments of the spinal cord
involved. Parietal pain may localize directly over the organ without
referral. Patients locate referred parietal pain in a body region distant from
the nociceptive site. For example, patients complain of pain in the shoulder
area when the cause is inflammation of the middle diaphragm.
Tumor invasion of adjacent blood vessels can generate nociception.
Mechanisms include perivascular lymphangitis causing vasospasm,
occlusion with resultant ischemia, venous engorgement, and edema.
Obstruction of hollow viscera from tumor with resultant distention may
cause pain. Distention causes intense contraction of smooth muscle that
generates nociception. Patients experience visceral pain that is poorly
localized and diffuse but usually localized in same dermatomal area of the
cord segments of the viscera.
Pain from tumor involvement of parenchymal viscera such as liver,
spleen, pancreas, and kidney typically results from acute distention of the
pain-sensitive fascia. These fascia contain many mechanical receptors, and
nociception occurs when they are acutely stretched or placed under
tension. This type of pain is poorly defined, dull, and generally located in
the dermatomal region of the involved organ. The properties of visceral
pain are discussed in Chapters 61–65.

2103
VISCERAL PAIN DESCRIPTIONS BY SITE
Esophageal cancer usually elicits a history of heartburn: a burning or
gnawing substernal discomfort. Patients usually describe the pain as being
located in the epigastric or retrosternal areas, which often radiates to the
back or interscapular region. The pain occurs often after eating and
possibly relates to body position changes such as reclining or bending
forward.
Gastric pain has a colicky quality associated with delayed emptying and
slowed motility and digestive symptoms. The pain also localizes in the
epigastrium, is usually sharply focused, and may radiate into the back.
Small intestine pain is usually crampy or colicky and localized in the
periumbilical area. The cause of pain is usually a lesion causing distention
with resultant abnormal mobility. Eating usually precipitates the pain, and
defecation or fasting may afford relief. Colon pain tends to occur in the
lower abdomen, varying according to which portion of the colon is
affected. Change in bowel habits and occult blood in the stool often
accompanies symptoms of discomfort. Peritoneal carcinomatosis is
frequently found with abdominal tumors and advanced ovarian cancer.
Pain may result from peritoneal irritation, mesenteric involvement, and
abdominal distention with ascites. Bowel obstruction often complicates
peritoneal carcinomatosis.
Liver parenchyma is insensitive to tumor distention and associated
chemical changes. Right upper quadrant pain from liver pathology occurs
only when there is acute distention of the liver capsule. It is usually a dull,
aching sensation in the right upper abdominal quadrant and flank and is
often referred to the right scapula and shoulder.
Perineal pain, worse when sitting and with aching and pressure-like
quality is the first and, can be for a long time, the only symptom of pelvic
tumors. The pain may be associated with tenesmus. Fistulas and recurrent
infections can aggravate the pain syndrome. Ureteral obstruction is
frequent. Direct invasion of the sacrum, sacral roots, plexus, or cauda
equina are frequent complications. Pain from the fundus of the uterus
typically occurs in the hypogastrium. Pain originating from the uterine
cervix is commonly referred to the low back and sacral area as well as to
the hypogastrium. Ovarian pain results from stretching of the surrounding

2104
peritoneum to which the ovaries adhere.

Neuropathic Pain
The following are among the most common cancer pain syndromes that
present with a major neuropathic component.

NEUROPATHIC PAIN SECONDARY TO CANCER-

RELATED PATHOLOGY IN CRANIAL NERVES
Painful cranial neuralgias may occur secondary to base of skull metastases,
LMs, or head and neck cancers.348 Base of skull metastases produce
several well-described pain syndromes349 and are often associated with
primary tumors of the breast, lung, and prostate. Constant localized aching
pain from bone destruction and neurologic deficits from progressive
cranial nerve palsies are cardinal manifestations. Orbital and parasellar
syndromes were characterized by frontal headache, diplopia, and first-
division trigeminal sensory loss. Proptosis may occur with the orbital
syndrome. The middle-fossa syndrome was characterized by facial pain or
numbness or dysesthetic neuropathic pain in the distribution of the second
or third divisions of the trigeminal nerve. Associated motor deficits
include weakness in the masseter or temporalis muscles or abducens palsy.
The jugular foramen syndrome was characterized by hoarseness and
dysphagia, with paralysis of the 9th through 11th cranial nerves and may
present as glossopharyngeal neuralgia.349 This pain is distributed over the
ear or mastoid region and may radiate to the neck or shoulder. Associated
deficits include a Horner syndrome and paresis of the palate, vocal cords,
sternocleidomastoid muscle, or trapezius muscle. It is sometimes
associated with syncope.350 The occipital condyle syndrome was
characterized by unilateral occipital pain and unilateral tongue paralysis
with patients complaining of a continuous, severe, unilateral, occipital pain
which kept them with the head rotated to the side of the pain and held with
their hands351 and occipital region pain typically preceding the
hypoglossal paresis by several days to 10 weeks.352
Occipital condyle syndrome, clinically mimics classical trigeminal
neuralgia, can occur secondary to tumors in the middle or posterior

2105
fossa.353–356 Middle fossa tumors may present as trigeminal neuralgia but
usually cause severe pain of an atypical nature and a progressive
neurologic deficit. Trigeminal neuralgia secondary to tumor usually
presents as a constant, dull, well-localized pain related to the underlying
pathology involving bone and other somatic structures associated with
paroxysmal episodes of lancinating or throbbing pain. A higher incidence
of hypesthesia in the trigeminal nerve regions as well as a reduced corneal
reflex was noted in patients with a mass lesion compared to those with
vascular compression.355 Posterior fossa tumors are most likely to cause
trigeminal neuralgia and are usually accompanied by subtle neurologic
deficits.353 This association between trigeminal neuralgia and tumor is
uncommon, and cancer patients with a new onset of trigeminal neuralgia
should have careful imaging of the base of skull.

Cervical Plexopathy
Tumor infiltration of the cervical plexus can produce several pain
syndromes, depending on the pattern of nerve involvement.357 The upper
four cervical ventral rami join to form the cervical plexus, which has both
cutaneous and muscular branches. The plexus lies close to C1–C4
vertebrae. Cutaneous branches include the lesser occipital nerve which
innervates lateral part of the occipital region; the great auricular nerve
(innervates skin near auricle and external acoustic meatus); the transverse
cervical nerve which innervates anterior region of the neck; and the
supraclavicular nerves which innervate shoulder, suprascapularis, and
upper thoracic region. The main contributor among muscular branches is
ansa cervicalis. Because sensory afferents from the cervical plexus enter
the spinal tract of the trigeminal along with the sensory afferents from
cranial nerves V, VII, IX, and X, nociceptive referral patterns from the
face and neck overlap. Symptoms usually include local pain with
lancinating or dysesthetic components referred to the retroauricular and
nuchal areas (lesser and greater auricular nerves), preauricular area
(greater auricular nerve), anterior neck and shoulder (transverse cutaneous
and supraclavicular nerves), and the jaw.348 Associated findings may
include ipsilateral Horner syndrome or hemidiaphragmatic paralysis. Due
to the proximity to the cervical spine, CT or MRI evaluation may be

2106
necessary to rule out associated epidural cord compression. Common
clinical settings include local extension of a head and neck tumor or
cervical lymph node metastases. In patients with head and neck tumors
who have undergone RND followed by radiation treatment, new onset or
worsening pain includes a differential diagnosis of post-RND syndrome or
tumor recurrence.

Tumor-Related Mononeuropathy
The most commonly described tumor-related painful mononeuropathy is
intercostal nerve injury secondary to rib metastases with local extension.
Patients with tumor invasion of the sciatic notch may present with
symptoms resembling sciatica. Isolated mononeuropathies particularly
from lymphomas are reported.358–360

Radicular Pain/Radiculopathy
Radiculopathy is compression of a nerve root. Frequent signs and
symptoms include varying degrees of sensory, motor, and reflex changes
as well as pain, dysesthesias, and paresthesias related to nerve root(s)
without evidence of spinal cord dysfunction (which is myelopathy).
Patients with radiculopathy may not have pain. Evaluation includes history
and physical examination. Imaging modalities commonly used for
evaluation include MRI, CT, and myelography. For lower extremity
issues, the most commonly used physical tests include Lasègue test*
straight leg raising or crossed straight leg raising; tendon reflexes; and
signs of weakness, atrophy, or sensory deficits.361 For cervical/upper
extremity radiculopathy, Spurling test† is a provocative maneuver
suggestive of radiculopathy. Patients with cancer-related radiculopathy
may present with pain on either or both sides of the midline. The pain
tends to be unilateral in the cervical and lumbosacral regions and bilateral
in the thorax. Radiculopathy may result from epidural tumor mass effects
with encroachment on exiting nerve roots or LMs. Coughing, sneezing,
recumbency, and strain exacerbate the pain, which often has dysesthetic
qualities. Radiculopathy may also develop secondary to LMs. Clinically,
LMs may produce multifocal neurologic signs and symptoms at a variety
of levels, including cranial neuralgias.362

2107
Leptomeningeal Metastases
LM is defined as the appearance of tumor cells in the leptomeninges or
CSF distant from the site of a primary tumor. It is also known as
carcinomatous meningitis, neoplastic meningitis, neoplastic meningosis,
leukemic meningitis (for leukemia), lymphomatous meningitis (for
lymphoma), and meningeal carcinomatosis (for carcinoma). This
complication occurs most commonly with cancers of the breast and lung,
melanoma, lymphomas, and acute lymphocytic leukemia with an estimated
survival at 1 year of approximately 10% that varies with the primary
tumor.363 Clinical evaluation, MRI, and CSF assessment including
cytology are the most important diagnostic measures.
Neurologic dysfunction most commonly involves one or more segments
of the neuraxis, including cerebral hemispheres, cranial nerves, spinal
cord, or spinal roots.364 Clinical manifestations that strongly suggest the
diagnosis of LM include cauda equina symptoms or signs, communicating
hydrocephalus, and cranial neuropathies. Early in the disease, neurologic
involvement can be subtle, such as an isolated diplopia or radicular pain.
Cerebral hemisphere symptoms such as altered mental status or seizures
may predominate.364 Symptoms may also include headache, back and
radicular pain, and multiple cranial and spinal nerve involvement. Pain
may occur in 30% to 76% of cases.365,366 Table 42.22 lists the frequency
of spinal cord symptoms and signs in patients with LMs. The most
common symptom is pain (80%), and patients may report a diffuse
headache (25%) or pain in a spinal, radicular, or meningeal pattern
(>50%). Localizing symptoms include cranial neuropathies, mononeuritis,
radiculopathy, urinary incontinence, and visual disturbance.

TABLE 42.22 Frequency of Spinal Cord Symptoms and Signs in

Patients with Carcinomatous Meningitis
Symptoms or Signs %
Weakness 33
Paresthesia 31
Back pain 25
Radicular pain 19
Bowel/bladder dysfunction 13
Reflex asymmetry 67

2108
 Weakness 4
Cauda equina syndrome 33
Sensory loss 31
Positive straight leg raise 13
Decreased tone of anal sphincter 12
Nuchal rigidity 11
From Zachariah B, Zachariah SB, Varghese R, et al. Carcinomatous meningitis: clinical
manifestations and management. Int J Clin Pharmacol Ther 1995;33(1):7–12. Reprinted by
permission of Dustri-Verlag Dr. Karl Feistle GmbH & Co. KG.

Solid tumors have the propensity to adhere to neural structures and form
nodules that become visible on MRI.367 MRI appearances include the
presence of subarachnoid nodules, leptomeningeal enhancement, nerve
root enhancement, parenchymal disease (intramedullary metastases), and
epidural metastases.368 These changes may occur intracranially and along
the spinal canal. T1-weighted gadolinium-enhanced sequence of the entire
neuraxis (brain and spine) plays an important role in supporting the
diagnosis, demonstrating the involved sites, and guiding treatment. MRI
images typically show enhancing nodular lesions.
Nearly all patients have some abnormality of CSF opening pressure,
protein, glucose, or cell count. The finding of tumor cells in CSF
establishes a definitive diagnosis. In patients with hematologic cancers,
CSF flow cytometry is more sensitive than CSF cytology and additionally
requires a comparatively smaller volume of CSF (<2 mL) for analysis.364

Myelopathies in Cancer
Spinal cord involvement may occur by direct or indirect mechanisms.
Direct mechanisms can be parenchymal (intradural intramedullary),
subarachnoid (intradural extramedullary), or epidural (extradural).
Intradural intramedullary involvement can result from metastases or a
primary spinal cord tumor, intradural extramedullary may occur from
leptomeningeal disease or primary tumors such as peripheral nerve sheath
tumors or meningiomas, and extradural disease is primarily related from
MESCC. Indirect mechanisms may result from radiation therapy (radiation
myelitis)369,370 and intrathecally administered chemotherapy resulting in
spinal cord injury.371,372 Paraneoplastic neurologic disorders may also
result in indirect injury.

2109
Brachial Plexopathy
The brachial plexus is formed from the C5–T1 ventral rami; the nerve
roots pass between the anterior and middle scalene muscles with the
subclavian artery to form the trunks. Trunks then split into anterior and
posterior divisions, form cords, and travel with the subclavian artery and
vein within the infraclavicular region. The cords form terminal branches at
the lateral margin of the pectoralis minor muscle and continue through the
axilla. Most tumors involving the brachial plexus originate from the lung
or breast (Fig. 42.12 and Table 42.23). Clinical features result from either
compression or tumor infiltration of the brachial plexus from contiguous
structures, such as axillary/supraclavicular nodes or vascular structures.
Neuropathic pain due to tumor infiltration of the brachial plexus usually
stems from lymph node metastases from breast carcinoma or lymphoma or
direct extension from lung carcinoma (i.e., Pancoast tumor). Lung cancers
that occur in the apex of the chest and invade chest wall structures are
called superior sulcus tumors or Pancoast tumors. The classical description
of such patients involves a syndrome of pain radiating down the arm as a
manifestation of brachial plexus involvement. A Pancoast tumor occurs
when it invades any of the structures at the apex of the chest, including the
most superior ribs or periosteum, the lower nerve roots of the brachial
plexus, the sympathetic chain near the apex of the chest, or the subclavian
vessels. These tumors are divided into anterior, middle, and posterior
compartment tumors depending on the location of the chest wall
involvement in relation to the insertions of the anterior and middle scalene
muscles on the first rib. A syndrome of pain radiating down the arm is not
a prerequisite for an apical tumor to be designated a Pancoast tumor.373
However, patients may complain of severe pain in the shoulder radiating
toward the axilla and/or scapula and along the ulnar distribution of the
upper arm and demonstrate atrophy of hand and arm muscles with
obstruction of the subclavian vein resulting in edema of the upper arm.

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FIGURE 42.12 Computed tomography scan with contrast of patient with triple negative breast
cancer involving the right brachial plexus. A: Axial view showing large mass encasing the brachial
plexus at the infraclavicular level (red arrows). The mass also indents the lung (yellow arrow). B:
Coronal view showing the mass the paraspinal muscles in proximity to transverse process from C5–
T1 (arrows).

TABLE 42.23 Frequency of Tumor-Associated Plexopathy by

Location
Brachial Plexus Tumors Lumbosacral Plexus Tumors
Lung 37% Colorectal 20%
Breast 32% Sarcoma 16%
Lymphoma 8% Breast 11%
Sarcoma 5% Lymphoma 9%
All others 18% Cervix 7%
All others 37%
From Jaeckle KA. Neurologic manifestations of neoplastic and radiation-induced plexopathies.
Semin Neurol 2010;30(3):254–262. Copyright © Georg Thieme Verlag KG.

The key features of malignant plexopathy are the neuropathic nature of

the pain, with numbness, paresthesias, allodynia, and hyperesthesias.
Typically, the pain begins in the shoulder girdle where it is often described
as pressure-like or aching and may radiate to the elbow, medial forearm,
and fourth and fifth fingers. It may also appear to localize at the posterior
arm or elbow. The patient may report a burning quality to the pain, with
hyperesthesia along the ulnar aspect of the forearm. Involvement of the
lower plexus occurs when tumor arises from the lung apex; associated pain
and dysesthesias involve the elbow, medial forearm, and fourth and fifth
fingers (C7, C8, and T1). Upper plexus involvement (C5, C6), if it occurs

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alone, will usually develop into a panplexopathy. Upper plexus pain
typically involves the shoulder girdle, with burning pain in the tips of both
the index finger and thumb. Lung tumors can also present with pain
involving the axilla and upper chest wall in the distribution of the
intercostobrachial nerve.374
Neuroradiologic evaluations for brachial plexopathy are CT, PET/CT,
and MRI. MRI is the preferred modality for imaging the brachial plexus.
Most commonly, a combination of fat-suppressed T2-weighted (either
frequency selective or short tau inversion recovery [STIR]) sequences and
T1-weighted MR sequences are used.375 FDG-PET scanning may also be
useful in distinguishing between radiation-induced and metastatic
plexopathy. Imaging the contiguous epidural space is recommended,
particularly with paraspinal involvement. Electromyography (EMG) can
also help distinguish malignant brachial plexopathy from radiation-
induced brachial plexopathy (RBP) or cervical radiculopathy (Table
42.24). In patients with brachial plexopathy, EMG usually shows
fibrillation potentials and positive waves (evidence of denervation) in
affected muscles. RBP is discussed later.

TABLE 42.24 Differentiating Features of Brachial Plexopathy

Induced by Tumor Infiltration, Radiation Fibrosis, and Reversible
Radiation Injury
Reversible Radiation
Tumor Infiltration Radiation Fibrosis Injury
Incidence of pain 89% 18% 40%
Typical location of Shoulder, upper arm, Shoulder, wrist, hand Hand, forearm
pain elbow, radiating to
fourth and fifth
fingers
Nature of pain Dull aching in Aching shoulder pain; Aching shoulder pain;
shoulder; Paresthesias in C5, Paresthesias in hand
Lancinating pain in C6 distribution in and forearm
elbow and ulnar hand
aspect of hand;
Occasional
dysesthesias,
burning, or freezing
sensations
Severity of pain Moderate to severe Mild to moderate Mild
(severe in 98% of (severe in 35% of

2112
 patients) patients)
Course Progressive Progressive weakness Transient weakness
neurologic with C5, C6 and atrophy
dysfunction; distribution; affecting C6–C7,
atrophy and stabilizing pain T1; complete
weakness with C7– with appearance of resolution of motor
T1 distribution; weakness findings
persistent pain;
Horner syndrome
CT scan findings Circumscribed mass Diffuse infiltration of Normal
with diffuse tissue planes
infiltration of tissue
planes
EMG findings Segmental slowing; Myokymia Segmental slowing;
no myokymia no myokymia
CT, computed tomography; EMG, electromyography.
Modified from Foley KM. Brachial plexopathy in patients with breast cancer. In: Harris JR,
Hellman S, Henderson IC, et al, eds. Breast Diseases. Philadelphia: JB Lippincott Co; 1987.

Lumbosacral Plexopathy
The lumbosacral plexus is formed from the L1–L5 ventral rami with
contributions from T12 and S1–S4. The lumbar roots emerge from the
psoas major muscle, form anterior and posterior divisions, and finally form
anterior and posterior branches to innervate the muscles of the anterior and
medial thigh. Anterior and posterior divisions also arise from the sacral
roots and course over the sacral promontory posterolateral to the internal
iliac vessels to form branches that innervate the muscles of the gluteal
region, lateral and posterior thigh, and lower leg. The sciatic nerve exits
the pelvis through the greater sciatic foramen usually below but sometimes
dividing the piriformis muscle. Direct tumor infiltration from adjacent soft
tissues or lymph nodes or by compression from metastases in the adjacent
bony pelvis can damage the lumbosacral plexus. Most lumbosacral
plexopathy reflects local extension or nodal metastases from colorectal and
other pelvic tumors (cervix, uterus, bladder, prostate), sarcomas, and
lymphomas, but it may also occur with metastases from breast or lung
cancer.376
Complete plexopathy causes weakness, sensory loss, and flaccid loss of
tendon reflexes in regions innervated by nerves in the L1–L4 distribution.
Sacral plexopathy causes the same abnormalities in segments L5–S3,
resulting in weakness and sensory loss in the gluteal (motor only),

2113
peroneal, and tibial nerve areas. The distribution of pain varies and may
localize in the pelvis, low back or hip, or refer in a radicular or
nonradicular pattern into the lower extremity. The local pain quality is
pressure-like or aching. Referred pain varies with the site of plexus
involvement and can be burning, cramping, or shooting. Sensory
symptoms of numbness and paresthesias as well as weakness and leg
edema usually develop. A “hot and dry foot” syndrome may result from
lumbosacral plexopathy and may reflect sympathetic fiber dysfunction.377
The most common clinical findings on examination include lower
extremity weakness (86%), sensory loss (73%), reflex loss (64%), and leg
edema (47%). Positive straight leg raising tests and sciatic notch
tenderness are often present.378
Lumbosacral plexopathy may cause different clinical syndromes
depending on the level of nerve involvement. Infiltration of the upper
plexus occurs in approximately one-third of patients, who present with
pain in the back, lower abdomen, flank, iliac crest, or anterolateral thigh.
This syndrome has associated L1–L4 distribution neurologic deficits.
Involvement of the lower plexus occurs in approximately one half of
patients, and these present with pain in the buttocks and perineum, with
referral to the posterolateral leg and thigh. Examination may reveal
associated L4–S1 neurologic deficits, leg edema, and bowel or bladder
dysfunction. Sacral plexopathy can signal direct bony extension of a bony
sacral lesion or a presacral mass. Numbness of the dorsal medial foot and
sole with associated weakness of knee flexion, ankle dorsiflexion, and
inversion is typical of lumbosacral trunk extension. Involvement of the
coccygeal plexus results in sphincter dysfunction and perineal sensory
loss. Panplexopathy occurs in one-fifth of patients, and pain may refer
anywhere in the territory of the plexus. Associated leg edema is relatively
common.377
Jaeckle et al.379 studied 85 cancer patients with lumbosacral plexopathy
and documented pelvic tumor by CT or biopsy. They discerned three
clinical syndromes: lower (L4–S1), 51%; upper (L1–L4), 31%; and
panplexopathy (L1–S3), 18%. Seventy percent of patients had the
insidious onset of pelvic or radicular leg pain, followed weeks to months
later by sensory symptoms and weakness. The quintet of leg pain,

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weakness, edema, rectal mass, and hydronephrosis suggests plexopathy
due to cancer. CT showed pelvic tumor in 96%. On myelography, epidural
extension, usually below the conus medullaris, occurs in 45%. With
treatment, only 28% of patients had objective responses on CT and 17%
on examination.
In previously treated patients, the main differential diagnostic
consideration is radiation-induced plexopathy (see in the following
discussion). MRI is the choice for the diagnostic workup of patients with
clinical and electrophysiologic evidence of plexopathy and suspected
systemic cancer. Studies should include the L1 vertebral body through to
the true pelvis. Neurologic findings include leg weakness, sensory loss,
reflex asymmetry, focal tenderness (in the lumbar region in an upper
plexopathy, sciatic notch and sacrum in a lower plexopathy, and
lumbosacral region in panplexopathy), rectal mass, decreased sphincter
tone, and positive direct and reverse straight leg raising signs.

Tumor Infiltration of the Sacrum and Sacral Nerves

Pain in a sacral distribution occurs usually as a result of the spread of
bladder, gynecologic, or colonic cancer. There is dull aching midline pain
and usually burning or throbbing pain in the soft tissues of the rectal or
perineal region. Sitting or lying usually exacerbates the pain. With bilateral
involvement, sphincter incontinence and impotence are common. There
may be tenderness over the sacrum and in the regions of the sciatic
notches. Sometimes there is limitation of both direct and reverse straight
leg raise exam maneuvers. Involvement of S1 and S2 roots will produce
weakness of ankle plantar flexion, and the ankle jerks may be absent.
There is usually sensory loss in the perianal region and in the genitalia, and
this may be accompanied by hyperpathia.

Spinal and Radicular Pain

Patients perceive radicular pain as arising in a limb or trunk wall. The
cause is ectopic activation of nociceptive afferent fibers in a spinal nerve
or its roots or other neuropathic mechanisms. The pain is lancinating in
quality and travels along a narrow band. It may be episodic, recurrent, or
paroxysmal according to the causative lesion or any superimposed

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aggravating factors. Although patients may experience radicular pain as a
deep tissue pain, it also has a cutaneous quality in proportion to the
number of cutaneous afferent fibers ectopically activated. Radicular pain
differs from nociception in the axons stimulated along their course; their
peripheral terminals are not the sites of stimulation. Ectopic activation may
occur as a result of mechanical deformation of a dorsal root ganglion,
mechanical stimulation of previously damaged nerve roots, inflammation
of a dorsal root ganglion, and possibly by ischemic damage to the DRG.
Acute spine pain may be described as cramping or knifelike but may also
be merely dull or aching. It is worse with movement. Chronic spine pain
without a radicular component is generally aching, dull, or burning, or any
combination of these three features. It also tends to be made worse with
movement.

Central Pain Syndromes Caused by Cancer

Central pain syndromes are relatively infrequent in the cancer population.
Although epidural spinal cord compression is almost always painful,
central pain is not the predominant symptom; nociceptive input from
progressive bony destruction by metastases is the usual cause of pain, with
or without concurrent radicular pain from nerve root compression.
Radiation myelopathy is also a possible cause of central pain syndrome.

Paraneoplastic Peripheral Neuropathy

Paraneoplastic syndrome refers to a group of disorders (caused by, or
associated with, cancers) that are neither direct effects of the primary
tumor mass nor metastatic to the involved organs. Various antibodies
discovered in paraneoplastic syndromes target proteins shared by both the
tumor cells and neurons.380 Antibodies directed against neural antigens
expressed by tumor (onconeural antibodies) may occur in most of those
affected by classical paraneoplastic syndromes, suggesting that an
autoimmune process underlies these disorders. In patients with anti-Hu
antibodies, infiltration by T cells is seen in the peripheral and the CNS.381
Clinically significant peripheral neuropathy in cancer patients is common,
but only a small minority is paraneoplastic in origin. These disorders can
affect virtually any portion of the nervous system. Peripheral nerves are a

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common target in paraneoplastic syndromes.211 SSN is a classical
paraneoplastic syndrome.212 The neuropathy generally develops
subacutely, accompanied by pain and rapidly progressive paresthesia.
Involvement of the upper extremities may occur with asymmetric sensory
deficit or multifocal with facial, thoracic, and abdominal involvement.
Many patients with SSN also have signs and symptoms suggestive of
multifocal involvement including areas of the CNS. Paraneoplastic
vasculitis of the peripheral nervous system usually precedes the tumor
diagnosis and presents as multineuritis or asymmetric distal sensory-motor
neuropathy with pain as a commonly reported symptom. This form is
generally associated with lymphoma or cancer at various sites (lung,
prostate, uterus, kidney, or gastric).213 Four types of polyneuropathy
constitute most of the cases of paraneoplastic peripheral neuropathy:
motor, sensory, sensorimotor, and autonomic. Most paraneoplastic
peripheral neuropathies are sensorimotor and axonal. A pure sensory
neuronopathy (i.e., pathology in the dorsal root ganglion) strongly suggests
a paraneoplastic syndrome associated with the anti-Hu antibody. A pure
motor neuropathy subacutely developing could be the Guillain-Barré
syndrome associated with Hodgkin disease or a multifocal motor
neuropathy with conduction block associated with plasma cell dyscrasias.
An autonomic neuropathy is sometimes associated with the anti-Hu
syndrome. Paraneoplastic disorders of the autonomic nervous system
usually arise in the setting of encephalomyelitis. However, autonomic
symptoms may predominate or rarely be the only symptoms or signs of a
paraneoplastic neuropathy. The most common symptom is pseudo-
obstruction of the bowel, but anhidrosis, orthostatic hypotension,
hypoventilation, sleep apnea, and cardiac arrhythmias can also present
either alone or, more commonly, as part of a more widespread autonomic
neuropathy. Most autonomic neuropathies are associated with SCLC and
the anti-Hu syndrome. Mononeuritis multiplex suggests a vasculitis,
possibly paraneoplastic in origin. The classic paraneoplastic
polyneuropathy is sensory neuronopathy. Typically, patients with this
disorder initially have an asymmetrical and painful sensory neuropathy,
which evolves into complete loss of proprioception. The pseudoathetotic
movement of the hands and severe sensory ataxia is very severe in most

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cases. Motor neuropathies may be acute or chronic, progressive or
remitting, demyelinating, axonal, or neuronal. Clinically, they are
indistinguishable from the more common nonparaneoplastic motor
neuropathies, unless they resolve after treatment of the cancer or are
associated with a paraneoplastic antibody. These disorders include the
Guillain-Barré syndrome, which occurs more frequently in patients with
Hodgkin’s disease than in the general population; a remitting and relapsing
polyneuropathy resembling relapsing chronic inflammatory demyelinating
polyneuropathy; and a subacute motor neuronopathy affecting patients
with Hodgkin’s disease or other lymphomas. The sensory neuropathies
include a subacute pan-sensory neuropathy and a predominantly distal
sensory neuropathy. Paraneoplastic vasculitis neuropathy may occur in
malignancy (solid tumors including gastric cancer), and the presentation is
similar to connective tissue-related vasculitic neuropathy with a painful,
asymmetrical polyneuropathy or mononeuritis multiplex pattern.380
Paraneoplastic peripheral neuropathies are important because they may
be the first sign of an otherwise occult cancer and/or because they may
substantially disable the patient even when the cancer itself is
asymptomatic. In about two-thirds of cases, patients with paraneoplastic
neurologic disorders present to the neurologist without a known tumor.
Polyneuropathy, organomegaly, endocrinopathy, myeloma protein, and
skin changes (POEMS) syndrome is a paraneoplastic syndrome due to an
underlying plasma cell neoplasm. The major criteria for the syndrome are
polyradiculoneuropathy, clonal plasma cell disorder (PCD), sclerotic bone
lesions, elevated VEGF, and the presence of Castleman disease. Minor
features include organomegaly, endocrinopathy, characteristic skin
changes, papilledema, extravascular volume overload, and thrombocytosis.
POEMS syndrome should be distinguished from the Castleman disease
variant of POEMS syndrome, which has no clonal PCD and typically little
to no peripheral neuropathy but has several of the minor diagnostic criteria
for POEMS syndrome.382

NEUROPATHIC PAIN SECONDARY TO THERAPEUTIC

INTERVENTIONS
Many pain syndromes occur in the course of or subsequent to treatment of

2118
cancer with surgery, chemotherapy, or radiation therapy. In most cases,
there is injury to the peripheral nervous system or spinal cord, with pain as
a major and often presenting complaint. In some cases, these syndromes
occur long after the therapy is implemented, resulting in a difficult
differential diagnosis between recurrent disease and a complication of
therapy.

Postsurgical Neuropathic Pain

1. Postmastectomy: Pain can be a prominent postsurgical finding in
breast cancer patients. It tends to appear in the postmastectomy
period, a consequence of the disruption of normal neural pathways,
or it may follow the development of lymphedema or the presence of
metastases. In most situations, however, pain occurs primarily as a
result of persistent restrictions in range of motion of the shoulder
girdle in the region of surgery with findings of tender or trigger
points in the associated muscle groups suggesting a nonneuropathic
source that is misdiagnosed as neuropathic. The IASP defines
postmastectomy pain syndrome as persistent pain soon after
mastectomy/lumpectomy affecting the anterior thorax, axilla, and/or
medial upper arm,383 but patients may experience persistent
postsurgical pain affecting one or more regions involving the scar,
breast, chest wall, shoulder, and upper arm with an incidence ranging
from 25% to 80%.384 Chronic neuropathic pain with inherent sensory
changes and somatosensory disturbances may overlap with persistent
postsurgical pain, and definitive diagnosis can be challenging.
Chronic pain after mastectomy may occur in patients whose
surgery included axillary dissection, although the problem can occur
in women who undergo any surgical procedure on the breast from
lumpectomy to radical mastectomy. Postaxillary dissection pain is
probably a more appropriate name than the usual postmastectomy
pain for this syndrome. A neuropathic pain pattern typically involves
paroxysms of lancinating pain against a background of burning,
aching, tight constriction in the axilla, medial upper arm, and/or
chest. Hyperesthesia, dysesthesia, hyperalgesia, allodynia, or
hypoesthesia in the intercostobrachial nerve distribution may

2119
 occur.385 The exact cause is unclear, but various theories include
dissection of the intercostobrachial nerve, intraoperative damage to
axillary nerve pathways, and pain caused by neuroma formation. The
intercostobrachial nerve is a cutaneous sensory branch of T1 and T2.
The nerve is highly variable in size and distribution, making it
difficult to avoid in these surgical procedures. Usually, the pain
develops shortly after surgery, but it can emerge months after
surgery. Late onset should prompt a search for other causes such as
recurrent chest wall disease or bone metastases. Postmastectomy pain
syndrome differs from metastatic or RBP in which there is a different
pattern of sensory loss, lymphedema, and, usually, more severe pain.
2. Neck dissection: Head and neck cancer encompasses tumors of the
upper aerodigestive tract and the skin of the region. Surgical
management may include the removal of lymph nodes from the neck
and is referred to as a neck dissection. A large spectrum of surgical
procedures is available for treatment of cervical lymph nodes.386
These may be classified as RND, extended RND, modified RND,
and selective neck dissection. RND for head and neck cancers can
result in an iatrogenic syndrome characterized by ipsilateral face and
neck pain with associated paresthesias. Pain usually emerges weeks
to months after surgery, consequent to injury to the cervical plexus or
cervical nerves.348 The most relevant functional sequel from RND is
impairment of shoulder function due to sectioning the spinal
accessory nerve and to the ensuing denervation of the upper trapezius
muscle. Sacrifice of the spinal accessory nerve during RND is
considered a critical factor in determining postoperative shoulder
function. Injury to the nerve and subsequent denervation of the
trapezius muscle reduces capacity to elevate the shoulder girdle
(scapular dyskinesis) and has been associated with patient reported
shoulder pain and functional loss.387 Patients who undergo a nerve-
sparing procedure (i.e., selective neck dissection or a modified RND)
exhibit significantly better shoulder function than did patients who
undergo RNDs.388 In patients treated for head and neck cancer, neck
dissection was considered a risk factor for the development of
MPS.389 Neck dissection was a predictive factor for reduced

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 sensitivity in the neck, reduced range of motion of the neck, and
MPS was strongly related to shoulder pain.390
Nahum et al.391 coined the term “shoulder syndrome” to describe a
clinical picture consisting of pain and limited abduction of the
shoulder, full passive range of motion, and anatomic deformities
such as scapular flaring, droop, and protraction. Pain is attributed to
strain placed on other supporting muscles, such as the rhomboids and
levator scapulae, as a consequence of shoulder drooping. A frequent
ancillary sign of shoulder syndrome is sternoclavicular joint
hypertrophy, due to the abnormal torque-like forces applied to the
medial head of the clavicle, potentially complicated by stress fracture
of the middle third of the clavicle. Recurrent tumor can also be a
cause of pain that occurs or escalates after neck dissection.
3. Postthoracotomy pain: Most surgical procedures can potentially
cause persistent pain which last months or years, and breast surgery
(including interventions for breast cancer, augmentation, and
reduction) and thoracic surgery (including open thoracotomies,
video-assisted thoracoscopic surgery [VATS], sternotomies) are two
with the highest reported prevalence (31% and 34%, respectively)
with the prevalence of probable or definite neuropathic pain being
approximately 66%.392 Shortly following thoracotomy, a neuropathic
pain can develop in the distribution of one or several intercostal
nerves near the thoracotomy scar.392,393 The pain may remain stable
after onset and gradually decreases over a period of months or years.
Hetmann et al.394 noted in patients who underwent thoracotomies by
an open posterolateral technique that the presence of preoperative
pain was a predominant predictor for persistent pain 12 months after
the procedure. Persistent postsurgical pain following anterior
thoracotomy occurred in 19% of lung cancer patients for up to 10
years postoperatively.395 Steegers et al.396 noted the prevalence of
chronic pain was 40% after thoracotomy and 47% after VATS.
Definite chronic neuropathic pain was present in 23% of the patients
with chronic pain, with an additional 30% having probable
neuropathic pain. The probability of neuropathic pain correlated with
more intense chronic pain and predictive factors for chronic pain

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 were younger age, radiation therapy, pleurectomy, and more
extensive surgery. Pain is most profound around the scar, as 82% to
90% of pain patients relate their pain directly to the surgical
site397,398 and is primarily described as aching, tender, with
numbness, and to a lesser degree burning.399 Guastella et al.400 noted
in patient who underwent a lateral/posterolateral thoracotomy for
cancer that the clinical picture in most patients with neuropathic pain
included electric shocks and severe multimodal hypoesthesia in the
sensory area of fifth/sixth intercostal nerves. Patients may also have
higher depression and anxiety scores and lower self-rated health and
demonstrate more evoked pain to mechanical stimuli and in
particular to pinprick hyperalgesia.401
In my experience, many patients experience chronic pain in the
shoulder girdle region following thoracic surgical procedures not
primarily from intercostal nerve damage but from a persistent
inability to normally range the shoulder girdle region. In effect, these
patients demonstrate persistent myofascial tenderness in the muscles
of the shoulder girdle region (pectorals, trapezius, rhomboids, and
deltoid).
4. Phantom pains: After amputation, patients may experience phantom
sensations (including temperature changes, itching, tingling) and/or
phantom pain. Phantom pain is typically associated with amputation
of limbs but may follow the amputation or loss of many body parts
including the eyes,402 teeth,403 tongue,404 nose,405 breast,406
genitals,407 or parts of the gastrointestinal tract.408,409 The onset is
within 1 week after amputation in the majority of patients, with 50%
of patients experiencing pain within 24 hours after amputation.410,411
Phantom pain should be distinguished from residual limb pain that is
localized to the residual limb. Patients may report that phantom
sensations are present all the time and that phantom limb pain is
intermittent with short episodes (lasting only seconds or minutes) of
pain (often severe) which can occur several times a day. Patients may
also report “telescoping” of their phantom which is a sensation in
which the body of the limb shortens into the stump often completely,
leaving the sensation of hands or feet very close to the stump.

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 Phantom pain disables a significant number of patients undergoing
amputation of different body parts for malignancy.412 Two years
after mastectomy, the percentage of patients with phantom breast
sensations was stable around 20%, and those with phantom breast
pain reduced from 7% in the first year to 1%.413 Phantom rectal
sensation (including pain) occurs in up to 18% of patients after
surgery for rectal carcinoma.414 The reappearance or worsening of
pain a long while after amputation can indicate tumor recurrence.

Radiation Myelopathy, Plexopathy, and Neuropathy

Tolerance of nervous system tissues to radiation therapy depends on
several factors such as volume, total dose, dose per fraction, duration of
irradiation, prior radiation, concomitant neurotoxic chemotherapy, and
genetic susceptibility.415 Radiation treatment may cause pain by damage to
peripheral nerves or spinal cord by altering the microvascular of
connective tissue surrounding peripheral nerves, via fibrosis and chronic
inflammation in connective tissues, or bringing about demyelination and
focal necrosis of the white and gray matter in the spinal cord. Typically,
these changes occur late in the course of a patient’s illness. The differential
diagnosis should always include recurrent tumor. In most instances, pain is
a component of the clinical picture, but it is rarely as severe as that
associated with recurrent tumor. Myelopathy is a devastating late effect of
radiation treatment and if the spinal cord dose does not exceed a total of 45
to 50 Gy in 1.8 to 2 Gy daily fractions, the risk of permanent injury is very
low, estimated from 0.03% to 0.2%.416 The pathologic findings of
radiation-induced progressive myelopathy may include demyelination,
focal necrosis and axonal loss, and vascular abnormalities such as
telangiectasias, endothelial swelling with fibrin exudates, hyaline
degeneration, thickening and fibrinoid necrosis of vessel walls with
perivascular fibrosis, and sometimes vasculitis.417 Early delayed radiation
myelopathy occurs from 6 weeks to 6 months after treatment, and
improvement follows in most cases within 2 to 9 months, although in some
instances, symptoms may persist for prolonged periods. The cervical and
thoracic spinal cord is the most commonly involved. Clinical signs are
generally limited to a Lhermitte’s sign.‡ The spinal cord MRI is usually

2123
normal. Transient demyelination, probably resulting from radiation injury
of oligodendrocytes, is likely the main pathogenic mechanism of early
delayed myelopathy.418 Late-delayed radiation-induced spinal cord
disorders complications include progressive myelopathy and spinal
hemorrhage. Progressive myelopathy or delayed radiation myelopathy may
follow radiation treatment by 6 months to approximately 10 years. Risk
factors include older age, previous irradiation (incidental or medical)
particularly during childhood, large radiation port involving the dorsal or
lumbar spinal cord, and large radiation dose and fractions. The clinical
onset of delayed radiation myelopathy may be acute, but it is more often
progressive. Patients can present with para- or tetraparesis with rapid
development of sensory and/or motor deficits. The development of a
Brown-Séquard syndrome** is a classic presentation. Another possible
presentation is an ascending transverse myelopathy with bilateral leg
weakness and sensory loss up to the level of irradiation. Patients may
develop bladder or bowel dysfunction; pain has been occasionally
reported. The involvement of the upper cervical spinal cord can cause
diaphragm dysfunction. The course of symptoms is difficult to predict;
some patients improve and others deteriorate. Despite its lack of
specificity, MRI findings are important. Other potential causes of
myelopathy should be carefully investigated.
Neuropathic syndromes associated with chest wall/axillary radiation
therapy include brachial plexopathy, malignant peripheral nerve tumors,
nerve entrapment in a lymphedematous shoulder, and ischemia. Both early
onset and late-onset brachial plexopathy occur. Clinically, the plexopathy
involves mixed sensory and motor deficits, with or without pain.
Most reports of radiation-induced plexopathy involve the brachial
plexus and, although much less common, radiation-induced injury of the
lumbosacral plexus has also been reported.419 The risk of RBP from
conventionally fractionated radiotherapy (i.e., 5,000 cGy in 200-Gy
fractions) is <1% and when the dose per fraction increases to between
2,200 and 4,580 cGy with a total dose of 4,350 and 6,000 Gy, the risk of
brachial plexus injury increases to 1.7% to 73%.420 Olsen et al.421
described the incidence and latency period of RBP in 79 patients with
breast cancer. Thirty-five percent of patients developed RBP. Fifty percent

2124
had involvement of the entire plexus, 18% of the upper plexus alone, 4%
of the lower plexus alone, and a definite level of involvement could not be
determined in 28% of patients. RBP began in most patients either during
or immediately after radiation treatment. RBP was more common in
patients who received combination treatment with chemotherapy and
radiation than with radiation alone. Clinically, plexopathy presents with
subjective paresthesia or dysesthesia and progresses with the development
of hypesthesia then anesthesia. Neuropathic pain is generally considered
rare and moderate in intensity. Motor weakness is progressive, often
delayed by several months, and then associated with fasciculations and
amyotrophy.221 Zeidman et al.422 estimate that up to 20% of patients with
radiation-induced plexopathy may report severe pain. Mondrup at al.423
noted that the most prominent symptoms for RBP were numbness or
paresthesia (71%) and pain (41%), whereas the most prominent objective
signs were decreased or absent muscle stretch reflexes (93%) closely
followed by sensory loss (82%) and weakness (71%). The neurologic
deficits are relentlessly progressive and ultimately result in a useless limb.
In contrast to malignant infiltration, patients with radiation injury to the
plexus tend to have abnormal sensory and normal motor nerve conduction
studies and characteristically manifest more fasciculations or myokymia
on EMG than patients with neoplastic disease.424
Radiation induced of the lumbosacral plexus has been reported after
intracavitary radium implants for carcinoma of the cervix.425 Paresthesias,
distal weakness progressing proximally, but rarely pain occur in the lower
extremities 2 to 3 months after radiation of the sacral plexus.426 Weakness
commences distally in the L5–S1 segments and slowly progresses.427
Painless, indolent leg weakness occurs early in radiation disease, whereas
pain with or without unilateral weakness usually characterizes tumor
plexopathy. Radiation disease often results in serious neurologic disability.
The diagnosis of radiation plexopathy can be supported by various
studies. Approximately 60% of patients with radiation-induced plexopathy
will show myokymia†† on EMG.428 MRI imaging of the plexus is also
helpful. Enhancement of nerve roots and T2-weighted hyperintensity
usually suggests tumor; generally, radiation plexopathy does not produce
nerve enhancement, MRI appearances for RBP are isointense of

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hypointense relative to muscle on T2-weighted images and thus
distinguishable from tumor infiltration which is usually hyperintense,429
although increase in T2 signal may be present.430 PET/CT scanning is also
helpful in distinguishing tumor from radiation changes.431 Features
distinguishing radiation plexopathy from neoplastic plexopathy are listed
in Table 42.24.

Chemotherapy-Induced Peripheral Neuropathy

Drug-induced neurotoxicity can affect nerve fibers or neuronal bodies
(generally the DRG of the primary sensory neurons). Among the toxicities
associated with chemotherapy, damage of the peripheral nervous system is
particularly frequent and potentially severe. CIPN causes numerous
debilitating symptoms, impairs functional capacity, and results in dose
reductions or possible cessation of chemotherapy. CIPN is a
predominantly sensory neuropathy that may be accompanied by motor and
autonomic changes. The drugs most commonly reported to cause CIPN
include the platinum-based drugs (particularly oxaliplatin and cisplatin),
the vinca alkaloids (particularly vincristine and vinblastine), the
epothilones (ixabepilone), the taxanes (paclitaxel, docetaxel), the
proteasome inhibitors (bortezomib), and immunomodulatory drugs
(thalidomide) (Table 42.25). The prevalence of CIPN is 68% in the first
month after starting chemotherapy, 60% at 3 months, and 30% at 6 months
or more with different drugs were associated with differences in CIPN
prevalence.432
The clinical manifestations of CIPN are frequently predominantly
subjective and manifest as pure sensory symptoms and are most commonly
reported as progressive distal symmetrically distributed symptoms of
numbness, tingling, pins and needles, burning, decreased or altered
sensation, or increased sensitivity that may be painful in the feet and
hands. The primary clinical objective in assessing patients is to determine
the presence and severity of CIPN-associated symptoms that result in
interference with activities of daily living because this finding is critical
for treatment decisions. Symptoms of motor weakness due to CIPN are
less commonly reported and when present are observed in patients with
more persistent and severe sensory findings. If the patient has coexisting

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diabetes, it can be quite difficult to differentiate the onset or progression of
diabetic neuropathy from CIPN, which may be mitigated in some instances
if the physician has carefully evaluated and recorded the patient’s baseline
neurologic findings and symptoms prior to initiation of the neurotoxic
chemotherapy. Diabetic neuropathy can be asymmetrical or symmetrical,
focal or diffuse, or manifests as mononeuritis multiplex in its involvement
and has many different clinical forms. The most common form of diabetic
neuropathy, distal symmetrical polyneuropathic form, has clinical
symptoms similar to CIPN.
The most commonly observed clinical findings of CIPN are
symmetrical progressive onset of the following sensory symptoms and
findings in a stocking-glove distribution: paresthesias, hyperesthesias,
hypoesthesias, and dysesthesias, which more commonly appear earlier and
with more pronounced symptoms in the toes and feet, with later
involvement of the fingers and hands. Concurrent loss of deep tendon
reflexes (loss of distal usually earlier than proximal) in the affected
extremities with sensory deficits is an important diagnostic sign associated
with greater neurosensory damage. Sensory findings, including diminished
or absent proprioception, vibration, touch, two-point discrimination,
sharp/dull discrimination, temperature, and touch/pain are typically
diminished in the stocking-glove distribution in symptomatic patients
(Table 42.25).

TABLE 42.25 Summary of the Most Frequent Symptoms and Signs

Associated with the Administration of Commonly Used
Chemotherapy Drugs
Class Drug Symptoms/Signs
Platinum Cisplatin Distal, symmetric, upper and lower limb
(carboplatin) impairment/loss of all sensory modalities
Large myelinated fibers are more severely
involved so that sensory ataxia and gait
imbalance are frequent.
Early reduction/loss of DTR
Coasting phenomenon is frequent.
Carboplatin is generally much less neurotoxic
than cisplatin.
Oxaliplatin Acute
Cold-induced transient paresthesias in mouth,

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 throat, and limb extremities
Cramps/muscle spasm in throat muscle
Jaw spasm
Chronic
Similar to cisplatin
Vinca alkaloids Vincristine Distal, symmetric, upper and lower limb and
impairment/loss of all sensory modalities
Reduction/loss of DTR
Neuropathic pain/paresthesia at limb extremities
is relatively frequent.
Distal, symmetric weakness in lower limbs
progressing to foot drop
Autonomic symptoms may be severe (e.g.,
orthostatic hypotension, constipation, paralytic
ileus)
Epothilones Ixabepilone, Similar to taxanes, but neuropathic pain is less
sagopilone frequent and recovery is reported to be faster
Antitubulin Taxanes Distal, symmetric, upper and lower limb
(paclitaxel, impairment/loss of all sensory modalities
docetaxel) Gait unsteadiness is possible due to
proprioceptive loss.
Reduction/loss of DTR
Neuropathic pain/paresthesia at limb extremities
is relatively frequent.
“Myalgia syndrome” is frequent, possible
expression of atypical neuropathic pain.
Distal, symmetric weakness in lower limbs is
generally mild.
Proteasome Bortezomib Mild to moderate, distal symmetric loss of all
inhibitors sensory modalities. Small myelinated and
unmyelinated fibers are markedly affected
leading to severe neuropathic pain.
Reduction/loss of DTR
Mild distal weakness in lower limbs is possible.
Immunomodulatory Thalidomide Mild to moderate, distal symmetric loss of all
sensory modalities
Reduction/loss of DTR
Relatively frequent neuropathic pain at limb
extremities
Weakness is rare.
More neurotoxic than lenalidomide or
pomalidomide
NOTE: Coasting is worsening of neuropathy signs/symptoms over months after drug withdrawal.
DTR, deep tendon reflex.
Modified from Cavaletti G. Chemotherapy-induced peripheral neurotoxicity (CIPN): what we need
and what we know. J Peripher Nerv Syst 2014;19:66–76.

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 CIPN has a high degree of similarity in the pattern and spectrum of
clinical manifestations caused by different chemotherapeutic agents (e.g.,
vinca alkaloids, platinum agents, thalidomide, bortezomib, and taxanes),
which includes the length-dependent, symmetrical stocking-glove
distribution with predominantly sensory symptoms noted by the patient.
CIPN generally arises as a consequence of the disruption of axoplasmic
microtubule-mediated transport, distal axonal (wallerian) degeneration,
and direct damage to the sensory nerve cell bodies of the DRG.
Demyelination (diffuse or segmental) secondary to chemotherapy is an
uncommon finding (but occasionally observed with cisplatin), and when
observed, it is typically a secondary and isolated finding relative to the
extent of axonal and DRG pathologic findings. It is important to recognize
that CIPN commonly follows the administration of chemotherapeutic
agents that cannot appreciably distribute across the blood–brain barrier
(e.g., taxanes, platinum agents, vinca alkaloids, thalidomide, and
bortezomib). CIPN is commonly characterized as a distal axonopathy,‡‡
less commonly as a neuronopathy,*** and may simultaneously manifest
with both forms in some patients. To improve accurate and reliable
reporting of chemotherapy-induced neuropathy, various grading systems
have been developed.433 Table 42.7 is an example of a grading scale for
evaluation of CIPN.

ORAL MUCOSITIS
Ulcerative lesions in the mucosa of patients undergoing chemo- or
radiation therapy characterize oral mucositis. Oral lesions can result in
dysphagia, dysarthria, and odynophagia. Patients may complain of oral
burning or severe pain that may disrupt oral intake resulting in parenteral
or enteral nutritional supplementation. The risk of oral mucositis increases
as a function of the type of cancer therapy used, with the lowest risk
occurring with “gentler” chemotherapeutics such as gemcitabine (Gemzar)
and the higher risk occurring with more aggressive agents such as 5-
fluorouracil (5-FU) and cisplatin and/or radiation therapy.434 It may
drastically affect cancer treatment as well as the patient’s QOL. The
incidence and severity of mucositis has both interpatient and treatment
variability. It is estimated that there is 40% incidence of mucositis in

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patients treated with standard chemotherapy, and this will increase not
only with the number of treatment cycles but also with previous
episodes.435 Oral mucositis is one of the most frequent adverse effects of
allogenic or autologous hematopoietic stem cell transplant with 67% to
80% developing a severe grade of mucositis particularly with allogenic
transplants.436,437 The overall incidence of oral mucositis and xerostomia
is approximately 80% in patients with squamous cell carcinoma of the
head and neck who are treated with radiation therapy directed at the oral
and pharyngeal regions438 and is a frequent cause of treatment breaks.439
Oral mucositis is typically diagnosed based on the clinical appearance,
location, timing of oral lesions, and use of certain types of therapy known
to be associated with mucositis. Other common conditions can have a
similar clinical presentation to oral mucositis and may confuse the
differential diagnosis. They include oral candidiasis, herpes simplex virus,
and graft-versus-host disease (GVHD) in transplant patients.
Commonly used scales for the assessment of oral mucositis include
National Cancer Institute Common Toxicity Criteria Stomatitis and WHO
toxicity grading scale. The WHO oral toxicity scale is a relatively simple
assessment for oral mucositis with grades 3 and 4 considered as evidence
of severe mucositis (Table 42.26).

TABLE 42.26 Assessment Tools for Oral Mucositis

A. World Health Organization Oral Toxicity Scale
Grade Assessment
0 Normal oral mucosa
1 Soreness, erythema
2 Erythema ulcers; patient can swallow solid food.
3 Ulcers with extensive erythema; patient cannot swallow solid food.
4 Extensive mucositis; alimentation is not possible.
B. NCI CTC Stomatitis
Grade Assessment
0 No stomatitis
1 Painless ulcers, erythema, or mild soreness in the absence of lesions
2 Painful erythema, edema, or ulcers, but patient can swallow
3 Painful erythema, edema, or ulcers that prevent swallowing or necessitate hydration or
parenteral (or enteral) nutritional support
4 Severe ulceration that requires prophylactic intubation or results in documented
aspiration pneumonia

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NCI CTC, National Cancer Institute Common Toxicity Criteria.
Modified from Cella D, Pulliam J, Fuchs H, et al. Evaluation of pain associated with oral mucositis
during the acute period after administration of high-dose chemotherapy. Cancer 2003;98:406–
412.

GRAFT-VERSUS-HOST DISEASE
Indications for SCT include the treatment of many different malignant and
nonmalignant hematologic conditions, solid tumors, and metabolic and
autoimmune diseases. SCT may be autologous, syngeneic, or allogeneic
depending on whether the owner patient, another genetically identical or
nonidentical individual, donates the hematopoietic stem cells (of bone
marrow, peripheral blood, or cord blood origin) to reconstitute
hematopoiesis. After transplantation, donor-derived T cells, GVHD can
result in a range of issues from a mild skin rash to a life-threatening and, in
some instances, life-ending complication. GVHD primarily occurs in many
organs but most notably in the skin, lungs, gastrointestinal tract, liver,
eyes, mucosa, and musculoskeletal system. GVHD is an immune-mediated
reaction in which donor T cells recognize the host as antigenically foreign,
causing donor T cells to expand and attack host tissues. GVHD may be
acute or chronic based on the time of onset after SCT. Acute GVHD
typically occurs within 100 days after transplantation and classically
presents as erythema, maculopapular rash, nausea, vomiting, anorexia,
profuse diarrhea, ileus, or cholestatic liver disease. Clinical manifestations
of chronic GVHD nearly always present during the first year after
transplantation, but some cases develop many years after transplant.
Chronic GVHD may occur in 30% to 70% of allogenic hematopoietic cell
transplantation patients.440 Chronic GVHD is a syndrome of variable
clinical features resembling autoimmune and other immunologic disorders,
such as scleroderma, Sjögren’s syndrome, primary biliary cirrhosis,
wasting syndrome, bronchiolitis obliterans, immune cytopenias, and
chronic immunodeficiency. All parts of the eye may be affected, and
keratoconjunctivitis sicca is the most common presenting manifestation of
chronic ocular GVHD. Manifestations of chronic GVHD may be restricted
to a single organ or site or may be widespread, with profound impact on
QOL. Unlike the acute form of the disease that is mediated by direct
cytotoxic T-cell attack on host tissues, pathophysiology of chronic GVHD

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is significantly more complex and the mechanisms of dysregulated
adaptive and innate immune responses are poorly understood.441

Metastatic Epidural Spinal Cord Compression

MESCC is compression of the dural sac and its contents, spinal cord or
cauda equina, or both, by an extradural tumor mass. Because of a rich
vascular supply of the bone marrow and extensive lymphatic drainage, the
spine is a common site for metastatic disease and up to 40% of patient with
cancer developing spinal metastases and 10% to 20% progressing to
symptomatic cord compression.442 The vast majority of spinal metastases
in people with MESCC are found in the vertebral body with or without
extension into the posterior elements and also into paravertebral regions
and the epidural space; these metastases most commonly affect the
thoracic spine (70%), followed by the lumbar spine (20%), multiple spinal
regions (20% to 35%), and less commonly the cervical spine and
sacrum.443,444 MESCC is the most common neurologic complication of
cancer after brain metastases. MESCC usually occurs in patients with
disseminated disease but may present as an isolated finding in patients not
diagnosed with cancer. Even though the progression of nearly all types of
malignancies can be complicated by the occurrence of spinal cord
compression, the most common tumors arise from breast, lung, or prostate
cancer, followed by renal cell cancer, gastrointestinal, thyroid, sarcoma,
and lymphoreticular malignancies.445,446 Patients may present with
malignant epidural spinal cord compression without a known history of a
primary cancer.447 If left untreated, virtually 100% of patients will become
paraplegic. Although most patients with MESCC have limited survival, up
to one-third will survive beyond 1 year.448

MECHANISM
Most epidural spinal cord compression comes from a solid tumor
metastasis to the vertebral body, which spreads posteriorly to the epidural
space (observed in 85% to 90% of cases) and presents as an osteolytic
bony lesion in 70% of patients resulting in anterior compression of the
spinal cord. Other tumors such as lymphoma, paragangliomas, and

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neuroblastomas invade the epidural space through the intervertebral
foramina from the paravertebral tissues account for 10% to 15% of cases.
The frequency of metastasis appears to correlate with the volume of bone
in that region of the spine, presumably related to blood flow and blood-
borne metastasis. As such, the thoracic spine is most likely to have a
metastatic lesion due to its 12 vertebral bodies; the lumbosacral spine is
the next most likely to have involvement due to the large size of the
vertebral bodies, and the small cervical vertebral bodies are the least likely
to be affected. MESCC damages the cord by direct compression, which
causes demyelination and axonal damage, and by secondary vascular
compromise. The most significant damage caused by MESCC appears to
be vascular in nature. The epidural tumor causes epidural venous plexus
compression, which leads to spinal cord edema. The increased vascular
permeability and edema lead to increased pressure on the small arterioles.
Capillary blood flow diminishes as the disease progresses, leading to white
matter ischemia. Prolonged ischemia eventually results in infarction and
permanent cord damage. The early mechanism of injury is vasogenic
edema of white matter with direct involvement of cytokines, inflammatory
mediators, and neurotransmitters.449 Production of VEGF is associated
with spinal cord hypoxia and has been implicated as a potential
mechanism of damage after spinal cord injury.450 The beneficial effects of
dexamethasone in the CNS are at least partly meditated by its
downregulation of VEGF expression.451 In the later stages of MESCC,
vasogenic edema is replaced by ischemic-hypoxic neuronal injury and by
onset of cytotoxic edema, a transition associated with the glutamate system
that is characterized by release of presynaptic glutamate, influx of calcium
through N-methyl-D-aspartate (NMDA)-linked ion channels, excitotoxic
neuronal injury, and neuronal disintegration.452

PATTERN OF PAIN
The pattern of pain associated with epidural metastases may be local,
radicular, referred, or funicular. The majority of patients have local pain.
Local pain over the involved vertebral body, which results from
involvement of the vertebral periosteum, is dull and exacerbated by
recumbency. The worsening of pain on recumbency is the most distinctive

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feature of the pain of epidural spinal cord compression. Many patients with
cord compression find they must sleep in a sitting position. Even if pain is
absent in the lying position, movements such as turning over in bed or
rising from a lying position may be particularly painful.
Radicular pain from compressed or damaged nerve roots is usually
unilateral in the cervical and lumbosacral regions and bilateral in the
thorax, where patients often describe it as a tight band across the chest or
abdomen. The pain is experienced in the overlying spine, deep in certain
muscles supplied by the compressed root, and in the cutaneous distribution
of the injured root. The pain is usually least severe when the patient is in a
position that minimizes compression of the root and most severe in
positions that compress or stretch the root. Increasing
intraspinal/intracranial pressure, for example, coughing, sneezing, and
straining, can also increase pain.
Referred pain in the midscapular region or in both shoulders may
accompany cervicothoracic epidural disease, and bilateral SI and iliac crest
pain occurs with L1 vertebral compression. The pain has a deep aching
quality and is often associated with tenderness of subcutaneous tissues and
muscles at the site of referral. Maneuvers that affect local pain usually
have the same effect on referred pain. When pain is referred from
pathologic processes in the low back, it is usually appreciated in the
buttocks and posterior thighs. Pain from the upper lumbar spine is often
referred to the flank, groin, and anterior thigh.
Funicular pain may be an early complaint in patients with cord
compression and presumably results from compression of the ascending
sensory tracts in the spinal cord. It usually occurs some distance below the
site of compression and has hot or cold qualities in a poorly localized
nondermatomal distribution. The pain is less sharp than radicular pain but
like root pain is usually exacerbated by movements that stretch the
compressed structure (neck flexion, straight leg raising) or that increase
intraspinal pressure (coughing, sneezing, straining). Funicular pain may be
experienced some distance from the site of compression. Patients with
cervical cord compression may present with lower extremity pain only453
or sciatica-type symptoms with cervical or thoracic cord
compression.454,455

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PRESENTATION AND PHYSICAL FINDINGS
The vast majority of patients have a known cancer diagnosis. Even without
a prior cancer diagnosis, MESCC should be suspected in anyone who
presents with progressively worsening back pain, incontinence, or
paraplegia, especially in the high-risk population such as long-time
smokers or women with a strong family history of breast cancer. The
clinical picture of MESCC is uniformly reported as various combinations
of pain, weakness, sensory loss, and autonomic dysfunction. Table 42.27
summarizes the signs of spinal cord compression.

TABLE 42.27 Signs of Spinal Compression

Sign/Deficit Spinal Cord Conus Medullaris Cauda Equina
Weakness Symmetrical, Symmetrical, variable Decreased
profound
Deep tendon reflexes Increased or absent Increased knee, Decreased
decreased ankle
Plantar response Extensor Extensor Plantar
Sensory Symmetric sensory Symmetric saddle Asymmetric, radicular
level
Sphincters Late onset Early onset Spared
Progression Rapid Variable Variable

Severe, local back pain that gradually increases in intensity over time is
the earliest and most common symptom. In general, pain occurs an
average of 7 weeks before other neurologic deficits.456 As the bone
marrow does not contain pain receptors, discomfort usually occurs only
when the enlarging mass invades the periosteum, paravertebral soft tissues,
or nerves. Pain may also be caused by the mass effect of the spinal cord
compression itself, spinal instability, pathologic fracture, and the
inflammatory and nociceptor stimulating substances that malignant cells
secrete. Progressive pain occurs practically always in patients with
MESCC. Weakness is the second most common symptom, which develops
in approximately 60% to 80% of patients.456 As the thoracic cord is the
most common site of epidural metastases, weakness usually involves the
lower limbs causing gait disorders. Gait difficulties may also be caused by
sensory ataxia presumably due to posterior column compression. Certain
spinal tracts appear to be more vulnerable to compression than others.457

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The corticospinal tracts and posterior columns are particularly vulnerable,
the spinothalamic tracts and descending autonomic fibers less so. As a
result, weakness, spasticity, and reflex hyperactivity tend to be the earliest
signs of spinal cord compression, with paresthesias and vibratory and
position sense loss occurring soon thereafter. Loss of pain and temperature
sensation and of bladder and bowel function usually occur late in the
course of spinal cord compression. The spinocerebellar pathways are also
sensitive to compression, and at times, ataxia may be the only sign of
spinal cord compression. Sensory symptoms are less common and may
predate objective sensory signs. Patients may complain of paresthesias,
decreased sensation, and numbness of the toes and fingers which may
extend one to five dermatomes below the true level of cord compression.
Cauda equina syndrome may occur when the site of the lesion is below the
first lumbar vertebra. The main clinical signs are decreased sensation over
the buttocks, posterior thighs, and perineal region in a saddle distribution,
with most patients exhibiting decreased anal sphincter tone on
examination. Urinary retention with overflow incontinence can be an
important predictor.458
Ventafridda et al.459 reported an association between Lhermitte’s sign
and epidural spinal cord compression. In their series, the sign appeared at
an early stage of compression, particularly with thoracic lesions but may
also be seen with cervical MESCC. Lhermitte’s sign, however, lacks
specificity and also occurs in patients with radiation myelopathy,460
following cisplatin461 or oxaliplatin462 chemotherapy, and in noncancer-
related problems such as multiple sclerosis463 and subacute combined
degeneration of the cord from vitamin B12 deficiency.464
Differential diagnosis for the individual patient with back pain includes
intramedullary metastases, herniated disks, epidural hematoma or abscess,
transverse myelopathy, and subluxation of the spine from pathologic
fractures.

INVESTIGATIONS
Definitive diagnosis of MESCC is by radiographic investigation. Bone
scan is an effective screening procedure of vertebral involvement, but
definitive diagnosis is by MRI. MRI not only demonstrates the extent of

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epidural involvement but also allows visualization of the degree of
involvement of bony structures and surrounding tissues. Epidural
metastases are best visualized with postcontrast imaging, which allows
clear delineation of the border of the metastasis in most cases.465

PROGNOSIS
MESCC is associated with reduced life expectancy and QOL.452 Outcome
of MESCC can be paraplegia or paraparesis. Without treatment, all
patients would develop paraplegia and survival rates for nonambulatory
patients are lower than for ambulatory patients.466 Treatments for MESCC
are intended to maintain or improve QOL by alleviating pain, preserving
neurologic function, and assuring spinal stability. The most predictive
factors for survival are primary tumor site and pretreatment neurologic and
functional status.467 The time lapse between diagnosis of the primary
cancer and first symptoms of MESCC directly correlated with survival
(e.g., a long interval denoted higher survival rate and vice versa). The most
important prognostic indicator for the prediction of ambulatory outcome is
a patient’s pretreatment motor function.467,468 The median survival time
for patients with MESCC is 3 to 6 months.469,470 Factors associated with
longer survival times are the ability to walk before and after
treatment,467,469,471 radiosensitive tumor histologies,469,472,473 no visceral
or brain metastases,469,474 and a single site of epidural cord compression
rather than more than one site.475 Survival is also related to the systemic
spread of the neoplastic disease. The presence of multiple spinal epidural
metastases (around 25% to 40% of patients) has been reported as an
independent prognostic factor for poorer survival.476

Stepwise Approach to Pain Assessment

Assessing cancer pain is more than quantifying pain with a tool and
recording it. A stepwise approach to cancer pain assessment begins with
data collection and ends with a clinically relevant diagnosis, which will
require a thorough understanding of the various components contributing
to the pain complaint. At a minimum, this involves determining the
etiology of the pain and forecasting its future trajectory. It also involves

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determining the number of sites from which pain originates and the
probable mechanisms involved. Assessment must include evaluation of the
impact of pain on sleep, functional capability, activity level, and
psychological well-being. In addition, the clinician must determine the
nature, course, and impact of the cancer on the patient. This is an imposing
challenge because of the multiple causes of cancer and its impact on the
patient. The clinician managing the patient’s pain complaint must have an
understanding of the disease process and the management strategy for that
disease. A thorough evaluation will allow the clinician to obtain a basis for
evaluating therapeutic intervention and determining the long-term goals of
the patient and/or the patient’s family.
The goals of the pain-related history are listed in Table 42.28. Optimal
assessment includes a detailed description of these goals and classification
by both pain syndrome and likely underlying mechanisms (see the
following discussion).

TABLE 42.28 Goals of the Pain-Related History

Define the pain characteristics
Outline the anatomical extent of the disease
Determine responses to previous disease-modifying and analgesic therapies
Anticipate response to planned disease therapies
Clarify the impact of the pain on activity of daily living, psychological state, familial, vocational,
and social function
Determine the presence of associated symptoms that may modify the perception of pain

FEATURES OF PAIN HISTORY

Table 42.29 lists the key components to assessing the characteristics of the
pain complaint.

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 TABLE 42.29 Key Components of Pain Characteristics
Onset
Location
Intensity
Character/quality
Timing
Exacerbating/relieving factors
Response to previous analgesic and disease-modifying therapies
Impact of pain
Effect of pain on activities of daily living
Psychological state
Familial, vocational, social function

Onset
The onset of tumor-associated pain frequently correlates to the diagnosis
of cancer. Preexisting chronic pain complaints need to be differentiated
from tumor-associated pain and defined accurately. In cancer survivors,
the onset of new pain may indicate the possibility of disease recurrence.477

Location
Many patients with advanced disease have multiple pains at different sites.
Pain of tumor origin may be characterized by its location. For example,
somatic pain resulting from bone metastases tends to be well localized,
whereas visceral pain tends to be diffuse and is often referred. Neuropathic
pain may be radicular in location.

Intensity
Numerous professional bodies recommend regular assessment of pain
intensity in cancer patients.478–482 These recommendations urge clinicians
teach patients and families to use assessment tools in the home to promote
continuity of pain management in all settings. Assessment tools for
determining the intensity of pain are discussed previously.

Quality
Tumor-associated pain can be nociceptive (somatic or visceral structures)
or neuropathic in origin. Each source of pain has distinguishing qualities.

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For example, patients tend to describe pain that is neuropathic in origin as
burning, shock-like, or shooting in quality, whereas they often describe
pain originating from somatic structures as aching, nagging, throbbing, or
sharp.

Timing
Cancer patients may have constant or intermittent pain. Constant pain is
present continuously and usually fluctuates in intensity. Intermittent pain
implies that pain is present for definite periods of time and that the patient
is relatively pain free between episodes of pain. Patients and their
caregivers need to understand the concept of BTP, as should health care
providers. BTP is discussed previously.

Exacerbating/Relieving Factors
Cancer patients with pain may experience a worsening of their pain over a
wide range of activities. Commonly, patients with metastatic disease to
weight-bearing bones experience an increase of their pain upon standing or
sitting. Patients with breast cancer metastatic to the axillary nodes may
have severe pain upon abduction of their upper extremity on positioning
for external beam radiation therapy. Knowledge of these factors helps
clinicians to design an appropriate pain treatment plan.

Responses to Previous Analgesic and Disease-Modifying

Therapies
It is important to determine previous opioid use and benefits or side effects
encountered during use. Previous unacceptable side effects to a particular
opioid may limit successful future titration with the same opioid.
Successful tumor shrinkage to chemotherapy or radiation therapy may
indicate the need for further evaluation on tumor recurrence.

Impact of Pain
The initial pain assessment should elicit information about changes in
activities of daily living, such as work and recreational activities, sleep
patterns, mobility, appetite, sexual functioning, and mood. Numerous
instruments, including symptom checklists and QOL measures may prove

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useful in this evaluation and are detailed in Chapter 22.

Effects of Pain on Activities of Daily Living

Many patients function quite effectively with a background level of mild
pain that does not seriously impair or distract them.122 As pain severity
increases, the pain passes a threshold beyond which it is hard to ignore. At
this point, it becomes disruptive to many aspects of the patient’s life.
Constant daily pain can significantly impact on a patient’s daily activities.
Williamson and Schulz483 showed that as pain increased over time,
restriction in activity occurred, which in turn predicted increases in
depressed affect. General measures of functioning should include
indicators of physical, psychological, social functional status, and, when
appropriate, vocational status. Some impact factors may include
interference on general activity, mood, walking, ability to work, relations
with others, and sleep. The Pain Disability Index was developed as a self-
report measure of general and domain-specific, pain-related disability and
is considered to be reliable and valid as a brief measure of pain-related
disability (Table 42.30).484

TABLE 42.30 Pain Disability Index

The rating scales below are to measure the degree to which several aspects of your life are
presently disrupted due to chronic pain. In other words, we would like to know how much your
pain is preventing you from doing what you would normally do, or from doing it as well as
you normally would. Respond to each category by indicating the overall impact of pain in your
life, not just when the pain is at its worst.
For each of the seven categories of life activity listed, please circle the number on the scale,
which describes the level of disability you typically experience. A score of 0 means no
disability at all, and a score of 10 signifies that all of the activities in which you would
normally be involved have been totally disrupted or prevented by your pain.
1. Family/home responsibilities
This category refers to activities related to the home or family. It includes chores or duties
performed around the house (e.g., yard work) and errands or favors for other family
members (e.g., driving the children to school).
0 1 2 3 4 5 6 7 8 9 10
no disability total disability
2. Recreation
This category includes hobbies, sports, and other similar leisure time activities.
0 1 2 3 4 5 6 7 8 9 10
no disability total disability
3. Social activity

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 This category refers to activities which involve participation with friends and acquaintances
other than family members. It includes parties, theater, concerts, dining out, and other
social functions.
0 1 2 3 4 5 6 7 8 9 10
no disability total disability
4. Occupation
This category refers to activities that are a part of or directly related to one’s job. This
includes nonpaying jobs as well, such as that of a housewife or volunteer worker.
0 1 2 3 4 5 6 7 8 9 10
no disability total disability
5. Sexual behavior
This category refers to the frequency and quality of one’s sex life.
0 1 2 3 4 5 6 7 8 9 10
no disability total disability
6. Self-care
This category includes activities which involve personal maintenance and independent daily
living (e.g., taking a shower, driving, getting dressed, etc.).
0 1 2 3 4 5 6 7 8 9 10
no disability total disability
7. Life-support activity
This category refers to basic life-supporting behaviors such as eating, sleeping, and
breathing.
0 1 2 3 4 5 6 7 8 9 10
no disability total disability
Reprinted with permission from Tait RC, Chibnall JT, Krause S. The Pain Disability Index:
psychometric properties. Pain 1990;40(2):171–182.

Multiple clinical and physiologic factors influence prognosis for patients

with advanced cancer. These include symptoms such as anorexia, dyspnea,
and fatigue; disease characteristics such as cancer diagnosis, site of
metastasis, and comorbidity; laboratory values such as hypoalbuminemia,
leukocytosis, and anemia; the clinician’s overall prediction of survival; and
performance status.485 Performance status represents a global assessment
of the patient’s level of function. Assessment of performance status is used
routinely in oncology and may be used to assess eligibility for clinical
trials, determine level of fitness to receive chemotherapy, and follow
treatment response. Performance status tables (Tables 42.20 and 42.31)
can help the physician assess physical activity levels.486,487

TABLE 42.31 Eastern Cooperative Oncology Group Performance

Status

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 Grade Performance Level
0 Fully active, able to carry on all predisease performance without restriction
1 Restricted in physically strenuous activity but ambulatory and able to carry out work
of a light or sedentary nature (e.g., light housework, office work)
2 Ambulatory and capable of all self-care but unable to carry out any work activities; up
and about more than 50% of waking hours
3 Capable of only limited self-care, confined to bed or chair more than 50% of waking
hours
4 Completely disabled; cannot carry on any self-care; totally confined to bed or chair
5 Dead

Psychological State
Psychological assessment of the cancer patient with pain is imperative and
should reflect an understanding of the many factors that modulate distress,
such as personality, coping, and both past and present psychiatric
disorders. Knowing that the patient has received outpatient or inpatient
psychiatric care helps to clarify the psychological risk. Information on how
the patient handled previous painful events may provide insight into
whether the patient has demonstrated chronic illness behavior.

Familial, Vocational, Social Function

The clinician must inquire about the patient’s familial and social resources,
financial situation, and the physical environment in which he or she lives.
Knowledge of the patient’s and family’s previous experience with cancer,
or other progressive medical disease, may provide useful insights into the
response to physical illness or the genesis of psychological symptoms.
Inquiry into a family history of addiction is helpful to define risk for pain
management strategies.488,489 Yellen and Cella490 demonstrated that
positive social well-being, as well as having children living at home,
predicted patient willingness to accept aggressive treatment.

QUALITY OF LIFE ASSESSMENT

Prolongation of survival and maintenance or improvement of health-
related QOL is the two important goals within the treatment of individual
patients. Due to the severity of symptoms and the toxicity of treatment,
QOL is a major area of concern when treating cancer patients in general
and elderly patients in particular.491–493 QOL is defined as the person’s

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evaluation of his or her well-being and functioning in different life
domains. It is a subjective, phenomenologic, multidimensional, dynamic,
evaluative, and yet quantifiable construct. The routine assessment of QOL
may have clinical uses at the individual patient level. These uses include
fostering patient–provider communication, identifying frequently
overlooked problems, prioritizing problems, and evaluating the impact of
palliative and rehabilitative efforts. QOL is sensitive to the treatment of
pain and treatment modalities, although pain is not synonymous with poor
QOL and constitutes only one important factor determining QOL. In
addition, pain reduction is not always attended by the expected
improvement in QOL. The Functional Assessment of Cancer Therapy:
General (FACT-G) was first developed in 1987 for adult cancer patients
and has become one of the most widely used health-related QOL measures
in clinical trials and other medical treatment evaluation studies. It has also
been validated in thousands of patients of different cancer types.494–496
FACT-G is self-reported and consists of questions on physical, functional,
emotional, and social/family well-being. Patient responses are recorded on
a 5-point Likert-type scale (Table 42.32)

TABLE 42.32 Functional Assessment Cancer Therapy: General

Version 4
Below is a list of statements that other people with your illness have said are important.
Please circle or mark one number per line to indicate your response as it applies to the past 7
days.
Not A
at Little Quite Very
Physical Well-being All Bit Somewhat a Bit Much
GP1 I have a lack of energy. 0 1 2 3 4
GP2 I have nausea. 0 1 2 3 4
GP3 Because of my physical condition, I have 0 1 2 3 4
trouble meeting the needs of my family.
GP4 I have pain. 0 1 2 3 4
GP5 I am bothered by side effects of treatment. 0 1 2 3 4
GP6 I feel ill. 0 1 2 3 4
GP7 I am forced to spend time in bed. 0 1 2 3 4
Not A
at Little Quite Very
Social/Family Well-being All Bit Somewhat a Bit Much
GS1 I feel close to my friends. 0 1 2 3 4

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GS2 I get emotional support from my family. 0 1 2 3 4
GS3 I get support from my friends. 0 1 2 3 4
GS4 My family has accepted my illness. 0 1 2 3 4
GS5 I am satisfied with family communication 0 1 2 3 4
about my illness.
GS6 I feel close to my partner (or the person who 0 1 2 3 4
is my main support).
Q1 Regardless of your current level of sexual
activity, please answer the following
question. If you prefer not to answer it,
please mark this box and go to the next
section.
GS7 I am satisfied with my sex life. 0 1 2 3 4
Not A
at Little Quite Very
Emotional Well-being All Bit Somewhat a Bit Much
GE1 I feel sad. 0 1 2 3 4
GE2 I am satisfied with how I am coping with my 0 1 2 3 4
illness.
GE3 I am losing hope in the fight against my 0 1 2 3 4
illness.
GE4 I feel nervous. 0 1 2 3 4
GE5 I worry about dying. 0 1 2 3 4
GE6 I worry that my condition will get worse. 0 1 2 3 4
Not A
at Little Quite Very
Functional Well-being All Bit Somewhat a Bit Much
GF1 I am able to work (include work at home). 0 1 2 3 4
GF2 My work (include work at home) is 0 1 2 3 4
fulfilling.
GF3 I am able to enjoy life. 0 1 2 3 4
GF4 I have accepted my illness. 0 1 2 3 4
GF5 I am sleeping well. 0 1 2 3 4
GF6 I am enjoying the things I usually do for fun. 0 1 2 3 4
GF7 I am content with the quality of my life right 0 1 2 3 4
now.
Copyright © 1987, 1997. Reprinted with permission, www.FACIT.org.

GENERAL ASSESSMENT
The initial step in the general assessment of the cancer patient is a
complete medical history that reviews the cancer diagnosis; the
chronology of significant cancer-related events; previous therapies; and all
relevant medical, surgical, and psychiatric problems (Table 42.33). A

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detailed history of drug therapy should include current and prior use of
prescription and nonprescription drugs, drug allergies/adverse drug
reactions, including current side effects. The clinician should inquire about
prior treatment modalities for pain. In the course of this assessment, the
interviewer should document the patient’s understanding of his or her
current disease status. Discussion with other providers involved with the
patient’s care will also help determine disease status. Table 42.34 lists the
different possible categories for a patient’s clinical status. Because of the
high use of opioids and other psychoactive substances in oncology care, a
risk assessment for opioid use should be performed. Opioid use risk
assessment tools generally are designed to detect opioid misuse prior to
initiating long-term opioid therapy, detection of signs of misuse in patient
currently using opioids, and general substance (e.g., alcohol) or illicit
substance abuse (Table 42.35).

TABLE 42.33 Components of Medical History: Cancer History,

Medications, Past Medical History, and Psychosocial Factors
Current Medications Psychosocial/Addiction
Cancer History Medical History Issues
Diagnosis and time of diagnosis Previous medical and Family history of
surgical illness addiction; includes
including illnesses personal history or
that may complicate current use of substance
pain management abuse (with alcohol use)
(e.g., sleep apnea,
pulmonary
hypertension)
Chronology of disease Concurrent medical Social resources and
conditions support
Therapeutic interventions including Drug allergies/adverse Impact of disease and
surgeries and treatments (particularly drug reactions symptoms on patient
chemotherapy and radiation therapy) and family
Current clinical status including extent Risk assessment for Patient’s and family’s
of disease (detailed imaging review) opioid use goals of care
Anticipated clinical course Review of systems Vocational status and
issues

TABLE 42.34 Clinical Status of Patients Defined by Disease State

and Treatment Strategy
Category Status

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 I Active disease; care—palliative and supportive only
II Active disease; treatment (e.g., chemotherapy, radiation therapy) in
progress
III Active disease, no current treatment, surveillance of tumor status
IV No active disease; treatment of tumor in progress
V No active disease; no current treatment, surveillance of tumor status
VI No active disease; no current treatment, specialized care (e.g., medical
oncology) not required

TABLE 42.35 Examples of Screening Tools for Assessment of

Opioid Risk
Time of
Tool Administration Completed By
Opioid Risk Tool (ORT) (Webster and Webster, Preinitiation of Clinician
2005506) opioid therapy
Screener and Opioid Assessment for Patients with Preinitiation of Patient
Pain (SOAPP) (Butler et al., 2004507) opioid therapy
Diagnosis, Intractability, Risk, and Efficacy Score Preinitiation of Clinician
(DIRE) (Belgrade et al., 2006508) opioid therapy
Current Opioid Misuse Measure (COMM) (Butler, Monthly during Patient
2007509) opioid therapy
Alcohol Use Disorders Identification Test: Preinitiation of Patient
Consumption (AUDIT-C) (Bush et al., 1998510) opioid therapy
Cut Down, Annoyed, Guilty, Eye-Opener Tool Preinitiation of Clinician
(CAGE) (Brown and Rounds, 1995511) opioid therapy

A physical examination, including a neurologic evaluation, is a

necessary part of the initial pain assessment (see the following text). A
careful review of previous laboratory and imaging studies can provide
information about the cause of pain and the extent of the underlying
disease (see the following text). Evaluation of concurrent concerns
includes other symptoms and related psychosocial problems. Additional
investigations are often needed to clarify uncertainties in the provisional
assessment. The extent of these investigations must be appropriate to the
patient’s general status and the overall goals of care (Table 42.36). In the
case of the patient illustrated in Table 42.36, monitoring of the patient’s
disease status required specialized testing over a period of time.

TABLE 42.36 Patient with Chronic Myeloid Leukemia

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 Abnormal Fluorescence In Situ Hybridization Result:
Date BCR/ABL1 Rearrangement
January 19, 2016 82%
January 25, 2016 67%
February 15, 2016 62.5%
March 2, 2016 73%
March 30, 2016 32%
April 15, 2016 16.5%
May 11, 2016 2.1%
June 29, 2016 0.5%
July 25, 2016 No evidence
September 28, 2016 No evidence
October 4, 2016 No evidence
November 23, 2016 No evidence
January 27, 2017 No evidence
NOTE: Patients with chronic myeloid leukemia have BCR-ABL gene (a.k.a. the Philadelphia
chromosome). The Philadelphia chromosome produces the BCR-ABL gene that signals the bone
marrow to continue making abnormal white blood cells. Polymerase chain reaction (PCR) is used
to detect and sometimes to quantify this gene. The clinical BCR-ABL assays for both p210 and
p190 previously showed undetectable transcripts for both assays. The patient was then identified
as having a rare e13/e14-a3 (also known as b2/b3-a3) transcript that is not detectable by. This
transcript cannot be detected using commercially available quantitative PCR assays 9 standard
P210 or P190 assays and requires a special qualitative assay to detect it. In this case, disease is
monitored by BCR-ABL fluorescence in situ hybridization and qualitative PCR that detects rare
variants. Over time, the patient went into complete remission after treatment with bosutinib.

ASSOCIATED SYMPTOMS
Cancer patients may experience multiple symptoms with symptoms
varying by type of treatment, gender, age, and cancer type. Cancer
treatment and survivorship can result in multiple concurrent symptoms
resulting in cognitive dysfunction, fatigue, insomnia, pain, dyspnea,
appetite loss, constipation, diarrhea, nausea, and vomiting.497,498 Some
data suggest that fatigue, cognitive limitations, depression, anxiety, sleep
problems, pain, and sexual difficulties persist, for up to 10 years after
treatment, regardless of cancer type.499 Not surprisingly, cancer patients
have a much greater symptom burden completed to a noncancer general
medical population.500 Symptoms can affect pain management, and it is
important to clarify the degree to which each symptom induces or
exacerbates other physical or psychological symptoms. The evaluation
should determine whether symptoms are concurrent but unrelated in
etiology, concurrent and related to the same pathologic process, concurrent

2148
with the one symptom directly or indirectly a consequence of a pathologic
process initiated by another symptom, or concurrent with one symptom a
consequence or side effect of therapy directed against the other. Fatigue
may be the most prevalent symptom reported by cancer patients with one
study suggesting that 45% of patients undergoing active treatment and
29% of survivors have moderate to severe levels of fatigue.500 Disease
progression increases the number of factors diminishing QOL as well as
the prevalence and severity of physical and psychological symptoms. In
addition to pain, patients with advanced cancer have fatigue, generalized
weakness, dyspnea, delirium, nausea, and vomiting. These symptoms may
have a major impact on both pain reporting and QOL. The Memorial
Symptom Assessment Scale (MSAS) is a patient-rated instrument that was
developed to provide multidimensional information about a diverse group
of common symptoms.501 The MSAS is a reliable and valid instrument for
the assessment of symptom prevalence, characteristics, and distress.

LABORATORY AND IMAGING DATA

Careful review of previous laboratory and imaging studies can provide
important additional information. Specific radiologic or laboratory tests
may help the clinician understand the pathophysiology of symptoms and
their relationships to the disease. This information provides the basis for a
provisional pain diagnosis that clarifies both the status of the disease and
the nature of other concurrent concerns that may require therapeutic focus.
Some patients require multiple studies to evaluate the pain problem,
clarify extent of disease, or to assess other symptoms. Assistance from
physicians in other disciplines, nurses, social workers, psychologists, or
others may prove necessary to evaluate related physical or psychosocial
problems identified during the initial assessment. It is appropriate and
useful to review the findings of this evaluation with the patient, family,
and other appropriate persons, so that they can prioritize problems
according to their importance for the patient. It is also useful to identify
potential outcomes that would benefit from contingency planning,
including the need for advanced medical directives, the evaluation of home
care resources, and prebereavement interventions with the family.

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PHYSICAL EXAMINATION
A physical examination, including a neurologic and musculoskeletal
examination, is a necessary part of the initial pain assessment. The need
for a thorough neurologic assessment is justified by the high prevalence of
painful neurologic conditions in the cancer population.502 The physical
examination should clarify the underlying causes of the pain problem,
detail the extent of the underlying disease, and discern the relation of the
pain complaint to the disease. The examination should also help define
biomechanical problems that impair or impede function.

DIAGNOSIS
The provisional pain diagnosis includes inferences about the
pathophysiology of the pain and an assessment of the pain syndrome.
Evaluation of concurrent concerns includes other symptoms and related
psychosocial problems. Additional investigations can often clarify
uncertainties in the provisional assessment. Accuracy in pain diagnosis
results in appropriate and disease-directed pain management.

Summary
Cancer is one of the medical conditions that patients fear the most. In
addition to anxiety about cancer as a potentially lethal disease, patient and
family expectancies that pain is an inevitable and untreatable consequence
are major sources of distress. Controlling pain associated with cancer is a
major health care problem. Lack of expertise by clinicians in assessing
pain is an important cause of poor pain control. A stepwise approach to
cancer pain assessment begins with a systematic clinical interview and
ends with a clinically relevant diagnosis that outlines the mechanisms and
contributing factors to the pain complaint. It involves determining the
etiology of the pain and forecasting its future trajectory. It also involves
determining the number of sites from which pain originates and the
probable mechanisms involved. Assessment must include evaluation of the
impact of pain on sleep, functional capability, activity level, and
psychological well-being. In addition, the clinician must determine the
nature, course, and impact of the cancer on the patient. A thorough

2150
evaluation will allow the clinician to obtain a basis for evaluating
therapeutic intervention and determining the long-term goals of the patient
and/or the patient’s family.
As many different health care professionals become involved with the
cancer pain patient before, during, and after cancer care, successful pain
management requires that the person or persons responsible for pain
management adopt, or at least, become familiar with an interdisciplinary
longitudinal approach to care. Pain management should never assume the
primary focus of oncology care but should be an important supportive
service throughout the care paradigm.

*Lasègue test (straight leg maneuver) is performed when the clinician lifts the extended leg of a
patient in a supine position. A positive response occurs when the pain pattern of the lumbar
radiculopathy is reproduced. The test should be stopped when the pain is reproduced or maximum
flexion is achieved. The crossed straight leg maneuver is performed by raising the unaffected leg in
a similar manner to the straight leg test. The examiner looks for the reproduction of radicular pain
with elevation of the opposite leg.
†Spurling test requires the examiner to patient extends the neck and rotates and laterally bends the
head toward the symptomatic side; an axial compression force is then applied by the examiner
through the top of the patient’s head; the test is considered positive when the maneuver elicits the
typical radicular arm pain.
‡Short, unpleasant sensation of numbness, tingling, and often electric-like discharge going down
from the neck to the spine and extremities, triggered by neck flexion.
**Brown-Séquard syndrome results in ipsilateral pyramidal deficit and posterior column signs and,
contralaterally, loss of spinothalamic function.
††Myokymia represents spontaneous discharges accompanied by wavelike muscle quivering.
‡‡An abnormality in peripheral nerve function resulting in degeneration of the terminal regions of
sensory axons and also to motor axons.
***The result of direct toxic damage of neuronal cells in the DRG.

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CHAPTER 43
Cancer Pain: Principles of
Management and
Pharmacotherapy
DERMOT FITZGIBBON

In 2008, the International Association for the Study of Pain (IASP)

launched a global year against cancer pain to focus attention on the pain
and suffering affecting patients with cancer. In 2011, the Institute of
Medicine1 recognized chronic noncancer pain management as a public
health challenge. In spite of increased attention on assessment and
management, pain continues to be a prevalent symptom in patients with
cancer.2 The consequences of unrelieved cancer pain can be devastating
and include functional impairment, social isolation, and emotional distress.
Inadequate treatment of cancer pain persists despite decades of efforts to
provide clinicians with information about analgesics and pain-relieving
techniques. The problems associated with undertreatment of cancer pain
are outlined in Table 43.1. Although the reasons for inadequate treatment
of cancer pain are complex, certain barriers to adequate pain relief are
identified. These barriers primarily relate to health care professionals;
patients, families, and the public; health care implementation and
reimbursement; and drug regulatory systems.3

TABLE 43.1 Factors Contributing to Undertreatment of Cancer

Pain in United States
Factor Reason
Patient-related Pain underreporting:
Fear of disease progression
Perceived lack of time or inadequate amount of time spent in
physician’s office discussing pain problems
Poor compliance with prescribed medications
Fear of addiction

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 Fatalistic beliefs about cancer pain
Physician-related Legal issues regarding overprescription or perceived
overprescription of opioids
Difficulty/inadequate training for pain complaints assessment
Lack of information or lack of expertise on contemporary
strategies for cancer pain management
Desire to provide the patient with the latest and greatest pain
management strategies may pose difficulties with untried or
unproven techniques or methods.

Cancer pain management guidelines typically incorporate

pharmacologic, anesthetic, neurosurgical, and behavioral approaches. The
World Health Organization (WHO) developed the most widely accepted
approach for the treatment of cancer pain. The WHO algorithm largely
focuses on pain intensity and the use of pharmacotherapy.4 Some have
questioned the current appropriateness of the WHO guidelines, which may
be considered outdated and not specific to the pharmacologic and
interventional options used in contemporary pain management practices.5
Although the amount and quality of evidence regarding the use of opioids
for treating cancer pain is low,6 opioid therapy remains the cornerstone for
pain management in oncology.7–12 In the United States, physicians’
concerns about regulatory scrutiny and the possibility of unwarranted
investigation by regulatory agencies negatively affect their prescribing of
opioid analgesics to treat pain.13 In addition, it is widely reported that the
United States is experiencing an epidemic of drug overdose deaths
particularly from the use of opioid medications.14–17 The past two decades
have been characterized by increasing abuse and diversion of prescription
drugs, including opioid medications (see “Substance Abuse in Oncology”
section).18 In a study of malpractice claims associated with medication
management for chronic pain, issues in care (including death) were noted
when patients did not cooperate in their care and with inappropriate
medication management by physicians.19 Factors associated with death in
this study included the use of long-acting opioids, additional concomitant
psychoactive medications, and the presence of three or more factors
commonly associated with medication misuse. In 2016, the U.S. Drug
Enforcement Administration indicated that prescription drugs, heroin, and
fentanyl were the most significant drug-related threats to the United
States.15 The misuse of prescription opioids is associated with misuse of

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illicit opioids and nonmedical use of prescription opioids is a significant
risk factor for heroin use,20 emphasizing the need for continued prevention
efforts around prescription opioids. Regardless of age, gender, or type of
user, the majority who misuse prescription pain relievers obtained the
drugs from a friend or relative with the second most common source from
a doctor.21 Particularly for chronic noncancer pain, there is insufficient
evidence to determine the effectiveness of long-term opioid therapy for
improving pain and function, but there is increasing evidence to support
the evidence for a dose-dependent risk for serious harm.22 Higher opioid
doses (50 mg per day or more of morphine) are associated with increased
risk of opioid overdose death or adverse drug-related events.23,24 Although
the overall rate of overdose is lower among patients with cancer compared
with other patients, there was a statistically significant association of
prescribing patterns with overdose risk among patients with cancer
receiving opioid therapy.23 In response to persistent public health concerns
regarding prescription opioids, the U.S. Food and Drug Administration
(FDA) developed a multipart action plan in response to the opioid
epidemic,25 and many states and health care systems have implemented
legislation and policies intended to regulate or guide opioid prescribing.26
Unfortunately, data on state policy and systems-level interventions are
limited and inconsistent.27 Patients with cancer and other significant
comorbidities have a higher prevalence for polypharmacy and greater risk
for drug–drug interactions, adverse drug events, hospitalizations, and
increased mortality.28–31 Concurrent sedative-hypnotic use even at low
opioid doses poses substantially greater risk of opioid overdose.32,33 In
spite of these concerns, clinicians have an ethical and professional
responsibility for safe and appropriate pain management in cancer patients.
Pain management and relief can be achieved by several means (Table
43.2). Successful pain management requires an accurate diagnosis of the
etiology of the pain complaint(s) and tailoring treatment to the individual
patient: matching drug treatment, anesthetic, neurosurgical, psychological,
and behavioral approaches to the patient’s needs. Successful management
requires that the person or persons responsible for pain management be
familiar with all these aspects of care and with the uniqueness and
challenges of pain in oncology patients. Evidence-based medicine,

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systematic reviews, meta-analyses, and guidelines are increasingly
incorporated into modern pain management. Scientific data and relevant
evidence employing methodologic, rational judgments, analysis, and
understanding of current knowledge can then be applied in clinical
settings. In the areas of chronic noncancer and cancer-associated pain,
evidence-based decision making for pharmacotherapy is lacking and
decisions for pain management in oncology is frequently extrapolated or
inferred from chronic pain situations. Often, practitioners must rely on
clinical practice guidelines, limited clinical trial data, case reports, or
anecdotal information for clinical decision making. Clinical practice
guidelines are systematically developed statements that aim to help
physicians and patients reach the best health care decisions. Guidelines
and recommendations for management of cancer pain have largely focused
on relieving acute pain or pain associated with advanced disease.34–37 Not
all patients with cancer experience tumor-related pain, and management
principles differ depending on the source of pain and these
recommendations are not appropriate for oncology patients with
nonmalignant sources of pain or for pain management in cancer
survivors.38,39 However, pharmacotherapy remains the optimal and
preferred modality for symptomatic pain management in oncology, but
safe and effective drug prescribing practices must be observed and
implemented. Since 1986, the focus of cancer pain treatment has been the
use of strong opioids based on the WHO’s analgesic ladder. Changing
societal factors in the last 15 years suggest changes in the distribution of
drug use disorders in the general US adult population. Prescriptions for
opioid analgesics and other psychoactive medications with addiction
potential have increased greatly, with consequences such as drug
overdoses.40 Comparisons of 12-month and lifetime Diagnostic and
Statistical Manual of Mental Disorders (4th ed., DSM-IV) drug use
disorder prevalence in the general adult population in 2001 to 2002 (2.0%
and 10.3%, respectively)41 and 2012 to 2013 (4.1% and 15.6%,
respectively)42 indicate that rates of 12-month drug use disorders more
than doubled, whereas rates of lifetime drug use disorders increased by
50%. Using Diagnostic and Statistical Manual of Mental Disorders (5th
ed., DSM-5) criteria drug use in 2012 to 2013 disorder, prevalence of 12-

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month and lifetime drug use disorder were 3.9% and 9.9%, respectively.43
Drug use disorder was generally greater among men, white and Native
American individuals, younger and previously or never married adults, and
those with lower education and income. A lower prevalence of drug abuse
has been reported in the cancer population, with 3% of psychiatry
consultations in a single cancer center in 1990 being requested for
managing issues related to drug abuse.44 Similarly, a low prevalence of
drug abuse was reported by the Psychiatric Collaborative Oncology Group
study in 1983, in which fewer than 5% of patients in ambulatory care met
the criteria for a substance abuse disorder.45 This low prevalence may not
be an accurate reflection of the true prevalence because of underreporting.
The prevalence of substance abuse in cancer patients is largely
understudied and needs clarification. Patients with cancer are known to
have an increased risk of psychiatric symptoms and disorders,
cardiovascular diseases, and suicide.46–48 Living or being diagnosed with
cancer can induce severe psychological stress.49 In a retrospective review
of 204 supportive care clinic oncology patients (with the majority having
active cancer) considered to be at risk for substance abuse based on history
or behaviors, 46% had evidence of use of nonprescribed opioids,
benzodiazepines, or illicit drugs such as heroin or cocaine, and 39% had
inappropriately negative urine toxicology, raising concerns for diversion.50

TABLE 43.2 Approaches to Pain Management in Cancer Patients

Psychological approaches (Chapters 29, 75, Understanding
84, and 88) Companionship
Modification of pathologic process (Chapters Cognitive-behavioral therapies
48 and 103–105)
Radiation therapy
Hormone therapy
Chemotherapy
Surgery
Drugs (Chapters 77–81) Analgesics
Antidepressants
Anxiolytics
Neuroleptics
Interruption of pain pathways (Chapters 44, Local anesthetics
98, 102–105) Neurolytic agents
Neurosurgery
Modification of daily activities Functional improvements/structure

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 Immobilization Rest
Surgical collar or corset
Plastic splints or slings
Orthopedic surgery
Modified with permission from World Health Organization. Cancer Pain Relief with a Guide to
Opioid Availability. Geneva, Switzerland: World Health Organization; 1996.

Safe and appropriate medication prescribing practices are of paramount

importance in the oncology pain population. The challenges presented to
clinicians are numerous and include educational deficits, time restraints,
and limited access to all types of care. New challenges to access are
occurring as a result of interventions designed to combat the prescription
drug abuse epidemic, with fewer clinicians willing to prescribe opioids,
pharmacies reluctant to stock the medications, and payers placing strict
limits on reimbursement.39 In the era of personalized medicine, Hui and
Bruera51 suggested that pain management may be tailored to the individual
need by use of a personalized pain goal, and this can be obtained by asking
a patient to identify the maximal intensity of pain from 0 to 10 (0, no pain;
10, worst pain) that would still be considered comfortable. The concept is
a personalized pain goal is attractive but managing pain by pain scores can
be problematic,52–54 and more appropriate goals may be to identify a pain
management plan that results in a reduction in interference in activities of
daily living and improvement in quality of life and overall functional
ability.

Cancer Pain Management Overview

Successful management of the cancer patient with pain ultimately depends
on the ability of the clinician to accurately assess problems, identify and
evaluate the components that contribute to the pain complaint, and
formulate a plan for continuing care that is responsible for the evolving
goals and needs of the patient and the patient’s family (see Chapter 42). In
general, the goals of patient care in oncology are often complex, but they
broadly include prolonged survival, and optimizing comfort and function
with associated improved quality of life. Adoption of these goals logically
leads to a multimodality treatment approach targeted to specific problems
(Fig. 43.1).

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FIGURE 43.1 Multimodality therapeutic management of cancer pain. Others include psychosocial
interventions, nursing care, alternative pain management strategies, and end-of-life issues.

Comprehensive cancer care encompasses a continuum that progresses

from disease-oriented, curative, life-prolonging treatment through
symptom-oriented, supportive, and palliative care extending to terminal-
phase hospice care. Pain management is, and should be, an integral
component of comprehensive cancer care.55–59 Designing an effective pain
control strategy for the individual patient requires knowledge of the ways
in which a patient’s cancer, cancer therapy, and pain therapy can interact.
Collaboration with different health care providers (such as medical
oncologists and radiation oncologists) is essential to successful pain
management.
Two important aspects of cancer affect management and include the
oncologist’s ability to treat the cancer and the ability to assess the
components of the tumor pathophysiology that of themselves do not cause
pain (the cancer’s “nonpain” pathophysiology).60 The ability to treat
cancer modifies the need for pain management (successful treatment
reduces the likelihood of persistent tumor-related pain) and the
appropriateness of invasive pain procedures. Cancer nonpain
pathophysiology can interfere with the oral administration of medications,
narrow the patient’s therapeutic window for analgesic drugs, limit the
effectiveness of psychological pain therapies, and complicate or preclude
invasive pain-reducing procedures. In addition, cancer therapy can
interfere with, or enhance, pain therapy and vice versa. Antineoplastic
treatment can interfere with pain therapy by causing additional pain or by
producing other adverse effects such as fatigue and gastrointestinal (GI)

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disturbances. Cancer treatment can enhance pain therapy by reducing the
extent of tumor burden, by acting as an adjuvant analgesic, and, often
times, by providing intravenous access for parenteral drug administration
to patients who require it. Pain therapy can sometimes interfere with
cancer therapy by increasing or complicating the adverse effects of cancer
therapy, for example, opioid-related bowel dysfunction. It can enhance
cancer therapy by improving patient function or sense of well-being, and
certain palliative surgical procedures may have the ancillary effect of
improving organ function.
The basic principles of tumor-directed pain control include:
1. Modifying the source of pain by treating the cancer and the
inflammatory effects of cancer
2. Altering the central perception of pain, for example, by the use of
analgesics, antidepressants, anxiolytics, and psychotherapy
3. Interfering with nociceptive transmission outside of and within the
central nervous system (CNS), for example, with anesthetic
techniques (e.g., neurolytic celiac plexus block, neuraxial analgesia,
and spinal neurolysis) or neurosurgery procedures (e.g., cordotomy
and myelotomy)
The pain experienced by most cancer patients responds to direct and
indirect modification of the source of the pain combined with
pharmacologic and nonpharmacologic alteration of the central perception
of pain.37,61–63 The guiding principle in developing pain management
goals is to individualize the approach to the patient’s needs. Part of the
process of developing treatment goals is to take into consideration the
burdens (adverse effects; opportunity costs) and benefits of different
treatment options.63 Clinicians may find that patient treatment goals differ
from their own, either because patients feel that pain is inevitable or
because patients expect pain to be relieved with minimal effort on their
part. Issues that physicians should discuss with patients include expected
lifestyle; cost and reimbursement issues; and concerns about opioid
tolerance, addiction, and side effects. Discussing these issues in advance
may uncover and address potential barriers to treatment. Moreover,
treatment goals may change during the course of the patient’s illness, and
all health care providers interacting with the patient during the course of

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the illness need to keep abreast of such changes. Medication adherence has
major implications for the effective treatments of different diseases.64–67
Inadequate adherence with an analgesic regimen is problematic in
oncology68,69 and adherence rates for scheduled around-the-clock (ATC)
regimens better than for as needed regimens.70 Most interventions to
improve cancer pain outcomes rely on psychoeducational approaches
which focus on knowledge transfer to address attitudes and barriers to
opioid use.71–74 However Bennett et al.75 found that patient-based
educational interventions resulted in modest benefits in the management of
cancer pain and did not have significant benefit on medication adherence
or on reducing interference with daily activities. A large variety of
approaches have been used with varying effect, and attempts to understand
the reasons for heterogeneity between results have so far been
unsuccessful.76 A patient-centered approach that includes good
communication between health providers and patients can promote
adherence and improve outcomes.74,77

PRIMARY ANTICANCER TREATMENT

Pain produced by tumor infiltration may respond to antineoplastic
treatment with radiation treatment and chemotherapy. These approaches to
pain control are elaborated in Chapters 42 and 48.

Surgery
The surgeon treating a patient with newly diagnosed cancer must meet
several responsibilities: biopsy for tissue diagnosis, adequate staging,
consultation with medical and radiation oncologists for adjuvant therapy,
and surgical resection. Surgery may also play a role in the relief of
symptoms caused by specific problems, such as obstruction of a hollow
viscus, unstable bone structures, and compression of neural tissues. A
variety of surgical disciplines (e.g., general surgery, orthopedic,
neurosurgical, plastic, and reconstructive) may participate in the care of
the cancer patient.
Although the development of metastatic cancer usually indicates
incurable disease, curative surgical resection is possible in rare instances.
These instances must meet several criteria before the surgeon can operate:

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the primary lesion must be controlled, there must be the potential for
complete resection of the metastases, there must be no other equally
effective or better antitumor therapy available, metastases should involve
only one organ, one should anticipate reasonable postoperative function,
expected survival should be better than if left untreated, and the patient
must be able to tolerate the surgical procedure. Sometimes, excision of the
primary tumor is indicated in the presence of unresectable metastatic
disease. Locally advanced tumor can be very painful and unsightly, can
interfere with vital functions such as breathing and swallowing, and
produce complications such as bleeding and local infection. Resection of
isolated metastatic colorectal cancer, GI stromal tumors, neuroendocrine
cancers, renal cell cancer, and sarcoma is associated with longer survival
or even cure.78 Most of the available information on metastasectomy
relates to disease involving the liver, lung, and brain. Resection of primary
renal cell cancer localized to the kidney has a 5-year survival rate
approaching 95%.79 However, the presence of metastasis reduces the
median survival to only 10 months. At the time of diagnosis of primary
renal cell cancer, about 20% of individuals will have metastases. The
benefit of resection of isolated colorectal cancer metastases to the liver and
lung and results in a 5-year survival reported in the range of 27% to
58%.80–82 Surgical interventions for osseous (nonvertebral) disease depend
on the severity of symptoms, location of tumor, expected associated
morbidity if a fracture occurred, and availability of alternative or adjuvant
treatments. The goal is primarily to decrease pain and to improve mobility
and quality of life. The most obvious indication for surgery is the presence
of a pathologic fracture in a weight-bearing long bone. Asymptomatic
lesions may be followed clinically and radiographically. For metastatic
spinal tumors, surgery can improve mechanical stability, cord
compression, and pain. Complications may occur in up to 25% of patients
who undergo surgery for spinal metastases, the most common being
wound infection.83,84 Life expectancy is usually determined by the overall
extent of disease and, to be of benefit, surgery must improve quality of
life.85

Stenting, Drainage Procedures, and Antibiotics

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Common complications of advanced cancer include GI, hepatobiliary, and
ureteric obstructions. Stents and laser treatment have a place in both upper
GI and rectal obstruction due to advanced malignancy (Fig. 43.2).86–89
Decompression for obstructive uropathy from advanced disease usually
involves placement of nephrostomy tubes or ureteral stents. Malignant
obstruction of the bile duct from cholangiocarcinoma, pancreatic
adenocarcinoma, or other tumors may cause debilitating symptoms.
Treatment of obstruction can be performed endoscopically,
percutaneously, or surgically. Stents, nasobiliary drainage, or percutaneous
drains may be used for liver hilar strictures. Endoscopic catheter-based
therapies such as photodynamic therapy or radiofrequency ablation may
prolong patient survival by achieving local tumor control.90

FIGURE 43.2 Patient with metastatic prostate cancer who presented with large bowel obstruction.
Endoscopy revealed extrinsic tumor compression of the proximal sigmoid colon that required
placement of a 10-cm metal stent (red arrows) with complete relief of obstruction. Patient has also
bilateral percutaneous nephrostomies (yellow arrows) for relief of bilateral hydronephrosis.

The goals of antibiotic use in terminally ill patients are sometimes to

prolong life and always to relieve symptoms.91 Treatment for cystitis, for
instance, does not usually prolong life but may relieve the patient from
painful dysuria and troublesome polyuria. Antibiotics may also have pain-
relieving effects when the source of pain involves infection, as illustrated
by the treatment of pyonephrosis or osteitis pubis.

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Symptomatic Cancer Pain Management
Successful management strategies usually require a team approach
focusing not only on the nociceptive processes but also on other factors
that influence the final perception of pain. Figure 43.3 outlines an
approach to tumor-related nociceptive and neuropathic pain.

FIGURE 43.3 Tumor pain management algorithm.

Increasing severe pain and/or increasing and intractable side effects

determine the appropriate treatment strategy. Most patients will respond
satisfactorily to relatively simple oral pharmacotherapeutic strategies.
When the patient requires drug treatment, therapy should comply with two
basic principles: use oral analgesics and other noninvasive routes of
administrations (e.g., transdermal and transmucosal) whenever possible
and administer them in accordance with the principles in the WHO
analgesic ladder (see later). Titrate opioid and adjuvant analgesics to
maximally effective doses or to the appearance of dose-limiting side
effects before considering alternative medications (e.g., opioid rotation) or
more specialized (and usually) invasive approaches. As an adjunct—and
occasionally as an alternative—to medication management, patients with
certain pain syndromes will benefit from relatively simple anesthetic
blocks, such as celiac and superior hypogastric plexus blocks, neurolytic
subarachnoid and intercostal blocks, and selected peripheral nerve blocks
(see Chapter 44).

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 Severe, uncontrolled pain and/or intractable side effects require
interventional pain management to achieve rapid pain control. Such
interventions may include neuraxial (epidural or intrathecal) analgesia
and/or parenteral opioid therapy (usually intravenous administration). As
many of these patients have large systemic opioid requirements, it is not
unusual to combine neuraxial and parenteral therapies. A small percentage
of patients may fail these therapies and should then be treated with
intrathecal drugs and/or cordotomy or myelotomy (see Chapter 44).
Occasionally, patients will have pain refractory to all interventional
measures outlined, and palliative sedation should be considered (see
Chapter 13).

WORLD HEALTH ORGANIZATION ANALGESIC

LADDER
In 1986, WHO proposed a method for relief of cancer pain, based on a
small number of relatively inexpensive drugs, including morphine.92 Ten
years later, a second edition93 took into account many of the advances in
understanding and practice that have occurred since the mid-1980s. The
groundwork for this revision was started in 1989, in the context of the
meeting of a WHO Expert Committee on Cancer Pain Relief and Active
Supportive Care.94
The WHO “analgesic ladder” is a simple and effective method for
controlling cancer pain (Fig. 43.4). The purpose was to make pain relief
readily available to patients with cancer by using effective and inexpensive
drugs. Opioid-based pharmacotherapy is the most important of these
options. In many countries, access to opioid treatment is limited by
governmental regulation intended to prevent misuse.95–98 Advocacy for
improved and affordable access to opioids for legitimate medical reasons
must continue. At the same time, clinicians have to acknowledge the
serious nature of drug misuse and addiction and the obligation to minimize
these outcomes. This obligation is particularly pertinent in the United
States because of the troubling increase in prescription drug misuse during
recent decades. Codeine and morphine were selected for the original WHO
analgesic ladder but have fallen from favor because of the genetically
established variation in the effects of codeine and the potential effect of

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morphine metabolites in patients with renal impairment. The WHO
analgesic ladder approach selects different opioids on the basis of pain
intensity and any single-entity full µ-agonist opioid is appropriate.
According to a Cochrane review, the amount and quality of evidence
around the use of opioids for treating cancer pain is low, but 19 out of 20
people with moderate or severe pain who are given opioids and can
tolerate them should have that pain reduced to mild or no pain within 14
days.6 Because of opioid-related side effects, 1 to 2 in 10 patients treated
with opioids will find adverse events intolerable resulting in a change in
treatment. Somnolence, dry mouth, and anorexia were common adverse
events in people with cancer pain treated with morphine, fentanyl,
oxycodone, or codeine.99 Historically, the proportion of cancer patients
who report effective pain relief varies from 75% to 90%.37,100,101

FIGURE 43.4 World Health Organization analgesic ladder. (With permission from World Health
Organization. Cancer Pain Relief with a Guide to Opioid Availability. Geneva, Switzerland: World
Health Organization; 1996.)

Treatment for cancer pain should begin with a straightforward

explanation to the patient of the causes of the pain or pains. Many pains

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respond best to a combination of drug and nondrug measures.
Nevertheless, opioids, nonopioid analgesics and adjuvant agents, alone or
in combination are the mainstay of cancer pain management (Table 43.3).

TABLE 43.3 A Basic Drug List for Cancer Pain Relief

Category Basic Drugs Alternatives
Nonopioids Acetylsalicylic acid (ASA) Choline magnesium
Acetaminophen Trisalicylate
Ibuprofen Diflunisal
Indomethacin Naproxen
Diclofenac
Opioids for mild to moderate Codeine Dihydrocodeine
pain Standardized opium
Tramadol
Opioids for moderate to Morphine Methadone
severe pain Hydromorphone
Oxycodone
Levorphanol
Buprenorphine
Opioid antagonist Naloxone Methylnaltrexone
Antidepressants Amitriptyline Imipramine
Anticonvulsants Carbamazepine Valproic acid
Corticosteroids Prednisolone Prednisone
Dexamethasone Betamethasone
Modified with permission from World Health Organization. Cancer Pain Relief with a Guide to
Opioid Availability. Geneva, Switzerland: World Health Organization; 1996.

Pharmacologic strategies for the control of tumor pain appear in Table

43.4.

TABLE 43.4 Pharmacologic Strategies for the Control of Tumor

Pain
Select the appropriate analgesic drug.
Prescribe the appropriate dose of that drug.
Administer the drug by the appropriate route.
Schedule the appropriate dosing interval.
Prevent persistent pain and treat breakthrough pain.
Titrate the dose of drug aggressively.
Prevent, anticipate, and manage drug side effects.

Table 43.5 lists the principles of pharmacotherapy endorsed by WHO.

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 TABLE 43.5 The Principles of Drug Therapy for Cancer Pain
By the mouth
By the clock
By the ladder
For the individual
With attention to detail
From World Health Organization. Cancer Pain Relief with a Guide to Opioid Availability. Geneva,
Switzerland: World Health Organization; 1996.

These principles are as follows:

By Mouth
When possible, patients should take analgesic medications by mouth.
However, alternative routes such as rectal, transdermal, transmucosal
(buccal, intranasal, sublingual), and parenteral (subcutaneous and
intravenous) administration may better serve patients with dysphagia,
uncontrolled vomiting, or GI obstruction.

By the Clock
After titration to optimal effect, patients with continuous pain should take
analgesic medications on an ATC schedule. Once baseline pain is
controlled, many patients will require breakthrough pain (BTP) therapy
with immediate or rapid-onset opioids because BTP is a common
occurrence in cancer patients.

By the Ladder
The WHO analgesic ladder93 is based on the premise that most patients
throughout the world will gain adequate pain relief if health care
professionals learn how to use a few effective and relatively inexpensive
drugs well (Fig. 43.4). Step 1 of the ladder involves the use of nonopioids.
If this step does not relieve pain, add an opioid for mild to moderate pain
(Step 2). When the opioid for mild to moderate pain in combination with a
nonopioid fails to relieve the pain, substitute an opioid for moderate to
severe pain (Step 3). Use only one drug from each of the groups at the
same time. Give adjuvant drugs for specific indications (see later).

For the Individual

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There are no standard doses for opioids. The “right” dose is the dose that
relieves the patient’s pain with the minimum of side effects. Adequate pain
relief may be judged by patient satisfaction with pain management and/or
meeting predefined functional goals. Combination opioid formulations
(i.e., those with the nonopioid analgesic acetaminophen or a nonsteroidal
anti-inflammatory drug [NSAID] are commonly used for mild- to
moderate-intensity pain. These have a dose limit due to toxic effects of the
coanalgesic.

With Attention to Detail

Carefully determine and monitor the patient’s analgesic regimen. Follow-
up regularly with the patient by monitoring adherence, drug efficacy,
functional outcomes, side effects, and aberrant drug-related behaviors.
Anticipate adverse effects, such as opioid-induced bowel dysfunction, and
treat them prophylactically or as soon as they become problematic.
The WHO ladder advocates the use of three classes of analgesics—
nonopioid, adjuvant, and opioid. Each of these classes will be considered
separately.

Nonsteroidal Anti-Inflammatory Drugs

NSAIDs are essential drugs for the management of a wide variety of acute
and chronic pain conditions. Clinicians should be familiar with the use,
efficacy, and adverse effects of these agents. NSAIDs include a variety of
drugs that differ in their clinical effects and pharmacokinetics. In general,
they have high bioavailability, with peak concentrations occurring within
the first 4 hours when administered orally. Intravenous forms of ibuprofen
and ketorolac are available in the United States. NSAIDs may function to
control pain independently (e.g., in the management of mild- to moderate-
intensity bone or muscle pain) or may help reduce the dose of opioid
required for pain control (opioid-sparing effect). A wide range of drugs
with varying effects and side effects are available. These medications are
discussed extensively in Chapter 78.
Cyclooxygenase (COX) is the pivotal enzyme in prostaglandin
biosynthesis. It exists in two isoforms, constitutive COX-1 (responsible for
physiologic functions) and inducible COX-2 (involved in inflammation

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and upregulated by cytokines, growth factors, and shear stress).
Pharmacologic inhibition of COX explains both the therapeutic effects
(inhibition of COX-2) and side effects (inhibition of COX-1) of NSAIDs.
COX-1 and COX-2 both metabolize arachidonic acid to an unstable
precursor, prostaglandin (PG) H2. A variety of PG isomerases use PGH2 as
the substrate to form PGs, prostacyclin (PGI2), and thromboxane (Tx) A2.
The analgesic and anti-inflammatory effects of NSAIDs are dependent on
the extent and duration of COX-2 inhibition in the spinal cord and
inflammatory sites. Aspirin differs from NSAIDs because aspirin
irreversibly acetylates the enzyme. Most NSAIDs inhibit both COX
isoenzymes with little selectivity, although some (coxibs, meloxicam)
mainly block COX-2.
PGE2 is the most physiologically abundant product of COX-2 as it
exists at some level in nearly all cell types. Apart from biologic effects,
such as induction of pain and inflammation, PGE2 also participates in the
mechanisms of cell proliferation, apoptosis, and metastasis, contributing to
the progression of several human cancers, including colon cancer, breast
cancer, and lung cancer, suggesting that NSAID use may be beneficial in
these cancers.102–105 COX-2 is markedly overexpressed in colorectal
neoplasm and multiple epidemiologic studies clearly demonstrated that
NSAID consumption prevents adenoma formation and decreases the
incidence of, and mortality from, colorectal cancer.106 COX-2 inhibition
can reduce proliferation, induce apoptosis, suppress tumor angiogenesis,
prevent immune suppression, and inhibit carcinogen conversion.106,107 The
efficacy of aspirin differs significantly according to COX-2 expression.
Aspirin reduces the risk of colorectal cancer in COX-2–expressing
cancers, but it is not an effective chemopreventive agent for cancers with
weak or absent COX-2 expression.108 In animal models, NSAIDs decrease
the number and risk of metastasis109 with some data now emerging of a
reduced risk of metastasis development in humans.110

EFFICACY IN CANCER PAIN

Although many NSAIDs are available to treat various painful conditions, it
is unclear which agent is most clinically efficacious for relieving cancer-
related pain, and if there are clinical differences between these agents that

2192
justify their cost differences. In a Cochrane review of the use of NSAIDs
either alone or in combination with opioids, the quality of evidence
supporting the use of NSAIDs was poor and suggested that moderate to
severe cancer pain was reduced to no worse than mild pain after 1 to 2
weeks in approximately 1 of 3 patients. One in 4 patients stopped taking
NSAIDs because the drug did not work, and 1 of 20 stopped because of
side effects.61 In effect, there is no evidence to support or refute the use of
NSAIDs alone or in combination with opioids for cancer pain. McNicol et
al.111 assessed and compared the efficacy of various NSAID and NSAID
plus opioid combinations in the treatment of cancer pain. They concluded
that most studies were of insufficient duration to demonstrate that the
long-term use of NSAIDs is safe and effective in patients with cancer.
They advised that clinicians should be as cautious in using NSAIDs in this
population as they would any other population, especially given additional
bleeding risks in cancer patients, and the probability that a patient with
cancer may be on a broad regimen of medications, some of which may
increase NSAID-related toxicity.

Acetaminophen
Acetaminophen (APAP) is one of the most popular antipyretic and
analgesic medications worldwide. It is used either alone or in combination
with other drugs. Its low cost and favorable side effect profile is attractive
for use in a variety of painful conditions. The mechanism of action of the
drug is not fully understood. However, it is known that acetaminophen is a
weak inhibitor of the synthesis of PGs. It may have a selective COX-2
inhibitor effect112 or a central effect, possibly due to activation of
descending serotonergic pathways.113 On average, APAP is considered a
weaker analgesic than NSAIDs or COX-2 selective inhibitors but is often
preferred because of its better tolerance. High use of APAP was associated
with an almost twofold increased risk of incident hematologic
malignancies such as myeloid neoplasms, non-Hodgkin lymphoma, and
plasma cell disorders excluding chronic lymphocytic leukemia/small
lymphocytic lymphoma114 but not for other nonhematologic
malignancies.115 Severe liver injury can occur when acetaminophen use

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exceeds maximum dosage (currently 4,000 mg within a 24-hour period) or
when an individual takes the drug and also consumes alcohol,116 and with
additional warnings that the drug may cause severe skin reactions
including Stevens-Johnson syndrome, toxic epidermal necrolysis, and
acute generalized exanthematous pustulosis.117 Of note, the use of
concentrated prescription APAP-containing medications (>500 mg) in
combination with other sources of APAP can result in severe liver injury
and death.118 Acute liver failure secondary to APAP is most often
associated with unintentional overdose, the use of a single product, an
opioid-APAP combination, duration of use <7 days, and a median dose of
7.5 g per day.119 Daily doses of APAP of 4 g for 10 days resulted in a
maximum increase of serum alanine aminotransferase (ALT) more than 3
times normal in over 30% of patients,120 and daily use of acetaminophen at
half the maximum recommended daily dose for 12 weeks in a healthy
adult population was associated with a small elevation in mean ALT of no
probable clinical significance.121 There is no high-quality evidence to
support or refute the use of APAP alone or in combination with opioids for
cancer-related pain122 or with advanced disease.123

Opioid-Induced Bowel Dysfunction

Constipation is prevalent in oncology patients even among patients not on
opioid therapy.124 GI side effects such as nausea, vomiting, diarrhea, and
constipation is associated with chemotherapy including alkylating agents,
antimetabolites, immunomodulating agents, and mitotic inhibitors.125 The
prevalence of constipation after cytotoxic chemotherapy may be as high as
16% with 5% classified as severe.126 Posttreatment constipation and
diarrhea among cancer (particularly colorectal) survivors is prevalent with
episodes persisting up to 10 years after treatment.127,128 Opioid-induced
constipation (OIC) and opioid-induced bowel dysfunction (OBD) are
associated with opioid therapy. OBD is a distressing condition that may
persist indefinitely in the clinical setting. Hard dry stool, gas distention,
incomplete evacuation, and straining are common sequelae. OBD can
affect quality of life significantly and result in hospitalization, pain, and
frequent changes in opioid and laxative treatment.129

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 Clinical reviews on OIC indicate the lack of a common definition130 and
may be defined as a change when initiating opioid therapy from baseline
bowel habits that is characterized by reduced bowel movement frequency,
development or worsening of straining to pass bowel movements, a sense
of incomplete rectal evacuation, or harder stool consistency.131 OBD
reflects the overall impact of opioids on the GI tract and include symptoms
such as dry mouth, gastroesophageal reflux–related symptoms (heartburn),
nausea, vomiting, chronic abdominal pain, bloating, constipation-related
symptoms: straining, hard stools, painful, infrequent and incomplete bowel
movements (BMs), and diarrhea-related symptoms: urgency, loose and
frequent BMs.132,133 OIC is the most common form of OBD.
Endogenous opioids and opioid receptors are widely distributed
throughout the body, with strong expression in the CNS, peripheral
nervous system, and enteric nervous system (ENS) and also within the
endocrine and immune systems. The ENS has a network of small ganglia
that can regulate GI motility and secretion independently of the CNS.
Neurons in the ENS form plexuses between the circular and longitudinal
muscle layers (the myenteric plexus) and between the mucosal and circular
muscle layers (the submucosal plexus). The myenteric plexus innervates
both the longitudinal and the circular muscle layers, and its primary role is
to coordinate motility patterns. Submucosal plexuses are found in the
small and large intestine and are primarily involved in the regulation of
secretion and local blood flow. Opioids inhibit enteric neuronal activity in
both the small intestine and the colon. The expression of µ-opioid
receptors on myenteric and submucosal ganglia suggests that receptor
agonists cause constipation by inhibiting peristaltic smooth muscle
contractions by effects on the myenteric ganglia and also by inhibiting
water and electrolyte movement across the lumen via effects on the
submucosal ganglia. Opioid receptors and endogenous opioid agonists are
altered in GI disease.134 The mechanisms for OBD are associated with
delays in gastric emptying, oral-cecal transit and colonic transit time, and
inhibition of defecation, all of which are predominately mediated through
peripheral µ receptors.135–137 The effects of opioids on the gut also are
partly a result of their ability to accumulate in the intestinal tissue and have
a direct local effect on the bowel.135 Centrally mediated antitransit effects

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are implicated in the pathophysiology of OBD. Opioids act centrally
through alterations in autonomic outflow to the gut; however, their overall
impact on GI motility appears to be correlated to their ability to penetrate
the CNS.138 Opioids mainly exert their action on the ENS where they bind
to opioid receptors in the myenteric and submucosal plexuses and on
immune cells in the lamina propria.139 The coordination of the contractile
and propulsive gut motility is determined by a balance between
acetylcholine and nitric oxide/vasoactive intestinal peptide release.140,141
Because opioids inhibit neurotransmitter release, administration will
directly disrupt this balance, resulting in abnormal coordination of
motility.142
The Bowel Function Index (BFI numerical analogue scale 0 to 100),
calculated as the mean of three variables (ease of defecation, feeling of
incomplete bowel evacuation, and personal judgment of constipation), was
developed to evaluate bowel function in opioid-treated patients with
pain.143 This clinician-administered tool allows easy measurement of OIC
from the patient’s perspective.
Metoclopramide is commonly prescribed for patients with symptoms of
gastroparesis.144–146 It is a dopamine receptor antagonist, serotonin 5-
hydroxytryptamine type 4 (5-HT4) receptor agonist, and weak inhibitor of
5-hydroxytryptamine type 3 (5-HT3) receptors. Activity appears to be by
both peripheral (in the upper GI tract) and central mechanisms by inducing
antidopaminergic effects. Recommended use of metoclopramide at the
lowest effective dose for each patient beginning with 5 mg three times
daily up to a maximum recommended dose of 40 mg per day.147 Adverse
events include restlessness, drowsiness, fatigue, and extrapyramidal
effects, especially in younger patients and in children. Patients may
experience extrapyramidal side effects at doses greater than 20 mg
daily.148 Metoclopramide is an inhibitor of CYP2D6 enzyme. Concurrent
use of antidepressants such as tricyclics, selective serotonin reuptake
inhibitors (SSRIs), and antidepressants acting as serotonin-norepinephrine
reuptake inhibitors (SNRIs) (venlafaxine or duloxetine) may enhance
adverse effects associated with metoclopramide.
The goals of therapy typically are threefold: keep stool volume
maximized to trigger enterochromaffin cell serotonin release via mucosal

2196
stretch, keep stool softer and mechanically make it easier to move, and
enhance peristalsis. Most treatment for constipation begins with
encouraging exercise, activity, fluid intake, and dietary fiber and the use of
stool softeners and laxatives. Fiber-bulking agents are organic polymers
that retain water in stool. It is important that adequate water be taken
concomitantly with fiber. Without sufficient fluid, fiber may worsen
constipation. Many practitioners recommend a combination of a stool
softener with a stimulant laxative for patients on chronic opioid therapy.
Stool softeners, such as docusate sodium, are detergents that allow better
water penetration into stool, making it softer and more voluminous.
Stimulant laxatives, such as senna and bisacodyl, induce peristalsis via
mechanisms that are not well understood. In vitro, applying senna to
intestinal mucosa leads to immediate contraction. After optimal titration of
these agents with persistent constipation, oral osmotics are commonly
added to enhance laxation by pulling along water due to osmotic forces.
Osmotics include sugars, such as lactulose or sorbitol; magnesium salts,
such as magnesium citrate; or inert substances, such as polyethylene
glycol. When unsuccessful, rescue oral and rectal interventions are also
often needed. Rectal interventions include such agents as bisacodyl
suppositories and phosphosoda enemas to soften, lubricate, and mobilize
hard, dry distal stool. Often, synergism of multiple categories of agents is
required for successful laxation. Another strategy has been the
development of peripherally acting µ-opioid receptor antagonists
(PAMORAs) that selectively target µ receptors in the GI tract. PAMORAs
agents currently available include oral naloxegol and alvimopan and
subcutaneously administered methylnaltrexone.
Naloxegol is a polymer conjugate of naloxone. The polyethylene glycol
(PEG) moiety limits the ability to cross the blood–brain barrier. PEGs are
also used as osmotic laxatives (e.g., macrogol 3,350/4,000), where they act
as nonmetabolized, nonabsorbable, osmotic agents, forming hydrogen
bonds with water in the intestinal lumen. PEGylation makes naloxegol a
substrate for the P-glycoprotein (P-gp) transporter. Due to the reduced
permeability and increased efflux of naloxegol across the blood–brain
barrier, related to P-gp transporter, the CNS penetration of naloxegol is
negligible and it reduces OIC in the GI tract without reversing the central

2197
analgesic effect.149 administration of naloxegol with food is associated
with increased bioavailability. The concentration and activity of naloxegol
are increased by the concurrent use of CYP3A4 inhibitors and reduced by
CYP3A4 inducers. Naloxegol is administered at a dose of 25 mg once
daily on an empty stomach at least 1 hour before the first meal of the day
or 2 hours after the first meal of the day. Cancer patients with symptoms of
bowel obstruction and those with increased risk of GI perforation
including GI or peritoneal tumors, recurrent or advanced ovarian cancer,
and patients treated with vascular endothelial growth factor (VEGF)
inhibitors should avoid the use of naloxegol.
Methylnaltrexone-bromide is a PAMORA and a quaternary methyl
derivative of naltrexone. The addition of a methyl group to the nitrogen
ring increases polarity and reduces lipophilicity such that the drug does not
pass the blood–brain barrier. It is administered subcutaneously and is
rapidly absorbed, with the peak plasma concentration attained within 30
minutes, and plasma elimination half-life (t1/2) is approximately 8
hours.150 It induces bowel movement in approximately 50% to 60%
treated patients within 4 hours of its administration.151,152 It is indicated
for OIC patients with advanced disease who are receiving palliative care
with inadequate response to laxative therapy.153 Recommended dosing is 8
mg for patients weighing 38 to less than 62 kg and 12 mg for patients
between 62 to 114 kg. Usual dosing is one dose every other day and not
more than one dose per day. Common side effects include abdominal pain,
flatulence, and nausea. Contraindications include administration to patients
with known or suspected mechanical bowel obstruction. Rare cases of GI
perforation involving various regions of the GI tract have been reported in
advanced illness patients.154 Alvimopan is another orally administered
PAMORA that does not cross the blood–brain barrier at clinically relevant
doses and does not reverse analgesia or cause opioid withdrawal
symptoms. The FDA approved alvimopan for postoperative ileus
following partial small or large bowel resection with primary anastomosis
in hospitalized patients.

Antiemetics

2198
Nausea and vomiting is a common problem in oncology. Although
opioids,155 chemotherapy,156 and radiation therapy157 are commonly
associated with nausea and vomiting, advanced disease is also frequently
associated with nausea particularly in the last week of life.158 Depending
on the anatomic area irradiated, an estimated 50% to 80% of patients
undergoing radiation therapy develop radiation therapy–induced nausea
and vomiting (RINV).159 Total body irradiation, half body irradiation, or
abdominal radiotherapy are at a major risk of nausea and vomiting. The
pathophysiology of nausea and vomiting is a complex process. The act of
vomiting is coordinated by the vomiting center of the brain located in the
lateral reticular formation of the medulla with efferent pathways through
the vagus, phrenic, and spinal nerves. The vomiting center receives
afferent input from various sources including the chemoreceptor trigger
zone (CTZ) in the area postrema in the floor of the fourth ventricle, the
vagus and sympathetic nerves, as well as impulses directly from the GI
tract and other sources. The CTZ is also activated by mediators in the
circulation, which may include hormones, peptides, medications, or toxins.
The act of vomiting involves neurotransmitters (including serotonin,
substance P, and dopamine found in the CTZ), the vomiting center, and
enterochromaffin cells in the GI tract release efferent impulses that are
transmitted to the abdominal musculature, salivation center, and
respiratory center. CTZ effects are largely mediated through central
dopamine type 2 (D2) receptors.
Opioids have emetogenic effects by central stimulation, vestibular
effects and by inhibiting gut motility. The primary mechanism of opioid-
induced nausea and emesis is central with direct stimulation of the CTZ.160
Although opioid stimulation of the CTZ involve opioid receptors,
signaling from the CTZ involves D2 and 5-HT3 receptors and opioid
stimulation of the vestibular apparatus and sensory input to the vomiting
center may involve H1 and muscarinic acetylcholine pathways (Fig.
43.5).161 The peripheral inhibitory effect of opioids on GI transit and
stimulation of the pyloric sphincter delays gastric emptying or causes
gastroparesis. Chemotherapy likely causes nausea and vomiting through
stimulation of the CTZ mediated by 5-HT3 and neurokinin type 1 (NK1)
receptors. Because of these effects, 5-HT3 and NK1 receptor antagonists

2199
are the most effective agents currently available. In most cases of
chemotherapy-induced nausea and vomiting (CINV), these agents are used
in conjunction with glucocorticoids.162–165 Glucocorticoids are effective
only for preventing nausea and vomiting and not for treating established
nausea and vomiting.166

FIGURE 43.5 Opioid-induced nausea and vomiting pathophysiology and antiemetic therapy. 5-
HT3, 5-hydroxytryptamine type 3; CTZ, chemoreceptor trigger zone; D2, dopamine type 2; DRA,
dopamine receptor antagonist; GI, gastrointestinal; H1, histamine H1; M1, O-desmethyl tramadol;
NK1, neurokinin type 1; NK1R, neurokinin type 1 receptor. (Modified from Smith HS, Laufer A.
Opioid induced nausea and vomiting. Eur J Pharmacol 2014;722:67–78. Copyright © 2014
Elsevier. With permission.)

Typical strategies for management and minimization of opioid-induced

nausea and vomiting include dose reduction, dose titration, opioid rotation,
and the use of antiemetics. Commonly used antiemetics are listed in Table
43.6. It is not uncommon for patients to experience nausea and/or vomiting
when starting opioid therapy, but these side effects tend to subside within
days or weeks167 unless opioid-induced bowel dysfunction develops. Until
the late 1970s, dopamine-receptor antagonists, such as metoclopramide,
prochlorperazine, and haloperidol, formed the basis of antiemetic therapy.
In 1991, the first 5-HT3–receptor antagonist, ondansetron, was approved
by the FDA for the treatment of chemotherapy-induced emesis followed
by two additional 5-HT3–receptor antagonists, granisetron and dolasetron,
in 1997. Droperidol and ondansetron have an FDA black box warning after
reports of prolonged rate-corrected QT (QTc) interval. Palonosetron is a

2200
second-generation 5-HT3–receptor antagonist that has a prolonged t1/2 with
higher receptor binding affinity than other antiemetic agents. Aprepitant,
the first NK1 receptor antagonist, was approved for chemotherapy-induced
emesis in 2003. In 2008, fosaprepitant, a prodrug and intravenous form of
aprepitant, was approved by the FDA. Dronabinol (Schedule III) and
nabilone (Schedule II) are cannabis-derived pharmaceuticals indicated for
the treatment of nausea and vomiting associated with cancer chemotherapy
and of anorexia associated with weight loss in patients with acquired
immune deficiency syndrome.168

TABLE 43.6 Antiemetics

Presumed Primary
Receptor Site of Major Adverse
Agent Action Dosage/Route Effects
Metoclopramide D2 (primarily in GI 5–20 mg orally or Dystonia, akathisia,
tract) or 5-HT3 (only subcutaneously or esophageal spasm,
at high doses) IV and colic (in GI
obstruction)
Haloperidol D2 (primarily in CTZ) 0.5–4 mg orally or Dystonia and akathisia
subcutaneously or
IV q6h
Prochlorperazine D2 (primarily in CTZ) 5–10 mg orally or IV Dystonia, akathisia,
q6h or 25 mg and sedation
rectally q6h
Chlorpromazine D2 (primarily in CTZ) 10–250 mg orally q4h, Dystonia, akathisia,
25–50 mg IV or IM sedation, postural
q4h, or 50–100 mg hypotension
rectally q6h
Promethazine H1, muscarinic 12.5–25 mg orally or Dystonia, akathisia,
acetylcholine IV q6h or 25 mg and sedation
receptor, or D2 rectally q6h
(primarily in CTZ)
Diphenhydramine H1 25–50 mg orally or IV Sedation, dry mouth,
or SQ q6h urinary retention
Scopolamine Muscarinic 1.5 mg transdermal Dry mouth, blurred
acetylcholine patch q72h vision, urinary
receptor retention, confusion
Hyoscyamine Muscarinic 0.125–0.25 mg SL or Dry mouth, blurred
acetylcholine orally q4h or 0.25– vision, ileus, urinary
receptor 0.5 mg SQ or IV q4h retention, confusion
Ondansetron 5-HT3 4–8 mg orally by pill Headache, fatigue,
or dissolvable tablet constipation
(ODT) or IV q4–8h

2201
 Aprepitant NK1 40 mg orally qd
5-HT3, 5-hydroxytryptamine type 3; CTZ, chemoreceptor trigger zone; D2, dopamine type 2; GI,
gastrointestinal; H1, histamine H1; IM, intramuscular; IV, intravenous; NK1, neurokinin type 1;
SL, sublingual; SQ, subcutaneous.

Postoperatively, ondansetron is more effective than metoclopramide for

the treatment of opioid-induced emesis.169 Nausea and vomiting after
acute administration of opioids may be partly related to serotonin receptor
signaling.170 Many consider dopamine receptor antagonists, including
prochlorperazine and haloperidol as the preferred drugs for managing
opioid-induced nausea and vomiting.171,172 Olanzapine, an atypical
thienobenzodiazepine antipsychotic agent that is indicated for the
treatment of schizophrenia and bipolar disorder, is also useful for the
treatment of intractable nausea particularly at reducing during the delayed
and overall phase of the CINV prevention.173 It is also useful for the
treatment of morphine-induced emesis and as an adjunct for the treatment
of neuropathic pain associated with sleep disturbance.161 It blocks multiple
neurotransmitter receptors, including dopaminergic (D2), serotonergic (5-
HT3), adrenergic, histaminergic, and muscarinic receptors. Dose titration
of olanzapine is over a period of 7 to 10 days (in the range of 2.5 to 7.5
mg) given at bedtime.
Many of the commonly prescribed antiemetic agents (e.g.,
phenothiazines, antihistamines, anticholinergic drugs, and
metoclopramide) are generally effective but are often associated with
undesirable side effects such as sedation, blurred vision, dysphoria, and
extrapyramidal reactions. 5-HT3 receptors are located centrally in the CTZ
as well as peripherally on vagal nerve terminals. Ondansetron is effective
for the control of opioid-induced nausea and vomiting.174 The antiemetic
actions noted from cannabinoids and endocannabinoids have been linked
to CB1 effects, where antagonists can provoke acute emesis and agonists
reduce acute nausea and vomiting.

Adjuvant Analgesics
An adjuvant analgesic is a medication with a primary indication other than
pain relief, but it may provide or enhance analgesia in certain

2202
circumstances. In the area of cancer pain, the common adjunctive
analgesics are corticosteroids, anticonvulsants, and antidepressants. These
drugs play an important role for some patients who cannot otherwise attain
an acceptable balance between relief and opioid side effects. Adjuvant
analgesics divide broadly into general purpose analgesics, adjuvants used
for musculoskeletal pain, and those with specific use for neuropathic,
bone, or visceral pain. Although ketamine has been used in the treatment
of cancer pain refractory to opioid therapy, it is not licensed for this
purpose and the evidence supporting its use is very low quality with
potentially serious adverse events at higher doses175 and will not be
considered further.

GENERAL PURPOSE ADJUVANTS

Corticosteroids are the most widely used general purpose adjuvant
analgesics and are available in a wide variety of formulations.176 Various
guidelines recommend the use of steroids as adjuvants for cancer pain but
these guidelines are based on expert opinion.177–181 Steroids are used to
treat pain associated with increased intracranial pressure, acute spinal cord
compression, superior vena cava syndrome, metastatic bone pain,
neuropathic pain due to infiltration or compression, symptomatic
lymphedema, and hepatic capsular distension. The mechanism for pain
relief is unknown but the anti-inflammatory effect of steroids is often
proposed as the putative mechanism.182 The available data suggest that
moderate doses of corticosteroids equivalent to methylprednisolone 32 mg
or dexamethasone 8 mg daily are well tolerated for up to 7 days but that
high doses equivalent to methylprednisolone 125 mg daily administered
over 8 weeks have a significantly adverse impact and may even increase
mortality.183 Overall, data supporting the role of steroids for cancer pain
control is weak and likely with only short-term benefit.182
Topical agents (see Chapter 80) may also be useful as an adjunctive
form of pharmacotherapy, without increasing systemic toxicity. These
agents are used for a variety of painful conditions such as strains or
sprains, muscle aches, osteoarthritis of hand or knee, or neuropathic pain.
Typical topical analgesic drugs include NSAIDs, salicylate rubefacients,
capsaicin, and lidocaine. Agents such as diclofenac Emulgel, ketoprofen

2203
gel, piroxicam gel, and diclofenac plaster work reasonably well for strains
and sprains. For hand and knee osteoarthritis, topical diclofenac and
topical ketoprofen rubbed on the skin for at least 6 to 12 weeks help reduce
pain by at least half in a modest number of people. For postherpetic
neuralgia, topical high-concentration capsaicin can reduce pain by at least
half in a small number of people.184 There are a number of drugs in the
area of pain management that have been formulated and compounded to
treat conditions such as diabetic neuropathy, fibromyalgia, postherpetic
neuralgia, joint pain, arthritis, and others. Significant portions of these
compounded analgesic preparations are topical/transdermal dosage forms
such as gels and creams. Although the efficacy and doses of these drugs in
systemic dosage forms have been widely established, little is known about
the permeation and efficacy of these compounds from these gels. A
multicenter, phase III, randomized, double-blind, placebo-controlled trial
was to investigate the efficacy of 2% ketamine plus 4% amitriptyline
cream for reducing chemotherapy-induced peripheral neuropathy (CIPN)
in 462 cancer survivors was ineffective for this problem.185 A study
examining topical 5% amitriptyline and 5% lidocaine in the treatment of
mixed sources (noncancer) neuropathic pain showed that topical lidocaine
reduced pain intensity but the clinical improvement was minimal and that
topical 5% amitriptyline was not effective.186 Although anecdotally,
topical lidocaine may benefit some patient, there is no evidence from good
quality randomized controlled studies to support the use of topical
lidocaine to treat neuropathic pain.187

MUSCULOSKELETAL PAIN ADJUVANTS

The term muscle relaxants or muscle relaxers is broad and includes a wide
range of drugs with different indications and mechanisms of action.
Muscle relaxers are either antispasmodic or antispasticity medications. The
antispasmodic agents are further subclassified into the benzodiazepines
and the nonbenzodiazepines. Nonbenzodiazepines include a variety of
drugs that can act at the brain stem or spinal cord level and include
carisoprodol, chlorzoxazone, cyclobenzaprine, metaxalone, meprobamate,
methocarbamol, tizanidine, zopiclone, and orphenadrine. Only three
muscle relaxants—baclofen, dantrolene, and tizanidine—are FDA

2204
approved to treat spasticity. Tizanidine is an agonist at α2-adrenergic
receptor sites and presumably reduces spasticity by increasing presynaptic
inhibition of motor neurons. It has linear pharmacokinetics over a dose of
1 to 20 mg.188 In multiple dose, controlled clinical studies, 48% of patients
receiving any dose of tizanidine reported sedation as an adverse event and
sedation appears to be dose related.189 A single dose of 8 mg of tizanidine
reduces muscle tone in patients with spasticity for a period of several
hours. The effect peaks at approximately 1 to 2 hours and dissipates
between 3 and 6 hours.
The FDA-approved muscle relaxers for spasms (including carisoprodol,
cyclobenzaprine, orphenadrine, metaxalone, chlorzoxazone, and
methocarbamol) have only been approved for short-term use (up to 21
days), and their long-term efficacy is unknown. Evidence supporting the
effectiveness of these drugs for muscle spasm is sparse; most trials are old
and not of good quality. Much of the evidence from clinical trials
regarding the use of these agents is limited because of poor methodologic
design, insensitive assessment methods, and small numbers of patients.190
These drugs are often used for treatment of musculoskeletal conditions,
whether muscle spasm is present or not. Pharmacologic and
nonpharmacologic approaches do not differ significantly from patients
with musculoskeletal pain who do not have cancer (see Chapters 80 and
89), other than disease- or treatment-specific issues relevant to the cancer
patient. Drug–drug and drug–disease interactions must always be
considered and be an ongoing component of reassessment.

NEUROPATHIC PAIN ADJUVANTS

Neuropathic pain, caused by a lesion or disease affecting the
somatosensory nervous system, is a common and oftentimes very
debilitating source of distress in patients with cancer (see Chapters 24 to
28 and 42). In cancer and chronic noncancer pain, there is a large variety
of causes. Most treatment strategies for cancer-related neuropathic pain are
extrapolated from noncancer-related neuropathic pain (see Chapters 24 to
28).191–194 Table 43.7 summarizes those agents that are used to treat
neuropathic pain in noncancer patients. Of note, opioids are recommended
as third line contrasting with previous recommendations.195 This is largely

2205
because of the potential risk of abuse, particularly with high doses, and
concerns about prescription opioid–associated overdose mortality,
diversion, misuse, and other opioid-related morbidity. In addition, high-
concentration capsaicin patches and cannabinoids are considered for the
first time in therapeutic recommendations for neuropathic pain.

TABLE 43.7 Drugs or Drug Classes with Strong or Weak

Recommendations for Management of Neuropathic Pain
Total Daily Dose and Dose
Regimen Recommendations
Strong Recommendations for Use
Gabapentin 1,200–3,600 mg, in three First line
divided doses
Gabapentin extended-release 1,200–3,600 mg, in two First line
or enacarbil divided doses
Pregabalin 300–600 mg, in two divided First line
doses
Serotonin-norepinephrine 60–120 mg, once a day First line
reuptake inhibitors (duloxetine); 150–225 mg,
duloxetine or venlafaxinea once a day (venlafaxine
extended release)
Tricyclic antidepressants 25–150 mg, once a day or in First lineb
two divided doses
Weak Recommendations for Use
Capsaicin 8% patches One to four patches to the Second line (peripheral
painful area for 30–60 min neuropathic pain)c
every 3 months
Lidocaine patches One to three patches to the Second line (peripheral
region of pain once a day neuropathic pain)
for up to 12 h
Tramadol 200–400 mg, in two (tramadol Second line
extended release) or three
divided doses
Botulinum toxin A 50–200 units to the painful Third line; specialist use
(subcutaneously) area every 3 months (peripheral neuropathic
pain)
Strong opioids Individual titration Third lined
aDuloxetine is the most studied, and therefore recommended, of the serotonin-norepinephrine
reuptake inhibitors.
bTricyclic antidepressants generally have similar efficacy; tertiary amine tricyclic antidepressants

(amitriptyline, imipramine, and clomipramine) are not recommended at doses greater than 75 mg
per day in adults aged 65 years and older because of major anticholinergic and sedative side
effects and potential risk of falls; an increased risk of sudden cardiac death has been reported

2206
 with tricyclic antidepressants at doses greater than 100 mg daily.
cThe
long-term safety of repeated applications of high-concentration capsaicin patches in patients
has not been clearly established, particularly with respect to degeneration of epidermal nerve
fibers, which might be a cause for concern in progressive neuropathy.
dSustained-release oxycodone and morphine have been the most studied opioids (maximum doses

of 120 mg per day and 240 mg per day, respectively, in clinical trials); long-term opioid use
might be associated with abuse, particularly at high doses, cognitive impairment, and endocrine
and immunologic changes.
Reprinted from Finnerup NB, Attal N, Haroutounian S, et al. Pharmacotherapy for neuropathic pain
in adults: a systematic review and meta-analysis. Lancet Neurol 2015;14(2):162–173. Copyright
© 2015 Elsevier. With permission.

The causes of neuropathic pain in noncancer patients are diverse and

generally can be considered as central or peripheral. Neuropathic pain has
been extensively discussed in Chapters 24 to 28. Although chronic
noncancer neuropathic pain occurs in oncology patients, unique sources of
pain including disease infiltration of central and peripheral nervous tissue,
paraneoplastic peripheral neuropathy, pain resulting from leptomeningeal
metastases and neuropathic pain secondary to therapeutic interventions
(postsurgical, radiation therapy, and CIPN) occur in cancer patients.
Furthermore, combinations of different sources of pain may also occur.
For example, a patient with persistent CIPN-associated pain may develop
both central and peripheral sources of pain (brachial plexus tumor
infiltration extending to the spinal canal causing cord compression).
Management of such pain complaints may require multiple approaches
including disease control (chemotherapy, radiation therapy) and
symptomatic pharmacologic approaches. Extrapolation of treatment
guidelines from noncancer pain patients are not appropriate for the
management of oncology-associated neuropathic pain. Data relating to the
use of neuropathic pain adjuvant medications for the management or
prevention of CIPN-associated pain is inconsistent. Chemotherapeutic
agents causing nerve dysfunction mainly target axons, dorsal root ganglia,
and terminal trees of intraepidermal nerve fibers.196 Purported
chemoprotective agents (acetylcysteine, amifostine, calcium and
magnesium, diethyldithiocarbamate, glutathione, Org 2766,
oxcarbazepine, retinoic acid, or vitamin E) for platin drug toxicity were
not beneficial.197 Typical medications used for management of CIPN are
antidepressants (tricyclics, SNRIs) or antiepileptic drugs (AEDs)

2207
(gabapentin, pregabalin). Venlafaxine is a reasonably well-tolerated
antidepressant and is a serotonin reuptake inhibitor and weak
norepinephrine reuptake inhibitor. Although some studies suggest benefit
for use in acute oxaliplatin-induced198 or acute taxane-oxaliplatin-
related199 neuropathy, others have found little compelling evidence to
support the use of venlafaxine in neuropathic pain.200 Because of the lack
of effective management for CIPN, the National Cancer Institute
sponsored a series of trials aimed at prevention and management.201 A
total of 15 studies were approved, evaluating use of various
neuromodulatory agents (including nortriptyline, gabapentin, and
lamotrigine) which have shown benefit in other neuropathic pain states.
Gabapentin doses were targeted to 2,700 mg per day for a total of 6 weeks.
Aside from duloxetine, none demonstrated therapeutic benefit for patients
with CIPN. Smith et al.202 studied the effect of duloxetine at initial doses
of 30 mg for 1 week then 60 mg for 4 additional weeks for painful CIPN
induced by paclitaxel, other taxane, or oxaliplatin. Fifty-nine percent of
patients experienced some decrease in pain after 5 weeks of taking
duloxetine, and more duloxetine-treated patients decreased their opioid
analgesic intake. In a retrospective review on the use of duloxetine for
paclitaxel-induced CIPN, some benefit was observed in younger patients,
but elderly patients (>60 years) tended to be less responsive and
experienced more drug-related adverse events.203 It should also be noted,
especially in breast cancer patients, that if duloxetine and tamoxifen are
taken together, duloxetine-induced CYP P450 2D6 enzyme inhibition
could inhibit tamoxifen conversion to its active metabolite, endoxifen.204

BONE PAIN ADJUVANTS

NSAIDs, corticosteroids, calcitonin, radiopharmaceuticals, and
bisphosphonates all have a potential place in the treatment of cancer-
related bone pain. The use of calcitonin has been disappointing in the
management of painful bone metastases.205,206 Dexamethasone is useful
for the management of radiation-induced bone pain flares,207 but there is
no evidence of benefit for management of painful bone metastases. The
risk of bone loss and fractures is increased with systemic glucocorticoid
use with the highest rate of bone loss that occurs within the first 3 to 6

2208
months of therapy.208 More than 10% of patients who receive long-term
steroid therapy are diagnosed with a fracture, and 30% to 40% have
radiographic evidence of vertebral fractures.209 Exposure to steroids is also
a leading cause of osteonecrosis (avascular necrosis).210,211

VISCERAL PAIN ADJUVANTS

The literature offers little support for the potential efficacy of adjuvant
agents for the management of bladder spasm, tenesmoid pain, and colicky
intestinal pain. Although there is no well-established pharmacotherapy for
painful rectal spasms, diltiazem can help in the management of proctalgia
fugax.212 Inhaled salbutamol also shortened the attack of severe pain in a
randomized double-blind trial in 18 patients with proctalgia fugax.213 Most
treatments for proctalgia fugax (e.g., oral diltiazem, topical glyceryl
nitrate, nerve blocks) act by relaxing the anal sphincter spasm. The
effectiveness of these treatments is supported only by case reports or case
series.214 For chronic proctitis associated with radiation therapy, anti-
inflammatory agents such as sulfasalazine or 5-aminosalicylic acid
(mesalamine) are usually first-line treatments, but they have low efficacy
even in combination with other agents such as steroids and antibiotics.215
Belladonna and opium suppositories have been used in the management of
moderate to severe pain associated with ureteral spasm. The recommended
adult dose of belladonna and opium rectal suppositories for the treatment
of moderate to severe pain associated with ureteral spasm is 1 suppository
(each suppository: belladonna 16.2 mg/opium 30 mg OR belladonna 16.2
mg/opium 60 mg) rectally once or twice a day; maximum of 4 doses per
day. Belladonna and opium rectal suppositories have not been found by the
FDA to be safe and effective and are not recommended for use.

Psychotropic Drugs
Psychoactive substances are substances that affect mental processes, for
example, cognition or affect. This and its equivalent, psychotropic drug,
are the most neutral and descriptive term for the whole class of substances,
licit and illicit, of interest to drug policy. In a large population study in The
Netherlands, cancer patients were often prescribed psychotropic drugs

2209
including benzodiazepines, antidepressants, and antipsychotics.216 The
pattern of use was more common soon after diagnosis with increases in the
terminal stage of the disease. The presence of pain and (to a greater extent)
poor pain control were associated with increased use of certain
psychotropic drugs, such as anxiolytics and hypnotics.217 Use of hypnotics
or anxiolytics drugs is associated with increased mortality and should be
used cautiously.218–221 Among drugs most frequently involved in drug
overdose deaths in the United States, alprazolam and diazepam are
featured.222 Concurrent benzodiazepine use was also associated with an
increased risk of death from overdose in patients receiving opioids.33
Cancer patients often require the use of a psychoactive drug. Some need it
for pain relief (e.g., tricyclic antidepressants for nerve injury pain),
whereas others need an antiemetic (e.g., lorazepam for CINV). Still, others
require an anxiolytic, such as clonazepam or alprazolam. Some require a
night sedative and others an antidepressant for identifiable depression. The
concurrent use of two centrally acting drugs (e.g., opioid with
psychotropic drug or two psychotropic drugs together) is more likely to
produce sedation in ill and malnourished cancer patients than in others. A
comprehensive review of psychotropic drugs in pain management appears
in Chapters 31 and 81.

Cannabinoids
Cannabis sativa contains over 450 compounds, with at least 70 classified
as phytocannabinoids. Of medical interest are delta 9-tetrahydrocannabinol
(THC) and cannabidiol (CBD). THC is the main active constituent, with
psychoactive and pain-relieving properties. CBD not only has lesser
affinity for the cannabinoid (CB) receptors and the potential to counteract
the negative effects of THC on memory, mood, and cognition but also has
an effect on pain modulation. The discovery of the endocannabinoid
system (cannabinoid receptors CB1 and CB2 and their endogenous
ligands) resulted in studies concerning the pharmacologic activity of
cannabinoids. Endocannabinoids act as ligands at cannabinoid receptors
within the nervous system (primarily but not exclusively CB1 receptors)
and in the periphery (primarily but not exclusively CB2 receptors).

2210
Cannabinoids have been recommended for the prevention of CINV223 and
may be effective in cancer patients who respond poorly to commonly used
agents.224 In a 2015 review, patients who received cannabinoids were 5
times as likely to report complete absence of vomiting, and three times as
likely to report complete absence of nausea and vomiting but when
compared with conventional antiemetic drugs, there was no evidence of a
difference for nausea, vomiting, or nausea and vomiting.225
The DEA lists marijuana and its cannabinoids as Schedule I controlled
substances, which means that they cannot legally be prescribed under
federal law. Two cannabinoids (dronabinol, nabilone) are approved by the
FDA and therefore can be legally prescribed in the United States.
Dronabinol contains the trans isomer of THC within a gelatin capsule.
Marijuana can be used to make hashish and hash oil, which contain
concentrated cannabinoids. Both marijuana and hash oil can be consumed
by inhalation (smoking and vaporizing) and by mouth (drinking it as a tea
or eating after it is mixed into foods, such as baked goods). Smoked
cannabis has been found to contain Aspergillosis, and immunosuppressed
patients should not use it.226 Vaporizing marijuana by heating it to
temperatures between 180°C and 200°C releases substantial amounts of
cannabinoids with only trace amounts of a few other chemicals. Maida et
al.227 assessed the effectiveness of nabilone in managing pain in advanced
cancer patients which significantly improved pain, nausea, anxiety, and
total distress. Johnson et al.228 compared the efficacy of a THC:CBD
extract (2.7 mg THC, 2.5 mg CBD delivered by oromucosal spray) and a
THC extract (2.7 mg THC delivered by oromucosal spray), with placebo
in 177 patients with refractory cancer pain to chronic opioid therapy
(average daily oral morphine equivalent dose [MED] 271 mg) and reported
that the THC:CBD extract was efficacious, but the number of THC
responders was similar to placebo. In a pilot study of 18 patients with pain
related to CIPN, nabiximols (THC/CBD oral mucosal spray) had an
efficacy comparable to the use of gabapentin for this problem.229 Both
cannabis and cannabinoid pharmaceuticals can be helpful for a number of
problems affecting patients with cancer.230,231 Data supporting the use of
these products for cancer-related pain is lacking.

2211
Opioid Analgesics
Opioids are the mainstay of pharmacotherapy for patients with moderate or
more intense pain resulting from virtually any cancer-related etiology. A
detailed discussion of opioid pharmacology and principles of prescribing is
found in Chapter 79.

SELECTION OF OPIOID THERAPY IN CANCER PAIN

MANAGEMENT
As in all patients who may have pain-related indications for opioid
therapy, the effective clinical use of opioid drugs requires familiarity with
drug selection, routes of administration, dosage guidelines, and potential
adverse effects. Several factors must be considered if opioids are to be
used effectively. These include:
• Previous opioid exposure and preference
• Severity, nature, and stage of disease
• Age of patient
• Extent of cancer, particularly hepatic and renal involvement altering
normal opioid pharmacokinetics
• Concurrent disease
• Available formulations
• Risk assessment for problematic opioid use (see “Substance Abuse in
Oncology” section)
The presence of renal impairment or failure affects the
pharmacokinetics of opioids (Table 43.8). Renal failure has different
effects on individual opioids with some opioids having active or toxic
metabolites. The effects from dialysis should also be considered with the
likelihood of removal of any molecule in blood by dialysis dependent on
the molecular weight, water solubility, degree of protein binding, and
volume of distribution. Fentanyl, for example, has high protein binding
and low water solubility, as well as a high volume of distribution, and a
moderately high molecular weight suggesting poor removal by
dialysis.232,233 Glomerular filtration rate (GFR) approximates the renal
excretion of many drugs, and some authors recommend adjustment of
opioid dosage based on the GFR.234 Unlike estimates of GFR in renal

2212
disease, adequate biomarkers relating to hepatic function and drug
elimination capacity, are not available. The most commonly used systems
to assess the severity of hepatic impairment are the Child-Pugh
classification and the Model for End-Stage Liver Disease (MELD) system.
Opioids used in patients with severe liver disease in patients with a history
of hepatic encephalopathy may precipitate or aggravate encephalopathy.235
Methadone is metabolized by oxidation, with principal involvement of
CYP3A4 and CYP2B6. The elimination of methadone and its metabolites
is urinary and fecal. The use of methadone was studied in 11 patients with
severe liver disease and although the t1/2 was longer, peak plasma levels
were lower. None of the patients had signs or symptoms of overdose and
six patients had flattened plasma methadone concentration-time curves
(Table 43.9).236

TABLE 43.8 Opioid Use in Renal Dysfunctiona and

Hemo/Peritoneal Dialysis
Removal by
Recommendations Hemo/Peritoneal
Drug for Safe Use Comments Dialysis
Preferred Opioid
HYDROmorphone Single dose safe Metabolized to active May be dialyzable
(Dilaudid) Consider a lower hydromorphone-3- to a certain extent
dose and less glucuronide Monitor for
frequent dosing Accumulation of this rebound pain after
intervals with metabolite may cause dialysis.
repeated use. neuroexcitatory
effects: Monitor for
agitation, confusion,
hallucination.
Potentially Acceptable Opioids
Fentanyl Single dose safe No active metabolites Poorly dialyzable
Intravenous Consider a lower Appears to have no
Transmucosal dose and less added risk of adverse
(Actiq) frequent dosing effects in renal
intervals with dysfunction except
repeated use. for drug
accumulation
Hydrocodone Single dose safe Metabolized to No data for parent
(Vicodin, Norco) Consider a lower HYDROmorphone, drug, some
dose and less which is metabolized removal of
frequent dosing to hydromorphone-3- metabolites

2213
 intervals with glucuronide Monitor for
repeated use. Accumulation of this rebound pain after
metabolite may cause dialysis.
neuroexcitatory
effects: Monitor for
agitation, confusion,
hallucination.
Methadone Should only be No active metabolites Not dialyzable
(Dolophine) used by prescribers Minimal
with expertise in accumulation in renal
methadone failure or impairment
management due to elimination by
Dose adjustment hepatobiliary
for renal clearance
impairment or Variable
failure unlikely to pharmacokinetics,
be needed difficult to titrate
dose
Oxycodone Single dose safe Active metabolite No data for
Immediate-release Consider a lower oxymorphone AND oxycodone or
(Roxicodone) dose and less parent drug can metabolites
frequent dosing accumulate in renal
intervals with failure
repeated use. CNS toxicity and
sedation have been
reported with
accumulation in renal
failure
Oxycodone Reduce dose until
Controlled release steady-state effects
(OxyContin) known (1–2 days)
Dialysis: lack of
data in dialysis
Avoid use
(preferred) OR
administer with
caution and careful
monitoring.
Avoid Use
Codeine Do not use Metabolites morphine- Not extensively
3-glucuronide and dialyzed
morphine-6-
glucuronide can
accumulate, causing
unpredictable
therapeutic and
adverse effects.
Fentanyl Do not use Long half-life and risk Poorly dialyzable

2214
 Transdermal of drug accumulation
(Duragesic)
Meperidine Do not use Toxic metabolite Limited data but
(Demerol) normeperidine can appears minimally
accumulate which removed by
can decrease seizure dialysis
threshold and may
cause neuroexcitatory
effects.
Morphine Avoid if possible Active metabolites Parent drug and
Immediate release If used, reduce (morphine-3- metabolites can
(MSIR) dose and extend glucuronide and both be removed
frequency with morphine-6- with dialysis.
repeated dosing glucuronide) can Monitor for
accumulate which rebound pain
may result in effect.
unpredictable
therapeutic and
adverse effects
Morphine/metabolites
are dialyzable and
can be used with
caution if patients
adhere to scheduled
dialysis and/or are on
a stable regimen.
However, there is
significant risk of
morphine/metabolite
accumulation with
missed dialysis
sessions and should
be used with caution.
NOTE: 2 mg IV morphine = 0.4 mg IV HYDROmorphone = 20 μg IV fentanyl = 5 mg PO
oxycodone (relative equivalency for opioid-naive patients).
aEstimated glomerular filtration rate for African or European American <50 mL per minute.

CNS, central nervous system.

TABLE 43.9 Opioid Pharmacokinetics in Patients with Severe

Liver Disease (Unless Otherwise Stated)
Recommendation and Dose
Drug Pharmacokinetic Changes Adjustments
Codeine Reduced metabolism to morphine Avoid use.
Tramadol 3-fold ↑ AUC and 2.5-fold ↑ t1/2 Prolong dosage intervals or reduce
doses.
Tapentadol 1.7- to 4.2-fold ↑ AUC and 1.2- to Moderate liver disease: reduce

2215
 1.4-fold ↑ t1/2 in mild and dose and prolong dosing interval.
moderate liver disease Severe liver disease: no data
Morphine ↑ Oral bioavailability; ↑ t1/2; ↓ CL 2-fold prolongation in dosage
intervals. Reduce oral doses.
Oxycodone ↑ AUC; ↑ t1/2; ↓ CL Lower doses with prolonged
dosage intervals.
Hydromorphone ↑ Oral bioavailability; no change in Reduce doses; consider prolonged
t1/2 in moderate liver disease. dosage intervals only in severe
liver disease.
Meperidine ↑ Oral bioavailability; 2-fold ↑ t1/2; Avoid repeated use; risk of
2-fold ↓ CL neurotoxic metabolite
accumulation
Methadone ↑ t1/2; possible risk of No dose changes in mild and
accumulation moderate liver disease; careful
titration in severe liver disease
Buprenorphine No data No recommendations
Fentanyl No change after single IV dose in Dose adjustment usually not
moderate liver disease needed; consider dose adjustment
with continuous infusion or with
transdermal patch.
NOTE: Disease severity is classified as mild, moderate, or severe (Child-Pugh classes A, B, and C,
respectively).
AUC, area under the plasma concentration-time curve; CL, total plasma clearance; t1/2, elimination
half-life.
Modified by permission from Springer: Bosilkovska M, Walder B, Besson M, et al. Analgesics in
patients with hepatic impairment: pharmacology and clinical implications. Drugs
2012;72(12):1645–1669. Copyright © 2012 Springer International Publishing AG.

The specific pathogenic mechanism that underlies a patient’s cancer

pain should not be a factor in deciding which opioid to use because the
mechanism of pain does not reliably predict the response to opioid
therapy.237 This particularly applies to situations in which tumor-
associated neuropathic mechanisms dominate the pain complaint. Opioids
should be used as first-line therapy in such situations, particularly if the
pain is considered moderate to severe in intensity. Haumann et al.238
demonstrated a beneficial effect from methadone compared to fentanyl on
head-and-neck cancer patients with neuropathic pain.
Oxycodone/naloxone and pregabalin were also deemed effective in lung
cancer patients with neuropathic pain.239 Controlled-release oxycodone
(average daily dose 28 mg with range 20 to 80 mg) was effective and well-
tolerated in patients with bortezomib-associated painful CIPN.240 There is
limited data on the use of opioids for neuropathic nonmalignant pain.

2216
Extended-release oxycodone was used for the management of painful
diabetic neuropathy and postherpetic neuralgia, but the data was
considered very low quality.241 Morphine was also studied for use in
painful diabetic neuropathy, CIPN, postherpetic neuralgia, phantom limb
or postamputation pain, and lumbar radiculopathy again with insufficient
evidence to support or refute use.242 Similarly, the data support the use of
methadone243 and fentanyl244 for diverse neuropathic pain syndromes
including postherpetic neuralgia is also inconclusive. Short-term studies
provide only equivocal evidence regarding the efficacy of opioids in
reducing the intensity of neuropathic pain. Intermediate-term studies
demonstrated significant efficacy of opioids over placebo, but these results
are likely to be subject to significant bias because of small size, short
duration, and potentially inadequate handling of dropouts.245
Patients surviving cancer typically experience a shift in the use of
opioids from the routine prescribing that occurred in the active treatment
phase to an approach more consistent with prescribing patterns for chronic
noncancer pain when pain is expected to persist for years.246 However, the
rate of opioid prescribing was significantly higher among survivors of
cancer compared with age/sex-matched controls without a prior cancer
diagnosis and higher prescribing rate persisted, even for survivors more
than 10 or more years postdiagnosis. The rate of prescriptions was greater
for survivors of lung, GI, genitourinary, or gynecologic cancer compared
with their corresponding controls.247
There is little high-grade data on opioid use specifically in the elderly
cancer patient. Elderly patients are more likely to have multiple
comorbidities, the potential for drug interactions, and are physiologically
more vulnerable to opioid use than younger patients. There are also age-
related differences in the perception of, and response to, pain.248 Because
the elderly have a higher incidence of cognitive impairment, confusion,
and memory loss, either from pathology or medication use, and
confounded by sight and hearing impairment, problems with prescription
adherence and medication-related adverse effects can occur. The
tolerability profile of opioids is important in elderly patients, as adverse
events such as drowsiness, dizziness, and motor imbalance can have
serious consequences in patients who are already more prone to falls and

2217
fractures.249 Daily use of three or more psychoactive medications was
associated with recurrent falls in the elderly.250 High-risk medications, in
particular benzodiazepines and benzodiazepine-receptor agonists, often
administered at higher-than-recommended geriatric daily doses, were
associated with falls in elderly, hospitalized patients.251
In general, the clinical circumstance dictates the choice of a short- or
long-acting opioid. For example, the treatment of acute or postoperative
pain usually requires frequent titration, and short-acting opioids, with
duration of action of 2 to 4 hours, are preferred. Short-acting agents may
be favored initially for the management of mild- to moderate-intensity
tumor pain as they are easier to titrate than long-acting or ATC opioids.
Short-acting opioids are characterized by a rapid rise and fall in serum
opioid levels, whereas serum levels of long-acting opioids increase slowly
to therapeutic levels, remain there for an extended period, and then slowly
decline.252 Conversely, the treatment of cancer pain or chronic, moderate
to severe nonmalignant pain usually can be treated with a long-acting oral
agent, with a duration of action of 12 to 24 hours, with less need for daily
titration. In patients treated with long-acting agents, short-acting opioids
should be provided as rescue medication for breakthrough pain, which is
very common in patients with cancer pain.253,254 An ongoing opioid
regimen should include provisions for rescue doses for the treatment of
breakthrough pain. The rationale for providing rescue medication instead
of increasing the dose of the ATC opioid is to prevent overmedication and
associated adverse events. Often, there is a narrow therapeutic window
between an opioid dose sufficient to achieve pain relief and one that is
associated with unacceptable adverse events.255 For patients treated with a
long-acting opioid, an immediate-release (IR) or short-acting opioid
formulation (often the same drug) may be used as the rescue medication.
In general, the rescue drug should be started at a dose equivalent to
approximately 10% of the 24-hour baseline dose and titrated upward to
achieve adequate pain relief.256 The dosing frequency of the rescue drug
depends on the time to peak effect and the route of administration; in
general, oral rescue doses can be administered as frequently as every 2
hours if needed but typically tend to be given every 3 to 4 hours as
needed.257 Generally, three types of breakthrough pain should be

2218
considered—spontaneous, incident, or end-of-dose failure.258 A key
principle in treating breakthrough pain is to optimize the background pain
control by appropriately adjusting the ATC opioid regimen. With end-of-
dose failure, the clinician can increase the dose or shorten the dosing
interval of the ATC opioid or increase the dose of the rescue opioid.
Similar strategies may be employed for spontaneous pain, but successful
management of spontaneous or incident pain may require the use of short-
acting, rapid-onset opioids (“Oral Transmucosal/Intranasal/Sublingual
Fentanyl” section).
Because of the substantial interpatient variability in opioid
responsiveness, clinicians who prescribe opioids for the treatment of
cancer pain should be familiar with at least three different agents
appropriate for the management of moderate to severe pain.259 The
pharmacology of these agents can be reviewed in Chapter 79.
The regimen for opioid medications should generally provide ATC
analgesia with provision for rescue doses for the management of
exacerbations of the pain not covered by the regular dosage. Various
extended-release oral and transdermal opioids are listed in Table 43.10. At
all times, causes of new or uncontrolled pain should be determined and
addressed by disease-modifying treatments and a gradual increase in the
opioid dose until either pain control is achieved or intolerable and
unmanageable adverse effects supervene. The management of pain with
opioid analgesics demands frequent patient assessment and a readiness to
reevaluate the therapeutic plan in the setting of either inadequate relief or
adverse effects. Predicting effectiveness of extended-release opioids
requires knowledge of associated pharmacokinetics. In particular, the onset
time and time to maximal concentration (Tmax) is particularly helpful.
Table 43.11 lists Tmax for various doses of transdermal fentanyl. After
initial application, the maximal concentration (peak analgesic effect or
associated side effects) is not reached until approximately 32 hours. The
dosing interval is determined by steady state. For the extended-release
opioids, the t1/2 is not particularly helpful because of altered absorption
characteristics into the central compartment.

2219
 TABLE 43.10 Extended-Release Oral and Transdermal Opioids
Used in the Treatment of Cancer Pain
Name Trade Name Generic
Morphine MS contin Various extended-release
Avinza tablets and capsules
Kadian
Morphabond ERa
Arymo ERa
Oxycodone OxyContina
Xtampza ERa
Troxyca ERa
(oxycodone/naltrexone)
Targiniqa
(oxycodone/naloxone)
Hydrocodone Hysingla ERa
Vantrela ERa
Hydromorphone Exalgo
Oxymorphone Opana ER Various extended-release
tablets
Fentanyl Duragesic Various extended-release
transdermal patches
Buprenorphine Butrans
Tapentadol Nucynta ER
a
Abuse-deterrent properties. Abuse-deterrent formulations target the known or expected routes of
abuse, such as crushing in order to snort or dissolving in order to inject, for the specific opioid
drug substance. Methadone is not included as it is not considered an extended-release (ER)
product.

TABLE 43.11 Pharmacokinetics of Transdermal Fentanyl

Following First 72-Hour Application
Tmax (h) Cmax (ng/mL)
Dose Mean (SD) Mean (SD)
12 μg/h 28.8 (13.7) 0.38 (0.13)
25 μg/h 31.7 (16.5) 0.85 (0.26)
50 μg/h 32.8 (15.6) 1.72 (0.53)
75 μg/h 35.8 (14.1) 2.32 (0.86)
100 μg/h 29.9 (13.3) 3.36 (1.28)
Tmax, time to maximal concentration; Cmax, maximal concentration.
Janssen MD. Duragesic (Fentanyl Transdermal System) for Transdermal Administration. Titusville,
NJ: Janssen MD; 2014.

2220
 There is no single optimal or maximal dose of an opioid analgesic drug.
In general, for progressive, tumor-related pain, the appropriate dose of an
opioid is one that relieves a patient’s pain throughout the dosing interval
without causing unmanageable or intolerable adverse events.260 The initial
dose may be based on the severity of pain and known response to prior
analgesic therapy, if any. Aggressive upward titration to a stable dose (i.e.,
one that provides adequate pain relief throughout the dosing interval) is
predicated on continuing assessment of the effectiveness of therapy.
Patients rarely benefit from combinations of different opioids given in
suboptimal doses; ideally, clinicians should prescribe a single opioid
analgesic and titrate to a stable dose.261 However, it is important to
recognize that there is significant interpatient variability with regard to
responsiveness to different opioid drugs, and patients who respond poorly
to one opioid may respond favorably to another.262 In situations in which
pain is not related to the tumor or its treatment, a dose limit should be
considered.263

TOLERANCE AND HYPERALGESIA

Opioid tolerance is a phenomenon in which repeated exposure to an opioid
results in decreased therapeutic effect of the drug or need for a higher dose
to maintain the same effect. Tolerance can be overcome by increase the
opioid dose. Opioid-induced hyperalgesia (OIH) is a state of nociceptive
sensitization caused by opioid exposure and is characterized by a
paradoxical response to opioid treatment where patients become more
sensitive to pain. In contrast to tolerance, dose increases make the pain
complaint worse. OIH is more commonly seen in patients receiving high
opioid doses. The majority of reports not only involve the use of systemic
(oral, intravenous, intramuscular) or intrathecal morphine264,265 but may
also occur with intrathecal sufentanil,266 fentanyl,267,268 remifentanil,269
and hydromorphone.270 In this setting, patients report increased pain as
well as allodynia and myoclonus. OIH has been reported in various clinical
settings including acute pain,269 chronic noncancer pain,271 cancer
pain,272,273 and opioid addiction.274 Very high intravenous and intrathecal
opioid doses can cause OIH. OIH should be recognized as a syndrome of
neuroexcitatory effects, which includes hyperalgesia, allodynia,

2221
myoclonus, and seizures. The predominant symptom of OIH is severe
allodynia (touch-evoked pain) and is often accompanied by myoclonus.
Placing a blanket on or gently turning a bedridden patient can evoke
excruciating pain. The diagnosis is confirmed if further dose escalation
exacerbates pain complaints or symptoms and temporarily holding opioid
therapy eliminates or reduces symptoms. Management strategies for
hyperalgesia usually require a reduction in opioid dosage and/or switching
to a different opioid, especially one that does not have known toxic
metabolites. However, the occurrence of OIH with normal clinical doses is
questionable.275,276 In a study on the presence of OIH following oral
administration of opioids (oxycodone and morphine in daily doses up to
200 mg) in both cancer and noncancer pain patients, OIH was not
observed.277 Not all patients develop OIH and the detection and
occurrence of OIH poses a significant clinical challenge in acute, chronic,
and cancer pain settings.
Theoretically, prolonged use of opioids is known to result in
antinociceptive tolerance, in which higher doses of the opioid are required
to elicit the same amount of pain relief or antinociception.278–280 Chu et
al.281 showed that patients receiving sustained-release morphine to an end
titration dose of 78 mg morphine per day developed tolerance after 1
month with an average 42% reduction in analgesic potency. Long-term
exposure to one drug often results in the development of tolerance to the
effects of other structurally similar drugs in the same pharmacologic class,
a phenomenon termed cross-tolerance. Opioids exhibit cross-tolerance, but
it is rarely complete, as evidenced by opioid rotation particularly in the
treatment of cancer pain.282–286 Clinically, opioid rotation is challenging
because of a lack of evidence-based medicine to support the dose
conversions with switching regimens largely based on anecdote or on
observational and uncontrolled studies.287 In practice, physical dependence
and tolerance does not prevent the effective use of these drugs in patients
with cancer pain. The evidence for the development of tolerance to the
analgesic effects of opioids with chronic administration in oncology is
mixed. Many of the studies were in cancer patients with severe pain and
showed that they maintained a stable opioid dose (for weeks to years) even
with different routes of administration.279,288 Patients with stable disease

2222
often remain on a stable dose for weeks or months.289 Collin et al.290
demonstrated a relationship between tumor progression and escalation of
opioid doses over time such that the development of opioid tolerance from
chronic opioid use was unlikely in cancer patients with pain.

MORPHINE
Morphine is the oldest opioid and is generally considered to be the gold
standard. In a Cochrane review, Wiffen et al.12 reported that morphine was
an effective analgesic for cancer pain and that pain relief did not differ
between extended (modified) release and IR preparations. Modified-
release morphine was effective for 12- or 24-hour dosing depending on the
formulation. Daily doses in studies ranged from 25 to 2,000 mg with an
average of between 100 and 250 mg. A small number of patients did not
achieve adequate analgesia with morphine and although adverse events
were common, they were predictable with approximately 6% stopping
treatment because of intolerable adverse events. The main disadvantage of
morphine in cancer patients who require high opioid doses, or who have
reduced renal clearance, is the accumulation of active (morphine-6-
glucuronide) and toxic (morphine-3-glucuronide), which may complicate
the clinical picture with excessive sedation or neurotoxic adverse
effects.291 Early signs of these effects should trigger consideration for
switching to a different opioid.

OXYCODONE
Oxycodone may exert its analgesic effects through µ-opioid receptor and κ
receptors.292 Modified-release oxycodone (OxyContin) reaches Tmax at
approximately 4.6 hours with an apparent t1/2 of 4.5 hours. OxyContin was
reformulated in 2010 with inactive ingredients intended to make the tablet
more difficult to manipulate for misuse and abuse and has an oral
bioavailability of 60% to 87%. With reformulation, the immediate
component (estimated up to 30% of the total dose) was eliminated. Unlike
morphine, the drug is not glucuronidated but metabolized primarily by
CYP3A4. Concomitant use of with a CYP3A4 inhibitor, such as macrolide
antibiotics (e.g., erythromycin), azole-antifungal agents (e.g.,
ketoconazole), and protease inhibitors (e.g., ritonavir), may increase

2223
plasma concentrations of oxycodone. Use with serotonergic drugs may
result in serotonin syndrome. Oxycodone is extensively metabolized by
multiple metabolic pathways to produce noroxycodone, oxymorphone, and
noroxymorphone. Oxymorphone is present in the plasma only at low
concentrations. Cancer cachexia can increase the plasma exposure of
oxycodone through the reduction of CYP3A metabolic pathway.293
Oxycodone offers similar levels of pain relief and adverse events to other
opioids including morphine for cancer-related pain.11,294 Like any opioid,
the benefits of recommending oxycodone as an alternative opioid for
moderate to severe cancer pain are in choice and flexibility.295 Choice
includes cost, perceptions, social or cultural factors, and availability.
Flexibility is having the ability to offer an alternative should another
opioid prove ineffective or poorly tolerated.

OXYMORPHONE
Oxymorphone is a semisynthetic µ-opioid agonist that exhibits greater
specificity for the µ-opioid receptor than for the δ- or κ-opioid
receptors.296,297 In 2006, the FDA-approved extended-release
oxymorphone HCl for the control of moderate to severe chronic pain. The
pharmacokinetic profile is predictable, linear, and dose-proportional.298
The t1/2 is 9 to 11 hours. The Tmax varies from 3 to 6 hours.299 The
absolute oral bioavailability is approximately 10%. Oxymorphone
undergoes minimal CYP450 metabolism, and is metabolized primarily by
UGT2B7 (and potentially UGT1A3) to the inactive metabolite
noroxymorphone. Consequently, oxymorphone ER, along with morphine
and hydromorphone, lacks significant potential for CYP-mediated drug
interactions and is unaffected by genetic factors influencing these
enzymes. In contrast, other opioids including methadone, oxycodone,
buprenorphine, and others metabolized by CYP enzymes have the
potential for clinically important pharmacokinetic interactions with other
drugs that share this metabolic pathway. Slatkin et al.300 evaluated the
effectiveness and tolerability over 52 weeks of oxymorphone ER in
patients with cancer and noted that the drug was well tolerated and
provided long-term stable pain control. Oxymorphone IR has a t1/2 longer
than that of morphine, hydromorphone, and oxycodone and a Tmax of 30

2224
minutes. Food does not affect the shape of concentration time curve.297

HYDROMORPHONE
Hydromorphone is a semisynthetic derivative of morphine. It primarily
acts on µ receptors and to a lesser degree on δ receptors.301
Hydromorphone binds more specifically to µ receptors than structurally
related morphine. The IR form is absorbed in the upper small intestine and
is extensively metabolized by the liver. Approximately 60% of the oral
dose is eliminated by the liver on first pass, partly accounting for oral
bioavailability in the range of 1:2 to 1:8.302 For orally administered, IR
preparations, the onset of action is approximately 30 minutes, Tmax 0.75
hours and duration of action is approximately 4 hours. Hydromorphone is
glucuronidated into hydromorphone-3-glucuronide, a metabolite that may
have neuroexcitatory effects.291,303 Hydromorphone-3-glucuronide follows
a similar time course to hydromorphone in plasma. Of note there is an
extended-release hydromorphone product (Exalgo). Hydromorphone in
clinically relevant concentrations has minimal potential to inhibit CYP
enzymes. After oral intake, plasma concentrations gradually increase over
6 to 8 hours, with a Tmax ranging from 12 to 16 hours and concentrations
are sustained for 18 to 24 hours. Mean t1/2 is approximately 11 hours, and
linear pharmacokinetics occur over a dose range from 8 to 64 mg. Steady
state is reached 3 to 4 days after once-daily dosing. The safety and
tolerability of Exalgo has been reported in opioid-tolerant patient with
moderate to severe chronic cancer and noncancer pain.304 The mean
duration of exposure was 43.1 days (range 1 to 396 days), and mean daily
dose was 43.4 mg. Patients demonstrated a safety and tolerability profile
consistent with the known safety profiles of opioids. Bao et al.305 reported
that in oncology pain, hydromorphone provides similar pain relief to
morphine and oxycodone and has similar side effects.

METHADONE
Methadone is a synthetic opioid and is a potent agonist at the µ- and δ-
opioid receptors. In animal studies, it has antagonist activity at the N-
methyl-D-aspartate (NMDA) receptor, resulting in interest in the clinical
application of the drug in neuropathic pain syndromes.306–309 In most

2225
countries, it is available as a racemic mixture of two isomers, levorotatory
(L) methadone and dextrorotatory (D) methadone. Following oral
administration, the drug is rapidly absorbed with measurable plasma levels
between 15 and 45 minutes. The peak plasma levels after an oral dose
occur at four hours and begin to decline 24 hours after dosing.310 Oral
bioavailability is over 85%. The primary route of elimination is oxidative
biotransformation. It is N-demethylated to 2-ethylidene-1,5-dimethyl-3,3-
diphenylpyrrolidine (EDDP). The major enzyme involved in N-
demethylation is CYP3A4 and CYP2B6. CYP2D6 genetic status affects
steady-state blood concentrations. The t1/2 ranges from 5 to 130 hours with
a mean of 20 to 35 hours.310 Concomitant administration of CYP3A4
inducers will increase methadone metabolism potentially causing a
reduction in methadone plasma concentrations. This may result in the need
for larger doses of methadone during the period of interaction. In addition,
doses of methadone may need to be reduced when a CYP3A4 inducer is
discontinued. Known inducers of CYP3A4 include rifampin, rifabutin,
carbamazepine, phenytoin, phenobarbital, and abacavir. The commonly
used dietary supplement for depression, St. John’s Wort, has also been
shown to lower the plasma concentrations of methadone.311 CYP2B6
plays a significant role in the stereoselective metabolism of (S)-methadone
to 2-ethyl-1,5-dimethyl-3,3-diphenylpyrrolidine, an inactive methadone
metabolite. Elevated (S)-methadone can cause cardiotoxicity by
prolonging the QT interval. One or more single nucleotide polymorphisms
(SNPs) located within the CYP2B6 gene can contribute to a poor
metabolizer phenotype with higher than predicted methadone levels and
can be associated with fatalities.312,313
Methadone is implicated in the prolongation of the QTc interval, which
is considered a marker for arrhythmias such as torsade de pointes (TdP).
Indications on the association between methadone, even at therapeutic
dosages, and TdP or sudden cardiac death are reported.314,315 A QTc of
500 milliseconds is generally accepted as a threshold of increased danger
for TdP.316 Evidence implicating the relationship between methadone and
TdP is limited, and the contributions of other known risk factors (including
other medications, drugs, electrolyte abnormalities, structural heart
disease, and others) are also implicated.317 In a pediatric oncology patient

2226
population, methadone dosage, and duration (mean dose was 27.0 mg per
day with range, 5 to 125 mg per day; mean duration of therapy was 49
days) were not correlated with QTc prolongation, even in the presence of
other risk factors at clinically effective analgesic doses.318 In a pilot study
on adult oncology patients treated with oral methadone (median dose 23
mg, range 3 to 90 mg) over an 8 week period, 28% of patients had
evidence of QTc prolongation prior to initiation of methadone and only 1
patient demonstrated a QTc >500 milliseconds without evidence of a
clinically significant arrhythmia.319 Of note, conventional chemotherapy
and targeted therapies are associated with an increased risk of cardiac
damage, including LV dysfunction and heart failure, treatment-induced
hypertension, vasospastic and thromboembolic ischemia, as well as rhythm
disturbances, including conduction system damage and potentially QTc
prolongation that may be rarely life-threatening.320 In addition, the use of
some medications used in supportive care during cancer therapy (e.g.,
antiemetics, antidepressants) in combination with cancer treatments can
lead to QT prolongation.321
Methadone is a versatile and potentially useful analgesic for cancer pain
control. It has no known active metabolites, and it is relatively inexpensive
compared with other modified-release opioid formulations. Because of a
highly variable t1/2, the use of methadone is complicated with potential for
accidental overdose if not titrated appropriately. Because steady state is
not attained for 3 to 5 days, dose changes need to be slow and situations
that require frequent dose changes (e.g., rapidly escalating tumor pain) are
not ideal for methadone use. Prescribers should be experienced with the
use of methadone in oncology, and patients need to be carefully counseled
and cautioned to use methadone only as directed in order to prevent
unintended dose accumulation. Based on very limited amounts of data,
there were no clear differences in participant-reported pain intensity or
pain relief between methadone and morphine or transdermal fentanyl.322
In a relatively small number of patients (146 patients) with cancer-related
pain, methadone was considered effective as a second-line alternative
opioid for patients with a lack of efficacy or intolerance issues with their
previous opioid.323

2227
LEVORPHANOL
Levorphanol is considered a full µ-opioid agonist and is relatively
selective for µ-opioid receptors although it also has multiple receptor
activity including δ, κ1, and κ3, with NMDA receptor antagonism and
reuptake inhibition of both norepinephrine and serotonin.324 It is well
absorbed after PO administration with peak plasma concentrations
occurring approximately 1 hour after dosing. Levorphanol has a t1/2 of 11
to 16 hours with a duration of analgesic effect between 6 and 15 hours.325
Expected steady-state plasma concentrations for a 6-hour dosing interval
can reach 2 to 5 times those following a single dose, depending on the
patient’s individual clearance of the drug. It has no known effect on QTc
interval or drug–drug interactions involving CYP450 enzymes. It is
metabolized to levorphanol-3-glucuronide which is inactive. From a
relative potency perspective at steady state, 2 mg oral dose of levorphanol
is approximately equivalent to 10 mg oral oxycodone. Dose conversion
suggestions for levorphanol are listed in Table 43.12. Typical initial doses
are 1 to 2 mg every 6 to 8 hours and are available as a 2-mg tablet.
Information on the use of levorphanol in cancer pain is limited.
McNulty326 reported on its use in a case series of 31 patients, 20 with
chronic nonmalignant pain in a palliative care clinic and 11 terminally ill
patients enrolled in hospice care whose severe chronic pain was not
relieved by treatment with other opioids, were treated with oral
levorphanol. Of those 31 patients, 16 (52%) reported excellent relief of
pain and 7 (22%) reported fair relief.

TABLE 43.12 Conversion Ratios to Levorphanol

Oral Morphine Equivalent Morphine–Levorphanol Ratio
<100 mg 12:1
100–299 mg 15:1
300–599 20:1
600–799 25:1
>800 mg No data
From McNulty JP. Can levorphanol be used like methadone for intractable refractory pain? J Palliat
Med 2007;10(2):293–296. The publisher for this copyrighted material is Mary Ann Liebert, Inc.
publishers.

2228
FENTANYL
Fentanyl is a synthetic full agonist at µ-opioid receptors and has a high
lipophilicity allowing rapid transfer from the plasma to cerebrospinal fluid
(CSF). Nonparenteral fentanyl products first became available in the last
1980s as a transdermal patch and then as a transmucosal product in 1993.
Nonintravenous formulations deliver fentanyl by transmucosal, intranasal,
or by transdermal routes. The main advantage of the patch was
maintenance of a steady-state plasma concentration ideal for the treatment
of background cancer pain. The main advantage of the transmucosal
product was its associated rapid absorption is ideal for the management of
breakthrough cancer pain. The pharmacokinetic and clinical parameters of
nonparenteral fentanyl formulations are listed in Table 43.13.

TABLE 43.13 Pharmacokinetic and Clinical Parameters of

Nonparenteral Fentanyl Formulation
Oral Transmucosal Intranasal Transdermal
Sustained-
SL SL Buccal Buccal Nasal Release
Parameter Lozenge Tablet Spray Tablet Film Spray Patch
Product and Actiq Abstral Subsys Fentora Onsolis Lazanda Duragesic
fentanyl (200, (100, (200, (100, (200, (100, (12.5, 25,
dosages (μg) 400, 200, 400, 200, 400, 400) 50, 75, 100
600, 300, 600, 400, 600, μg/h every
800, 400, 800) 600, 800, 72 h)
1,200, 600, 800) 1,200,
1,600) 800) 1,600)
Bioavailability 50 ~70 76 65 71 120, 92
(%) relative
to Actiq
Tmax 40 min 40 min 40 min 45 min 60 min 20 min Constant
from 14–24
h based on
venous
blood
samples
t1/2 7.6 h 11.5– 5.25 13.3 h 19.03 h 15–24.9 h 17 h after
25 h (100 patch
μg) removal
8.45
(200
μg)
11.03

2229
 (400
μg)
10.64
(600
μg)
11.99
(800
μg)
Onset of pain 4.2 min 15 min 5 min 10 min 15 min 10 min 12–24 h
relief (for for 400
both μg
200,
800
μg)
Duration of 145 60 min At At At At least Up to 12 h
pain relief min for least least least 60 min after patch
(200 100– 60 min 60 min 60 min removal
μg) 800 μg
215
min
(800
μg)
SL, sublingual; t1/2, elimination half-life; Tmax, time to maximal concentration.
Modified by permission from Springer: Lotsch J, Walter C, Parnham MJ, et al. Pharmacokinetics of
non-intravenous formulations of fentanyl. Clin Pharmacokinet 2013;52(1):23–36. Copyright ©
2012 Springer International Publishing Switzerland.

Transdermal Fentanyl
Transdermal therapeutic system fentanyl (fentanyl-TTS) patches are
rectangular transparent units each comprising a protective liner and four
functional layers. These layers consist of a backing layer of polyester film,
a drug reservoir of fentanyl and alcohol USP gelled with hydroxyethyl
cellulose, an ethylene-vinyl acetate copolymer membrane that controls the
rate of fentanyl delivery to the skin surface, and a fentanyl-containing
silicone adhesive. The amount of fentanyl released from each system per
hour is proportional to the surface area (25 µg per hour per 10 cm2). Each
patch contains a proportional fentanyl content, for example, the 12 µg per
hour patch has a total fentanyl content of 1.25 mg and the 25 µg per hour
patch 2.5 mg fentanyl content. The Duragesic patch has a protective liner
and four functional layers consisting of a backing layer of polyester film, a
drug reservoir of fentanyl and alcohol USP gelled with hydroxyethyl
cellulose, an ethylene-vinyl acetate copolymer membrane that controls the

2230
rate of fentanyl delivery to the skin surface, and a fentanyl-containing
silicone adhesive. The initial formulation consisted of a liquid fentanyl
drug reservoir separated from the adhesive layer by a rate-limiting
membrane, and ethanol as coabsorbent to provide controlled drug release.
This formulation was problematic because of the high concentration of
fentanyl present, which could be easily syphoned off.327–330 Newer
transdermal fentanyl formulations exclusively use the matrix technique,
with the drug dissolved in an inert polymer matrix that diminishes the risk
of incidental drug leakage and complicates the extraction of the drug for
abuse.331
The transdermal system releases fentanyl from the reservoir at a nearly
constant amount per unit time. The concentration gradient existing
between the saturated solution of drug in the reservoir and the lower
concentration in the skin drives drug release. Fentanyl moves in the
direction of the lower concentration at a rate determined by the copolymer
release membrane and the diffusion of fentanyl through the skin layers. A
cutaneous depot of fentanyl forms in the upper layers of the skin, the
stratum corneum, from where it passively diffuses to the dermis and
ultimately removed by the cutaneous microcirculation. Although the actual
rate of fentanyl delivery to the skin varies over the application period, each
system is labeled with a nominal flux, which represents the average
amount of drug delivered to the systemic circulation per hour across
average skin. Although there is variation in dose delivered among patients,
the nominal flux of the systems is sufficiently accurate to allow individual
titration of dosage for a given patient. Following patch application, the
skin under the system absorbs fentanyl, and a depot of fentanyl
concentrates in the upper skin layers. Fentanyl then becomes available to
the systemic circulation. There is a lag time of approximately 2 hours
before plasma levels of fentanyl are detected with therapeutic levels after
12 to 16 hours postapplication.332 Tmax for the patch is approximately 34
hours (see Table 43.13). The system delivers fentanyl continuously for up
to 72 hours with a bioavailability of approximately 92%. After sequential
48- or 72-hour applications, patients reach and maintain steady-state serum
concentrations that are determined by individual variation in skin
permeability and body clearance of fentanyl. A number of studies

2231
demonstrate that constant serum levels are maintained with the second
transdermal system and that fluctuations of serum levels are small after the
first 72 hours.333,334 After system removal, serum fentanyl concentrations
decline gradually and has an apparent t1/2 of 17 hours. Because of the
possibility of temperature-dependent increases in fentanyl release from the
system, it is important to advise patients to avoid exposing the application
site to direct external heat sources, such as heating pads, heat lamps, and
heated waterbeds. Prolonged exposure to heat or use in patients who are
febrile can cause a toxic overdose.335,336 Fentanyl is metabolized primarily
via cytochrome P450 3A4 isoenzyme system. Concomitant use of
CYP3A4 inhibitors may increase fentanyl plasma concentrations. Fentanyl
undergoes rapid and extensive first-pass metabolism that accounts for its
poor oral bioavailability (less than 30%) and the lack of oral products. The
patch should not be used in patients who are not opioid-tolerant, for acute
pain issues, for postoperative pain management and in the management of
intermittent pain.

TABLE 43.14 Dose Conversions for Transmucosal Immediate-

Release Fentanyl Medications
Initial Max Dose per
Drug Dose Treatment Event Frequency Titration
Actiq 200 μg Repeat same dose Wait >4 h Follow over time and plan
after 30 min if BTP for dose with single unit.
not adequately additional
relieved. Max doses treatment.
per event = 2.
Abstral 100 μg Repeat same dose Wait >2 h May use multiples of 100
(unless after 30 min if BTP for μg tabs and/or 200 μg tabs
being not adequately additional for any single dose; no
converted relieved. Max doses treatment. more than 4 tabs at one
from per event = 2. time
Actiq
≥400 μg)
Fentora 100 μg Repeat same dose Wait >4 h Follow over time and plan
(unless after 30 min if BTP for dose with single unit. May
being not adequately additional use multiple tablets (one on
converted relieved. Max doses treatment. each side of mouth in
from per event = 2. upper/lower buccal cavity)
Actiq until maintenance dose
≥600 μg) achieved

2232
 Lazanda 100 μg Only 1 dose per Wait >2 h Follow over time and plan
episode for dose with single unit.
additional Patients should confirm
treatment. dose that is adequate with
second episode of BTP.
Onsolis 200 μg Single episode Wait >2 h Titrate with 200 μg
treatment only; no for increments. No more than
redosing additional 4 films at once. If
treatment inadequate pain relief after
800 μg (×4 200 μg films)
and patient tolerates 800
μg dose, next episode may
be treated with 1,200 μg.
Subsys 100 μg Repeat same dose Wait >4 h Follow over time and plan
(unless after 30 min if BTP for dose with single unit.
being not adequately additional
converted relieved. Max doses treatment.
from per event = 2.
Actiq
≥600 μg)
BTP, breakthrough pain.

The transdermal patch is widely used in the treatment of both malignant

and nonmalignant chronic pain. Clinically, cachectic cancer patients may
require higher transdermal doses for adequate pain relief than normal
weight or obese patients. Heiskanen et al.337 studied the pharmacokinetic
profile in 10 cachectic (mean body mass index [BMI] 16 kg/m2) and noted
that plasma fentanyl concentrations adjusted to dose were significantly
lower at 48 and 72 hours in cachectic patients than normal weight patients
suggesting that the absorption was impaired in cachectic patients. The
cachectic patients had a significantly thinner upper arm skin fold, but no
differences were found in local blood flow, sweating, or skin temperature.
Hypoalbuminemia (albumin <3.5 g/dL) is also associated with poor
absorption from fentanyl-TTS.338 Although fentanyl-TTS is widely used in
palliative care settings, there are relatively few studies in its use in cancer
pain making judgment on efficacy difficult.339 Rash and pruritus,
commonly a concern with transdermal preparations, were infrequent and
improved with time. A number of studies compared the impact of
constipation between fentanyl-TTS and slow-release morphine.340–342
Fewer study participants experienced constipation with fentanyl (28%)
than with oral morphine (46%). Tassinari et al.343 assessed the role of

2233
transdermal fentanyl as a first-line approach for moderate to severe cancer
pain bases on the GRADE approach and concluded that the risk/benefit
ratio was uncertain and that the quality of evidence was low. Finally, there
is insufficient evidence to support or refute the suggestion that fentanyl has
any efficacy in any neuropathic pain condition.244 In the absence of any
supporting evidence, it should probably not be recommended, except at the
discretion of a pain specialist with particular expertise in opioid use.

Oral Transmucosal/Intranasal/Sublingual Fentanyl

IR fentanyl is available in oral transmucosal and intranasal preparations
(see Table 43.13). The oral products include lozenge (Actiq), sublingual
tablet (Abstral), sublingual spray (Subsys), buccal tablet (Fentora), and
buccal film (Onsolis). The intranasal product is a metered nasal spray
(Lazanda). The first IR fentanyl was the lozenge. Compared to IR
morphine, this drug with its rapid onset of action (5 minutes) and relatively
short duration of effect was significantly better in treating breakthrough
cancer pain.344 There are no head-to-head trials comparing any of the
newer transmucosal formulations with each other.345 Oral and nasal
transmucosal fentanyl formulations were an effective treatment for
breakthrough pain. When compared with placebo or oral morphine, study
participants reported lower pain intensity and higher pain relief scores for
transmucosal fentanyl formulations at all time points. Global assessment
scores also favored transmucosal fentanyl preparations.253
In 2011, the FDA approved a single shared-system risk evaluation and
mitigation strategy (REMS) for the entire class of transmucosal
immediate-release fentanyl (TIRF) medications. TIRF medicines include
Abstral (fentanyl) sublingual tablet, Actiq (fentanyl citrate) oral
transmucosal lozenge and its generic equivalents, Fentora (fentanyl citrate)
buccal tablet, Lazanda (fentanyl) nasal spray, and Onsolis (fentanyl)
buccal soluble film. The TIRF REMS program required prescribers,
pharmacies, distributors, and outpatients to enroll in order to prescribe,
dispense, or receive all drugs in the category. In outpatient settings, all
health care providers must complete and sign a TIRF REMS Access
Patient-Prescriber Agreement Form with each new patient before writing
the patient’s first TIRF prescription. Health care providers must also

2234
provide patients with a copy of the Medication Guide during counseling
about the proper use of their TIRF medicine. Health care providers who
prescribe TIRF medicines for inpatient use only (e.g., hospitals, hospices,
or long-term care facilities) are not required to enroll in the TIRF REMS
Access program. TIRF medications are approved only to manage
breakthrough pain in adults with cancer who are routinely taking and are
tolerant to other opioid pain medicines ATC for pain. Opioid tolerance is
the use of an opioid for one week or longer in doses equivalent to 60 mg
oral morphine per day or an equianalgesic dose of another oral opioid.
TIRF medications are contraindicated in the management of acute or
postoperative pain, including headache/migraine and dental pain. Of note,
TIRF medications are not interchangeable with each other nor equivalent
to any other fentanyl product including another TIRF medication on an µg-
per-µg basis. The only exception is the substitution of a generic equivalent
for a branded TIRF medication. Dose conversions with initial dosing and
titration schedules are listed in Table 43.14.

Fentanyl-Associated Deaths
Drug overdose is an important, yet an inadequately understood, public
health problem with substantial increase in incidence and prevalence in
several countries worldwide over the past decade, contributing to both
increased costs and mortality.346 The increase of fentanyl abuse (both
legally and illegally produced) is a growing public health problem with
multiple states reporting increases in fentanyl-involved overdose deaths.16
One hundred and twelve fentanyl-related deaths were identified in Canada
between 2002 and 2004.347 Routes of administration included transdermal
application of patches, intravenous injection of patch contents or fentanyl
citrate solution, oral/transmucosal administration, and volatilization and
inhalation of Duragesic systems. The high potency and narrow therapeutic
range of fentanyl compounds and patches available may explain the
potential of fentanyl abuse and associated deaths.348 In the United States,
between 2013 and 2014, the age-adjusted rate of deaths involving
synthetic opioids increased by 80%14 and by 250% among younger
people.349 Several fentanyl derivatives (initially sufentanil, alfentanil,
remifentanil, carfentanil, and, more recently, acetylfentanyl, 6-

2235
butyrfentanyl, 4-MeO-butyrfentanyl, isobutyrylfentanyl, furanylfentanyl,
α-methylfentanyl, 3-methylfentanyl or TMF, p-methylfentanyl,
methylacetylfentanyl, acrylfentanyl, 2-fluorofentanyl,
fluoroacetylfentanyl, ocfentantanyl, and many others) are illegally
manufactured.350 The catastrophic emergence of potent fentanyl analogs
mixed with street heroin is a major public safety concern. Concerns about
legally prescribed fentanyl have also been expressed for some time. In July
2005, FDA issued a Public Health Advisory and Information for
Healthcare Professionals that emphasized the appropriate and safe use of
the fentanyl transdermal system (fentanyl patch), marketed as Duragesic
and generics.351 Despite these efforts, FDA has continued to receive
reports of death and life-threatening adverse events related to fentanyl
overdose that have occurred when the fentanyl patch was used to treat pain
in opioid-naive patients and when opioid-tolerant patients have applied
more patches than prescribed, changed the patch too frequently, and
exposed the patch to a heat source. There is also a variety of methods
associated with intentional abuse of fentanyl patches including attempts to
extract the drug from the patch and inject intravenously, chewing or
swallowing patches, inserting patches into the rectum, and inhaling
fentanyl gel.330,352–355 Aberrant behaviors have been associated with the
use of transmucosal fentanyl in chronic pain patients.356 Concerns about
abuse and death have also been expressed with transmucosal fentanyl even
among cancer patients with active disease.357,358

BUPRENORPHINE
Buprenorphine is a semisynthetic derivative of thebaine. It is available in
the United States for the treatment of addiction and for the treatment of
chronic pain. It is a potent partial agonist of the µ-opioid receptor with
high affinity but low intrinsic activity. The slow dissociation (t1/2
association/dissociation is 2 to 5 hours) accounts for its prolonged
therapeutic effect. It is metabolized in the liver through CYP3A4 N-
dealkylation. The relative bioavailability of the sublingual tablet is 29%
with a t1/2 of 20 to 73 hours. The transdermal buprenorphine product
Butrans is available in strength of 5, 7.5, 10, 15, and 20 µg per hour
delivering 7-day dosing and is indicated for pain severe enough to require

2236
daily, ATC opioid therapy. The 10 µg per hour patch corresponds to
approximately 30 to 80 mg per day of oral morphine equivalents. The
maximum recommended dose is 20 µg per hour. The median time for the
10 µg per hour patch to deliver quantifiable buprenorphine concentrations
(≥25 pg/mL) was approximately 17 hours. After removal of the patch,
mean buprenorphine concentrations decrease approximately 50% within
10 to 24 hours, followed by decline with an apparent terminal t1/2 of
approximately 26 hours. Sublingual formulations of buprenorphine are
available in the United States market as monotherapy (generic tablet) and a
combination therapy of buprenorphine with naloxone (Suboxone, Zubsolv
as a tablet or film) for opioid addiction. One Zubsolv 5.7 mg/1.4 mg
sublingual tablet provides equivalent buprenorphine exposure to one
Suboxone 8 mg/2 mg sublingual tablet.
Buprenorphine should not be used for acute pain management, for
example, when there is a need for rapid dose titration for severe pain in
cancer and palliative care settings. One potential issue is that because of
the high affinity for µ-opioid receptors with a slow dissociation profile,
buprenorphine may potentially displace or prevent the binding of
competing µ-opioid receptor agonists, including IR opioids, in a dose-
dependent manner. This may be less of an issue with the relatively lower
doses of transdermal buprenorphine used in the United States.359,360 There
is insufficient evidence to make buprenorphine a valid first-line choice for
the management of cancer-related pain with no clear dose-response
relationship for transdermal buprenorphine.361,362

HYDROCODONE
Hydrocodone is a prodrug opioid, and the parent compound is a full µ-
opioid receptor agonist and can interact with other opioid receptors at
higher doses. It is metabolized into its active moiety, hydromorphone, by
CYP2D6 and also by CYP3A to the inactive metabolite, norhydrocodone,
although the extent of CYP3A metabolism of hydrocodone is unclear.
In 2013, the FDA approved the use of extended-release hydrocodone
(Zohydro ER). Hydrocodone ER is a hard gelatin capsule. Measurable
drug levels are obtained within 30 minutes after oral intake. The Tmax is
between 6 and 8 hours, and mean t½ was 4.9 and 6.5 hours.363 IR

2237
hydrocodone exists in various combinations with acetaminophen or
ibuprofen. The most common forms of hydrocodone-acetaminophen
preparations are 5/325 mg, 7.5/325 mg, and 10/325 mg. The common
hydrocodone-ibuprofen preparations are 2.5/200 mg, 5/200 mg, 7.5/200
mg, and 10/200 mg. In oncology patients, hydrocodone at higher doses
(≥40 mg per day) is equipotent to morphine and at lower doses (<40 mg
per day) may be twice as potent as morphine and just as potent as
oxycodone.364 There are relatively few studies on the use of hydrocodone
for cancer pain. Hydrocodone/acetaminophen at starting doses of 25
mg/2,500 mg per day was not more effective than tramadol 200 mg per
day on patients with chronic cancer pain.365

CODEINE
Codeine is a synthetic opiate alkaloid. It is considered a prodrug that lacks
intrinsic antinociceptive activity and must be metabolically converted to
active forms. Eighty percent of codeine is conjugated with glucuronic acid
to codeine-6-glucuronide with only 5% O-demethylated by CYP2D6 to
morphine suggesting that the majority of its analgesic effect is from
codeine-6-glucuronide.366,367 The value of codeine is limited in cancer
pain management by the increasing incidence of side effects at doses
above 1.5 mg per kilogram of body weight.62,368 Codeine is rapidly
absorbed from the GI tract reaching a peak level within 1 hour with a
clinical duration of 4 to 6 hours.369 The available evidence (which is of
low quality) indicates that codeine is more effective against cancer pain
than placebo but with increased risk of nausea, vomiting, and
constipation.370 The principal adverse effect associated with chronic
dosing is constipation.
Dihydrocodeine is an equianalgesic semisynthetic analogue of codeine.
It is used as an analgesic, antitussive, and antidiarrheal agent. The
analgesic effect is probably twice as potent as that of codeine for the
parenteral and slightly stronger for an oral route.371 Dihydrocodeine has
active metabolites (dihydromorphine and dihydromorphine-6-
glucuronide).372 The most common side effect that occurs in patients
treated with dihydrocodeine is constipation.373 Duration of effect is
approximately 6 hours. In the United States, it is available only in

2238
combination with acetaminophen, caffeine, or aspirin.

TRAMADOL
Tramadol is a centrally acting analgesic with a µ-opioid receptor activity
and also has weak effects on serotonin and norepinephrine reuptake
inhibition. Opioid activity of tramadol is due to both low affinity binding
of the parent compound and higher affinity binding of the O-desmethyl
tramadol metabolite (M1) to µ-opioid receptors. The analgesic activity is
due to both parent drug and the M1 metabolite. Oral formulations include
those designed for immediate release and for modified release. Side effects
associated with tramadol include typical opioid adverse events of nausea,
dizziness, and dry mouth, although vomiting and constipation are
considered to be less of a problem than with traditional opioids. Tramadol
may also cause orthostatic hypotension. Use of tramadol with concurrent
serotonergic therapy poses a risk of serotonin syndrome.374 Seizures can
occur with the recommended dosage range, and the risk is increased with
concomitant use of SSRIs and tricyclic antidepressants. The daily
maximum recommended dose of tramadol IR is 400 mg and 300 mg per
day for tramadol ER. Tramadol ER should not be used concomitantly with
other tramadol products. The IR preparation has a bioavailability of 75%,
Tmax 2.3 hours, and t1/2 of 7 hours. The bioavailability of tramadol ER 200
mg tablet administered once daily relative to a 50 mg IR tramadol
hydrochloride administered every 6 hours is approximately 85% to 90%.
Tmax of tramadol ER and M1 is 12 hours and 15 hours, respectively.
Steady state is achieved within 4 days of once-daily dosing. The mean
terminal plasma elimination half-lives of racemic tramadol and racemic
M1 after administration of extended-release tablets are approximately 7.9
and 8.8 hours, respectively. The metabolic pathways are N-demethylation
(mediated by CYP3A4 and CYP2D6), O-demethylation (mediated by
CYP2D6), and glucuronidation or sulfation in the liver. Concomitant
administration of CYP2D6 and/or CYP3A4 inhibitors may reduce
metabolic clearance of tramadol increasing the risk for serious adverse
events including seizures and serotonin syndrome.
Although advocated for the management of neuropathic pain,193,375 the
information supporting use is modest from small largely inadequate

2239
studies with potential for risk bias.376 Overall, patients with cancer who
are most likely to benefit from tramadol appear to be those with mild to
moderate pain not relieved by acetaminophen, who cannot tolerate
NSAIDs, and wish to avoid taking opioids that are more potent.

TAPENTADOL
Tapentadol is a centrally acting opioid agonist. The exact mechanism of
action is unknown, but it has both µ-opioid receptor activity and is a
norepinephrine reuptake inhibitor. It is available in both immediate- and
extended-release formulations. FDA-approved indications are for pain
severe enough to require daily ATC opioid use and also pain diabetic
peripheral neuropathy. The Tmax for tapentadol IR is approximately 1.25
hours with a t1/2 of 4 hours. It is available in both tablet form and solution.
The mean absolute bioavailability after single-dose administration of
Nucynta ER is approximately 32% due to extensive first-pass metabolism
with a Tmax between 3 and 6 hours. Steady-state exposure of tapentadol is
achieved after the third dose (i.e., 24 hours after first twice-daily multiple-
dose administration). The oral equivalent dose of tapentadol to morphine is
approximately 2.5:1.377,378 The major pathway of tapentadol metabolism is
conjugation with glucuronic acid to produce glucuronides. Drug
metabolism mediated by CYP450 system is of less importance than phase
2 conjugation. Initial dosing for patients who are not opioid-tolerant is 50
mg bid. Doses greater than 600 mg daily are not recommended. In a small
study of 22 patients with CIPN-associated pain, patients initially were
treated with tapentadol 50 mg bid and then titrated as tolerated over a 3-
month period.379 Nineteen patients showed a response to treatment (30%
reduction in pain intensity) with 15 patients showing a 50% reduction in
pain intensity over the study period, but 7 patients stopped therapy during
the first week because of side effects (drowsiness, nausea, dizziness, dry
mouth). In a Cochrane review of four studies with 1,029 patients with
chronic tumor-related pain with twice-daily dosing varying from 50 mg to
500 mg, effects were comparable to those of equivalent doses of morphine
or oxycodone.380 The most common events were GI including nausea,
vomiting, or constipation, and there was no advantage of tapentadol over
morphine or oxycodone in terms of serious adverse events.

2240
OPIOIDS NOT RECOMMENDED FOR ROUTINE USE IN
CANCER PAIN CONTROL
There are several opioids that should be avoided in cancer pain
management, including meperidine, pentazocine, butorphanol, dezocine,
and nalbuphine. Meperidine has a short t1/2, and its metabolite,
normeperidine, is toxic.381 Mixed agonist-antagonists such as pentazocine,
butorphanol, dezocine, and nalbuphine present other problems. Although
these agonist-antagonists are often classified as a κ receptor agonist and a
µ-receptor antagonist, they are more accurately described as a partial
agonist at both κ and µ receptors. These agents have a low maximal
efficacy and have the potential to reverse µ-receptor analgesia and even
precipitate a physical withdrawal syndrome when taken by patients already
receiving full agonists such as morphine.382 In addition, agonist-antagonist
opioids have a ceiling effect.382,383

OPIOID-RELATED SIDE EFFECTS

Prevention or Minimizing Opioid-Related Side Effects
Appropriate dosing of opioids requires minimizing or preventing opioid-
related side effects. For patients with constant pain, the early use of a long-
acting opioid in preference to short-acting opioids as soon as dose titration
permits may help attenuate side effects. If side effects are significant, the
clinician should allow time for tolerance to develop. This may require a
period of 3 to 7 days. Minimizing severe side effects during this period is
appropriate. For example, a patient with nausea could benefit from a 1-
week course of antiemetic medication at the outset of opioid therapy.
If side effects do not diminish satisfactorily over time, there are two
alternatives: changing drugs and introducing supplementary medications
that control the side effects. Changing from one opioid to another may
enhance pain relief and reduce opioid-related side effects, particularly if
incomplete cross-tolerance to opioid effect is experienced.384–386 In some
cases, changing the route of administration for a particular drug may
eliminate certain difficult side effects. It is possible to alleviate many of
the most difficult side effects pharmacologically when necessary. For
example, prudent administration of methylphenidate to the cancer patient
can help protect the cognitive functioning of patients using high doses of

2241
opioids.387 Table 43.15 lists opioid-related side effects and their
treatments. In cancer patients, certain pathophysiologic conditions
commonly contribute to side effect problems or masquerade as side effect
problems. For example, renal insufficiency in patients using morphine can
lead to accumulation of morphine-6-glucuronide, which in turn can
exacerbate side effects. Nausea is a frequent opioid toxicity, but it has
other potential causes: gastric irritation, constipation or other changes in
gut motility, chemotherapy, or hypercalcemia induced by bone metastases.
Similarly, opioid-induced changes in mental status become less probable
when the patient has been on a stable dose without recent significant dose
escalation.

2242
 TABLE 43.15 Pharmacologic Treatments for Opioid-Related Side
Effects
Side Effect Treatment
Constipation Stool softener, laxative, PAMORA, ? opioid rotation
Sedation Methylphenidate, modafinil
Pruritus Diphenhydramine, hydroxyzine
Nausea Prochlorperazine, haloperidol, metoclopramide, ondansetron,
antihistamine, olanzapine
Dysphoria Haloperidol, opioid rotation
Hypnogogic Haloperidol
imagery
Cognitive Methylphenidate, modafinil, opioid rotation
impairment
Respiratory Naloxone
depression
Myoclonus Clonazepam, dose reduction, opioid rotation
PAMORA, peripherally acting μ-opioid receptor antagonist.

Opioid-induced bowel dysfunction is addressed earlier.

OPIOID EFFECTS ON COGNITION, MOTOR SKILLS,

AND DRIVING ABILITY
Patients with advanced cancer may develop a wide range of symptoms,
including cognitive dysfunction, which interfere with their daily life,
compliance to treatment, social interactions, and quality of life. Causes for
development of cognitive alterations are multiple and may be attributed to
the cancer disease itself, comorbidities, and treatments including opioid
therapy.388 The spectrum of cognitive dysfunction attributed to opioid use
can vary from subtle evidence of cognitive impairment, largely related to
initial dosing or dose increases to delirium.389 Opioids can interfere with
acquirement, processing, storage, retrieval of information, altering
cognitive processes associated with memory, psychomotor function, mood,
concentration, and other mental capabilities.390 Patients receiving daily
opioid doses of 400 mg or more (oral morphine equivalents) had 1.75
(95% confidence interval [CI], 1.25 to 2.46) times higher odds of having
lower Mini-Mental State Examination (MMSE) scores compared with
those receiving daily doses less than 80 mg.391 In addition, patient with

2243
lung cancer, older age, lower performance status, time since diagnosis
(<15 months), and absence of breakthrough pain were more at risk of
developing opioid-induced cognitive dysfunction. Opioids may cause
measurable cognitive impairment, even at low doses (especially during
initial or occasional use), and equianalgesic doses of different opioids may
have nonequivalent adverse cognitive effects.392 Although sedation and
confusion may accompany opioid use, other potential causes in the cancer
patient such as raised intracranial pressure, metabolic disturbances (e.g.,
hypercalcemia), sepsis, or concomitant psychoactive medication use merit
consideration and should be excluded. Cognitive dysfunction can be
associated with opioid dose increases and use of supplemental doses of
short-acting opioids. However, the use of benzodiazepines has substantial
more effects on cognitive and psychomotor function compared to opioid
use.393,394 In cancer survivorship, the evidence is mixed regarding long-
term cognitive deficits associated with the use of chemotherapy. Studies in
patients with breast cancer previously treated with chemotherapy suggest
observed cognitive deficits are small in magnitude and limited to the
domains of verbal ability and visuospatial ability.395 The presence of
chronic pain can also be a factor in cognitive dysfunction. Basic
neurocognitive function is impaired in a substantial portion of patients
with persistent severe pain.396 Use of psychostimulants (e.g.,
methylphenidate, modafinil) has been reported to be helpful in overcoming
daytime drowsiness and mental clouding, but their use must be monitored
carefully, both for adverse effects and overuse.397 Modafinil in a single-
dose regimen was beneficial for improving psychomotor speed and
attention and for improving subjective scores of depression and drowsiness
in patients with advanced cancer.398
An additional major concern that has arisen from long-term opioid
therapy is the effect of long-term opioid use on motor skills such as
driving.399,400 Driving is considered an important activity affecting quality
of life for many patients. Often, both prescribing clinicians and patients are
unaware of the legal risk associated with driving and the use of legally
prescribed opioids. Driving under the influence of drugs other than alcohol
(DUID) is of concern to the medical and legal communities. “Under the
influence” typically describes a level of impairment that interferes with

2244
driving abilities and is therefore considered criminal; however, this level
of impairment is interpreted differently among various states.401 Of the
prescribed psychoactive medications, benzodiazepine use is associated
with a significant increase in the risk of traffic accidents with the
association being more pronounced in the younger driver. The motor
vehicle accident risk is markedly increased with the coingestion of
alcohol.402,403 The prevalence of prescription opioids detected in fatally
injured drivers has increased in the past two decades but of the drivers
testing positive for prescription opioids, 30% had elevated blood alcohol
concentrations (≥0.01 g/dL), and 66.9% tested positive for other drugs.404
Results have been inconsistent regarding decrements in cognitive
performance. Patients with chronic pain who have been using opioids for
more than 3 days exhibit relatively few differences when cognitive
performance is compared with performance before taking opioids or with
that of a comparable patient population not taking opioids.405 The majority
of research has revealed that the greatest potential impairment in cognitive
function from opioids occurs during the first several days of use. During
longer periods, impairment has been demonstrated primarily in studies that
have compared patients with significant pain with healthy volunteers.
Twenty chronic pain patients using long-term stable doses of opioids, and
19 healthy controls were studied using standardized on-the-road driving
tests in normal traffic.406 Performance of controls with a blood alcohol
concentration of 0.5 g/L was used as a reference to define clinically
relevant changes in driving performance. Driving performance of the
chronic pain patients did not significantly differ from that of controls
suggesting that in clinical practice determination of fitness to drive in
patients who receive opioids should be based on an individual assessment.
Gomes et al.407 found among drivers prescribed opioids that a significant
relationship existed between opioid dose and risk of road trauma.
Compared with patients prescribed very low opioid doses (MED <20 mg),
those prescribed low (20 to 49 mg MED) and moderate (50 to 99 mg
MED) doses had a 21% and 29% increased odds of road trauma, and
patients prescribed high (100 to 199 mg MED) and very high (≥200 mg
MED) doses of opioids had a 42% and 23% increased odds of road trauma,
respectively, when compared with patients prescribed very low doses. The

2245
effects of opioid use specifically on driving ability has become a
contentious issue, predictably because a growing number of patients are
taking opioids and driving, and also because insurers may seek to assign
liability in cases of motor vehicle accidents involving drivers who use
opioids. Vainio et al.408 examined the effects of continuous morphine
medication on the driving ability of cancer patients. They conducted
psychological and neurologic tests, originally designed for professional
motor vehicle drivers, in two groups of cancer patients who were similar
apart from their experience of pain. Twenty-four patients received
continuous morphine (mean 209-mg oral morphine daily) for cancer pain,
and 25 were pain-free without regular analgesics. Although the results
were a little worse in the patients taking morphine, there were no
significant differences between the groups in intelligence, vigilance,
concentration, fluency of motor reactions, or division of attention. Of the
neural function tests, reaction times (auditory, visual, associative), thermal
discrimination, and body sway with eyes open were similar in the two
groups; only balancing ability with closed eyes was worse in the morphine
group. These results indicate that in cancer patients receiving long-term
morphine treatment with stable doses, morphine has only a slight and
selective effect on functions related to driving. Galski et al.409 published a
structured, evidence-based review on the issue of opioids and driving.
Overall, the majority of studies in the evidence-based review appeared to
indicate that patients who use opioids are not impaired by the opioids with
regard to driving ability. Byas-Smith et al. reported that many patients
with chronic pain, even if treated with potent analgesics such as morphine
and hydromorphone at equivalent average daily morphine doses of 118
mg, showed comparable driving ability as normal subjects.409
Clearly, opioids may affect cognitive function and impair driving ability
in patients who are opioid-naive or in patients who are not on stable opioid
regimens. Whether some degree of “cognitive tolerance” develops with
chronic opioid use is unknown. Other unresolved questions include the
effects of different types of opioids, dose effects, and interactions with
other medications on driving ability. Each of these areas deserves further
study, and clinicians need to counsel patients about potentially dangerous
activities on a case-by-case basis. Guidelines are provided regarding

2246
opioid medications and driving (Table 43.16).

TABLE 43.16 Driving Instructions for Patients Taking Opioids

Opioid medications can cause side effects that impair your ability to drive. Driving while taking
opioid medication is controversial. The final decision on whether you should drive while taking
them is a legal issue and should be addressed with your automobile insurance carrier. Out of
concern for your safety and the safety of others, please observe the following guidelines:
Do not drive for 4–5 d after beginning opioid treatment or following a dose increase.
Never drive if you feel sedated or if you feel your thinking is impaired. Take any concerns that
others express regarding your ability to drive safely seriously.
Report sedation, unsteadiness, or unclear thinking to our office as soon as possible.
Please remember that the use of alcohol or other drugs such as cannabis (“marijuana”) can
increase the effects of opioid medications.
Avoid taking over-the-counter medications that may cause drowsiness such as cold and allergy
medications.
Nurse: ___________________________________________ Date: _________________
I have reviewed these follow-up instructions and understand and accept them before starting the
procedure.
Patient/Guardian Signature: ___________________________ Date: _________________

OPIOID ROTATION IN CANCER PAIN

Opioid rotation refers to the practice of converting from one opioid to a
second when the opioid analgesic response is inadequate and/or if opioid-
related adverse events are intolerable or unmanageable.410,411 Reasons for
initiating opioid rotation are listed in Table 43.17. In cancer patients, the
most common reasons for opioid rotation are intolerable side effects such
as, cognitive failure, hallucinations, myoclonus, nausea, and uncontrollable
pain.282,283,412 In all cases of opioid rotation, patients must be followed
closely to assess the adequacy of pain relief and the effect on opioid-
related adverse events. As with any opioid regimen, subsequent dose
adjustments will probably be necessary. Use of opioid rotation requires
familiarity with a range of opioids and with the use of equianalgesic dose
tables (see Chapter 79). However, it is also important to consider that the
evidence to support dose ratios in standard equianalgesic tables refers
largely to the context of single-dose administration; they do not necessarily
reflect the clinical realities of chronic opioid administration in the
treatment of cancer pain with repeated dosing of opioids at steady state.
Thus, the doses listed in most standard equianalgesic dose tables may not
be accurate in patients who have developed tolerance or have been taking

2247
opioids for long periods of time. In addition, the phenomenon of
incomplete cross-tolerance can lead to unexpected potency in the newly
introduced agent.262,384,385,413

TABLE 43.17 Reasons for Undertaking Opioid Rotations

1. Reduced ability to control pain due to:
a. Worsening of existing pain or underlying disease process
b. Pharmacodynamic factors Development of opioid analgesic tolerance
c. Pharmacokinetic factors
Drug absorption (inability to swallow oral medications/poor vascular status or edema
limiting transdermal delivery)
Interaction with other drugs
Changes in protein binding
Biotransformation and metabolism (accumulation of metabolites)
Reduced clearance—renal failure
2. Development of intolerable side effects/opioid toxicity
a. Gastrointestinal (i.e., constipation, nausea, vomiting)
b. CNS (i.e., sedation, somnolence, dysphoria, hallucinations, myoclonus)
c. Cardiovascular (i.e., orthostatic hypotension due to histamine release)
3. Practical concerns
a. Dose required to produce analgesia exceeds maximum daily dose (patients taking
combination products, e.g., acetaminophen)
b. Cost of drugs
c. Drug availability
d. Need for large doses of drug to be delivered
e. Changes in route of administration
CNS, central nervous system.

Special care is required with methadone rotations. The process of

switching from a high-dose opioid agonist to methadone is complex and
should and should only be attempted by experienced physicians.414–416
Even among experienced physicians, serious toxicity can occur during the
administration of methadone.417,418 Various studies provide guidelines for
opioid dose conversions in cancer pain.284,386,419–422

PARENTERAL OPIOID THERAPY

Parenteral routes (subcutaneous or intravenous) should be considered for
patients who require rapid onset of analgesia and for highly tolerant
patients who require doses that cannot otherwise be conveniently
administered.423 Intravenous opioids allow for rapid control of pain.
Ideally, patients with severe, uncontrolled pain who require intravenous

2248
therapy should start treatment in a monitored in-patient setting. High doses
of intravenous opioids via patient-controlled analgesia (PCA) and/or by
continuous infusion offers a means of rapidly controlling increasing severe
pain. Intravenous therapy can employ any of several opioids: morphine,
hydromorphone, fentanyl, and, less commonly, methadone. A brief
hospitalization for stabilization of the intravenous regimen is preferable.
Continuous subcutaneous infusion of opioids is both an efficacious and
safe method to control the chronic pain of the homebound and hospitalized
patient.424,425 Administration of opioids by continuous infusion via
intravenous or subcutaneous routes have equal effects in similar doses.426
In a pilot study in cancer patients comparing the efficacy of
hydromorphone administered subcutaneously by continuous infusion only
versus basal rate infusion with PCA, both methods provided adequate
overall pain control in most patients, but a large interindividual variation
was noted with some patients reporting marked discomfort during
hydromorphone administration by PCA and few patients preferring the
PCA modality.427 Stuart-Harris et al.428 studied the pharmacokinetics of 5
mg of morphine (and its metabolites) given intravenously, by
subcutaneous bolus, and by subcutaneous infusion over 4 hours. After a
single intravenous bolus, plasma morphine was typically detected up to 6
hours with a maximal concentration (Cmax) of 283 ± 74 nmol/L with a
Tmax of 0.08 hour. After subcutaneous bolusing, plasma morphine was
typically detected up to 8 hours, the Cmax was similar to intravenous bolus,
but the Tmax was significantly longer (0.25 vs. 0.08 hour). Morphine
administered by subcutaneous infusion was first detected in all subjects
after 2 hours and was still detectable at 12 hours in some subjects at end of
sampling. The median Tmax was longer at 4 hours, and Cmax was lower at
46 ± 8 nmol/L. The authors concluded that although intravenous and
subcutaneous bolusing is bioequivalent with regard to their
pharmacodynamic effects, it was likely that circulating morphine
concentrations would have been higher immediately after the intravenous
bolus was completed than at the first sampling point at 0.08 hour, and
these early high concentrations may influence penetration into the brain. In
contrast, the bioavailability of morphine was less after subcutaneous
infusion versus bolusing by either method. Moulin et al.429 noted that

2249
mean bioavailability from subcutaneous infusion of hydromorphone was
78% of that with intravenous infusion. This in combination with its
solubility and the availability of a high-concentration preparation (10
mg/mL) makes hydromorphone a good choice for subcutaneous infusion.
Parenteral hydromorphone is six times as soluble in aqueous solutions as
morphine and five times as potent, allowing for smaller injection or
infusion volumes in patients who require parenteral opioids.430 Moulin et
al.429 compared the safety and efficacy of subcutaneous versus intravenous
infusion of hydromorphone in cancer patients. Pain intensity, pain relief,
mood, and sedation did not differ between the two techniques. Paix et
al.431 described the successful substitution of subcutaneous fentanyl and
sufentanil for morphine, noting the benefits of sufentanil when the patient
needs a very high dose of opioid that can be infused in a relatively small
volume. Nelson et al.426 compared continuous intravenous and
subcutaneous morphine for chronic cancer pain and concluded that both
routes were equianalgesic for most patients when administered as a
continuous infusion.
Most patients will require a weekly change of the site of subcutaneous
infusion.424 The usual initial concentrations of morphine and
hydromorphone are 5 mg/mL and 1 mg/mL, respectively, calculated
according to the hourly infusion rate. Ideally, the subcutaneous rate should
not exceed 2 mL per hour, although some have established considerably
higher rates (rates of 20 to 80 mL per hour by adding hyaluronidase to the
infusion to promote hypodermoclysis).432 Due to a longer time to peak
plasma levels after bolus injection with subcutaneous use than with
intravenous use, the subcutaneous route requires a longer lockout interval
(10 to 15 minutes compared to 6 to 8 minutes for the intravenous). PCA
doses may equal 25% to 50% of the hourly infusion rate every 10 to 15
minutes as needed. Subcutaneous administration of opioids may prove
impractical in patients with generalized edema, who develop erythema,
soreness, or sterile abscesses with subcutaneous administration; in patients
with coagulation disorders; and in patients with very poor peripheral
circulation.

INTRACEREBROVENTRICULAR OPIOIDS

2250
Intracerebroventricular (ICV) opioid delivery may be beneficial for highly
selected cancer patients who are not obtaining adequate relief or
experiencing intolerable side effects via other routes. The site of action of
opioids via the ICV route appears to be predominantly supraspinal433
although spinal effects are also observed. After ICV administration of
morphine 0.28 to 0.61 mg, peak lumbar CSF morphine levels were
observed after 4.5 ± 1.3 hours.434 Ventricular morphine was approximately
20,000 ng/mL and declined to approximately 10 ng/mL at 24 hours.
Lumbar morphine reached approximately 200 ng/mL at about 4 hours and
declined to about 10 ng/mL at 24 hours. A short latency to onset of pain
relief (20 minutes) corresponds to high levels of morphine in
periventricular tissues and the duration of effect is enhanced by the
morphine at the spinal level. With neurosurgical consultation, it is possible
to deliver opioids directly into cerebral ventricles through ICV catheters
from subcutaneous reservoirs. Morphine sulfate, the usual drug, gains a
marked increase in potency when delivered ICV as compared to intrathecal
or epidural infusion routes, and the ICV route appears to affect supraspinal
pathways for analgesia.435 Daily morphine doses for ICV delivery range
from 0.3 to 2.5 mg per day436 with an average daily dose of 1 mg per
day437 although higher doses have also been reported.438 For
administration, an Ommaya reservoir is placed subcutaneously and
connected to the ventricular catheter placed into the lateral ventricle. The
duration of pain relief after ICV injections appears to be significantly
longer than with intraspinal delivery, and some patients gain adequate
relief via an implanted ventricular catheter connected to a subcutaneous
Ommaya reservoir–type device with 1 to 2 injections per day. This form of
drug delivery is indicated for head and neck cancer pain, or, rarely, for
patients with a good initial response to intraspinal infusions of opioids and
subsequent development of apparent tolerance, but with limited (1 to 3
months) remaining survival time. The safety and side effects of ICV
injections or infusions resemble those for intraspinal infusions with
reservoir infection being the most common.438 In a meta-analysis of 2,402
cancer patients, Ballantyne and Carwood439 compared ICV (337 patients)
with the more common epidural (1,343 patients) and intrathecal (722
patients) opioid treatments in an attempt to establish the utility and safety

2251
of ICV therapy. All patients considered had intractable cancer pain that
proved resistant to systemic treatment. Persistent nausea, urinary retention,
and pruritus occurred more frequently with the two spinal treatments than
with ICV therapy but respiratory depression (4.3%), sedation (11%), and
confusion (13% protracted, 20% transient) were most common with ICV.
Data from these uncontrolled studies reported excellent pain relief among
73% of ICV patients compared with 72% epidural and 62% subarachnoid
catheters. Unsatisfactory pain relief was low in all treatment groups. The
incidence of major infection when pumps were used with epidural and
subarachnoid catheters was zero. There was a lower incidence of other
complications with ICV therapy than with epidural or subarachnoid
catheters.

Substance Abuse in Oncology

The misuse or abuse of prescription medications should be of particular
concern to oncology care providers, opioid therapy is central to the
management of cancer-related pain, and benzodiazepines are frequently
prescribed for a variety of issues (predominantly sleep disturbance, anxiety
disorders, and nausea control). Although substance use disorders may be
diagnosed via detection of aberrant behaviors displayed by patients,440,441
patient reporting and documentation of issues in the medical record are
inadequate to screen for these issues.442–444 In a retrospective review of 82
oncology patients at high risk for substance misuse, 46% had evidence of
nonprescribed opioids, benzodiazepines or potent illicit drugs such as
heroin or cocaine, and 39% had inappropriately negative urine drug
screening, raising concerns for diversion.50 In a study of urine drug testing
in over 900,000 test samples in patients on chronic opioid therapy for
chronic pain, 75% of patients were unlikely to be taking their medications
in a manner consistent with their prescribed pain regimen. Thirty-eight
percent of patients were found to have no detectable level of their
prescribed medication, 29% had a nonprescribed medication present, 27%
had a drug level higher than expected, 15% had a drug level lower than
expected, and 11% had illicit drugs detected in their urine.445 In a study to
determine the frequency of undiagnosed alcoholism among patients with

2252
advanced cancer referred to palliative care and to explore its correlation
with alcoholism, tobacco abuse, and use of illegal drugs, alcoholism was
highly prevalent and frequently underdiagnosed. Using the CAGE
questionnaire as a screening tool, CAGE-positive patients were more
likely to have a history of, or to actively engage in, smoking and illegal
recreational drug use.446 Passik et al.447 indicated in oncology and HIV
patients seldom reported current aberrant drug-related behaviors and that
many cancer patients would consider behaving aberrantly if pain or
symptom management was suboptimal. One hundred and eleven patients
were randomly selected from a group of 215 patients who underwent urine
toxicology screening in a cancer center.448 Fifty-six of the 111 patients had
evidence of one or more illicit drug use, a prescription medication that had
not been ordered, or alcohol use.
Opioid abuse and misuse may manifest as self-medication, use for
reward, compulsive use because of addiction, and diversion for profit. Risk
factors for opioid misuse are listed in Table 43.18. There is a clear
association between opioid prescription and opioid overdose, abuse, and
death. Among opioid-related deaths, approximately half involved a
prescription opioid.449 Prescription opioid-related overdose deaths and
admissions for treatment of opioid use disorder have increased in parallel
with increases in opioids prescribed in the United States, which
quadrupled from 1999 to 2010.450 Because of these associations, health
care providers are advised to carefully weigh the benefits and risks when
prescribing opioids, follow evidence-based guidelines, and consider
nonopioid therapy for chronic pain treatment.449 Safe prescribing practice
guidelines for noncancer patients suggest screening for the risk of
substance abuse, the use of prescription monitoring programs, and
monitoring with urine drug screens.451–456 In addition, clinicians are
advised to avoid concurrent opioids and benzodiazepines whenever
possible, prescribe the lowest effective dose, and carefully reassess
benefits and risks when considering increasing dosage to 50 morphine
milligram equivalents or more per day.457 There are relatively few
guidelines in this area for cancer patients, and standard screening tools are
not validated in oncology populations. Anghelescu et al.451 suggest
patients undergo evaluation through clinical psychological interview

2253
and/or Revised Screener and Opioid Assessment for Patients with Pain
(SOAPP-R) assessment at the initiation of chronic opioid therapy for
chronic cancer pain, and follow-up risk evaluation with Current Opioid
Misuse Measure (COMM) assessment. Urine drug testing is recommended
at the initiation of chronic opioid therapy and periodically throughout
treatment to augment objective data about the patient’s behaviors. Table
43.19 suggests establishment of policies for all patients being considered
for chronic opioid therapy.

TABLE 43.18 Risk Factors for Opioid Misuse

History of substance abuse—personal, family
Young age
History of criminal activity and/or legal problems including DUIs
Regular contact with high-risk individuals or high-risk environments
Significant psychiatric comorbidities (e.g., severe depression, anxiety) including ongoing issues
with family members, and friends
Risk taking or thrill seeking behavior.
Continued tobacco use
Persistent psychosocial stressors including lack of support system
Prior drug and/or alcohol rehabilitation
DUI, driving under the influence.
Modified from Jamison RN, Serraillier J, Michna E. Assessment and treatment of abuse risk in
opioid prescribing for chronic pain. Pain Res Treat 2011:941808.
http://dx.doi.org/10.1155/2011/941808. Copyright © 2011 Robert N. Jamison et al.

TABLE 43.19 Policies for Risk Evaluation and Monitoring for

Continued Opioid Therapy in Oncology Patients
Category Policy
Universal risk Screening tool such as Opioid Risk Tool (ORT)
stratification—all Personal history of substance abuse including prescription opioids,
patients psychoactive medications, illicit substances, alcohol
Family history of substance abuse including prescription opioids,
psychoactive medications, illicit substances, alcohol
Review of support system (family, friends, social, etc.)
Universal Risk versus benefit
education opioid Consent for opioid therapy
use and safety— Safe medication keeping
patient and Adherence to prescription instructions
support system
Screening and Regular telephone follow-up with pill counts/opioid reconciliation
monitoring— Prescription monitoring program review at each refill
ongoing Current Opioid Misuse Measure (COMM) at each clinic visit
Presence of aberrant drug behaviors

2254
 Urine toxicology screening (to include alcohol, illicit drug,
comprehensive panel for opioids) at minimum yearly or as clinically
indicated
High-risk patients Review of medical indication for opioid use
—no evidence of Referral for addiction specialist assessment (as indicated)
current substance Frequent random urine drug screening (to include alcohol, illicit drug,
use comprehensive panel for opioids) based on aberrant behaviors
Elimination of other psychoactive medications when possible
Consequences for unsanctioned substance/nonprescribed medication use
including alcohol
High-risk patients No initiation of controlled substance prescriptions with ongoing illicit
—evidence of substance use including alcohol
current substance Referral for addiction assessment and management
use Frequent urine drug screening (to include alcohol, illicit drug,
comprehensive panel for opioids)
Elimination of other psychoactive medications when possible
Consequences for unsanctioned substance/nonprescribed medication use
including alcohol.
NOTE: The use of an opioid contract is not considered mandatory in oncology care. High-risk
patients include patients with ORT score >7, history of chemical coping, or issues with
prescription adherence. Aberrant drug-related behavior is behavior suggestive of a substance
abuse and/or addiction disorder. Examples include diversion, prescription forgery, stealing or
“borrowing” drugs from others, obtaining prescription drugs from nonmedical sources, multiple
episodes of prescription “loss,” repeatedly seeking prescriptions from other clinicians, evidence
of deterioration in function not explained by illness (work, home, and family), and repeated
resistance to changing therapy despite evidence of physical and psychological problems.

Home Infusion Therapy

Advances in pain management technology, such as ambulatory PCAs and
the use of silicone subcutaneously tunneled neuraxial catheters, have
expanded the scope and success of interventional pain management
beyond the hospital to the home. Potential benefits of home infusion
therapy include decreased health care costs, patient/caregiver convenience,
less time spent in hospital with the ability to extend interventional pain
management strategies into the patient’s home. A possible disadvantage to
home infusion therapy may include the additional burden placed on the
patient/caregiver in terms of role responsibilities and schedules. Home care
agencies must have explicitly defined policies and procedures consistent
with regulatory bodies and national and regional standards of practice.
A provider of infusion therapy must be a licensed pharmacy or work in
conjunction with a licensed pharmacy. Skilled and qualified home nursing

2255
services are an essential component of home-based care, necessary to
educate patients and their caregivers regarding administering the drug
therapy, complying with the prescribed dosing schedule, understanding the
drug delivery device being used (an infusion pump or other device), and
other important information regarding the treatment regimen. Additional
roles include monitoring for adverse effects, infection, displacement of
catheters, and equipment malfunction.
Drug therapies commonly administered via infusion at home include
antibiotics, chemotherapy, analgesics, parenteral nutrition, and immune
globulin. Diagnoses commonly requiring infusion therapy include
infections that are unresponsive to oral antibiotics; cancer and cancer-
related pain; GI diseases or disorders, which prevent normal functioning of
the GI system; congestive heart failure; immune disorders; growth
hormone deficiencies; and more.
Ambulatory infusion pumps are either designed to be therapy-specific,
or are multipurpose, enabling treatments such as chemotherapy, systemic
antibiotics, total parenteral nutrition, hydration therapy, and opioid pain
control. Recent developments in pump design include remote access
capability by modem with the ability to change pump settings and
download data.
Home-based PCA therapy provides select patients with the ability to
deliver analgesia based on their own perception of need. PCA therapy may
be superior to oral analgesia, especially in the treatment of severe
oscillating pain. Patient selection criteria include intact cognition and
proper supervision from a family member or health professional. A
collaborative interdisciplinary approach is necessary for effective pain
control for the cancer patient receiving interventional pain management at
home. Collaboration between the patient, the patient’s family, the home
care nurse and home care agency, and the patient’s physician is necessary.
The physician remains responsible for determining the appropriate drug,
bolus dose, background infusion rate, and lockout interval.
PCA is increasingly more common in the home setting as an effective
option in pain management. As discussed in the preceding text, the
subcutaneous and intravenous routes are the primary methods of
administration. The availability of a central vascular access device such as

2256
a tunneled or peripherally inserted central catheter (PICC) offers
advantages over peripheral access to ensure safe and consistent
administration of intravenous analgesia.
The safety and efficacy of home-based PCA opioid therapy has not been
extensively reported as in-hospital use. One study reported on the use of
morphine PCA in the home environment of 143 preterminally and
terminally ill tumor patients suffering either from excruciating chronic
pain or severe chronic/acute complex pain that could not be relieved
adequately by oral analgesia.458 After initial dose adjustment, which lasted
2 to 3 days, the median morphine dose was 93 mg per day (range 12 to 464
mg per day). This median was 28% lower than the median dose
administered orally prior to PCA therapy. During the course of treatment,
morphine requirements increased by a median of 2.3 mg per day (range
29–52 mg per day). Most patients were treated continuously in the home
care setting until death; the median duration of treatment was 27 days
(range 1 to 437 days). Terminal morphine demands reached a median of
188 mg per day (range 15 to 1,008 mg per day). The authors concluded
that PCA was both safe and effective in the home environment, attaining
excellent results in 95 (66%) patients and satisfactory pain relief in 43
(30%). PCA was considered insufficient in five (4%) cases. Side effects, in
general, were considered mild: the most common being constipation,
fatigue, and nausea. PCA use has also been reported in outpatients with
cancer during the last week of life and deemed to be effective.459

Integrative Oncology
Integrative oncology, the diagnosis-specific field of integrative medicine,
addresses symptom control with nonpharmacologic therapies.460 Known
commonly as complementary and alternative medicine (CAM), these
therapies are used widely among cancer patients,461 but patients frequently
do not discuss CAM therapies with physicians.462–464 These therapies have
been used as an alternative to conventional medicine (alternative
medicine) and complementary to conventional medicine (complementary
medicine). Most cancer patients use CAM with the hope of boosting the
immune system, relieving pain, and controlling side effects related to

2257
disease or treatment. Only a minority of patients include CAM in the
treatment plan with curative intent. Integrative therapies have been used
during and after breast cancer treatment and include indications for
managing anxiety/stress, depression/mood disorders, fatigue, quality of
life/physical functioning, CINV, lymphedema, CIPN, pain, and sleep
disturbance.465 For example, music therapy, meditation, stress
management, and yoga are recommended for anxiety/stress reduction.
Meditation, relaxation, yoga, massage, and music therapy are
recommended for depression/mood disorders. Meditation and yoga are
recommended to improve quality of life. Acupressure and acupuncture are
recommended for reducing CINV. The CAM domains of mind–body
medicine, CAM botanicals, manipulative practices, and energy medicine
are widely used as complementary approaches to palliative cancer care and
cancer symptom management.466 Psychoeducational interventions, music
interventions, acupuncture plus drug therapy, Chinese herbal medicine
plus cancer therapy, compound Kushen injection, reflexology, lycopene,
transcutaneous electrical nerve stimulation (TENS), qigong, cupping,
cannabis, Reiki, homeopathy, and creative arts therapies might have
beneficial effects on cancer pain,467 but there is a lack of multi-
institutional randomized controlled trials evaluating CAM therapies for
cancer pain.468,469 In a systematic review of CAM therapies for cancer-
related pain, Bardia et al.468 demonstrated a paucity of well-designed,
multi-institutional trials with most being of short duration, with small
numbers, without sample size justification, and inadequate reporting of
adverse effects of CAM intervention. A National Institutes Health (NIH)
consensus conference on the use of acupuncture for pain concluded that
although there have been many studies of its potential usefulness, many of
these studies provide equivocal results because of design, sample size, and
other factors.470 However, promising results have emerged, for example,
showing efficacy of acupuncture in adult postoperative and chemotherapy
nausea and vomiting and in postoperative dental pain. There are other
situations such as addiction, stroke rehabilitation, headache, menstrual
cramps, tennis elbow, fibromyalgia, myofascial pain, osteoarthritis, low
back pain, carpal tunnel syndrome, and asthma, in which acupuncture may
be useful as an adjunct treatment or an acceptable alternative or be

2258
included in a comprehensive management program. Guidelines have been
proposed to assist clinicians in making decisions about acupuncture
treatment for cancer pain patients and to promote best practice.471 Three
systematic reviews472–474 and two meta-analyses475,476 on the use of
acupuncture on cancer-related pain have generated equivocal results.
Because patients use acupuncture for other benefits and it is considered an
intervention with few side effects, it can be used provided patients are
aware of its limitations.

Summary
Although pain control is a high-priority goal of cancer care, the ultimate
goal of most cancer patients is cure from disease and in most situations
pain is often an undesirable by-product of treatment or disease. Pain
management should be integrated into oncology care, but it should not
become the focus of care. As a very common and debilitating component
of disease or treatment, aggressive treatment of pain to maximize both
quality and quantity of the patient’s life with functional improvement is
imperative. The ability to integrate this requires a detailed assessment of
the pain compliant with accurate diagnosis of the cause or causes of pain
and other quality-of-life concerns. Typically, the pain experience is
multidimensional, and treatment must address physical, psychological,
social, and existential components and not focus on a single component.
Failure to sufficiently understand the etiology of the pain complaint will
invariably result in poor pain management. Interdisciplinary collaboration
is essential for comprehensive care of the cancer patient. Disciplines and
specialties involved in care commonly include pain management
specialists, oncologists, surgeons, psychiatrists, psychologists, physical
therapists, pharmacists, nurses, and social workers. Aggressive therapy of
both cancer and pain are mutually beneficial and are best done by skilled,
interdisciplinary teams that understand and respond to the changing
demands of oncology care.
Most patients can attain adequate symptomatic relief of cancer pain
using appropriate oral pharmacotherapy. Comparatively, opioids are very
effective for pain management compared to other agents, and the focus on

2259
pharmacotherapy should be safe, appropriate, and effective opioid use
irrespective of the source of pain. Long-term use of opioid therapy is
controversial and continued use of opioids requires a system that can
assess, monitor, modify, and, if appropriate, reduce or taper opioid therapy
as required. Modern guidelines on long-term opioid therapy commonly
suggest upper limits of opioid therapy that are useful reminders of the
potential hazards and risks that can occur with inappropriately high-dose
opioid therapy particularly in the setting of failure to meet anticipated
functional gains from therapy. The concurrent use of adjunctive or
specialized therapies or complementary therapies is sometimes necessary,
however, and referral for specialized surgical, anesthetic, or psychological
intervention benefit a significant number of patients. However, the
introduction of multiple psychoactive medications can be hazardous, and
frequent efforts should be made to eliminate all unnecessary or ineffective
medications. The continued growth of the home care industry and hospice
and emphasis away from inpatient care has broadened the possibilities of
extending basic and sophisticated pain management strategies into the
home.

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414. Moryl N, Santiago-Palma J, Kornick C, et al. Pitfalls of opioid rotation: substituting another
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415. Mercadante S, Porzio G, Ferrera P, et al. Sustained-release oral morphine versus transdermal
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416. Kilonzo I, Twomey F. Rotating to oral methadone in advanced cancer patients: a case series. J
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418. Hagen NA, Wasylenko E. Methadone: outpatient titration and monitoring strategies in cancer
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419. Mercadante S, Caraceni A. Conversion ratios for opioid switching in the treatment of cancer
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421. O’Bryant CL, Linnebur SA, Yamashita TE, et al. Inconsistencies in opioid equianalgesic
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422. Gabrail NY, Dvergsten C, Ahdieh H. Establishing the dosage equivalency of oxymorphone
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427. Vanier MC, Labrecque G, Lepage-Savary D, et al. Comparison of hydromorphone continuous
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430. Roy SD, Flynn GL. Solubility and related physicochemical properties of narcotic analgesics.
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433. Tafani JA, Lazorthes Y, Danet B, et al. Human brain and spinal cord scan after
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434. Sandouk P, Serrie A, Urtizberea M, et al. Morphine pharmacokinetics and pain assessment
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435. Tseng LF, Fujimoto JM. Differential actions of intrathecal naloxone on blocking the tail-flick
inhibition induced by intraventricular beta-endorphin and morphine in rats. J Pharmacol Exp
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436. Lazorthes YR, Sallerin BA, Verdie JC. Intracerebroventricular administration of morphine for
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437. Karavelis A, Foroglou G, Selviaridis P, et al. Intraventricular administration of morphine for
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438. Obbens EA, Hill CS, Leavens ME, et al. Intraventricular morphine administration for control
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440. Layton D, Osborne V, Al-Shukri M, et al. Indicators of drug-seeking aberrant behaviours: the
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441. Chabal C, Erjavec MK, Jacobson L, et al. Prescription opiate abuse in chronic pain patients:

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442. Hamill-Ruth RJ, Larriviere K, McMasters MG. Addition of objective data to identify risk for
medication misuse and abuse: the inconsistency score. Pain Med 2013;14:1900–1907.
443. Ready LB, Sarkis E, Turner JA. Self-reported vs. actual use of medications in chronic pain
patients. Pain 1982;12:285–294.
444. Fishbain DA, Cutler RB, Rosomoff HL, et al. Validity of self-reported drug use in chronic
pain patients. Clin J Pain 1999;15:184–191.
445. Couto JE, Romney MC, Leider HL, et al. High rates of inappropriate drug use in the chronic
pain population. Popul Health Manag 2009;12:185–190.
446. Dev R, Parsons HA, Palla S, et al. Undocumented alcoholism and its correlation with tobacco
and illegal drug use in advanced cancer patients. Cancer 2011;117:4551–4556.
447. Passik SD, Kirsh KL, McDonald MV, et al. A pilot survey of aberrant drug-taking attitudes
and behaviors in samples of cancer and AIDS patients. J Pain Symptom Manage
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448. Passik SD, Schreiber J, Kirsh KL, et al. A chart review of the ordering and documentation of
urine toxicology screens in a cancer center: do they influence patient management? J Pain
Symptom Manage 2000;19:40–44.
449. Guy GP Jr, Zhang K, Bohm MK, et al. Vital signs: changes in opioid prescribing in the United
States, 2006-2015. MMWR Morb Mortal Wkly Rep 2017;66:697–704.
450. Centers for Disease Control and Prevention. Vital signs: overdoses of prescription opioid pain
relievers—United States, 1999–2008. MMWR Morb Mortal Wkly Rep 2011;60:1487–1492.
451. Anghelescu DL, Ehrentraut JH, Faughnan LG. Opioid misuse and abuse: risk assessment and
management in patients with cancer pain. J Natl Compr Canc Netw 2013;11:1023–1031.
452. Chou R, Fanciullo GJ, Fine PG, et al. Clinical guidelines for the use of chronic opioid therapy
in chronic noncancer pain. J Pain 2009;10:113–130.
453. Manchikanti L, Abdi S, Atluri S, et al. American Society of Interventional Pain Physicians
(ASIPP) guidelines for responsible opioid prescribing in chronic non-cancer pain: part 2—
guidance. Pain Physician 2012;15:S67–S116.
454. Busse JW, Craigie S, Juurlink DN, et al. Guideline for opioid therapy and chronic noncancer
pain. CMAJ 2017;189:E659–E666.
455. Bailey RW, Vowles KE. Using screening tests to predict aberrant use of opioids in chronic
pain patients: caveat emptor. J Pain 2017;18:1427–1436.
456. Manchikanti L, Kaye AM, Knezevic NN, et al. Responsible, safe, and effective prescription of
opioids for chronic non-cancer pain: American Society of Interventional Pain Physicians
(ASIPP) guidelines. Pain Physician 2017;20:S3–S92.
457. Dowell D, Haegerich TM, Chou R. CDC guideline for prescribing opioids for chronic pain—
United States, 2016. JAMA 2016;315:1624–1645.
458. Meuret G, Jocham H. Patient-controlled analgesia (PCA) in the domiciliary care of tumour
patients. Cancer Treat Rev 1996;22(suppl A):137–140.
459. Schiessl C, Sittl R, Griessinger N, et al. Intravenous morphine consumption in outpatients
with cancer during their last week of life—an analysis based on patient-controlled analgesia
data. Support Care Cancer 2008;16:917–923.
460. Deng G, Cassileth B. Integrative oncology: an overview. Am Soc Clin Oncol Educ Book
2014:233–242.
461. Cassileth B, Trevisan C, Gubili J. Complementary therapies for cancer pain. Curr Pain
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462. Adler SR, Fosket JR. Disclosing complementary and alternative medicine use in the medical
encounter: a qualitative study in women with breast cancer. J Fam Pract 1999;48:453–458.
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464. Tasaki K, Maskarinec G, Shumay DM, et al. Communication between physicians and cancer
patients about complementary and alternative medicine: exploring patients’ perspectives.
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465. Greenlee H, DuPont-Reyes MJ, Balneaves LG, et al. Clinical practice guidelines on the
evidence-based use of integrative therapies during and after breast cancer treatment. CA
Cancer J Clin 2017;67:194–232.
466. Mansky PJ, Wallerstedt DB. Complementary medicine in palliative care and cancer symptom
management. Cancer J 2006;12:425–431.
467. Bao Y, Kong X, Yang L, et al. Complementary and alternative medicine for cancer pain: an
overview of systematic reviews. Evid Based Complement Alternat Med 2014;2014:170396.
468. Bardia A, Barton DL, Prokop LJ, et al. Efficacy of complementary and alternative medicine
therapies in relieving cancer pain: a systematic review. J Clin Oncol 2006;24:5457–5464.
469. Gorski DH. Integrative oncology: really the best of both worlds? Nat Rev Cancer
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470. National Institutes of Health Consensus Conference. Acupuncture. JAMA 1998;280:1518–
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471. Filshie J, Hester J. Guidelines for providing acupuncture treatment for cancer patients—a
peer-reviewed sample policy document. Acupunct Med 2006;24:172–182.
472. Lee H, Schmidt K, Ernst E. Acupuncture for the relief of cancer-related pain—a systematic
review. Eur J Pain 2005;9:437–444.
473. Lian WL, Pan MQ, Zhou DH, et al. Effectiveness of acupuncture for palliative care in cancer
patients: a systematic review. Chin J Integr Med 2014;20:136–147.
474. Chiu HY, Hsieh YJ, Tsai PS. Systematic review and meta-analysis of acupuncture to reduce
cancer-related pain. Eur J Cancer Care (Engl) 2017;26:e12457.
475. Choi TY, Lee MS, Kim TH, et al. Acupuncture for the treatment of cancer pain: a systematic
review of randomised clinical trials. Support Care Cancer 2012;20:1147–1158.
476. Paley CA, Johnson MI, Tashani OA, et al. Acupuncture for cancer pain in adults. Cochrane
Database Syst Rev 2015;(10):CD007753.

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CHAPTER 44
Interventional Pain Therapies
SHANE E. BROGAN, JILL SINDT, and ASHWIN VISWANATHAN

The World Health Organization (WHO) analgesic ladder, as described in

the previous chapters on cancer pain management, is practical, easy to
implement, and has been taught extensively to health professionals.
However, even when the WHO approach is implemented appropriately
and aggressively, 10% to 20% of patients do not attain acceptable pain
control. Traditionally, it has been this refractory group of patients that has
been considered for interventional pain management, but the approach of
reserving interventional management as a last resort has been called into
question.1–4 This is particularly true in relation to intrathecal (IT) therapy,
where a multicenter study suggests that early implementation of treatment
leads to improved outcomes.5 Another type of interventional therapy,
namely, neurolytic celiac plexus block (NCPB), may be useful as an early
intervention in controlling pancreatic cancer pain and other gastrointestinal
system pain-producing malignancies.6 Furthermore, there has been a
recent resurgence in interest in neurosurgical techniques in refractory pain
due to the precision afforded by recent advances in image-guided surgical
approaches. Two interventions, in particular, cordotomy and myelotomy,
are being increasingly considered for refractory somatic and visceral pain,
respectively.
Impediments to the appropriate use of interventional and neurosurgical
techniques include inaccessibility to suitably trained physicians and
absence of up-to-date knowledge among cancer care providers of the
various techniques available, including indications and timing, benefits,
risks, and costs (Table 44.1).

TABLE 44.1 Overview of the More Commonly Performed

Interventional Cancer Pain Therapies
Major Adverse

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Intervention Indications Effects and Risks Comments
Intrathecal (IT) therapy 1. Cancer pain Infection, postdural Various delivery
(lumbar region refractory to usual puncture methods
catheter placement; pharmacotherapeutic headache, and available
see Chapter 41 for a approaches spinal cord injury depending on
discussion of 2. The presence of are rare the prognosis.
intracerebroventricular unacceptable complications. Cost of
therapy) medication side Long-term use of implanted
effects IT opioids may be programmable
associated with delivery system
suppression of the may be
pituitary-gonadal comparable to
axis. conventional
medical therapy
after several
months of
ongoing
treatment,
barring surgical
complications.
Neurolytic celiac plexus Visceral abdominal Transient Efficacy of up to
block (epigastric and hypotension, 90% and good
referred) pain, diarrhea; very safety profile
originating from rarely, spinal cord
disease involving the injury
distal stomach
through the
transverse colon;
pancreatic cancer
pain is the most
typical indication.
Neurolytic superior Visceral pain Serious adverse
hypogastric plexus originating from the effects are rare.
block pelvic organs
Ganglion impar block Anal, perineal pain Serious adverse
effects are rare.
Intercostal block Somatic pain of the Low risk of
chest or abdominal pneumothorax if
wall ultrasound is used
Spinal neurolysis Pain refractory to other Dependent on level Alcohol or phenol
forms of therapy, blocked. Cervical is the typical
particularly when IT or lumbar agents used.
therapy is neurolysis carries
contraindicated or the risk of
inefficacious extremity motor
weakness.
Lumbosacral
neurolysis risks

2284
 are bowel and
bladder
dysfunction,
which are usually
transient;
deafferentation
pain at any level
Vertebral augmentation Painful compression Cement spread to Better outcomes
fracture of the the spinal canal are noted with
vertebral body causing fractures <6 mo
without involvement neurologic injury; of age.
of the spinal canal allergy to cement;
pulmonary
embolus
Image-guided tumor Painful bony Bone instability and Still not in
ablation metastases fracture widespread use
but preliminary
studies are
promising

The primary purpose of this chapter is to target this latter group of

individuals. It is anticipated that a general understanding of interventional
approaches to cancer pain control will lead to more appropriate and timely
consideration of all potential therapeutic options.

Intrathecal Drug Therapy

IT drug delivery involves drug administration into the cerebrospinal fluid
(CSF) through a small catheter. This route allows the medication to
circulate in the CSF and adsorb directly onto central nervous system
(CNS) effector sites. This direct delivery to the CNS reduces the systemic
toxicity of medication administered via enteral, parenteral, or transdermal
routes. Opioids, N-type calcium channel blockers, among other pain
modulating agents, have been successfully infused intrathecally in the
treatment of cancer pain. Effective analgesia using IT opioids is typically
obtained using a small fraction (i.e., 1/100th) of the systemic dose. The
addition of adjunctive IT agents that have specific activity within the
neuraxis, such as local anesthetics and α2 agonists, may be used to
improve overall effectiveness of IT opioid therapy in refractory cases.7

INDICATIONS
2285
IT therapy is usually indicated in the small proportion of cancer patients
for whom comprehensive medical management (CMM) has produced
suboptimal pain control or unacceptable, dose-limiting, analgesic-related
toxicity. Other factors may make IT therapy an attractive option, including
inability to adhere to a more conventional analgesic regimen. Furthermore,
cancer pain with a strong neuropathic component (e.g., plexopathy,
complex regional pain syndrome) may respond better to IT therapy,
particularly when adjunctive agents such as local anesthetics and clonidine
are used.8 In the setting of severe pain and the prospect of a very
aggressive chemotherapy regimen, when the oral route will likely be an
unreliable means of administering analgesics, strong consideration should
be given to adopting an IT approach to pain management.

INTRATHECAL DRUG DELIVERY SYSTEMS

Simple Percutaneous Intrathecal Catheter
This is a minimally invasive technique that can be done at the bedside for
short-term use. It may be implemented as a trial method (i.e., to assess
efficacy of IT opioids, with the intent of placing an implantable system if
the trial is deemed a success) or it can be used as a definitive method of
delivering IT drug when life expectancy is extremely short (i.e., days
rather than weeks to months). In the setting of a patient with severe pain
and only several days of expected life, this method will allow for rapid
control of pain. Because the catheter is not tunneled, infection risk and
mechanical failure is higher, markedly reducing successful longer term
use.

Tunneled Intrathecal Catheter

Tunneled IT catheters are typically placed in the operating room under
sterile conditions. A dorsally placed catheter is tunneled subcutaneously
for a variable distance and usually exits from the lateral abdominal wall.
With appropriate infection control measures, including the use of
antimicrobial filters and meticulous exit site care, tunneled IT or epidural
catheters can be used for months to years.9,10 The catheter is usually not
sutured internally, so it can be readily removed in the office if necessary.
An advantage of the exteriorized system is that nonpain specialist

2286
palliative care clinicians, including those in-home hospice settings, may
become proficient in its management with minimal training. Toward the
end of life, when analgesic requirements may be rapidly escalating,
hospice registered nurses can easily give IT boluses or increase the
infusion rate as indicated and alter the drug(s) used with relative ease.
With an implanted system (see the following discussion), drug changes are
more complex than intravenous (IV) or oral dosing, and rapid dose
titration is not as easily accomplished because of the need for pump
reprogramming by trained specialists. Disadvantages of a tunneled system
versus a self-contained implanted device are the need for an externalized
pump apparatus, increased risk of infection, decreased patient mobility,
and the possibility of inadvertent catheter dislodgment or removal.

Implantable Drug Delivery Systems

The implanted drug delivery system (IDDS) uses a small, programmable,
computerized electronic pump to deliver drug to the IT space through a
catheter (Figs. 44.1 and 44.2). The pump is placed subcutaneously in the
anterior abdominal wall or buttock and has a reservoir that can be refilled
via a port accessed by a specialized needle through the skin. The pump is
programmed by an external handheld device that can alter the rate of
infusion and deliver boluses and also allows for a patient-controlled
analgesia function. The battery life is typically 5 to 7 years, so it is
unlikely that a replacement would be necessary during the average lifetime
of the cancer patient with advanced disease. Drug refills are office-based
and minimally uncomfortable. Refills are needed every 1 to 6 months
depending on the drug concentration and infusion rate.

2287
FIGURE 44.1 Schematic of an intrathecal (IT) drug delivery system showing the pump in the
anterior abdominal wall and the catheter tunneled to the dorsal spine and into the IT space.
(Courtesy of Medtronic, Inc.)

2288
FIGURE 44.2 Intrathecal pump and catheter system. The pump is refilled percutaneously with a
needle through the orifice in the center of the device. (Courtesy of Medtronic, Inc.)

Contraindications to an IDDS are generally related to difficulties forming a

suitable subcutaneous pocket for the pump, as would be the case in severe
ascites, emaciation, skin infection, or other abdominal wall pathology.
Patients with systemic infection, concurrent bleeding diathesis, or clotting
abnormalities are poor candidates until these abnormalities are corrected or
stabilized. Advantages of this system, compared to an exteriorized system,
include increased patient freedom of mobility, low maintenance, and lower
infection risk. Disadvantages are the need for an initially more invasive
surgery, high upfront costs, and the logistical problems concerning pump
refills and programming. See Table 44.2 for a comparison of exteriorized
versus implanted pump delivery systems.

TABLE 44.2 Comparison of Intrathecal Drug Delivery Systems

Exteriorized Intrathecal
IDDS Delivery System
Cost High initial cost but more Lower cost for short-term use

2289
 cost-effective after 3
months
Indications Refractory cancer pain and Refractory cancer pain with
prognosis >3 mo prognosis <3 mo; pain crisis
requiring rapid control
Infection risk Early infection risk; low-risk Higher
longer term
Advantages Patient freedom; low Easier to change infusate;
maintenance easier to give boluses for
aggressive symptom
control; can be removed in
the office
Disadvantages More invasive; requires more Risk of dislodgment and
operator expertise in tertiary failure
care setting
IDDS, implantable drug delivery system.

INTRATHECAL VERSUS EPIDURAL DRUG DELIVERY

IT drug delivery has largely replaced the epidural route as the preferred
neuraxial route of administration for various reasons. With all neuraxial
administration of opioids, the target sites are opioid receptors of the dorsal
horn of the spinal cord, which requires either direct CSF delivery or
absorption of drug from the epidural space. Compared to IT delivery,
epidural infusions require a 10-fold greater volume and dose of opioid in
order to diffuse passively across the dura and enter the subarachnoid (IT)
space. This large difference in infusion volumes and doses has a major
impact both on cost and the frequency of drug reservoir changes, which
necessitates breaking the system’s sterility more frequently and likely
results in a higher infection rate. Furthermore, treatment failure is more
frequent with the epidural route due to inadvertent catheter dislodgment
and the development of epidural fibrosis which impedes diffusion of drug
to the subarachnoid space.11 Technical complication rates have been
shown to be higher with long-term epidural (55%) compared to IT (5%)
infusions.12 Finally, ziconotide, an increasingly used agent in refractory
cancer pain, is not approved for epidural use.
Notwithstanding these considerations, there remain some specific
indications for epidural analgesia. Pain in a pattern involving specific,
consecutive dermatomes may be blocked with local anesthetics with an
appropriately positioned epidural catheter. An example of this would be a

2290
thoracic epidural catheter for isolated thoracic pain caused by rib
metastases, in the setting of a short life expectancy. This technique may
allow for complete analgesia using local anesthetics alone without the use
of epidural opioids.

IMPLANTABLE OR EXTERIORIZED INTRATHECAL

DRUG DELIVERY: COST ANALYSIS
With an IDDS, the initial costs are relatively high ($15,000 to $20,000).
Over time, the accruing and total care costs may be less in patients with an
IDDS compared to those with an exteriorized system due to greater labor-
related costs (including managing mechanical failures) with externalized
systems. An older study suggested that, compared to an externalized
system, an IDDS will be more cost-effective after approximately 3 months
of therapy.13 There are no recent cost comparisons available.

OUTCOME STUDIES
A 2002 study by Smith et al.5 randomized 202 patients with advanced
cancer to CMM or an IDDS plus CMM. Patients were eligible if they had
a Visual Analog Scale (VAS) pain intensity rating of ≥5 at two
measurements within a week of randomization, despite 200 mg per day or
more of oral morphine or its equivalent. Patients on lower doses of opioids
were also permitted entry if opioid side effects refractory to conservative
management prohibited further escalation of total opioid dose. All patients
were ≥18 years of age, had life expectancy ≥3 months, and were suitable
for IDDS (no active infection, obstruction of CSF flow, or mechanical
barriers). The primary outcome measure was pain control (VAS
improvement ≥20%) combined with an improved toxicity profile, as
measured by the National Cancer Institute Common Toxicity Criteria, 4
weeks after randomization. Clinical success was defined as a ≥20%
reduction in VAS scores or equal scores with a ≥20% reduction in toxicity.
At 4 weeks, both groups had an improvement in pain scores and
toxicity. Sixty of 71 IDDS patients (84.5%) achieved clinical success
compared with 51 of 72 CMM patients (70.8%, P = .05). IDDS patients
more often achieved ≥20% reduction in both pain VAS and toxicity
(57.7% [41 of 71] vs. 37.5% [27 of 72], P = .02). The mean CMM VAS

2291
score fell from 7.81 to 4.76 (39% reduction); for the IDDS group, the
scores fell from 7.57 to 3.67 (52% reduction, P = .055). The mean CMM
toxicity scores fell from 6.36 to 5.27 (17% reduction); for the IDDS group,
the toxicity scores fell from 7.22 to 3.59 (50% reduction, P = .004). The
IDDS group had significant reductions in fatigue and depressed level of
consciousness (P < .05). IDDS patients also had improved survival, with
53.9% alive at 6 months compared with 37.2% of the CMM group (P =
.06). The authors concluded that IT therapy, compared to CMM alone,
improved clinical success by reducing drug toxicity, trended toward
improving pain reduction, and possibly improved survival. It should be
noted that the data were analyzed on an intent-to-treat basis, but that some
crossover (five patients) from CMM to the IDDS group did occur. When
the data are interpreted on the basis of the actual treatment received, there
was a significant difference between the VAS scores between groups, in
favor of IT therapy.
In 2005, the same group of authors published a second paper examining
the 6-month follow-up of the patients in the aforementioned trial.14 The
approach in this paper was to compare outcomes in terms of the actual
treatment received (i.e., an IDDS vs. CMM alone) rather than the intent to
treat at randomization approach used in the 2002 study. Outcome measures
were the same as in the initial study but were also assessed in patients alive
at 12 weeks after the initial randomization. At 4 weeks, 88.5% of IDDS
patients achieved clinical success compared with 71.4% (P = .02) of non-
IDDS patients and more often achieved a ≥20% reduction in both pain
VAS and toxicity (67.3% vs. 36.3%; P = .0003). At 12 weeks, of the 56
patients remaining in the CMM group, 19 had received an IDDS. By 12
weeks, 82.5% of IDDS patients had clinical success compared with 77.8%
(P = .55) of non-IDDS patients and more often had a ≥20% reduction in
both pain VAS and toxicity (57.9 vs. 33.3%; P = .01). At 12 weeks, the
IDDS VAS pain scores decreased from 7.81 to 3.89 (47% reduction)
compared with 7.21 to 4.53 for non-IDDS patients (42% reduction; P =
.23). The 12-week drug toxicity scores for IDDS patients decreased from
6.68 to 2.30 (66% reduction) and for non-IDDS patients from 6.73 to 4.13
(37% reduction; P = .01). All individual drug toxicities improved with
IDDS at both 4 and 12 weeks. At 6 months, only 32% of the group

2292
randomized to CMM and who did not crossover to IDDS were alive,
compared with 52% to 59% for patients in those groups who received
IDDS. This study concluded that an IDDS improved clinical success,
reduced pain scores, relieved most toxicity of pain control drugs, and was
associated with increased survival for the duration of the 6-month trial.

PATIENT-CONTROLLED INTRATHECAL ANALGESIA

A shortcoming of the studies mentioned in the previous section is that
patients relied only on basal infusions of morphine, without the ability to
self-administer IT boluses.
Consequently, breakthrough medications were continued, and although
drug toxicities were much improved, ongoing opioid-related side effects
were likely observed. Several years after the completion of the original
studies, the technology to self-administer IT opioid (and adjuncts) with a
“remote control” device became available. A retrospective analysis of 43
patients with refractory cancer pain treated with intrathecal therapy (ITT)
with the ability to self-administer IT boluses showed that, 1 month after
implant, 50% stopped all conventional opioids, with the mean oral
morphine equivalence decreasing from 796 mg.15
A follow-up prospective observational study of 98 refractory cancer
pain patients performed satisfaction and symptom surveys, including a
breakthrough pain survey, before and after ITT. Average “worst” pain
scores decreased from 8.32 (SD, 1.73) pre-ITT to 4.98 (SD, 2.92) post-ITT
(P < .001). The prevalence of severe pain (numerical rating score ≥7)
decreased from 84% to 35% (P < .001). Mean daily morphine equivalent
dosing decreased from 805 mg per day to 128 mg per day, with 65.5% of
discontinuing all non-IT opioids. The mean M. D. Anderson Symptom
Inventory symptom severity score decreased from 4.98 to 3.72 (P < .0001)
and the symptom interference score from 6.53 to 4.37 (P < .001). When
assessing breakthrough pain pharmacotherapy, pain intensity reduction
was 46.8% with pre-ITT breakthrough medications and 65.2% with
patient-controlled intrathecal analgesia (PCIA; P < .001). Median time to
onset was 30 minutes with pre-ITT breakthrough medications and 10
minutes with PCIA (P < .001). Patient satisfaction was also higher with
PCIA compared with conventional breakthrough pain medications: “a lot

2293
better” in 60.7% and “a little better” in 28.6%. Overall pain control
satisfaction was also improved, with 78.2% “a lot better” and 10.9%
reporting no pain.16

PHARMACOLOGY
Over a dozen different agents have been reported to be used intrathecally
in the management of cancer pain, and most of these have never been
approved by the U.S. Food and Drug Administration (FDA) for IT use
(Table 44.3). Morphine sulphate, one of the few agents the FDA approved
for IT use, is the standard first-line drug used in IT pain therapy.
Additional agents are usually then added in a stepwise fashion depending
on the response to morphine alone; it is not uncommon that one to three
adjunctive agents are added to the infused solution. Consensus documents
have attempted to standardize the therapeutic approach to IT drug selection
and dosing in the cancer patient (see Table 44.3).7,17

TABLE 44.3 Intrathecal Drugs Used in Cancer Pain Management

Drug Receptor Indication Adverse Effects Notes
Opioids μ-Opioid Nociceptive Sedation, The lipophilic
Morphine receptors and mixed respiratory opioids like
Sulphate pain, first- depression, fentanyl and
Hydromorphone line therapy; urinary sufentanil are
Fentanyl neuropathic retention, generally added
Sufentanil pain second- nausea, when first-line
line therapy pruritus, treatments have
cognitive failed.
impairment
Ziconotide N-type calcium First- or Ataxia, auditory With careful
channels second-line hallucinations, titration, adverse
therapy psychosis effects are
minimized; no
withdrawal
phenomenon
Local Neural sodium Neuropathic Motor weakness, The chemical
anesthetics channels and mixed hypotension, sympathectomy
Bupivacaine pain, first- urinary caused by
line therapy; retention intrathecal
nociceptive bupivacaine may
pain, second promote
line gastrointestinal
motility.

2294
 Clonidine α2 Adjunct in Orthostatic
Adrenoceptor neuropathic hypotension,
pain states sedation,
edema
Baclofen γ-Aminobutyric Coexisting Ataxia, sedation, Abrupt
acid (GABA) spasticity; auditory discontinuation
third line for disturbance may cause a
neuropathic serious
pain withdrawal
syndrome.
Ketamine N-methyl-d- Used only at Anxiety, Ketamine, given
aspartate end of life agitation, intravenously at
(NMDA) when other facial subanesthetic
IT agents flushing, doses has also
have failed delusions; been used
neurotoxicity effectively for
refractory pain
syndromes,
especially in
terminal care.117
Based on the practice guidelines published by Deer TR, Pope JE, Hayek SM, et al. The
Polyanalgesic Consensus Conference (PACC): recommendations on intrathecal drug infusion
systems best practices and guidelines. Neuromodulation 2017;20(2):96–132.

Opioids
IT µ-opioid agonists directly activate dorsal horn and brainstem opioid
receptors. Morphine sulphate is FDA-approved for IT use, and it remains
the first-line agent for IT analgesia. Numerous other IT opioids have been
used successfully including hydromorphone, fentanyl, sufentanil,
meperidine, and methadone. The choice of agent is largely idiosyncratic.
Many practitioners purport that hydromorphone causes less nausea than
morphine, although there are no comparative trial data to support this
view. The comparatively greater lipophilicity of fentanyl and sufentanil
leads to relatively rapid absorption into proximate neural structures with
less CSF recirculation and migration to the brainstem. This has some
theoretical advantages when a more regional analgesic effect is desired,
with less risk of opioid activity (respiratory depression) at the brainstem
level.

Ziconotide
Ziconotide (formally SNX-111) is a novel marine snail peptide that is an

2295
N-type voltage-sensitive calcium channel blocker. Ziconotide can only be
given intrathecally and appears to act at the dorsal horn to decrease
afferent sensory input by mechanisms different from those of other IT
drugs.18 Ziconotide has emerged as an indispensable tool in the
management of advanced cancer pain, either as a first-line agent or as
adjunct when IT opioids have failed either due to toxicity or inefficacy.7
An advantage of ziconotide is the lack of any respiratory depressant effect
as well as the absence of any withdrawal phenomenon. A randomized,
placebo-controlled trial including cancer patients demonstrated improved
mean visual analog scores of 53% in the ziconotide group compared with
18% in the placebo group (P < .001); 53% of patients in the ziconotide
group reported moderate to complete pain relief compared with 18% in the
placebo group (P < .001).19
Ziconotide has a distinct set of side effects that can hamper its use,
including ataxia, auditory hallucinations, and psychosis. However, with
more measured guidelines, including careful and slow titration, most of
these side effects can be limited to mild events and major side effects are
now rare.7,20

Local Anesthetics
Local anesthetics, such as bupivacaine and lidocaine, are sodium channel
blockers which interrupt neural action potentials along sensory and motor
nerves. When given intrathecally, local anesthetics can block incoming
sensory nerves and produce complete analgesia. However, this comes at
the price of motor blockade resulting in weakness and sympathetic nervous
system blockade which may result in hypotension. High doses of local
anesthetics may also result in neuro- or cardiotoxicity (seizure or
arrhythmia).
Bupivacaine, given in doses less than 30 to 60 mg per day, is an
excellent adjunct to IT opioids and generally causes minimal motor block.
In the terminally ill patient who is bedbound and does not object to lower
extremity weakness, higher doses of local anesthetics may be used to
provide profound analgesia with no cognitive side effects. Supportive
means to evacuate the bowels and void urine must be anticipated.

2296
Clonidine
Clonidine is an α2-adrenergic agonist that acts at the dorsal horn by
modulating the transmission of noxious sensory signals. This modulation
is accomplished by mimicking the activation of descending noradrenergic
pathways and inhibiting neurotransmitter release.21 Epidural and IT
clonidine has been studied extensively in postoperative pain settings and in
obstetric care for labor analgesia, but little data exist from cancer pain
treatment studies. It is generally considered a very useful adjunct to
opioids and local anesthetics when there is a predominant neuropathic pain
component. Dosing is limited by side effects including sedation and
hypotension. The consensus guideline by Deer et al.7 now includes
clonidine as a possible second-line adjunct (with an opioid) for both
nociceptive and neuropathic pain.

Other Drugs
A diverse group of drugs have been reported to be useful IT adjuncts,
including baclofen, ketamine, neostigmine, midazolam, ketorolac, and
droperidol.

CONTRAINDICATIONS AND RISK MANAGEMENT

Absolute contraindications to IT analgesia are rare. Skin infection over the
intended catheter site, bacteremia/sepsis, and uncorrectable coagulopathy
represent absolute contraindications to IT catheter placement, given the
respective risks of CNS infection and spinal hematoma. Coumadin needs
to be held until the international normalized ratio is 1.5 or less. If
indicated, a low molecular weight heparin (LMWH) may be used,
provided it is held for 24 hours before the catheter placement. Given the
plethora of novel anticoagulants on the market, specific guidelines have
been created.7 Hematologic relative contraindications include a lowered
white cell count ≤2 × 109/L, an absolute neutrophil count ≤1,000/µL, or a
platelet count ≤20 × 103/µL.17 Depending on the patient circumstances,
thrombocytopenia may be treated with a platelet transfusion prior to
implantation. Special consideration must be given to the feasibility of
implanting available pump devices in the anterior abdominal wall,
particularly in emaciated patients or children. A smaller 20-mL capacity

2297
pump is available and may be more practical in these instances.

COMPLICATIONS AND SIDE EFFECTS

In general, most of the commonly reported drug-related adverse effects are
well tolerated or readily managed with palliative or supportive
interventions. The usual IT-opioid side effects are similar to those
experienced with the oral or transdermal route but usually much less
pronounced and include sedation, nausea, pruritus, and urinary retention.
The serious complication of respiratory depression is rare, especially in
opioid-tolerant patients. Local anesthetics may cause lower extremity
weakness, hypotension, and bowel or bladder dysfunction. Clonidine may
cause hypotension and sedation.
Meningitis is the most feared complication of IT drug delivery, but it
occurs infrequently when standard infection control measures are
followed. Localized skin infection is more common and can usually be
managed by oral antibiotics and close observation.
Occasionally, catheter or pump explantation will be necessary.
Guidelines about the prevention and treatment of IT drug delivery system
infection have been published.22,23 Typical surgical complications may
develop, including seroma formation and pump pocket hematoma. These
are usually self-limiting, but ongoing assessment for infection is required,
and they may add to postimplant discomfort. The best prophylaxis is an
appropriately sized surgical pocket with fastidious hemostasis, and this is
achieved through experience.
Catheter tip inflammatory masses (granuloma) are now a well-
recognized complication of IT drug delivery. These granulomatous masses
can present with new onset lower extremity neurologic symptoms and are
associated with high doses and high concentrations of opioid infusate.
Clinicians must have a high index of suspicion for this complication; to
ignore it may result in permanent neurologic damage, whereas with early
recognition and minimally invasive treatment, there are seldom any long-
term sequelae.24
Postdural puncture headache can result from persistent CSF leak around
the catheter. This uncomfortable and often distressing experience is
usually self-limiting, resolving spontaneously over days to weeks.

2298
Conservative management includes rest, fluids, additional analgesia, and
caffeine. A headache that persists may be treated with a fluoroscopically
guided epidural blood patch, provided that there are no contraindications
related to bleeding risk or leukopenia.

INTRATHECAL THERAPY AND ONGOING

ONCOLOGIC CARE
The initiation or continuation of IT therapy need not interfere with
chemotherapy or radiotherapy regimens. The superior symptom control
offered by IT therapy may in fact allow patients to tolerate aggressive
treatment more comfortably and increase the efficiency of the oncology
suite by decreasing the amount of time spent managing complicated
cancer-related symptoms. Particularly aggressive chemotherapy protocols
may require that the implantation of an IT drug delivery system be
strategically timed to avoid a white cell count or platelet count nadir.
Radiation therapy may affect the battery life of IDDS and may result in
electrical failure. The pump may be protected by lead shielding and, if
possible, radiation field avoidance.

Spinal Chemoneurolysis
Spinal chemoneurolysis involves the destruction of nerve root axons or
other spinal cord elements by chemical means, using alcohol or phenol.
The destruction of selected nerve roots interrupts nociceptive pathways
and can potentially create excellent analgesia in a relatively selective body
area. Alcohol or phenol ablation of central neural structures has largely
fallen out of favor in recent decades, mostly because of advances in the
pharmacologic treatment of pain, including via the IT route as previously
described.
Nevertheless, it remains a useful and effective technique in developing
countries with limited opioid access and where a rapidly effective therapy,
requiring little or no follow-up, is required. Like other interventional pain
management techniques, intraspinal neurolysis offers the advantage of
localized pain control while minimizing the burden of systemic side
effects. However, the potential adverse effects of the procedure are

2299
significant, including motor nerve root dysfunction, bowel or bladder
dysfunction, and dysesthesias in the denervated dermatomes.25,26 In
experienced hands, these adverse effects may be minimized, but the
potentially high morbidity of these problems has generally placed
intraspinal neurolysis toward the end of the treatment spectrum in modern
day practice.27

SPINAL CHEMONEUROLYSIS TECHNIQUE

Spinal chemoneurolysis, or simply neurolysis, notwithstanding its value in
appropriately selected patients, is rapidly becoming a forgotten technique,
and therefore, physicians with experience with this treatment modality,
and the ability to teach it to trainees, are becoming relatively scarce.
Neurolysis is targeted at the sensory nerve root and dorsal root ganglion
within the subarachnoid space while attempting to spare the more
anteriorly located motor nerve roots. Neurolysis may be performed at the
cervical, thoracic, or lumbosacral levels, with the last being the most
common site of intervention. Neurolysis in the epidural space has also
been described but is less favored because of pain on injection and
disappointing outcomes.28 Knowledge of the chemical properties of
alcohol and phenol is essential to the safe and effective use of each agent.
The disposition of alcohol and phenol are distinctly different when
deposited in the IT space (Figs. 44.3 and 44.4). Alcohol is hypobaric
relative to CSF and therefore will “float” upward, whereas phenol is
hyperbaric and will “sink” within the subarachnoid space relative to the
position of the needle tip. These properties allow for reasonably selective
targeting of nerve roots using careful patient positioning and needle
placement. The patient is placed in the lateral decubitus position, with the
painful side uppermost for alcohol neurolysis, and dependent for phenol
neurolysis. Because it is most common for patients to be intolerant of
having the painful side down (dependent), alcohol ablation is the preferred
technique. For alcohol neurolysis, the patient is rolled 45 degrees away
from the operator who is on the dorsal side of the patient, so that the
hypobaric alcohol preferentially floats to the dorsolateral subarachnoid
space where the sensory dorsal roots reside. To treat this same anatomic
location with phenol, the patient needs to be rolled toward the operator. A

2300
small-bore spinal needle is advanced into the IT space at the appropriate
nerve root level for the affected pain site to be treated. Recall that nerve
roots and their respective dermatomal, myotomal, and sclerotomal levels
do not necessarily line up anatomically.
Very small aliquots (0.1 to 0.2 mL) of the neurolytic agent are then
injected incrementally with careful monitoring of sensory changes and
dermatomal spread until the desired region is blocked. A detailed
description of spinal neurolysis technique is contained within the text
Neural Blockade in Clinical Anesthesia and Management of Pain.25

FIGURE 44.3 Lateral supine position used for injection of intrathecal phenol, with the hyperbaric
solution falling toward the sensory dorsal roots.

2301
FIGURE 44.4 Lateral prone position used for injection of intrathecal alcohol, with the hypobaric
solution rising toward the sensory dorsal roots.

Lumbosacral Neurolysis
Lumbosacral spinal neurolysis can provide excellent pain relief of the
pelvis, perineum, rectum, and genital area in patients who have been
refractory or intolerant of aggressive conventional management. Patients,
who are confined to bed due to their symptom burden or who have already
had urinary and bowel diversion procedures, can expect good pain relief
with an acceptable risk of complication. Prior to proceeding with
lumbosacral subarachnoid neurolysis, consideration should be given
instead to performing a superior hypogastric plexus block (SHPB) because
this procedure may be equally effective yet considerably safer.

Cervical and Thoracic Neurolysis

Cervical neurolysis is seldom performed due to the technical difficulty of
subarachnoid access at this level, the compactness of anatomy in this
region making selective neurolysis more difficult, as well as the inherent
risk of causing injury to the cervical spinal cord with consequent
neurologic deficits and adverse symptoms (including pain). Thoracic

2302
neurolysis for thoracic wall pain is also technically difficult, but the
consequences of motor root dysfunction are less pronounced, in that the
loss of several levels of intercostal muscle function is usually well
tolerated. Thoracic neurolysis does have the advantage of not placing the
innervation of the bowel, bladder, and lower extremities at risk and
consequently has less risk of significant morbidity.

ADVERSE EFFECTS
Studies reporting on bladder and bowel dysfunction after lumbosacral
neurolysis report that about one quarter of patients develop urinary
incontinence, with most resolving within 10 days.29–31Bowel dysfunction
and lower extremity weakness was relatively less frequent. Yet, it should
be noted that some of these patients may already have had urinary and
bowel diversion for surgical reasons, making the decision to proceed with
neurolysis somewhat easier. Other adverse effects of IT neurolysis include
deafferentation pain and headache. Rare complications include infection,
spinal cord damage, and posterior spinal artery thrombosis causing
paraplegia.

CONTRAINDICATIONS
IT neurolysis is contraindicated when (1) the patient has spinal cord tumor
or tumor obliteration of the subarachnoid space at the selected level; (2)
skin infection is present at the needle puncture site; (3) the patient is
unable to tolerate appropriate positioning; and (4) there is a primary pain
source, such as a bone metastasis or fracture, that is amenable to more
definitive procedural treatment.

Celiac Plexus Block

Chemical neurolysis of the components of the celiac plexus can be a
highly effective treatment for visceral pain of the upper abdomen and is
the most commonly performed interventional cancer pain technique.

INDICATIONS
NCPB is typically performed for cancer-related visceral pain originating in
the upper abdomen. Pain originating from the somatic nerve fibers

2303
emanating from the upper abdominal wall will not be blocked by NCPB,
and therefore, it is very important to distinguish between visceral versus
somatic pain before contemplating this procedure. The celiac plexus
carries afferent fibers from the upper abdominal organs from the stomach
to the mid transverse colon, including pancreas and gallbladder. Deep
visceral pain related to pancreatic adenocarcinoma and
cholangiocarcinoma are typical indications for NCPB. As will be
discussed later, this is a highly efficacious and safe procedure, so it should
be considered early in the treatment of upper abdominal cancer pain.32

ANATOMY OF THE CELIAC PLEXUS

Understanding the path of the needle and the position of its tip in relation
to the local anatomy is crucial to the safe and effective performance of any
interventional procedure. The celiac plexus is a complex grouping of one
to five ganglia of various sizes interconnected by a dense network of
neural fibers. The plexus is located in the upper abdomen typically
anterolateral to the aorta at the L1 vertebral level, just caudal to the takeoff
of the celiac artery; however, some variability has been noted, and the
plexus can be found anywhere from the level of T12–L1 disk space to the
level of the L2 vertebral body.33 Just lateral to the celiac plexus are the
adrenal glands and inferiorly are the renal arteries. The celiac plexus is
formed by the convergence of sympathetic preganglionic and afferent
fibers from the greater (originating from the T5–T10 spinal level), lesser
(T10–T11), and least (T12) splanchnic nerves. The splanchnic nerves are
composed of preganglionic autonomic efferent fibers to the upper
abdominal viscera that synapse in the celiac ganglia and ascending afferent
fibers capable of carrying nociceptive signals from abdominal viscera
including the distal portion of the stomach; pancreas; gallbladder; and
other hepatobiliary structures, the duodenum, the small intestine, and the
large intestine, as far distal as the transverse colon. The splanchnic nerves
travel from the spine in the posterior mediastinum, anterolateral to the
thoracic vertebral bodies, and pierce the diaphragmatic crus to enter the
retroperitoneal abdominal cavity. Parasympathetic preganglionic and
afferent fibers originating from the vagus nerves also contribute to the
celiac plexus.

2304
GENERAL CONSIDERATIONS
Preparation of patients should include counseling regarding the potential
adverse effects and complications of the procedure. Anticoagulants should
be discontinued long enough to allow normalization of coagulation
profiles. IV access is mandatory so that sedation may be administered,
adverse effects can be treated, and prehydration can be accomplished. The
latter point is important because celiac plexus blockade will cause
splanchnic vasodilation potentially leading to systemic hypotension,
particularly in the cancer patient who may already be dehydrated and
hypovolemic. An important factor to consider is whether the patient will
be able to tolerate lying in the prone position; a patient with gross ascites,
even with sedation, will be unable to assume the appropriate position and
may be a better candidate for an anterior or endoscopic approach.
Tumor location within the pancreas and the degree of local tumor
burden has been shown to impact NCPB outcome, with pain related to
head of pancreas lesions having a more favorable outcome compared to
lesions of the body and tail of the pancreas.34 Computed tomography
(CT)-guided celiac plexus studies using a radiopaque injectate have shown
that outcome may also be affected by local anatomic distortion caused by
tumor infiltration.35,36

ADVERSE EFFECTS
NCPB is a relatively safe and well-tolerated procedure. Serious
complications include transient or permanent spinal cord damage and
paraplegia due to spread of the lytic injectate to the nerve roots, epidural,
or IT space. Neurologic damage may also ensue after damage to an
anterior spinal artery, such as the artery of Adamkiewicz, disrupting the
vulnerable arterial supply of the spinal cord.37,38 Fortunately, serious
neurologic complications are very rare, with an incidence of less than
0.2% in one series of 2,730 NCPBs.39 Side effects are common and
generally mild and well tolerated. NCPB will predictably cause a
disruption of the sympathetic nervous supply to the proximal bowel
resulting in unopposed parasympathetic (vagal) tone. This excessive
parasympathetic tone will typically result in transient gastrointestinal
hypermotility and diarrhea in approximately 44% of patients, side effects

2305
that are seldom considered a problem by the patient who has been
constipated due to opioid consumption and debilitation. The loss of
sympathetic tone also results in splanchnic vasodilation, intravascular fluid
shift to the bowel, and hypotension in approximately 38% of patients.6
This should be anticipated and prevented with preprocedural volume
enhancement and sufficient means to monitor and treat hypotension.

CELIAC PLEXUS BLOCK TECHNIQUES

Numerous approaches to the celiac plexus have been described, ranging
from traditional blind landmark techniques, sophisticated CT-guided
methods, and endoscopic ultrasound (EUS) techniques. A 1992 study by
Ischia et al.40 compared the outcomes of the retrocrural technique, a
transaortic approach, and neurolysis of the splanchnic nerves at the T12
level. No statistically significant differences (P > .05) were found among
the three techniques in terms of either immediate or up-to-death results.
Procedure mortality was zero with the three techniques and morbidity
negligible. NCPB provided excellent pain relief in 70% to 80% of patients
immediately after the block and in 60% to 75% until death. Celiac plexus
neurolysis may also be achieved intraoperatively at the time of diagnostic
or therapeutic laparotomy, with reported good success.41

Posterior Approach to the Splanchnic Nerves and Celiac

Plexus
The most common celiac plexus block technique is the posterior approach
using a needle on either side of midline. This was first described as a blind
technique but is now performed with the help of fluoroscopy or CT. The
L1 vertebral body is identified with fluoroscopy and then the C-arm is
rotated obliquely so that a skin puncture site 6 to 8 cm (6 cm for smaller,
cachectic individuals; more toward 8 cm for obese patients) lateral to the
midline will allow for coaxial needle advancement to the anterolateral
aspect of the upper half of L1 vertebral body. A 15 cm or longer 20-gauge
needle is then advanced toward the anterolateral shadow of the L1
vertebral body. The intention is to just miss contact with the vertebral body
because this can be quite uncomfortable for the patient. Care should be
taken not to touch the L1 transverse process because this can be mistaken

2306
for the vertebral body, giving an incorrect, and potentially dangerous,
estimate of depth. This author typically performs the left side first, so if an
inadvertent aortic puncture is obtained, a transaortic approach can be
completed, assuring good placement anterior to the aorta and avoiding the
need for a second needle placement (the transaortic approach has been
advocated as a safe,42 alternative technique and involves intentionally
piercing the aorta in order to provide direct chemoneurolysis to the celiac
ganglia anterior to the aorta). The second needle is placed in identical
manner from the right side, aiming for the space anterolateral to the right
side of the L1 vertebral body. Final needle advancements should be done
under lateral fluoroscopic guidance: The left needle tip should be advanced
0.5 cm ventral to the anterior edge of the L1 vertebral body (further
advancement may result in aortic puncture); the right needle tip is
advanced 1 cm beyond the anterior edge of the vertebral body (Fig. 44.5).
As the aorta is approached, transmitted arterial pulsations may be
appreciable at the needle hub, but this is unreliable. The anatomic location
of these needle tips is likely to be retrocrural and in good position to block
the splanchnic nerves as they pierce the diaphragm. Note that the celiac
plexus itself is not the primary target when using the retrocrural technique,
but this appears to be of little clinical significance.40

FIGURE 44.5 Fluoroscopic images of a retrocrural celiac plexus block. A: Anteroposterior view
with the needle tips anterolateral to the L1 vertebral body. Contrast has been injected through the
left needle with spread cephalad along the course of the splanchnic nerves. B: Lateral fluoroscopic
view showing the needle tips advanced anterior to the anterior shadow of the L1 vertebral body and
contrast spreading in the retrocrural fascial plane.

2307
 If an anterocrural needle position is desired, with direct lysis of the
celiac plexus itself, the needles need to be further advanced through the
crus of the diaphragm. The final anatomic position of the needle can only
be determined by injecting several milliliters of a radiopaque contrast
agent through each needle in an anteroposterior (AP) and lateral
projection. Retrocrural contrast will spread cephalad along the
anterolateral aspect of the T12 and L1 vertebral bodies, whereas
anterocrural spread will be noted in a more anterior and caudal plane. In
either case, spread toward the midline should be present. While injecting
the radiopaque contrast, meticulous attention should also be given to avoid
(1) vascular uptake which might result in neurolytic being delivered to the
spinal cord or other organs; (2) posterior spread toward the neuroforamina,
the nerve roots, and the epidural space; and (3) contrast uptake into the
intima of the aorta (this is seen, under real-time fluoroscopy, as a pulsating
“streaking” outlining the assumed position of the aorta). Once the needles
are in a radiographically satisfactory position, 5 to 10 mL of lidocaine 2%
is injected through each needle after attempting aspiration of blood, CSF,
or urine and confirming proper needle placement. After several minutes,
the patient is questioned about the presence of any unwanted lower
extremity weakness or other neurologic symptoms. A reduction in
abdominal pain should also be noted, although this may be unreliable if the
patient has received IV analgesics or sedatives.
Finally, neurolysis is achieved by injecting 10 to 12 mL of ethyl alcohol
(60% or higher concentration) or phenol (6% or higher concentration)
through each needle.

Anterior Approaches
Numerous anterior approaches to the celiac plexus have been described
with efficacy and safety profiles comparable to those of the posterior
approaches. A single needle may be placed through the anterior abdominal
wall under CT guidance, potentially traversing the bowel, stomach, and
pancreas, to the preaortic region where the celiac plexus elements
reside.35,43 An increasingly popular approach to the celiac plexus is via
EUS endoscopy. A needle is advanced through the endoscope under
ultrasound guidance through the posterior wall of the stomach into the

2308
preaortic area in the vicinity of the celiac plexus.44–46 This technique
requires that the patient can tolerate esophagogastroscopy and typically
require deeper sedation or general anesthesia. However, if a patient is
having EUS for diagnostic purposes, it is very expedient to complete a
celiac neurolysis simultaneously.

OUTCOME STUDIES
Numerous case reports, uncontrolled case series, and several randomized
controlled trials40,41,47–49 report a preponderance of favorable outcomes
with NCPB. A 1995 meta-analysis by Eisenberg et al.6 revealed 24 papers
(with 1,145 patients) suitable for inclusion. Included were 2 randomized
controlled trials, 1 prospective case series, and 21 uncontrolled
retrospective case series. When analyzed, good to excellent pain relief was
reported in 89% during the first 2 weeks after NCPB. This effect persisted
after 2 weeks, with partial or complete pain relief reported in 90% of living
patients at 3 months and in 70% to 80% until death. The most frequent
indication was unresectable pancreatic cancer (63%), with the balance
being a variety of nonpancreatic pain sites including the stomach and
esophagus. The pancreatic and nonpancreatic cases did not appear to have
a significantly different outcome. The bilateral posterior approach with 15
to 50 mL of 50% to 100% ethyl alcohol was the most common technique
used. No procedure-related mortality was reported, and adverse effects
were minimal. The most common adverse effects reported were transient
hypotension, diarrhea, and transient pain at the site of injection.
A controlled trial by Wong et al.48 randomized 100 patients with
unresectable pancreatic adenocarcinoma to either NCPB or systemic
analgesia therapy (SAT) and a sham injection. A blinded observer
recorded patient pain intensity, quality of life (QOL) measures, opioid
consumption and related side effects, and survival time for 1 year.
Baseline pain scores were relatively low, but comparable, in both groups
(VAS 4.4 ± 1.7 vs. 4.1 ± 1.8, respectively). The first week after
randomization, pain intensity and QOL scores were improved (pain
intensity, P ≤ .01 for both groups; QOL, P < .001 for both groups), with a
more significant decrease in pain for the NCPB group (P =.005). Using
repeated measures analysis, pain was found to be lower for NCPB over

2309
time (P = .01). However, opioid consumption (P = .93), frequency of
opioid adverse effects (all P > .10), and QOL (P = .46) were not
significantly different between groups.
In the first 6 weeks, fewer NCPB patients reported moderate or severe
pain (pain intensity rating of ≥5/10) compared to opioid-only patients
(14% vs. 40%, P = .005). At 1 year, 16% of NCPB patients and 6% of
opioid-only patients were alive, but this was not a statistically significant
difference.
Although the previous study did not show a difference in life
expectancy, a randomized, placebo-controlled study by Lillemoe et al.41 in
patients with abdominal pain and unresectable pancreatic cancer
demonstrated longer survival when an intraoperative chemical
splanchnicectomy was performed compared to patients who received
saline. A subsequent study by Staats et al.49 involved additional follow-up
and analysis of this same group of patients. Data on visual analog pain
scores, mood, and interference with activity were collected preoperatively
and every 2 months postoperatively until death. Univariate and
multivariate analyses of variance showed that neurolysis, compared to the
medical management, had a significant positive effect on mood scores,
pain interference with activity, and had an associated increase in life
expectancy (9.15 ± 9.04 vs. 6.75 ± 4.65 months, P < .05).

Superior Hypogastric Plexus Block

Pelvic pain is common in advanced cervical, uterine, ovarian, bladder,
rectal, and prostate cancers. When pain is primarily visceral in origin, the
use of SHPB can be a safe and effective treatment to reduce pain and
opioid needs.

INDICATIONS
The primary indication for superior hypogastric plexus nerve block is
visceral pelvic pain that has been refractory to medical management. A
local anesthetic block is sometimes performed first; however, in the setting
of severe pain and advanced cancer, proceeding directly to neurolytic
block may be preferred.

2310
ANATOMY OF THE SUPERIOR HYPOGASTRIC
PLEXUS
The superior hypogastric plexus spans the anterior surfaces of the lower
L4 and L5 vertebral bodies and upper sacrum, posterior to the psoas fascia
and peritoneum, and bounded laterally by the iliac vessels. This plexus
innervates the pelvic viscera through the hypogastric nerves and inferior
hypogastric plexus.

GENERAL CONSIDERATIONS
Prior to SHPB, normal coagulation studies should be confirmed, and
anticoagulants should be discontinued for a period of time sufficient to
allow normal coagulation. A discussion of the potential risks and benefits
of SHPB should be undertaken and IV access obtained prior to the
procedure to allow appropriate sedation and to allow the patient to
comfortably lay in the prone position during the procedure. In the setting
of severe ascites that precludes the prone position, the patient may be
better treated with an anterior ultrasound or CT-guided approach. Of note,
in contrast to celiac plexus neurolysis, there are no hemodynamic effects
associated with SHPB.

ADVERSE EFFECTS
There have not been any reports of serious complication related to superior
hypogastric plexus diagnostic block or neurolytic procedure. Given its
location, potential adverse effects include neuraxial injection of neurolytic
substance with resulting damage to the cauda equina, discitis, bladder
injury, iliac vessel injury, intravascular injection, and retroperitoneal
hematoma.

TECHNIQUES
SHPB is most commonly performed using fluoroscopy and a bilateral
posterior approach, with appropriate needle placement confirmed with
radiographic contrast (Figs. 44.6 and 44.7). A single needle technique,
traversing the L5–S1 intervertebral disk, has also been described in
patients with difficult anatomy compromising the bilateral approach, with
good outcomes and a favorable safety profile in a case series of eight

2311
patients.50 Additionally, CT-guided and ultrasound-guided approaches
have also been reported that has success using radiofrequency ablation
rather than chemical neurolysis.51–53

FIGURE 44.6 Fluoroscopic anteroposterior image of superior hypogastric plexus neurolysis.

FIGURE 44.7 Fluoroscopic lateral image of superior hypogastric plexus neurolysis.

OUTCOME STUDIES
Evidence supporting the use of superior hypogastric plexus neurolysis is

2312
limited to case reports, several prospective case series, and one
randomized controlled trial. These studies have consistently demonstrated
good to excellent pain relief in a majority of patients, reduced opioid
consumption, and no significant adverse effects or complications.32,54–58
The largest study was published in 1997 by Plancarte and colleagues
and reported on 227 patients with gynecologic, colorectal, or genitourinary
cancer and cancer-related pelvic pain with poor pain control despite the
use of oral opioids. All patients reported a VAS pain score of 7/10 or
greater before a diagnostic block with 0.25% bupivacaine was performed.
A positive response to the diagnostic block was obtained in 79% of
patients, and these patients then went on to receive a neurolytic SHPB
utilizing a bilateral percutaneous approach with 10% phenol. A second
neurolytic block was offered in the event of suboptimal response to initial
neurolytic block. SHPB reduced the VAS to <4/10 in 72% of patients, and
the remaining 28% of patients had moderate reduction of VAS to 4 to
7/10. Oral opioid therapy was reduced 43% following neurolysis, no
complications related to the procedure were reported, and no additional
neurolytic blocks were required during the 3-month follow-up period.56
In the randomized controlled trial by Mishra et al.57 50 patients were
randomized to anterior ultrasound-guided neurolytic SHPB plus oral
morphine or oral morphine alone for severe pelvic pain associated with
gynecologic malignancy. Patients treated with SHPB had a greater
reduction in pain, lower total morphine consumption, greater patient
satisfaction, and no increased incidence of adverse effects.57
A 2008 review of the literature applied evidence grades to 10 articles,
including 4 case reports and 5 case series which received a grade of 1c and
1 prospective, randomized trial which received a grade of 1b in support of
SHPB.59 The European Association for Palliative Care (EAPC) conducted
a systematic review in 2015 which lead to a weak recommendation for
superior hypogastric plexus neurolysis for cancer-associated pelvic pain.60

Ganglion of Impar Block

The ganglion of impar, also known as the ganglion of Walther, is the
terminal sympathetic ganglion in the body and neurolytic blockade of this

2313
ganglion that can aid in pain relief from visceral perineal pain as a result of
neoplastic disease.

INDICATIONS
Ganglion of impar neurolysis is indicated for the treatment of visceral
perineal pain as a result of primary or metastatic lesions of the distal
rectum, anus, vulva, or perineum.

ANATOMY OF THE GANGLION OF IMPAR

The ganglion of impar is a solitary sympathetic ganglion located on the
anterior inferior surface of the sacrum near the sacrococcygeal junction
and supplies visceral innervation to the perineum and distal rectum/anus.

GENERAL CONSIDERATIONS
Normal coagulation profile should be confirmed and a discussion of the
risks and benefits of ganglion impar neurolysis undertaken prior to the
procedure. There are no hemodynamic effects of ganglion impar
neurolysis, and the procedure often does not require sedation.

ADVERSE EFFECTS
Ganglion of impar neurolysis is a safe and technically straightforward
procedure to perform. Reports in the literature of complications are rare.
Given its location in close approximation to the rectum, care should be
taken to avoid rectal perforation. Other potential risks include local
infection or bleeding as well as intravascular injection.

TECHNIQUE
Neurolytic block of the ganglion of impar is most commonly performed
using a percutaneous transcoccygeal approach with fluoroscopic guidance
(Fig. 44.8).61 A lateral view of the sacrum is obtained, and a needle
inserted midline through the sacrococcygeal ligament until the tip lies just
anterior to the sacrum, taking care to avoid perforating the rectum.
Appropriate position is confirmed with contrast and a small amount of
local anesthetic is administered, followed by phenol or alcohol as a
neurolytic agent. Approaching the ganglion of impar using an

2314
anococcygeal approach has also been described as having CT-guided
approaches.62

FIGURE 44.8 Fluoroscopic lateral view of ganglion of impar neurolysis.

Data regarding the efficacy of neurolytic ganglion of impar block for

cancer-associated perineal pain are limited to case reports and case series.
However, these studies consistently report significantly improved pain
with no significant adverse effects.59,61–64 In its 2017 Clinical Practice
Guidelines in Oncology for Adult Cancer Pain, the National
Comprehensive Cancer Network (NCCN) recommends consideration of
ganglion impar block in the setting of cancer-associated rectal or perineal
pain.65

Intercostal Nerve Block

Chest wall pain is a common symptom accompanying many cancers due to
local tumor invasion as well as metastatic lesions to the area. Breast, lung,
melanoma, and renal cell carcinomas are often associated with chest wall
involvement and associated pain.
Oncologic chest wall pain often has both somatic and neuropathic

2315
components, making it potentially difficult to treat with conventional
medications. Intercostal nerve block (ICNB) can be a useful adjunct in this
setting.

INDICATIONS
ICNB is indicated in patients with cancer-associated chest wall pain
recalcitrant to conservative medical treatment and palliative therapies such
as radiation therapy.

ANATOMY OF THE INTERCOSTAL NERVES

The intercostal nerves and branches innervate the thoracic chest wall and
parietal pleura. They arise from the ventral primary rami of T1–T12,
which traverse the paravertebral space and then divide into anterior and
posterior branches. The anterior branch forms the intercostal nerve and is
initially located deep to the innermost intercostal muscle and superficial to
the pleura. At approximately the midscapular line, the nerve pierces the
innermost intercostal muscle and travels in a facial plane between the
innermost intercostal and inner intercostal muscles until it terminates at the
sternum. The intercostal nerve is reliably accessed at each level at the
inferior aspect of the rib in close approximation but inferior to the
intercostal artery and intercostal vein.

GENERAL CONSIDERATIONS
ICNB can be conducted as a diagnostic block with local anesthetic only or
with therapeutic intention using either local anesthetic plus steroid or
neurolytic agent. In many cases, a diagnostic block is first performed and
if this provides short-term pain relief, neurolysis is then performed. Phenol
is most commonly used; however, successful use of alcohol has also been
described. Neurolysis will result in denervation of the associated
intercostal muscles; however, this is rarely clinically significant unless
multiple levels and/or bilateral blockade are performed in a patient with
significantly compromised pulmonary function.

ADVERSE EFFECTS
There is a noteworthy risk of pneumothorax with ICNB due to the nerve’s

2316
location in relation to the pleura. The ability to directly visualize the pleura
and its relationship to the needle tip increasingly favors the use of
ultrasound guidance with ICNB. Bleeding from intercostal vein or artery
puncture can be a dangerous complication in patients who are
anticoagulated.
As a result of the communication between the fascial planes of the
intercostal muscles and the paravertebral space, there is also risk for
neuraxial spread of medication. A 2016 study by Matchett66 reported
paravertebral extension of contrast dye in 11/11 patients, and epidural
extension in 1/11 patient, who underwent diagnostic ICNB. In the setting
of local anesthetic, this results in a temporary unilateral paravertebral
block or thoracic epidural block; however, there are two published case
reports of permanent spinal cord injury resulting from intercostal
neurolysis with phenol.67,68 There is also a risk of deafferentation pain
with neurolytic procedures using phenol or alcohol. Nevertheless,
intercostal neurolysis is generally a safe and well-tolerated procedure with
few reports of complications in the literature.

TECHNIQUE
Prior to the procedure, any available imaging should be reviewed to ensure
correlation between the chest wall pathology and the patient’s reported
symptoms, with identification of the most likely rib level(s) affected.
ICNB can be accomplished using either fluoroscopic or ultrasound
guidance. In the case of fluoroscopic guidance, the appropriate rib is
identified, and at a point 8 to 12 cm lateral to midline, the needle is
inserted and advanced to contact bone, at which point it is carefully
“walked off” the inferior aspect of the rib and advanced several
millimeters. Contrast is then used to confirm spread along the inferior rib
and rule out vascular uptake or neuraxial spread. Next, 2 to 3 mL of local
anesthetic, local anesthetic plus steroid, or neurolytic substance is then
injected slowly (Fig. 44.9).

2317
FIGURE 44.9 Fluoroscopic view of intercostal neurolysis with the needle tip inferior to the rib.

For ultrasound-guided procedures, the appropriate level is identified,

often by counting up from the 12th rib. The needle is inserted in an out-of-
plane or in-plane approach, and hydrodissection is used to visualize the
needle tip advancing into the fascial plane between the internal intercostal
and innermost intercostal muscles, pushing pleura downward with
medication administration, taking care to remain superficial to the pleura
at all times (Fig. 44.10).

2318
FIGURE 44.10 Ultrasound view of intercostal neurolysis with appropriate needle position
indicated.

In addition to intercostal chemical neurolysis, a 2017 report detailed the

successful use of thermal radiofrequency ablation of the intercostal nerves
in 25 patients with uncontrolled cancer-related breakthrough pain arising
from rib metastasis. More than half of patients experienced a 50%
reduction in intensity and frequency of breakthrough pain episodes with
minimal adverse effects.69

OUTCOME STUDIES
Published reports are limited to case reports and case series.70 A 2007
publication detailed 25 patients with metastatic rib lesions who underwent
neurolytic intercostal block. Optimal local pain control was reported in
80% of patients, and 56% reduced their analgesic use after the
procedure.71
In 2015, Gulati et al.72 reported on their experience with thoracic chest
wall pain in the oncologic population between 2004 and 2014. Among 146
patients who underwent a diagnostic ICNB with local anesthetic and
steroid, 79% had improvement in pain (defined as a reduction in VAS >1
point). Interestingly, 22% of patients had prolonged improvement in pain
with an average duration of 21.5 days. However, only 32% of patients
overall who responded to diagnostic blockade chose to undergo neurolytic
ICNB with alcohol ablation, with a success rate of 62%. Additionally, the

2319
authors present an interventional treatment paradigm based on their review
and clinical experience to guide the appropriate interventional modality for
oncologic chest wall pain. In patients with peripheral tumor or anterior
chest wall pain, they recommend diagnostic ICNB followed by neurolysis
with good response to the diagnostic injection. However, with a more
central location of tumor in the paravertebral area and posterior chest wall
pain, they advocate for diagnostic paravertebral nerve block followed by
paravertebral neurolysis as indicated if the tumor is not encroaching the
thoracic nerve root and pulsed radiofrequency ablation of the thoracic
nerve root in the setting of tumor encroachment on the neuroforamen (Fig.
44.11).

FIGURE 44.11 Interventional procedure based on location of tumor for oncologic chest wall pain.
ICN, intercostal nerve block; IT, intrathecal; PRF/ESI, pulsed radiofrequency/epidural steroid
injection; PVN, paraventricular nucleus. (Reprinted with permission from Gulati A, Shah R,
Puttanniah V, et al. A retrospective review and treatment paradigm of interventional therapies for
patients suffering from intractable thoracic chest wall pain in the oncologic population. Pain Med
2015;16[4]:802–810. Reproduced by permission of American Academy of Pain Medicine.
Published online 2014 Sep 19. doi: 10.1111/pme.12558.)

2320
Blocks of the Head and Neck
Head and neck cancers have among the highest rates of cancer-associated
pain, and these patients rate pain control just behind treatment outcome
and life expectancy among their priorities after diagnosis.73 Interventional
targets for managing cancer-associated head and neck pain most
commonly include the trigeminal ganglion and its branches; however, the
autonomic sphenopalatine and stellate ganglia have also been successfully
targeted.

Nerve Blocks of the Trigeminal Nerve and Its

Branches
INDICATIONS
The trigeminal nerve is the fifth cranial nerve and has both motor and
sensory function. In addition to innervating the muscles of mastication, it
is responsible for sensation over most of the face. Neurolytic blockade of
the trigeminal ganglion and its branches is indicated for patients with
primary or metastatic head and neck cancer and associated severe pain. In
the setting of cancer-associated pain, neurolytic blocks are most common,
although local anesthetic block with indwelling catheter, thermal and
pulsed radiofrequency ablation, and cryoablative techniques have all been
described.74–77

ANATOMY OF THE TRIGEMINAL NERVE AND ITS

BRANCHES
The trigeminal, or gasserian, ganglion arises from the brainstem and
divides into its three primary branches, the ophthalmic nerve (V1),
maxillary nerve (V2), and mandibular nerve (V3), just prior to exiting the
skull via the superior orbital fissure, foramen rotundum, and foramen ovale
respectively (Fig. 44.12).

2321
FIGURE 44.12 Trigeminal nerve distribution. (Reprinted with permission from Hoppenfeld JD.
Fundamentals of Pain Medicine. 1st ed. Baltimore, MD: Lippincott Williams & Wilkins; 2014:20.
Figure 2.1.)

The ophthalmic nerve supplies sensory innervation to the skin of the

scalp, forehead, upper eyelid, and tip of the nose via its terminal branches,
the supraorbital and supratrochlear nerves. The maxillary nerve innervates
the skin of the cheek, lower eyelid, nares, upper lip, upper teeth and gums,
palate and roof, and the pharynx via its infraorbital and superior alveolar
branches. In addition to supplying motor function to the muscles of
mastication, the mandibular nerve innervates the skin of the chin, jaw,
lower lip, external ear, and lower teeth and gums via its branches, the
auriculotemporal, lingual, buccal, and inferior alveolar and mental nerves,
all of which may be affected by direct tissue invasion, anatomic distortion,
or metastatic lesions.78

2322
GENERAL CONSIDERATIONS
Nerve blocks in the setting of head and neck cancer may present technical
challenges owing to significant anatomic distortion from direct tumor
invasion as well as prior surgical intervention. Both fluoroscopic and CT-
guided approaches have been described for neurolytic blocks of the head
and neck. The most common trigeminal nerve targets are summarized in
Table 44.4.

TABLE 44.4 Summary of Trigeminal Nerve Targets

Anatomic Target Innervation
Trigeminal ganglion Sensory innervation of face
Motor innervation of muscles of mastication
Maxillary nerve Sensory innervation of middle 1/3 of face
Mandibular nerve Sensory innervation of lower 1/3 of face
Motor innervation of muscles of mastication
Supraorbital nerve Sensory innervation of forehead, upper eyelid, and anterior
scalp
Supratrochlear nerve Sensory innervation of medial forehead, bridge of nose, medial
upper eyelid
Infraorbital nerve Sensory innervation of lower eyelid, medial cheek, lateral naris,
upper lip
Mental nerve Sensory innervation of lower lip and chin

ADVERSE EFFECTS
The trigeminal ganglion lies in close proximity to both the dura as well as
the middle meningeal and carotid arteries, and care must be taken to avoid
dural puncture, intrathecal injection, bleeding, or intravascular injection.
Neuritis or deafferentation pain is a possible complication of neurolysis of
the trigeminal ganglion or its branches. In the case of the ophthalmic (V1)
branch, neurolysis can result in impaired corneal reflex and corneal
anesthesia, whereas neurolysis of the mandibular branch may denervate
the ipsilateral muscles of mastication. However, this is typically not
clinically significant unless bilateral neurolysis blockade is performed,
which can result in significant difficulties in chewing and swallowing.

TECHNIQUES
The trigeminal ganglion is most commonly accessed via the foramen
ovale. A submental fluoroscopic view is used to identify the foramen and a

2323
needle is inserted 2.5 cm lateral to the corner of mouth. The needle is
advanced in a trajectory in line with the ipsilateral pupil and an AP plane
bisecting an imaginary line bisecting the angle between the external
auditory meatus and the lateral canthus of the eye. Needle advancement
should be discontinued when a lateral view shows appropriate placement
in the foramen ovale, directly inferior to the sella turcica (Figs. 44.13 and
44.14). Iodinated contrast 0.1 to 0.5 mL is used to verify correct placement
of the needle followed by neurolysis with 0.3 to 0.5 mL of neurolytic
agent, mostly commonly phenol.

FIGURE 44.13 Fluoroscopic view of foramen ovale with needle in place—anteroposterior view.

2324
FIGURE 44.14 Fluoroscopic view of foramen ovale with needle in place—lateral view.

To access the maxillary or mandibular nerve selectively, the coronoid

notch is palpated just anterior to the external auditory meatus and inferior
to the zygomatic arch, with the patient in a “slack jaw” position. Lateral
fluoroscopy is used to identify the pterygopalatine fossa as a V-shaped
structure superior to the upper molars and inferior to the orbit. The needle
is inserted and directed in a plane perpendicular to the skull toward to
pterygopalatine fossa. Once the lateral pterygopalatine plate is
encountered, the needle is then be redirected anteriorly and superiorly for
the maxillary nerve, or posteriorly and inferiorly for the mandibular nerve,
and advanced approximately 0.5 to 1 cm to enter the pterygopalatine fossa.
The position is confirmed with AP fluoroscopic view showing the needle
tip lateral to the middle nasal turbinate as well as with appropriate contrast
spread (Figs. 44.15 and 44.16). In this location, chemical neurolysis has
been reported anecdotally using phenol or alcohol, but no case reports or
studies have been published. More commonly, local anesthetic and steroid
or pulsed radiofrequency ablation is utilized.

2325
FIGURE 44.15 Lateral view of maxillary nerve block with needle in the superior anterior part of
the pterygopalatine fossa.

FIGURE 44.16 Anteroposterior view of maxillary nerve block.

The terminal branches of the maxillary and mandibular nerves are also

2326
interventional targets for cancer-related facial pain. Given their more
superficial positions, chemical neurolysis is used infrequently, and local
anesthetic and steroid as well as pulsed radiofrequency ablation are
preferred.
The supraorbital nerve, innervating the skin of the ipsilateral forehead,
is accessed by identifying the supraorbital foramen using fluoroscopy or
palpating the supraorbital notch above the pupil along the orbital rim. The
needle is then advanced toward the notch in a slight medial direction,
taking care not to enter the foramen itself. The supratrochlear nerve,
innervating the medial aspect of the forehead, is found by palpating the
supratrochlear notch along the medial aspect of the supraorbital ridge just
lateral to the junction of the supraorbital ridge and the bridge of the nose.
The needle is advanced toward the notch until bone is contacted and then
withdrawn slightly.
In the case of the infraorbital nerve, which innervates the lower eyelid,
medial cheek, and lateral nares and upper lip, the infraorbital notch is
identified using AP fluoroscopy and a needle is inserted 1 cm inferior and
lateral to this. The needle is in an upward lateral trajectory toward the
foramen. Finally, the mental nerve can be found by identifying the mental
foramen using fluoroscopy or with palpation slightly superior to the
mandible approximately 1 cm medial to the angle of the lip. A needle is
directed toward the foramen in a slightly medial direction until bone is
contacted.

OUTCOME STUDIES
Most published reports on trigeminal nerve interventions address its use
for trigeminal neuralgia, with a reported success rate of 80% to 90%.76
The literature in cancer pain is limited to case reports.74,75,77 However,
given the high burden of pain in the head and neck cancer population, the
use of interventional treatment targeting the trigeminal ganglion and its
distal branches should be considered for pain refractory to conservative
treatment.

OTHER HEAD AND NECK INTERVENTIONAL

TARGETS

2327
The sphenopalatine ganglion (SPG) is a mixed parasympathetic and
sympathetic ganglion that lies in close approximation to the maxillary
nerve in the pterygopalatine fossa and has multiple connections to
trigeminal and facial nerve fibers. It has been implicated in many facial
pain and headache conditions and can be targeted in a similar fashion to
the maxillary nerve block detailed previously, with the needle positioned
slightly more inferiorly in the pterygopalatine fossa.79,80 Varghese and
Koshy81, in 2001, reported good results with endoscopic neurolytic block
of the SPG with phenol, but data on percutaneous approaches has been
limited. In 2017, Sanghavi et al.82 published a report of 33 patients with
severe pain related to advanced head and neck cancer who underwent
thermal radiofrequency ablation of the SPG following successful
diagnostic block. Pain was reduced from an average VAS 8.4 to 1.4 after
the procedure, and morphine consumption decreased to one-third the
preprocedural level, with relief persisting for an average of 18 weeks.82
Similarly, Rana83 published a report of 20 patients with cancer-related
orofacial pain, half of whom underwent pulsed radiofrequency ablation of
the SPG and half who underwent SPG neurolytic block with alcohol. The
authors did not report their technique for the procedures, but both groups
experienced improved pain, with the radiofrequency ablation group having
slightly better pain control at 1 month.83
Similar to SPG, the stellate ganglion is a sympathetic ganglion
implicated in headache and neuropathic facial pain syndromes. It is formed
from fusion of the inferior cervical first thoracic ganglia and overlies the
anterolateral T1 and T2 vertebral bodies. It can be accessed under
fluoroscopic or ultrasound guidance at Chassaignac tubercle at the C6
level. Ghai et al.84 reported in 2016 on the use of stellate ganglion block
with phenol and corticosteroid for intractable cancer-related facial pain
and edema not amenable to trigeminal or sphenopalatine approaches due to
anatomic distortion.

Spinal Cord Stimulation

The need for frequent magnetic resonance imaging (MRI) studies in cancer
patients has previously limited the use of spinal cord stimulation in

2328
treating cancer-related pain. However, there are now multiple spinal cord
stimulator systems that have MRI-conditional labeling, indicating these
devices pose no known hazards in the specified MRI environment under
specified conditions.
The use of spinal cord stimulation for cancer pain has expanded in
recent years with this change, although data are limited to case reports and
small case series. Spinal cord stimulation has been used successfully for
multiple types and locations of cancer pain, including pain directly
resulting from anal cancer, metastatic colon cancer, testicular cancer, and
angiosarcoma.85–88 There are also reports of its use for pain related to
cancer treatment, including chronic chest wall pain following thoracotomy
and radiation, chemotherapy-induced peripheral neuropathy, phantom limb
pain following amputation, and failed back surgery syndrome related to
resection of spinal tumors.85,89,90

Vertebral Augmentation
The percutaneous treatment of painful vertebral collapse secondary to
metastatic tumor has emerged as a very promising therapy in recent years.
Metastatic spread to the skeleton is common, and 30% to 80% of bony
metastases involve the vertebrae (see Chapter 46).91 Vertebroplasty is a
minimally invasive outpatient procedure whereby painful vertebral
compression fractures are stabilized by the injection of the bone cement
polymethyl methacrylate (PMMA). Access to the vertebral body is
typically achieved by passing a specialized needle under fluoroscopic
guidance through the pedicles bilaterally.
Kyphoplasty differs in that the injection of cement is preceded by the
creation of a cavity with a percutaneously placed intravertebral balloon, as
demonstrated in Figure 44.17. Traditionally, the balloon inflation was
intended to restore vertebral height loss, but this often requires very high
pressures which may have been responsible for morbidity.

2329
FIGURE 44.17 Kyphoplasty. A: Lateral projection of a thoracic vertebra with cannula in an
appropriate position to traverse the pedicle and enter the vertebral body. B: Lateral projection
demonstrating inflation of the balloon. C: Lateral projection demonstrating completed kyphoplasty
following injection of cement. D: Anteroposterior projection of the completed kyphoplasty with the
deposition of cement into the fracture site.

Vertebral height restoration is now considered less important, and the

emphasis is now on creating a cavity so the cement injection can be
performed under lower hydrostatic pressures with more predictable filling
of the fractured vertebrae. A meta-analysis comparing vertebroplasty and
kyphoplasty studies showed that vertebroplasty produced more significant
pain relief but had a higher risk of cement extravasation into the spinal
canal.92

INDICATIONS
Vertebroplasty or kyphoplasty are indicated in an acute or subacute (<6

2330
months) painful vertebral body pathologic (secondary to osteoporosis or
tumor) fracture without the involvement of the spinal canal and its
elements.92,93 Careful clinical correlation between the pain symptoms and
the radiographic findings should be established because not all
radiographically evident fractures are symptomatic. If there is doubt about
the significance of a fracture, or in the presence of fractures at multiple
levels, clinical correlation is often best achieved by examining the spine
with the aid of fluoroscopy while palpating or percussing the spinous
process of the vertebrae in question to see if concordant pain can be
elicited. In the case of a fracture involving the spinal canal, actual or
impending neurologic deficits are best treated by a surgical approach with
decompression and probable spinal fusion.

CONTRAINDICATIONS
Absolute contraindications to vertebroplasty and kyphoplasty include
asymptomatic stable fractures, clinically effective medical therapy,
osteomyelitis of target vertebra, uncorrected coagulation disorders, allergy
to any required component, and local or systemic infection. Relative
contraindications include radicular pain or radiculopathy caused by a
compressive syndrome unrelated to vertebral body collapse, a retropulsed
fragment with >20% spinal canal compromise, tumor extension into
epidural space, and severe vertebral body collapse (vertebra plana). The
need for subsequent radiation to the area is not a contraindication because
PMMA has been shown to be resilient to radiation at therapeutic doses.

OUTCOMES
Both vertebroplasty and kyphoplasty have consistently shown a significant
improvement in postprocedure pain scores. In a meta-analysis by Eck et
al.,92 168 eligible studies on vertebroplasty and kyphoplasty were assessed
for their comparative analgesic efficacy and rates of complication. The
mean pre- and postoperative VAS scores for vertebroplasty were 8.36 and
2.68, respectively, with a mean change of 5.68 (P < .001). The mean pre-
and postoperative VAS scores for kyphoplasty were 8.06 and 3.46,
respectively, with a mean change of 4.60 (P < .001). The pain reduction
for vertebroplasty was noted to be statistically greater (P < .001) compared

2331
with kyphoplasty. However, the risk of new vertebral fracture was 17.9%
with vertebroplasty versus 14.1% with kyphoplasty (P < .01), and the risk
of cement leak was 19.7% with vertebroplasty versus 7.0% with
kyphoplasty (P < .001).
An important 2011 study by Berenson et al.94 looked at balloon
kyphoplasty versus conservative management in cancer-related vertebral
compression fractures. There were 134 patients randomly assigned to
either group, with the primary follow-up at 1 month. The kyphoplasty
group, compared to conservative management group, demonstrated
improved function relating to back pain as measured by the Roland-Morris
Disability Questionnaire (RDQ), with the mean score in the kyphoplasty
group changing from 17.6 at baseline to 9.1 (mean change −8.3 points,
95% CI −6.4 to −10.2; P < .0001) and the mean score in the control group
changing from 18.2 to 18.0 (mean change 0.1 points; 95% CI −0.8 to 1.0;
P = .83). At 1 month, the kyphoplasty treatment effect for RDQ was −8.4
points (95% CI −7.6 to −9.2; P < .0001). The most common adverse events
were back pain (4 of 70 in the kyphoplasty group and 5 of 64 in the control
group) and symptomatic vertebral fracture (two and three, respectively).
One patient in the kyphoplasty group had an intraoperative non–Q-wave
myocardial infarction, which was not directly related to the procedure.
A possible, emerging adjunct to vertebral augmentation for cancer of the
spine is radiofrequency ablation followed by cementoplasty, although
there is presently no data to support this therapy over vertebral
augmentation alone.95

Spinal Cord Ablation

Spinal ablation remains a relevant and important technique for the
treatment of medically refractory cancer pain. Interruption of the
spinothalamic tract (cordotomy) or the dorsal column’s visceral pain
pathway (myelotomy) can be achieved either through open surgical
techniques including laminectomy or percutaneously. Advantages of these
techniques as compared with IT drug delivery include immediate onset
pain relief, no ongoing medical visits for maintenance of therapy, and cost-
effectiveness.

2332
Cordotomy
INDICATIONS
Cordotomy, a lesion of the spinothalamic tract, is highly effective for the
treatment nociceptive pain due to cancer. Cordotomy is safest when
performed unilaterally, so as to avoid the well-documented complication
of inducing sleep apnea by disrupting the bilateral interruption of
reticulospinal fibers.96,97 Due to the decussation of spinothalamic fibers,
cordotomy is effective for pain arising two to five segments below the
targeted spinal level. Because cordotomy is usually performed
percutaneously at the C1–C2 level, it can usually have an effect on pain
arising from the C5 or C6 dermatomes and below (Fig. 44.18).

FIGURE 44.18 Cordotomy. Axial section of the cervical spine showing the spinothalamic tract
ascending in the anterolateral quadrant of the spinal cord. A radiofrequency electrode is used to
create a thermal lesion.

SURGICAL TECHNIQUES
Although fluoroscopy can be used as the primary imaging modality for
cordotomy, the additional safety and accuracy afforded by intraoperative
CT imaging has improved outcomes for this procedure. Cordotomy may
be performed either in an operating room equipped with a CT scanner or in
the diagnostic radiology suite.
On the day of the procedure, the patient is transported to the diagnostic

2333
CT scanning area. A lumbar puncture is performed and IT contrast is
administered to obtain an adequate cervical myelogram. The patient is
placed in the Trendelenburg position for 15 to 20 minutes to allow
adequate dispersion of the contrast. IV sedation is provided, and local
anesthetic is infiltrated in the skin approximately 1 cm inferior and
posterior to the tip of the mastoid. A CT scan of the cervical spine is
obtained, focusing on the C1–C2 region. A disposable percutaneous
cordotomy electrode (LCED; Cosman Medical, Burlington,
Massachusetts) kit may be used for this procedure. A 20-gauge spinal
needle is advanced toward the C1–C2 interspace, and intermittent short-
segment CT scans spanning 15 mm are used to direct the needle toward
the dura. For lower extremity pain, the target for the spinal needle is just
anterior to the AP midpoint of the spinal cord; for pain in the chest or
upper extremities, the target is 1 to 2 mm more anterior to this. The tip of
the spinal needle is advanced further until it is adjacent to the spinal cord.
At this point the stylet was replaced with the electrode.
Electrical impedance measurement along with tactile feedback is used to
determine the location of the electrode. When the electrode is in CSF, the
impedance will measure a few hundred ohms (<300 Ω). As the electrode
abuts and presses into the pia of the spinal cord, the impedance will
increase significantly into the range of several hundred ohms (300 to 500
Ω). Entrance of the electrode into the spinal cord is met with a clear
popping sensation, and the impedance will increase dramatically to greater
than 700 Ω. At this point, another CT scan is obtained to confirm the
position of the radiofrequency electrode.
Intraoperative physiologic testing is then performed to test for both
sensory and motor effects. Sensory testing is performed at 100 hertz (Hz)
and a 0.1-msec pulse width, whereas motor testing is performed at 2 Hz.
At this point in the procedure, the patient’s cooperation is needed, and
hence, the sedation is adjusted until the patient can intelligibly answer
questions. Sensory testing is performed to physiologically confirm the
electrode tip’s presence within the spinothalamic tract. Testing for motor
contractions is also performed up to 1 V stimulation, indicating a safe
distance from the corticospinal tract.
When the radiofrequency electrode is in the appropriate radiologic and

2334
physiologic location, lesioning is performed using increasing levels of
temperature starting at 60° C for 60 seconds and proceeding up to 80° C
for 60 seconds. Because lesioning the spinothalamic tract is not painful,
additional sedation is not required for the ablation. Between lesions,
testing for the development of hyperesthesia is helpful, because an
additional lesion may be required if the patient has no decreased pinprick
sensation. The goal of the cordotomy is to create a moderate hypoalgesia.

OUTCOMES
Two important neurosurgical series of CT-guided cordotomy have been
published. In a prospective study of 41 patients who underwent
cordotomy, 80% of patients had no pain postoperatively and for 1 month
postprocedure.98 At 6 months postprocedure, 32% of patients had no pain,
and another 48% of patients had partially satisfactory pain relief.
Similarly, in Kanpolat et al.’s99 series of 207 cordotomies, a significant
improvement in the pain intensity from a mean of 7.6/10 preoperatively to
a mean of 1.3/10 postoperatively was achieved. When Kanpolat reported
his subset of 108 patients with lung cancer, 89% of patients had no pain
postoperatively.

COMPLICATIONS
Cordotomy has become a much safer procedure in the era of CT guidance.
The risk associated with spinal needle insertion and penetration of the
radiofrequency electrode into the pia of the spinal cord appears to be
negligible. The radiofrequency ablation itself can be a source of
complication for cordotomy. Hence, the art of cordotomy is determining
the appropriate balance between an aggressive lesion to optimize a durable
pain outcome and a safe lesion to avoid undesired side effects.
In 2008, Raslan98 reported his series of 41 patients who underwent
cordotomy, and no patients were found to have new neurologic deficits. In
Kanpolat et al.’s99 series of 207 cordotomies, 5 patients (2.4%) developed
temporary weakness and 5 patients (2.4%) developed temporary ataxia.
These symptoms resolved within 3 weeks after the procedure. In the 251
CT-guided cordotomies reported in the literature, four patients (1.6%) had
dysesthetic pains. Respiratory complications or serious neurologic injury

2335
has not been reported using a CT-guided approach.

Myelotomy
INDICATIONS
Preclinical studies have augmented our understanding of the midline
dorsal columns visceral pain pathway. The primary afferents for this dorsal
column visceral pain pathway travel to cell bodies situated in the nucleus
proprius and in the region of the spinal grey matter dorsal to the central
canal of the spinal cord. From here, the axons ascend ipsilaterally along
the midline portion of the dorsal columns prior to synapsing in the nucleus
gracilis.100–102
Midline myelotomy seeks to interrupt this dorsal column visceral pain
pathway. Candidates for midline myelotomy include patients with
intractable visceral pain associated with malignancy in the abdominal or
pelvic region.

SURGICAL TECHNIQUE
Myelotomy can be performed percutaneously or with a limited open
surgical technique.

PERCUTANEOUS RADIOFREQUENCY LESIONING

Kanpolat et al.’s103 first reported the technique for performing
percutaneous radiofrequency myelotomy. This procedure can be
performed either at the occiput-C1 level or in the thoracic spine. As
Kanpolat et al.103 has reported better experience using a larger diameter
electrode for myelotomy, a custom 26-gauge radiofrequency electrode of
diameter 0.46 mm (Cosman Medical, Burlington, Massachusetts) is the
electrode of choice. This compares with the cordotomy electrode of 0.33
mm in diameter which has also been explored for myelotomy.
A spinal myelogram is performed prior to the procedure to visualize the
spinal cord, and the patient is positioned prone with head flexed under
monitored anesthesia care.
Intraoperative CT guidance is used to target the space between the
occiput and C1 level or the relevant thoracic level. The spinal needle is

2336
advanced toward the midline of the spinal cord from a posterior approach.
The radiofrequency electrode is introduced into the spinal cord
parenchyma with the goal of advancing the electrode to the AP midpoint
of the spinal cord (Fig. 44.19). Impedance measurements are used to
confirm the presence of electrode in the spinal cord parenchyma, and
sensory stimulation (100 Hz, 100 µs) is performed, which can elicit lower
limb paresthesias, usually at voltages less than 0.2 V. Two radiofrequency
ablations at 70° C to 80° C for 60 seconds are performed.

FIGURE 44.19 Myelotomy. Axial section of the thoracic spine showing the dorsal columns
visceral pain pathway ascending bilaterally at the medial extent of the dorsal columns. A spinal
needle is used to create a mechanical lesion during myelotomy.

OPEN LIMITED MYELOTOMY

A technique initially described by Nauta and others can be used to perform
an open punctate myelotomy.104–108 Under general anesthesia, patients are
placed in the prone position and the surgical level is confirmed using
fluoroscopy. With the understanding that the goal of surgery is the
interruption of an ascending pain pathway, a spinal level is chosen which
is rostral to the source of pain. Based on previous reports, the T3 or T4
level is chosen for upper abdominal pain, and the T6 to T8 level is chosen
for perineal pain. A single-level thoracic laminectomy is performed at the
intended level of lesioning. As the procedure is performed in the thoracic
spine which is stabilized by the rib cage, a wide laminectomy is performed

2337
to allow visualization of the root entry zone bilaterally. Visualization of
the root entry zone bilaterally helps to confirm the midpoint of the spinal
cord. A midline dural incision is made, and dural retention sutures are
placed. Preservation of the midline dorsal vein is attempted in all cases by
mobilization of the vein if it obscured the dorsal median sulcus. Once the
midline is confirmed, the pia is coagulated with a microbipolar. A 16-
gauge angiocatheter is used to create the lesion. The catheter portion of the
angiocatheter assembly is cut to allow an exposed tip of 5 mm, the desired
lesion depth. Four lesions are made in one location by rotating the
angiocatheter 90 degrees between lesions. The goal is to create a lesion
that extends 0.5 mm from the midline bilaterally, with a lesion depth of 5
mm. The dura is closed with running sutures without the use of dural
sealants, relaying on meticulous fascial closure to prevent CSF leak. The
patient is mobilized on the evening of surgery.

OUTCOMES
Clinical studies for patients undergoing limited midline myelotomy have
shown satisfactory pain relief in the majority of patients, lasting a few
weeks to over 30 months.106,109 The long-term durability of pain relief is
difficult to assess given the short survival times due to the malignancy.
Gildenberg and Hirshberg110 reported excellent outcomes in 12 patients
undergoing open limited myelotomy as compared to 2 patients undergoing
percutaneous mechanical myelotomy. Kanpolat et al.’s103 observed poorer
outcomes in patients undergoing radiofrequency lesioning with smaller
electrodes (0.25 mm diameter and 1 mm tip). Many reports, however, have
not used a standardized outcome scale to evaluate pain relief, and
therefore, a detailed comparison between open and percutaneous
approaches is difficult to perform.

COMPLICATIONS
Motor complications when using image-guided percutaneous techniques
are rare, given the opportunity for intraoperative motor stimulation and the
relative distance of the corticospinal tract from the midline of the spinal
cord. Using an open surgical technique is similarly safe, provided that care
is taken to ensure the lesion is made in the midline.

2338
 We have found spinal cord motor and sensory monitoring to be a
valuable adjunct to open punctate myelotomy.
As the lesion in myelotomy is between the dorsal columns, transient
dysfunction of the dorsal columns can occur. This may manifest as
decreased proprioception, sensations of coolness, or tingling. These side
effects are generally mild and well tolerated.

Dorsal Root Entry Zone Lesioning

Dorsal root entry zone (DREZ) lesioning, an effective intervention for
brachial plexus avulsion, has also been applied to the care of patients with
cancer pain. DREZ may be considered for conditions such as radiation-
induced brachial plexopathy and Pancoast tumors. However, in routine
care of cancer patients, DREZ is not commonly used because it is a
relatively large intradural operation which involves a multilevel
laminectomy. The interested reader is directed to Gadgil and
Viswanathan.111

IMAGE-GUIDED ABLATION OF PAINFUL BONE

METASTASES
Isolated bone pain secondary to metastatic tumor activity is typically
treated with external beam radiation, analgesics (opioids and nonsteroidal
anti-inflammatory agents), and systemic therapies including
bisphosphonates, radiopharmaceuticals, corticosteroids, and chemotherapy
(see Chapters 43, 46, and 48). A recent advance has been the use of
radiologically guided needle placement into selected painful metastases to
provide thermal destruction using radiofrequency energy,112 laser, and
cryoablative113,114 techniques. Another technique is percutaneous alcohol
injection using selective arterial embolization115 or direct tumor
infiltration.116
A multicenter study by Goetz et al.112 treated 43 patients who had failed
standard therapy for painful osteolytic metastases with image-guided
radiofrequency ablation. Ninety-five percent of patients had a clinically
significant reduction in pain (VAS decrease of ≥2 on a 10-point scale).
Before treatment, the mean worst pain score was 7.9; after treatment, the

2339
average worst pain score was 4.5 (P < .0001) at 4 weeks, 3.0 (P < .0001) at
12 weeks, and 1.2 (P < .0005) at 24 weeks. Pain interference scores and
opioid consumption also improved during the 24 weeks of reported follow-
up. Complications were seen in three patients: Two were not serious,
whereas one involved an acetabular fracture following radiofrequency
ablation to this area.

Summary
Interventional therapies have a well-defined and beneficial role in the
treatment of appropriately selected patients with various cancer pain
syndromes. Optimizing outcomes depends on timely referral with adequate
assessment and patient selection; managing expectations of referring
physicians, patients, and family members; assuring adequacy of
postinterventional care; and an experienced, skilled interventionalist who
will assume full responsibility for pre- and postintervention evaluation and
follow-up care as indicated by the dictates of each patient’s circumstances.

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81. Varghese BT, Koshy RC. Endoscopic transnasal neurolytic sphenopalatine ganglion block for
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83. Rana SPS. Pulsed RFA of sphenopalatine ganglion vs. alcohol neurolysis for facial pain in
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89. Cata JP, Cordella JV, Burton AW, et al. Spinal cord stimulation relieves chemotherapy-
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91. Mercadante S. Malignant bone pain: pathophysiology and treatment. Pain 1997;69(1–2):1–18.
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 95. Anchala PR, Irving WD, Hillen TJ, et al. Treatment of metastatic spinal lesions with a
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116. Gangi A, Kastler B, Klinkert A, et al. Injection of alcohol into bone metastases under CT
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pain. Support Care Cancer 2005;13(3):188–193.

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CHAPTER 45
Pain Caused by Cancer of the
Head and Neck and Oral and
Oropharynx
ANDREI BARASCH and JOEL BRIAN EPSTEIN

Malignant diseases are generally associated with high morbidity, as both

the disease and therapy tend to be invasive and may be life-threatening.
Head and neck pain in cancer patients has various etiologies, including the
tumor and/or metastases, surgical and cytotoxic therapies, or conditions
unrelated to the cancer or its treatment (Table 45.1). Reportedly, pain is
present in head and neck cancer (HNC) in 50% or more of patients before
diagnosis, 80% during treatment, and 70% posttherapy.1 In one-third of
treated patients, pain continues for longer than 6 month, and its severity is
higher than in the pretherapy period.

TABLE 45.1 Orofacial Pain in Cancer Patients

I. Acute
1. Caused by disease: invasion of bone, nerve, muscle, mucosal damage; tumor pressure
2. Caused by cancer therapy: surgery, radiation therapy, and chemotherapy
a. Oral/dental pain: mucositis, infection (e.g., Candida, dental, HSV), neuropathy
3. Unrelated conditions causing pain (e.g., myofascial pain, trauma)
II. Chronic
1. Caused by persisting/progressive disease
2. Caused by cancer therapy: surgery, radiation therapy, and chemotherapy
a. Mucosal atrophy/xerostomia
b. Mucosal infection
c. Neuropathy
d. Temporomandibular (myofascial) disorders
e. Dental caries
f. Osteonecrosis/mucosal necrosis
g. Postherpetic neuralgia
3. Unrelated conditions causing pain
HSV, herpes simplex virus.

2347
 One of the most common cancer-related pain-producing conditions
affecting the head and neck region is ulcerative upper aerodigestive tract
mucositis. Mucositis can be a dose- and rate-limiting toxicity of cancer
therapy. Furthermore, mucositis can lead to new admission to hospital or
extend admission to hospital and is the most debilitating patient-reported
complication due to pain and effect on oropharyngeal function. This
chapter reviews the pathogenesis of mucositis, mechanisms of pain in
HNC, and current strategies for preventing and managing these algesic
conditions. Pain due to HNC and/or mucositis includes multiple
mechanisms that affect soft tissues, vascular, bone, and nervous system
structures, including molecular mechanisms associated with reactive
oxygen species (ROS), inflammatory mediators, neuropeptide release, and
stimulation of sensory receptors.2–4 Phenotypic changes may occur,
involving all levels of the sensory and autonomic nervous system, and are
impacted by individual variables including genetic and psychosocial
features. Understanding these mechanisms may lead to additional
approaches for prevention and management of pain.

Pain Mechanisms Due to Local and Regional Cancer

of the Head and Neck
TUMOR-INDUCED ALGESIA
A tumor may compress and/or invade adjacent tissues, affecting afferent
nerves directly or through production of inflammatory cytokines. For
example, potential mechanisms of musculoskeletal pain due to malignancy
include periosteal pressure, invasion of nerves, vascular damage,
microfractures of bone, and muscle spasm. Inflammatory mechanisms can
be activated by both tumor cells and cancer therapies and include release
of cytokines and other algesic molecules that induce pain in the tumor
environment of hypoxia and low pH. Tumors and tumor necrosis release
growth factors and cytokines that activate inflammation and nociceptive
pathways. In HNC, inflammation is a major cause of pain,3,4 initiated by
ROS, and release of mediators from tumor cells, leukocytes, platelets,
endothelial cells, and immune cells resident in the affected tissue and
sensory fiber stimulation (sensory and sympathetic). ROS may cause

2348
endothelial cell damage and increase vascular permeability, whereas nitric
oxide (NO) may induce second messenger mechanisms within neurons
that may cause neuropathic pain. Oxidative stress activates transcription
factors that cause upregulation of proinflammatory cytokines and may
trigger apoptosis that release cell contents leading to increased
inflammation and sensory stimulation.
Tissue inflammation increases circulating kallikreins leading to
production of bradykinin (BK) that produces and amplifies pain induced
by serotonin (5-HT). Glutamate is upregulated at sites of inflammation and
affects amino-3-hydroxy-5-methyl-4-isoazolepropionic acid (AMPA), N-
methyl-D-aspartate (NMDA), stimulating pain receptors. Furthermore,
inflammation increases the expression and sensitivity of ion channels
(such as sodium channels) on nociceptors, which may be stimulated,
increasing pain sensation.
The low pH in solid tumors appears to be due to inflammation, tumor
cell metabolism, and apoptosis. The release of cellular contents may cause
pain due to activation of sensory neurons through acid-sensing ion
channels (ASICs). In addition, cancer-induced activation of osteoclasts
results in lower pH and dissolution of bone mineral.
Tumor necrosis factor (TNF) may activate cytokines and growth factors
that play a significant role in inflammation and neuropathic pain. TNF is
also a key mediator in mucositis. Nerve growth factor (NGF) production is
mediated by interleukin (IL)-1β and is upregulated by TNF-α. NGF
activates cutaneous mast cells, leading to release of inflammatory
mediators that induce pain and may also activate the sympathetic nervous
system. Norepinephrine (NE) causes hyperalgesia at sites of tissue injury.
Prostaglandins (PGs) synthesized by cyclooxygenase pathways (COX-1
and COX-2) are induced by inflammatory cytokines and growth factors.
Increased levels of PGs are seen in locoregional tumors and in metastases.
PGs cause sensitization of afferent nerve fiber including C-fiber and Aδ
high-threshold mechanonociceptors and mediate hyperalgesia induced by
BK and NE. COX-2 pathways are also upregulated in HNC and in
mucositis.5
Modulation of sensory transmission involves presynaptic upregulation
of the primary signal by excitatory and inhibitory input from adjacent

2349
neurons and from descending pathways. In addition to local modulation,
second-order neurons and central pathways are also subject to modulation
from higher centers. Modulation may be mediated by interactions with
receptors including AMPA, NMDA, and by neurotransmitters including
substance P (SP), 5-HT, NE-A, opioid, cholecystokinin (CCK), and γ-
aminobutyric acid (GABA). Modulation of pain signaling is impacted by
stress, learned behavior, social/cultural background, and acute pain.
Perception of pain is impacted by attention, expectation, anxiety, and
depression. Mucosal changes, hyposalivation, chronic infection,
neurovascular changes, musculoskeletal changes, persisting/recurrent
cancer, and secondary complications of cancer or therapy may result in
chronic pain.
Neuropathic pain may result from insult to the peripheral nervous
system (PNS) and/or the central nervous system (CNS), including
alteration in sensory and autonomic function, and may result in peripheral
and/or central sensitization. Surgery or cytotoxic and targeted agents may
lead to neuropathy due to nerve damage due to surgery or inflammation,
resulting in ectopic firing and changes in receptive field leading to
neuronal excitability and spontaneous activity or “wind-up.” Neuronal
hyperexcitability may be due to overexpression of sodium channels and
activation of the NMDA receptor, which develops at voltage-gated sodium
channels. Persistent input may also result in increased receptive fields in
second-order neurons and centrally.
Interactions between the sympathetic nervous system and nociceptors
are thought to be associated with neuropathic pain. Injured C-fiber
terminals may atrophy and be replaced by Aβ fibers that may contribute to
sensory abnormalities following peripheral nerve injuries. SP in Aβ fibers
may be increased and lead to pain.
In addition to neuronal sensitization, TNF-α, IL-6, and IL-11 promote
osteoclast formation, which may play a role in malignant bone pain. The
effects of IL-1 are probably mediated by induction of NO, BK,6 and PGs
and endothelin-1 (ET-1) that may cause pain in cancer involving bone.
Prevention and treatment of pain based on increased understanding of
cellular and molecular mechanisms may lead to novel approaches and
improved pain prevention and management.

2350
Pain Mechanisms Due to Chemotherapy and/or
Radiotherapy
Peripheral neurotoxicity is associated with a number of chemotherapeutic
agents, including vinca alkaloids, and platinum agents may lead to damage
or loss of large myelinated sensory fibers. NGF and induction of lysosomal
storage defects occur in the dorsal root ganglion (DRG) following the use
of these agents. The taxanes (paclitaxel, docetaxel) cause microtubular
aggregation leading to neuropathy and increase the risk of neurotoxicity
when combined with platinum agents. Other agents including
noncytostatic drugs used in cancer treatment (e.g., interferon, thalidomide)
or in supportive care (e.g., amphotericin-B) may also induce sensory
neuropathy. Drug-induced neurotoxicity is typically dose dependent and
has an idiosyncratic tendency. Additive effects may occur from
combinations of drugs.
Treatment of neuropathy focuses on use of centrally acting
medications.7,8 Unfortunately, strategies for prevention of neuropathy are
not well documented. Amifostine and lipoic acid have been assessed in the
prevention of neurotoxicity caused by platinum agents.9,10 Melatonin was
shown in one clinical trial to reduce chemotherapy-induced
neurotoxicity,11 and the potential role of glutamine has been
examined.12,13 Continuing study of approaches to prevent and manage
cancer therapy-induced neurotoxicity are urgently needed.
Bisphosphonates are key medications used in the treatment of malignant
disease involving bone and are commonly used in patients with multiple
myeloma and metastatic breast, prostate, lung, and colon cancers. Benefits
of bisphosphonate therapy include prevention of skeletal-related events,
hypercalcemia of cancer, and reducing bone pain associated with
malignancy. One of the acute side effects associated with bisphosphonate
administration can be bone pain, including mandible pain that may present
with vague symptoms, but can occasionally mimic dental pain. Since late
2002, bisphosphonates have been associated with avascular necrosis
involving dentoalveolar bone. In cancer patients on bisphosphonates, the
most frequent risk factor for bisphosphonate-associated osteonecrosis
(BON) is dental extractions, but other dental procedures appear to be

2351
safe.14–20 Prevalence of BON is also associated with type and duration of
bisphosphonate treatment. Pain associated with BON, when present, is
usually associated with secondary infection of the soft and hard tissues
surrounding the areas of exposed bone.21,22 Chronic BON can spread to
involve nerve bundles (e.g., the inferior alveolar nerve) and produce nerve
pain and/or numbness.

Pain Due to Surgery

Pain is common at the time of diagnosis for those patients with HNC23 but
is typically of mild severity (Visual Analog Scale [VAS] 3/10).24 Surgical
extirpation may alleviate pain, but more often, following treatment for
HNC, pain increases due to the procedure and generally improves with
healing of the surgical site.25 Furthermore, surgery on the neck is
associated with fibrosis that may be increased with postoperative radiation
therapy, leading to shoulder and arm pain.23
Wittekindt et al. showed that subcutaneous botulinum toxin A may
reduce chronic neuropathic pain following neck dissection.26,27 Botulinum
toxin A achieves pain relief by preventing acetylcholine release at the
neuromuscular junction. Further investigation of the potential effects on
posttreatment fibrosis in the neck is warranted to guide clinical care.
Spread of disease to regional lymph nodes is a prognostic factor in
HNC.28 Treatment for cervical metastasis traditionally includes resection
of lymph nodes from levels I through V, the sternocleidomastoid (SCM)
muscle, internal jugular vein (IJV), and spinal accessory nerve (SAN),
known as radical neck dissection, originally described by Crile29 in 1906.
Recent studies show that neck dissection has a negative impact on
quality of life (QOL) and health status.30–34 It has been demonstrated that
more extensive neck dissections are associated with higher shoulder-
related disability.32,33,35,36 Fortunately, over the latter half of the 20th
century, neck dissection has evolved to more conservative surgical
approaches that has led to improved QOL; however, shoulder and neck
pain after neck dissection continues to be a common cause of
postoperative morbidity in HNC patients.37 It has been postulated that
mechanical overload of the shoulder secondary to postsurgical change

2352
leads to shoulder pain.38 However, even with preservation of the SAN,
patients may have shoulder pain.39,40 Dissection of level V lymph nodes
(the posterior triangle of the neck) is associated with neck pain and
shoulder pain.41
Attention to the preservation of cervical sensory nerves and effect on
QOL has been assessed. Roh et al.,41 in a retrospective cohort study of 53
patients treated with selective or modified radical neck dissection, suggest
that cervical sensory root branch preservation reduces postoperative
sensory deficits.

Pain Due to Mucositis

Oral mucositis is a frequent complication of cancer chemotherapy and
radiotherapy. A five-stage model for oral mucositis has been proposed
where ROS are generated during the initial phase,5,42–44 leading to cell
damage and upregulation of secondary mediators by activation of nuclear
factor-κB (NFκB) in the epithelium and connective tissue. NFκB increases
proinflammatory cytokines such as TNF-α, IL-1β, and IL-6, which
increases inflammation-causing algesia. NO may also be a key factor
causing pain. The ceramide pathway has been implicated in amplification
of oral mucositis and may modulate pain. Ulceration of the mucosa
exposes nerve fiber endings, thus sensitizing the entire surface.
Additionally, these ulcerations can become secondarily colonized/infected
and further increase cytokine release and mucosal pain.
In addition to mucosal damage, radiation therapy affects bone by
damage to osteocytes, osteoclasts, and osteoblasts. Further radiation
irreversibly damages endothelial cells in the vasculature throughout the
high-dose radiated volume, which may result in hypocellular,
hypovascular, and hypoxic oral soft tissue. These changes increase the risk
of soft tissue necrosis and osteonecrosis.

EPIDEMIOLOGY
Mucositis is the most common cause of oral pain during intensive
treatment of cancer involving chemotherapy, radiation, or
chemoradiotherapy45–73 (Table 45.2). Oral mucositis affects a majority of

2353
patients on myeloablative conditioning regimens used in hematopoietic
cell transplantation (HCT) and is essentially universal in patients treated
with tumoricidal radiation therapy in the oropharynx. The increasing use
of combined chemotherapy and radiation treatment modalities and
generally more aggressive therapy protocols to improve cancer cure rates
have increased the frequency, severity, and duration of oral
complications.45,47,48,50,53,56,58,61,66,73

TABLE 45.2 Frequencies of Oral Pain Associated with Cancer

Therapy
Acute Pain during Treatment
Oropharyngeal mucositis
Chemotherapy 15% to 70%
Bone marrow transplant 50% to 85%
Radiation therapy Up to 100%
Postsurgical therapy Up to 100%
Chronic Pain following Cancer Therapy
Mucosal pain Up to 33%
Pain associated with mucosal infection
Candidiasis
After stem cell transplant Up to 50%
After radiation therapy 20% to 33%
Herpes simplex in seropositive stem cell transplant patients Up to 90%
Neuropathy 16%
TMD/myofascial (patients with head and neck squamous cell 25% to 30%
carcinoma)
TMD, temporomandibular disorder.

Recent advances in cancer therapy have produced a significant increase

in the use of targeted therapies. These typically consist of disease- and
cell-specific inhibition of enzymes or receptors that interferes with tumor
growth or its microenvironment. The potential impact of targeted
monoclonal antibodies and other tumor-specific targeting molecules on
mucositis has not been fully documented. Prospective studies that assess
mucositis as a primary or secondary outcome with targeted agents have not
been conducted,74,75 although the pattern of oral mucosal involvement and
dermatologic involvement appears different than that seen in traditional
chemotherapy, suggesting that different mechanisms are involved.
Targeted therapy adverse events are generally assumed to be milder than

2354
those of cytotoxic agents. Nevertheless, these adverse events can be severe
or even dose limiting. Most of these effects are cutaneous and commonly
affect the oral mucosa.76 The oral effects generally consist of aphthous-
like or, in the case of immune checkpoint inhibitors, lichenoid or bullous
lesions and tend to be mild to moderate. However, lesions may become
severe, particularly with the recently approved combination of immune
checkpoint inhibitors.77,78
Advances in cancer pain management and supportive care now include
the use of antimicrobial prophylaxis/therapy and the use of growth factors
to speed hematopoietic recovery; these therapies have increased the focus
on oral mucositis as a significant and treatment-limiting complication.79–81
Oral mucositis is often coincident with therapy-related toxicity at other
sites, including veno-occlusive disease in HCT73 and gastrointestinal
toxicity.82 The potential for systemic infection caused by oral
opportunistic and acquired flora associated with oral mucositis has been
documented in studies of leukemia and HCT patients.83–86

PATHOGENESIS
Intensive cytotoxic chemotherapy and radiation therapy directly affect the
proliferation of epithelial cells leading to damage of the epithelium and
submucosal tissues and potentially to loss of integrity of the mucosal
barrier (Fig. 45.1 and Table 45.3). Epidermal growth factor (EGF)
secretion may increase the risk of mucositis,87 and conversely, cytokines
that reduce epithelial cell proliferation during cytotoxic therapy have the
potential to decrease the severity of tissue damage. Interaction with
cytokines produced in the connective tissue such as granulocyte-
macrophage colony-stimulating factor (GM-CSF), TNF, IL-6, IL-11, and
others may affect the extent tissue damage.79,82,88,89 The oral microflora
may play a role in progression of mucosal damage, as suggested in studies
of gram-negative bacterial flora in radiation-induced mucositis. The
outcomes of microflora-associated mucosal damage are influenced by the
potential effect of cancer therapies on the hematopoietic system and
damage to local and systemic immune function. Resolution of mucositis
may be dependent on production of pluripotential growth factors affecting
epithelial and connective tissues.56,79–82 During resolution, cytokines

2355
inducing epithelial cell proliferation and migration as well as angiogenesis
also play a role.56,90–96 Pain associated with mucositis is dependent on the
degree of tissue damage, sensitization of nociceptors, and secretion of
inflammatory and pain mediators.

FIGURE 45.1 Mild mucositis with erythema and minor erosion of the cheek mucosa in a patient
following autologous bone marrow transplant (at day +14). Mild mouth discomfort was reported.

TABLE 45.3 Factors Contributing to Oropharyngeal Mucositis

Direct Factors Indirect Factors
Radiation therapy Myelosuppression
Dose/fraction Immunosuppression
Total dose/days T-cell loss/dysfunction
Chemotherapy B-cell loss/dysfunction
Drug/dose/schedule Reduced secretory immunoglobulin A
Bone marrow transplant Infections
Chemotherapy Bacterial
Irradiation Plaque control
Salivary gland dysfunction Viral
Mucosal trauma Herpes simplex
Physical Varicella zoster
Chemical Cytomegalovirus
Thermal Other
Microbial flora Fungal
Graft-versus-host disease
Manifestations
Prophylaxis
Therapy
Patient susceptibility

2356
 In patients with HNC treated with radiation, pain intensity and pain
interference scores directly correlate with mucositis severity. Symptoms
increase at week 3, often peak at week 5, and persist for 4 to 6 weeks
following the end of treatment. Concurrent chemoradiotherapy and
intensified radiation protocols increase the severity and duration of oral
mucositis.97–99 However, marked improvement may take up to 12 months
posttreatment, with general functional and physical appearance slowly
returning toward baseline level. Follow-up of oropharyngeal cancer
patients (up to 1 year) treated with radiation showed that mouth pain is
common (58.4%) and interfered with daily activities in approximately one-
third of subjects.100

HEMATOPOIETIC CELL TRANSPLANTATION

Ulcerative mucositis is the most debilitating patient-reported toxicity of
HCT protocols and other treatments for hematologic cancer.58,59,64,66
Mucositis is compounded in patients with herpes simplex virus (HSV)
reactivation and in those with poor oral hygiene.57,64,69,70,101 HSV
prophylaxis has altered the frequency and severity of mucosal ulceration in
HCT patients; however, even when acyclovir prophylaxis is used, oral
ulcerative mucositis occurs in up to 75% of patients.59
Mucositis symptoms can be increased in HCT patients with
hyposalivation,67 and the related oral microflora and dental plaque changes
may influence its severity.101–107 Intensive oral hygiene has been
documented to reduce the severity and duration of oral mucositis.101
Studies have demonstrated that approximately 48% of the bacteremia
cases in the early period post-HCT are associated with oral flora. Concerns
about the risk of bacteremia secondary to gingival bleeding due to
brushing and flossing in the first 3 weeks post-HCT are not supported by
evidence. Septicemia was not increased in patients who continued
intensive oral care.101 Immunoglobulins and other antimicrobial proteins
in saliva are decreased after HCT conditioning, which may be an
additional factor in the increased risk of mucosal infection.82
Clinically, oral mucositis in autologous HCT patients becomes evident
approximately 2 to 5 days after marrow infusion (day +2 to 5) with
resolution in more than 90% of patients by day +15.59 Allogeneic HCT

2357
patients generally show a slightly slower onset and slower resolution of
mucositis. Damage to the mucosa typically presents in a bilateral pattern,
primarily involving the nonkeratinized mucosa of the cheeks, lateral and
ventral surfaces of the tongue, floor of the mouth, soft palate, and labial
mucosa. The mucosal reaction may begin shortly after exposure to the
conditioning regimen and progress to erythema and ulceration (Fig. 45.2;
also see Fig. 45.1). Increased mucosal toxicity is usually seen in patients
additionally conditioned for HCT with total body irradiation.66,68,79

FIGURE 45.2 Severe ulcerated mucositis in a patient receiving an unrelated donor bone marrow
transplant (day +14) requiring systemic opioid analgesic.

Oral pain (including odynophagia/dysphagia and trismus) closely

parallels development and severity of mucositis. Ulcerative lesions usually
result in moderate to severe discomfort, leading to difficult or impossible
oral nutrition and loss of oral function. Grades 3 and 4 mucositis typically
require parenteral feeding and topical and systemic analgesics, usually
opiates. Medications for the neuropathic components of pain are typically
administered in the setting of mucositis. Symptoms recede as oral lesions
heal but may be persistent in cases of mucosal atrophy and neuronal
sensitization.

HEAD AND NECK RADIATION THERAPY

Tumor-related pain is commonly present at the time of diagnosis of head
and neck/oral cancer (85%), although the intensity is usually not
severe.62,108 The presence and severity of pain are related to tumor stage

2358
and bone involvement.62 All treatment methods for HNC can result in
pain. Surgical resection of tumor is followed by postoperative algesia,
which is related to the extent of tissue removed and whether bone was
involved. Chemoradiation therapy affects tissue in the field of radiation
producing pain that increases gradually as the treatment advances.45,62,71,72
Radiotherapy-related mucositis is the most frequent complication in
patients during radiation for HNCs (see Table 45.1; Figs. 45.3 and 45.4).
Mucositis-related pain increases during radiation treatment and typically
resolves within 1 to 2 months, or longer with combined radiation and
chemotherapy. However, mucosal discomfort often continues for 6 to 12
months or longer, although the severity of pain decreases over time after
treatment.62 Chronic complaints include mucosal sensitivity attributed to
mucosal atrophy (33%), musculoskeletal syndromes (temporomandibular
disorder, fibrosis) (25%), and neurologic syndromes attributed to
deafferentation (16%) and neuropathy.62 The most common persisting
complaints after radiation treatment include xerostomia (57%), pain
involving the muscles of the jaw or joint (27%), and a 10% increased rate
of dental caries.109 Chronic complications of radiation therapy were
assessed in 676 HNC patients treated in a multicenter study, and 11% were
reported to have severe complications (grade 3 or 4) involving the oral
mucosa, bone, or muscle.110 These late complications were related to total
radiation dose; complications in bone were more common with large
radiation fields, and complications in bone and muscle were related to
radiation fraction size. The severity of chronic mucosal damage may relate
to severity of acute mucosal reaction.

2359
FIGURE 45.3 A: Initial tissue reaction in a patient receiving radiation therapy (dose received
1,400 cGy of planned 6,000 cGy) resulting in erythema and sensitivity of the right buccal mucosa.
B: Late tissue reaction in the same patient receiving radiation therapy (total dose received 6,000
cGy) resulting in oral pain and mucosal ulceration within the radiation field.

FIGURE 45.4 Localized ulcerative mucositis following brachytherapy for a squamous cell

2360
carcinoma of the middle portion of the lateral border of the tongue.

COMBINED RADIATION THERAPY, SURGERY,

AND/OR CHEMOTHERAPY
Treatment of locally advanced head and neck carcinoma is associated with
significant complications affecting oral function. Hyperfractionated
radiotherapy and chemotherapy may improve survival, but treatment is
frequently limited by the severity of oral toxicity.45,48,50,61,111,112 Severe
oral mucositis occurs in essentially all patients treated with accelerated
fractionated irradiation for supraglottic cancer2 and in those treated with
combined chemo radiation.111,112 Severe mucositis may cause
considerable pain, limit or prevent oral intake, and may lead to suspension
of cancer therapy.45,112 Intensity-modulated radiation therapy (IMRT) may
be associated with less skin and mucosal damage113 but still results in
significant ulcerative mucositis and symptoms.99 Helical IMRT is a newer
technique for radiation delivery, which unfortunately does not appear to
provide a better profile of side effects.114 Mucosal reactions in patients
receiving radiation treatment for HNC are currently regarded as
unavoidable side effects, but advances in knowledge of pathogenesis and
new therapeutic models are expected to change this view, with
prophylaxis, intervention, and improved symptom management.
The importance of fungal colonization and infection in radiation
mucositis has not been clearly defined.115–117 One study showed fewer
cases of candidiasis in patients on prophylactic fluconazole and a 50%
reduction in the number of breaks in radiation therapy than those not
provided prophylaxis with fluconazole.115 However, others have not found
an association between candidiasis or oral colonization and mucositis
during cancer therapy.115,117
Targeted chemotherapy with monoclonal antibodies and small
molecules is becoming part of current HNC protocols. The impact on
mucositis has not been well defined, as mucositis has only been recorded
with multiple toxicities and no studies have assessed mucositis using a
validated scale as a primary or secondary endpoint. However, the available
data suggest that oral mucositis is not more common than that seen with
standard therapy, although it may occur less frequently and be less

2361
severe.74,75,118–124

Pain Assessment
Most studies use a VAS or various Likert scales to assess oral pain; some
use the more extensive McGill Pain Questionnaire.60,125 The latter was
compared with two different factor models in patients with oral mucositis
pain after HCT, and it was recommended that a single pain rating may
provide a better practical measurement.125 Patients may be unable or
unwilling to complete lengthy questionnaires, particularly when their
overall condition including pain is at its worst. Notwithstanding analgesic
use, most of the variance in pain reports is explained by the severity of the
mucositis rather than psychosocial variables.55

Management of Oral Mucositis

Wide variation exists in quality of mucositis prevention and management
studies. Many enroll a small number of patients, using outcome measures
that are not validated, and may lack sensitivity. This makes assessment of
outcomes difficult, mandating careful review of the methods employed in
every study before generalizable conclusions can be drawn. Guidelines for
the use of outcome measures and more refined study design and protocols
in the management of mucositis are improving the value of more recent
studies. Evidence-based guidelines126–128 have been developed and will
continue to evolve as new approaches to prevention and management are
studied.
Development of strategies for the prevention and management of oral
mucositis has been enhanced by an improved understanding of the
multifactorial nature of the condition (Table 45.4). Radiation shields are
recommended during standard radiation therapy. The use of midline
mucosa-sparing blocks for protection of the mucosa during radiation
therapy, thereby reducing mucositis, resulted in less weight loss, fewer
hospitalizations for nutritional support, and a trend toward fewer treatment
interruptions (P = .07) than in control patients.52 The impact of IMRT on
oral mucositis pain is not well understood, with reduced area of severe

2362
tissue damage but broader areas of low-dose radiation exposure.99

TABLE 45.4 Prevention and Management of Oral Mucositis

Pretreatment Oral/Dental Stabilization
Eliminate sites of infection, trauma
Dental cleaning
Good oral hygiene
Saline mouth rinses
Antimicrobial Approaches
Systemic antimicrobials
Antibiotics
Antivirals acyclovir, valacyclovir, ganciclovir
Antifungal fluconazole
Topical antimicrobials
Chlorhexidine
Antimicrobial lozenges (polymyxin, tobramycin, amphotericin)
Anti-inflammatory Approaches
Topical agents
Prostaglandins
Benzydamine
Corticosteroids
Biologic Response Modifiers
Granulocyte-macrophage colony-stimulating factor
Granulocyte colony-stimulating factor
Epidermal growth factor
Transforming growth factor, interleukin-11
Miscellaneous Approaches
Good oral hygiene
Saline/bicarbonate mouth rinses
Low-energy lasers
Mucosal coating agents
Vitamin supplements
Anticholinergic agents (xerogenergic agents)
Modification in cancer treatment protocols

Palifermin (Kepivance; Biovitrum Inc, Stockholm, Sweden) is the only

approved agent for prevention of oral mucositis in HCT.17,129 Further
study of patients with metastatic colon cancer treated with fluorouracil-
based chemotherapy showed benefit of palifermin in reducing
mucositis,130 suggesting broader potential application than currently
indicated. Benzydamine (not available in the United States) is
recommended for use in patients receiving radiotherapy (>220 cGY per
day). Oral cryotherapy is recommended for prevention of mucositis in

2363
those receiving bolus 5-fluorouracil (FU) or edatrexate treatments, or high-
dose melphalan conditioning regimens for HCT. Low level laser therapy
(LLLT), also called low-energy lasers have been studied in the prevention
and management of mucositis associated with HCT and head and neck
radiation with consistent positive findings across studies.131–134 LLLT,
also known as photobiomodulation (PBM), affects the cellular redox status
by changes in the mitochondrial metabolism and influences cytokine
release and vascularization.135,136

Pain Management
With only a small number of approaches documented to prevent the
incidence or shorten the duration of oral mucositis, current clinical
management depends on palliative approaches. The use of a stepped
protocol for pain management is currently the most appropriate approach.
The elements of this protocol include the progressive utilization of (1)
basic oral care, (2) bland rinses, (3) topical anesthetic and mucosal coating
agents, and (4) systemic analgesics.

BASIC ORAL CARE

A growing body of evidence is being accrued that supports the importance
of maintaining oral care protocols to remove bacterial dental plaque from
teeth and periodontal tissues during intensive cancer therapies.126,127
Patients should maintain good oral hygiene by brushing, flossing, and
possibly using antimicrobial rinses.

BLAND ORAL RINSES

Although there are no studies demonstrating the effectiveness of normal
saline or bicarbonate rinses in decreasing mucositis, they have been shown
to reduce mucosal pain.137,138 Frequent use of bland rinses can provide
relief for mild mucositis, help remove debris, and moisturize mucosal
surfaces. However, some rinses may have the opposite effect. In a study of
40 patients undergoing radiotherapy to more than 50% of the oral cavity,
half were randomized to an oral care protocol using either saline or
hydrogen peroxide rinses, and the latter was associated with increased

2364
mucosal sensitivity.139

TOPICAL ANESTHETICS AND ANALGESICS

Topical anesthetics represent the next step in the strategy to manage
mucositis pain. Although there are no studies specifically examining
efficacy of various topical anesthetics, any agent that can be safely applied
to oral mucosa to induce numbness and is tolerated by the patient can be
used.65 Lidocaine viscous solution is frequently recommended, but other
useful agents include benzocaine, dyclonine, and diphenhydramine.
Topical anesthetics can cause mild initial irritation, obtund taste, and
diminish the gag reflex if gargled or swallowed. Hence, swallowing of
these agents to control pharyngeal pain is not generally recommended also
due to possible systemic side effects and toxicities. Benzydamine has been
shown to reduce mucositis and associated oral pain in radiation-induced
mucositis by initially producing an anesthetic effect, which is also longer
acting.65,72 Local applications of topical anesthetic creams or gels may be
especially useful for localized painful mucosal ulcerations.
Topical analgesics have also shown effect in mucositis pain. Initial
studies of topical morphine have shown analgesic effects,140 and doxepin
in single and multidose studies has shown extended duration pain relief
without burning sensation when applied to ulcerated tissue.141,142
Coating agents used as oral rinses such as milk of magnesia and
loperamide have been recommended frequently but have not been
subjected to controlled studies.65,126 Sucralfate suspension has been
studied in mucositis, but results have been inconsistent and its use for
radiation or chemotherapy mucositis is not supported.71,143–145
A number of mucosal coating agents or rinses have been licensed by the
U.S. Food and Drug Administration (FDA) for the management of oral
mucositis, including Gelclair (EKR Therapeutics, Bedminster, NJ),
MuGard (Access Pharmaceuticals Inc, Dallas, TX), and Caphosol (EUSA
Pharma Inc, Langhorne, PA). However, there is insufficient evidence to
recommend their use for prevention or treatment of mucositis.146,147

TOPICAL ANTIMICROBIALS
Early studies suggested that topical antimicrobials may have utility in

2365
preventing oral mucositis, but follow-up research has failed to provide
evidence to support their use.126 Chlorhexidine has been assessed in HCT
patients in a number of studies, but conflicting results with its use in
mucositis have been seen and the majority of follow-up studies do not
demonstrate a prophylactic effect on mucositis.148 It is important to note
that the effectiveness of chlorhexidine rinsing on plaque levels, gingival
inflammation, and caries risk have not been endpoints in these studies, and
the use of chlorhexidine for bacterial plaque control during cancer therapy
may still be useful.
Studies of antimicrobial lozenges combining agents such as polymyxin,
tobramycin, and amphotericin B in head and neck radiation therapy were
shown in a single-center trial to be effective.103 However, follow-up
studies to duplicate the benefit of using either topical antimicrobials or β-
defensin, while reducing oral microbial colonization, did not significantly
impact on mucositis.149–152

SYSTEMIC ANALGESICS
Symptom management for oral mucositis often requires the use of
systemic analgesics. Mucositis is the most common condition requiring the
use of systemic opioid analgesics during cancer therapy.49 A wide range of
agents can be used, including acetaminophen, nonsteroidal anti-
inflammatory agents (NSAIDs), and opiates/opioids.
Systemic analgesics should be prescribed following the World Health
Organization (WHO) analgesic ladder.65 These recommendations include
the use of nonopioid analgesics alone, or in combination with opioids and
adjunctive medications, based on pain severity and effectiveness of
therapy (see Chapter 39). In patients with oral mucositis pain, topical
approaches should be used initially and should continue to be used in
combination with systemic analgesics in order that the best pain
management can be achieved with the least potent and lowest doses of
systemic pain medications. Studies have shown that optimum pain control
may be achieved by moving directly from WHO ladder level I analgesics
to titrated doses of WHO ladder level III analgesics. Improvement in pain
control is achieved by combining level III analgesics with adjuvants at
lower total doses of analgesics, and therefore, modification of the

2366
analgesic ladder has been discussed.153
A number of different delivery methods can be used for delivery of
systemic analgesics. Oral, transmucosal, transdermal (patches),
intravenous, and suppository routes can be used. Patient-controlled
analgesia (PCA) is recommended in pain management for hospitalized
cancer patients with severe mucositis.154 A study of preteen children
receiving HCT assessed morphine or hydromorphone PCA for mucositis
or other painful conditions and found that children successfully mastered
PCA to control pain associated with HCT.49 No instance of drug overdose
or difficulty stopping the opioid was noted.49 As has been previously
voiced, addiction is not a significant risk in these patients with severe and
debilitating pain as is underuse and underdosing of analgesics.65
Persisting high levels of pain are common even with controlled opiate
dosing due to mucositis pain, and it has been suggested that the
neuropathic component of pain must be addressed to provide improved
pain control, with gabapentin showing additional effect.155

ANTI-INFECTIVE APPROACHES
Infection may result in direct mucosal damage, initiating or complicating
mucosal pain. Acyclovir prophylaxis in HSV-seropositive HCT patients is
strongly supported in the literature as it prevents both viral reactivation
and shedding (seen in 2.9% of patients) in most cases.156 Oral ulcerations
may also be due to reactivation of cytomegalovirus (CMV) in HCT,157 and
shedding of CMV was detected in 13.3% of CMV-seropositive patients.
No correlation between severity of mucositis and serologic status of HSV
or CMV was seen in patients provided acyclovir prophylaxis.156
Ganciclovir after stem cell transplantation has been shown effective in
suppressing CMV infection,158 and acyclovir prophylaxis has also been
shown to lower shedding of CMV by approximately half in these
patients.159
Bacterial infections are also common in the setting of immune
suppression. Consecutive HCT patients at risk of streptococcal bacteremia
were treated for 5 days with clindamycin and ceftazidime for the initial
management of fever associated with severe oral mucositis.86 Bacteremia
caused by viridans streptococci occurred in 70% of patients with severe

2367
mucositis, and blood culture results were positive a day prior to fever in
approximately one-third of cases, showing that mucosal ulceration
predisposes to systemic infection by oral flora. Approaches to reduce
mucosal damage will also reduce pain and infection risk and have been
suggested as a better means of minimizing systemic infection as compared
to antimicrobial approaches.86
In a series of patients with leukemia receiving HCT, fluconazole
prophylaxis was compared with no prophylaxis,117 and a trend toward
reduction in oropharyngeal colonization by Candida albicans was seen (P
= .07). However, the clinical implications are unclear because no
relationship was seen between Candida spp., antifungal prophylaxis, and
mucositis, suggesting that Candida spp. was not involved in the etiology of
mucosal damage in these patients.116 In a randomized controlled trial,
fluconazole prevented systemic fungal infections (7% of fluconazole
versus 18% of placebo patients)160 and the incidence of mucosal infection
and oropharyngeal colonization by C. albicans was reduced.161,162
Therefore, although Candida may complicate oral mucositis and cause
mucosal sensitivity and systemic infection, it does not appear to be a risk
factor of mucositis.163

Hyposalivation
Preventing mucosal toxicity also reduces the pain of oral mucositis.
Mucosal toxicity is a dose-limiting toxicity for patients on etoposide and
may be related to direct effects of myeloablative doses of etoposide
secreted in saliva.63 Twelve patients received propantheline, an
anticholinergic agent, or placebo, and mucositis was less frequent and less
severe (P = .05) in the propantheline arm. Another study investigated the
effect of drug-induced hyposalivation on mucositis during HCT by
comparing patients with historic controls.164 Propantheline was found to
significantly reduce oral mucositis due to high-dose etoposide, although no
effect was seen on esophagitis and enteritis. These findings suggest that for
chemotherapeutics that are secreted in saliva, pharmacologically induced
hyposalivation may decrease the exposure to the mucosa to the cytotoxic
drug and thereby reduce local tissue damage. It is unclear whether this

2368
strategy may apply to other regimens. These studies were small, and
results must be interpreted cautiously.

BIOLOGIC RESPONSE MODIFIERS AND CYTOKINES

The effects of KGF-1 (palifermin) on mucositis are discussed above.
Studies on KGF-20 (velafermin) have been terminated early due to the
drug’s association with Parkinson disease.165
A study on the effect of radiation on EGF in the oral cavity determined
that the quantity decreased because of decreased volume of saliva and also
decreased in concentration per milliliter of saliva as mucositis increased
throughout the course of therapy.87 These findings suggested that EGF
may represent a marker of mucosal damage and has the potential to
promote resolution of radiation-induced mucositis. Further studies on this
topic are necessary.
Mixed results on prevention of mucositis have been seen with GM-CSF
in several human trials.79–82,89,90 Studies assessing granulocyte colony-
stimulating factor (G-CSF) have also presented mixed outcomes. These
results may be due to mucositis being a secondary endpoint in these
studies that evaluated mainly the effects on white blood cells.56,90,91
Overall, these conflicting results do not provide sufficient information to
recommend use of white blood cell growth factors for the treatment of
mucositis.

COGNITIVE AND BEHAVIORAL INTERVENTIONS

Relaxation, imagery, biofeedback, hypnosis, and transcutaneous electrical
nerve stimulation have been employed in the management of cancer pain
with varying patient acceptance and efficacy.65,166,167 Cognitive-
behavioral interventions in pediatric oncology and HCT included
providing information before procedures and positive reinforcement after
procedures and, less commonly, behavioral interventions such as rhythmic
breathing, distraction, and imagery.168 Psychological services were
primarily available on an as-needed basis, and support groups were not
generally offered. Increasing emphasis on psychological support and
techniques for pain management may be useful for patients during HCT.
A controlled clinical trial of psychological interventions in cancer-

2369
related pain was conducted in 94 HCT patients with oral mucositis divided
in four groups, and relaxation and imagery training was shown to reduce
pain associated with oral mucositis. However, adding cognitive-behavioral
skills to relaxation and imagery did not improve pain relief.169 The reader
is referred to other chapters in this text for more detail with regard to
psychological approaches to pain and an in-depth review of treatment of
bone pain, use of nonopioid and opioid pharmacotherapy for cancer pain,
radiopharmaceuticals, and interventional approaches to pain control in
cancer.

Conclusion
Pain in the oropharynx of cancer patients has a significant impact upon
treatment implementation, prognosis and QOL, and needs to be dealt with
aggressively in order to prevent other comorbidities. Cancer and cancer
therapy result in release of ROS, growth factors, cytokines, and enzymes
that may cause nerve irritation or damage that may result in neurogenic
acute and chronic pain. Anxiety and depression compound the pain
experience. Mucosal damage, particularly in the presence of
immunosuppression and neutropenia, may significantly increase the risk of
systemic infection (Fig. 45.5). Oropharyngeal pain in cancer patients
frequently requires systemic analgesics, adjunctive medications, and
physical and psychological therapy, in addition to oral care and topical
treatments (see Table 45.4). Good oral hygiene including tooth brushing
and dental flossing reduces the severity of oral mucositis and does not
increase the risk of bacteremia.

2370
FIGURE 45.5 A model of the pathogenesis of oral mucositis.

Clinically apparent mucositis is the result of drug toxicities, tissue

damage, and inflammation. The primary event is cell damage from
chemotherapy, radiotherapy, or both. Secondary influences include
indirect toxicities resulting in immunosuppression, neutropenia,
reactivation of latent viruses (herpes viruses), and opportunistic microbial
(bacterial and fungal) infections. Salivary gland dysfunction caused by
dehydration and direct effects of the cancer therapy on gland function may
alter the local mucosal defenses. Because the etiology is multifactorial (see
Table 45.3), approaches to prevention and treatment also have been
multifactorial (see Table 45.4). Effective prevention and management of
mucositis affect the pain experienced during cancer treatment, and when
mucositis is present, symptomatic management is needed (Table 45.5).

2371
 TABLE 45.5 Symptomatic Management of Pain of Oral Mucositis
Maintain good oral hygiene.
Prevent mucosal damage (see Table 45.4).
Coating agents (e.g., milk of magnesia, aluminum hydroxide gel [Amphojel], sucralfate,
loperamide [Kaopectate], Gelclair, Caphosol)
Topical analgesic/anti-inflammatory (benzydamine)
Topical anesthetics/analgesics
Systemic analgesics
Adjuvant systemic medications
Adjuvant cognitive/psychological support
Physical therapy (rinsing, ice chips)
Miscellaneous agents

Systemic analgesics remain an important mainstay in pain treatment

along with topical analgesics and anesthetics. Pain management including
adjunctive analgesics are often underutilized in HNC-related pain
syndromes. Novel approaches of potential interest are agents that affect
neurotransmitters that modulate pain such as SP and potentially ROS,
cytokine production, PGs, and other neurotransmitters.
Biologic response modifiers offer the potential for prevention and to
speed healing. Oral care and continuing good oral hygiene are
recommended prior to and during cancer therapy. Keratinocyte growth
factor (Kepivance) is the only approved and recommended medication for
prophylaxis of mucositis in HCT. Benzydamine is recommended in head
and neck radiation therapy, but it is not available in the United States. Oral
cooling (cryotherapy) with ice chips is recommended for patients receiving
bolus infusion, short half-life systemic chemotherapy. Available local
agents of uncertain value include a coating agent (Gelclair) and a
mineralizing oral solution (Caphosol), with MuGard, the best documented
of these devices in mucositis.170 Meanwhile, a number of agents with
different mechanisms of action are undergoing investigation. Of potential
value is the use of PBM (LLLT), which has been shown in several studies
to mitigate prevalence, severity, and duration of both chemotherapy and
radiotherapy-induced mucositis.171
Whereas antimicrobial approaches have been shown to not prevent
mucositis, there may be a positive effect on dental and gingival health and
on mucosal candidiasis. Other approaches that require further study
include low-energy lasers and anti-inflammatory medications.

2372
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CHAPTER 46
Cancer-Related Bone Pain
EDGAR ROSS, LALITHA SUNDARARAMAN,
and MARY ALICE VIJJESWARAPU

Epidemiology Review
Bone pain due to cancer is caused by primary bone tumors and those
malignant diseases that commonly metastasize to the bones. Bone is the
third most common site of metastasis after lung and liver.1 Metastatic bone
pain most commonly results from cancers of the breast, prostate, and
lung.2 Other malignancies involving bone are renal cell carcinoma, thyroid
cancer, lymphoma, and multiple myeloma.3 The longer these malignancies
persist, the higher the probability of finding bone metastases. Current
therapies have increased survival time of patients suffering from many of
these malignancies. This has resulted in an increasing prevalence of
metastatic bone disease. Li et al.4 estimated that 279,679 (95% confidence
interval: 274,579 to 284,780) US adults alive on December 31, 2008, had
evidence of metastatic bone disease in the previous 5 years (Table 46.1).
Breast, prostate, and lung cancers accounted for 68% of these cases.
Prostate cancer is very likely to metastasize to bone rather than other
organs. Because patients are living longer than other patients with
metastatic diseases, prostate cancer patients are at increased risk of having
prolonged periods of pain secondary to bony invasion.5

TABLE 46.1 Estimated Number of Prevalent Cases of Metastatic

Bone Disease in the National Commercially Insured Population
Aged 18–64 Years, The National Fee-for-Service Medicare
Population Aged ≥65 Years, and the US Adult Population on
December 31, 2008, All Cancers and by Specific Cancer Types
Commercially Insured, Fee-for-Service Medicare, US adult
Cancer Ages 18–64 years Ages ≥65 years populationa

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 Type (n = 120,694,145) (n = 25,950,760) (n = 230,118,000)
All 60,411 (59,134–61,689) 128,540 (125,485–131,595) 279,679 (274,579–
cancers 284,780)
Female 25,754 (24,911–26,596) 35,960 (34,341–37,579) 90,904 (88,095–
breast 93,714)
Prostate 4,969 (4,609–5,329) 37,240 (35,593–38,887) 62,841 (60,253–
65,429)
Lung 7,879 (7,421–8,337) 15,900 (14,823–16,977) 35,222 (33,415–
37,030)
Other 21,809 (21,046–22,573) 39,440 (37,745–41,135) 90,712 (87,843–
93,580)
NOTES: Data presented as estimated number of patients with metastatic bone disease (95%
confidence interval).
aUS Census 2008.

From Li S, Peng Y, Weinhandl ED, et al. Estimated number of prevalent cases of metastatic bone
disease in the US adult population. Clin Epidemiol 2012;4(1):87–93. Reproduced with
permission of Dove Medical Press in the format Republish in a book via Copyright Clearance
Center.

Vertebral involvement is the most common site of bony metastases. The

incidence ranges from 30% to 70%.6 Most patients with metastatic disease
of the vertebrae experience back pain.7
Bony metastases compromise both the bone’s integrity and strength. In
the vertebrae, this leads to the increased risk of a pathologic fracture,
found most commonly in the elderly. Compression fractures affect
between 8% and 30% of cancer patients with vertebral body
involvement.8,9 In many cases, the fracture occurs without an initial
traumatic event suggesting that vertebral load is an independent factor in
the etiology of a pathologic fracture.10 Other factors that can lead to
pathologic fractures include iatrogenic causes such as steroids,
malnutrition-induced osteoporosis, bone mineral loss as a result of
inactivity, and destruction of bone secondary to radiation therapy.11
Complications from vertebral fracture include a redistribution of load
across affected vertebral bodies creating the increased risk of fractures at
adjacent levels, increased risk of embolic phenomena as a result of
inactivity and pain, kyphosis-induced restriction of vital capacity,12
predisposition to atelectasis, and early satiety-induced anorexia.13 Because
of this, bony metastases contribute significantly morbidity and decreased
life span.3,14

2383
PATHOPHYSIOLOGY
Over the past 10 years, animal models for bone tumor growth, bone
remodeling, and bone pain have demonstrated a correlation with many
features found in human bony metastatic pain. Mouse studies using murine
sarcoma cells injected into the intramedullary space of the femur
demonstrate mechanical as well as movement-related pain behaviors.
These behaviors15 increase with time and with increasing tumor-induced
bone destruction offering a model that appears to replicate the human
experience of how metastatic bone cancer contributes to bone pain. In
normal mice, a nonnoxious stimulus to the femur does not elicit the
synthesis of any tissue factors, whereas in mice with bone cancer, a
nonnoxious stimulus elicits the synthesis of substance P, which binds to
the neurokinin-1 receptor expressed in the spinal cord. Likewise, c-fos is
not expressed at the level of the spinal cord in normal mice, but this
protein is found in a population of mice with bony tumors.16
Both osteolytic and osteoblastic changes in bone occur in some tumor
types such as lung, breast, and renal tumors. A predominance of osteolysis
is found in multiple myeloma and sarcomas, leading to increased
destruction of bone with time. The predominant lesion in men with bone
metastases from prostate cancer is osteoblastic which leads to increased
numbers of irregular bone trabeculae weakening bone.17
In the prostate model, colonies of malignant prostate tissue exist along
the length of the intramedullary canal divided by newly formed bone.18 In
the sarcoma model, there is no new bone formation, only destruction,
which is greatest at the proximal and distal head with little to no
destruction at the midshaft of the bone. The prostate model also
demonstrates the formation of new bone along the length of the long bone
involving diaphysis and proximal and distal endpoints with an increase of
osteoclasts throughout the length of the intramedullary canal. These cells
stimulate osteolytic remodeling inducing an inflammatory reaction
mediated by macrophages. It is suspected that this macrophage-induced
inflammatory activity may be the basis for neuropathic type of pain found
in malignancies of the bone.19
Multiple studies have demonstrated that the periosteum is richly
innervated by both sympathetic and sensory nerve fibers.20,21 The

2384
periosteum receives the greatest amount of afferent sensory fibers per unit
area in bone. In addition, the periosteum, bone marrow, and mineralized
bone are also innervated by both sensory and sympathetic fibers.
Osteolytic animal models demonstrate microscopic fragmentation and
disruption of the bony matrix secondary to tumor growth. In the
osteoblastic model, there is evidence of destructive injury as well as an
increase in the density of sensory fibers compared to normal bone. An
increase in specific transcription factors has also been demonstrated,
including activating transcription factor-3 (ATF-3). Expression of ATF-3
is usually detectable in peripheral nerve injury models. It is also expressed
in the nucleus of sensory neurons damaged by osteolytic tumor cells.
However, this transcription factor is not detectable in normal sensory
neuron nuclei or in sensory neurons affected by peripheral inflammation.
Animal models with increased ATF-3 demonstrate an increase in
movement-related pain behavior. Gabapentin improved pain-related
behavior in this model22 but did not change tumor growth, bone
destruction, or changes in peripheral sensory fibers that were impacted by
tumor infiltration. These changes suggest that pain experienced secondary
to tumor infiltration is neuropathic.23
Osteolytic metastases in breast cancer secrete parathyroid hormone-
related peptide (PTHrP) which, in turn, binds to the parathyroid hormone-
related peptide receptor (PTHR1) on marrow stromal cells, resulting in the
production of receptor activator of nuclear factor-κB ligand (RANKL).
RANKL stimulates osteoclast differentiation which then demineralizes
bone, leading to increased levels of insulin-like growth factor 1 (IGF-1)
and TGF-β from bony matrix, supporting neoplastic proliferation increased
PTHrP supporting growth of metastatic disease. This is exploited in the
advent of the new antibody to RANKL denosumab that is used to combat
bony metastatic proliferation and complications caused by it.24
Osteoclastic-induced changes in pH also play a role in bone pain. Tumor
cell growth can exceed its vascular supply leading to tumor cell death and
further decrease in tissue pH and more pain. Additionally, as tumors grow,
associated inflammatory cells which may comprise as much as 80% of the
tumor mass reduce local pH. This localized decrease of pH in the bony
matrix will lead to an increased absorption of bone as manifested by

2385
osteoclastic activity.25 The administration of a transient receptor potential
vanilloid (TRPV) antagonist within the mouse model correlates with a
decrease in pain behaviors in all stages of tumor growth, suggesting a new
potential therapeutic target to reduce cancer-related bone pain.25 Tumor
cells also produce formaldehyde through a demethylation process by
serine hydroxymethyltransferase and lysine-specific histone demethylase
1. When the cancer cells migrate into the bone marrow, formaldehyde
leads to upregulation of the transient receptor potential vanilloid subfamily
member 1 (TRPV1) in the peripheral nerve fibers. IGF-1 produced by
osteoblasts also increases TRPV1 receptors that contribute to neuropathic
pain associated with cancer spread.
Osteoprotegerin (OPG) is a secreted soluble receptor, which is a tumor
necrosis factor receptor (TNFR). This receptor prevents the activation of
osteoclasts via a binding–sequestering of the OPG ligand. This has been
shown to decrease the amount of pain-related behavior in the mouse
sarcoma model. The monoclonal antibody (AMG-162) can inhibit bone
destruction by reducing osteoclast function leading to a reduction in
inflammatory-mediated changes in the dorsal root ganglion (DRG) which
has been correlated with bony metastatic pain.26
Inflammatory cells associated with tumor stroma secrete a variety of
compounds that sensitize or excite afferent neurons. Compounds include
prostaglandins, tumor necrosis factor-α, endothelins, interleukin-1 and
interleukin-6, epidermal growth factor, transforming growth factor-β, and
platelet-derived growth factor. Receptors for these factors are directly
expressed by afferent neurons. All may play a role in bone pain suggesting
new targets. In clinical practice, only prostaglandin and agents targeting
endothelin have been used to control metastatic bone pain. Prostaglandins
play a role in both sensitization and excitation of nociceptors via direct
binding to the prostanoid receptor.26
Nerve growth factor (NGF) is a neurotrophic factor expressed in tissue
following nerve injury by both the nerves injured as well as surrounding
tissues. Upregulation of NGF is thought to be a component in the
hyperalgesia following nerve injury. Anti-NGF therapy could be effective
in the control of pain related to bone cancer.27 In the osteolytic sarcoma
mouse model, anti-NGF antibody demonstrated effectiveness in

2386
attenuation of pain behaviors and was found to be more effective than
acute administration of 10 and 30 mg/kg doses of morphine sulfate.28

EVALUATION OF THE PATIENT WITH BONE CANCER

The two most important imaging modalities in the evaluation of
malignancy of the bone are plain radiography and radioisotope bone scans.

Radiography
Radiographic studies should be ordered first in the evaluation of patients
with complaints of bone pain in the context of malignancy. Radiographic
patterns fall into osteolytic, osteoblastic, or mixed presentation.
Osteoblastic lesions appear opaque and sclerotic. Osteolytic lesions appear
more radiolucent compared to surrounding bone. Risk of fracture is
greatest if more than 50% of long bone is involved.7,29

Bone Scan
Radioisotope bone scans are very good at identification of multifocal
lesions.30 Radioisotopes accumulate in areas of new bone growth and are
diminished in areas of metastasis secondary to decreased blood flow to the
area. Cancers such as melanoma and multiple myeloma may have false
negatives when reviewed on bone scan secondary due to their lack of
reactive bone activity.

Computed Tomography
Computed tomography (CT) offers improved spatial resolution in the
evaluation of cortical bone destruction.31 CT is beneficial in evaluation of
the three-dimensional characteristics of diseased bone identified by plain
radiographs and isotope scans. CT scan evaluations are optimal to study
the pelvic and shoulder girdles and spinal lesions. Additionally, CT-guided
needle biopsies can be used to identify cell types.

18F-FDG-PET-CT
The visualization of glucose metabolism by positron-emission tomography
with 18F-fluorodeoxyglucose, coupled with a simultaneously obtained CT
(18F-FDG-PET-CT), is now a standard diagnostic technique in oncology.

2387
In patients with highly metabolically active cancers such as lung cancer or
malignant melanoma, PET-CT with FDG has replaced other techniques for
the detection of bone metastases. In highly active tumors, bony metastases
can be detected with high sensitivity and specificity.32

Magnetic Resonance Imaging

Magnetic resonance imaging (MRI) provides better contrast resolution in
defining soft tissue and marrow involvement. Also, it can define vascular
relationships without contrast enhancement.31 MRI is very beneficial in
the evaluation of tumor infiltration of muscle and bone marrow, spinal
cord compression, and lesions which are otherwise insufficiently imaged
by the previously listed approaches.

TREATMENT
The site and distribution of bone metastases and the skeletal sequelae, such
as pathologic fracture and spinal cord compression, can impact the
patient’s prognosis. The focus of treatment should be directed at tumor
regression, relief of cancer-related symptoms, and preservation of
functional capacity. In some cases, metastatic disease is so advanced that it
is resistant to both chemotherapy and radiotherapy. When metastatic
involvement cannot be completely treated, the best way forward is to focus
on symptom management. Impaired neurologic function, pathologic
fractures, and debilitating pain are the most important reasons for
aggressive treatment. Palliation may employ radiotherapy,
radiopharmaceuticals, chemotherapy, hormone therapy, bisphosphonates,
calcitonin, analgesics (opioids and antiinflammatory drugs), adjuvant
analgesics (e.g., corticosteroids), and surgery.33 Details for these
interventions are found elsewhere.
Analgesic medications provide pain relief during therapy with more
definitive modalities (e.g., surgical fixation, radiation therapy) as well as
when malignant bone pain is resistant to other modalities of treatment.
Conventional administration of opioids and nonsteroidal anti-inflammatory
drugs (NSAIDs) may not produce adequate analgesia because of the
incidental and intermittent nature of pain a patient might experience. These
medications also have dose-limiting side effects. NSAID use is often

2388
limited by the risks of gastrointestinal (GI) bleeding and inhibition of
platelet function, especially in patients with low platelet counts and taking
steroids. In these latter patients, a cyclooxygenase-2 (COX-2) inhibitor
may be preferred (see the following section). Patients can have renal and
cardiovascular complications with both selective and nonselective
NSAIDs. These patients are also prone to having comorbidities that may
place them at increased risk of complications, particularly patients
undergoing cancer chemotherapy and with advanced disease. Targeted
pharmacotherapeutic and interventional approaches can be used to
improve these risk–benefit ratios. The remainder of this chapter focuses on
those therapies that have been studied specifically for the treatment of
cancer-related bone pain to supplement material presented elsewhere in
this text.

CYCLOOXYGENASE-2-SPECIFIC INHIBITORS
COX-2-specific inhibitors (coxibs) have demonstrated efficacy in the
treatment of chronic and acute pain comparable to traditional
(nonselective) NSAIDs without the severity of GI complication during
short-term use or platelet inhibition effects.34 The superior safety profile of
coxibs in conjunction with similar efficacy of conventional NSAIDs
supports their use in analgesic regimens for bone cancer. Many tumors
express the COX-2 isoenzyme, which is involved in the synthesis of
prostaglandins.35 In the murine sarcoma model, acute administration of a
selective COX-2 inhibitor attenuated both ongoing and movement-evoked
bone cancer pain, whereas chronic inhibition of COX-2 significantly
reduced ongoing and movement-evoked pain behaviors and reduced tumor
burden, osteoclastogenesis, and bone destruction by >50%. COX-2 is
expressed in 40% of human invasive breast cancers, and bone is the
primary site of metastasis in cases of breast cancer.36,37 COX-2 inhibition
also inhibited bone metastasis in both a prevention and treatment regimen.
This suggests COX-2 produced in breast cancer cells are significant in
supporting progression of osteolytic bone metastases in patients with
breast cancer, and that COX-2 inhibition may halt this process.
Furthermore, COX-2 inhibition may benefit iatrogenically caused tumor
progression.38 COX-2 inhibitors, such as celecoxib, have also been shown

2389
to increase apoptosis and decreased progression of osteosarcoma cell
lines.39
Morphine has been shown to stimulate angiogenesis supporting tumor
growth in mice. COX-2 inhibition can prevent tumor growth without
compromising opioid-dependent analgesia in a murine breast cancer
model. Chronic morphine treatment alone stimulated angiogenesis in
breast cancer with a corresponding increase in metastasis and reduced
survival, whereas coadministration of a coxib prevented these morphine-
induced effects and improved analgesia over either agent independently.40

CORTICOSTEROIDS
Corticosteroids are established analgesics in the treatment of pain
secondary to metastatic bone pain. This analgesia is thought to occur
through the blockade of cytokine synthesis that contributes to both
inflammation and nociception.41,42 The analgesic benefits of
corticosteroids are dose-dependent and limited in their duration of activity.
In a small uncontrolled study, approximately 40% of patients with
metastatic prostate cancer were found to have analgesic benefit with the
administration of oral corticosteroids. This was speculated to be secondary
to suppression of hormone-sensitive disease that was stimulated by weak
androgens of adrenal origin by negative feedback on secretion of
adrenocorticotropic hormone.43 Dexamethasone is the most commonly
used agent because it has the least effect on mineralocorticoid activity.

BISPHOSPHONATES
Bisphosphonates are pyrophosphate analogues which bind to
hydroxyapatite bone mineral surfaces acting to inhibit osteoclasts and thus
bone resorption.44 The optimal dose for this class is a function of the
disease stage.45
Oral clodronate given to patients with breast cancer metastatic to bone
reduced the frequency of skeletal events by more than one-fourth.46 In two
randomized placebo-controlled trials comparing monthly pamidronate
infusions to placebo infusions showed that skeletal morbidity rate could be
reduced by 30% to 40%.
A large, randomized, multicenter trial using intravenous (IV) zoledronic

2390
acid demonstrated a reduction of 20% in the risk of developing skeletal-
related events compared with pamidronate for patients with breast
cancer.47 Moreover, these trials demonstrated for the first time that a
bisphosphonate significantly reduces the occurrence of skeletal events in
hormone-refractory prostate cancer, non–small-cell lung cancer, and a
large range of solid tumors. Evidence from in vitro studies have shown
that bisphosphonates are able to directly affect tumor cell growth.46
Of the available bisphosphonates, IV zoledronic acid has demonstrated
the broadest clinical activity and is approved in many countries for the
treatment of bone metastases from all solid tumors.48,49 The indications for
bisphosphonate therapy in breast cancer patients include correction of
hypercalcemia and the prevention of cancer treatment-induced bone loss.50
In phase III clinical trials, denosumab, a human antibody to RANKL, is
highly effective for preventing complications in patients with bone
metastasis from prostate cancer, breast cancer, and other solid tumors. In
addition, it decreased treatment-related bone loss in patients treated with
androgen deprivation therapy for prostate cancer and women with breast
cancer who are treated with aromatase inhibitors.51,52 Limited
postmarketing analysis has raised concerns regarding denosumab because
of the potential for osteonecrosis of the jaw.53
Bisphosphonates, although effective in decreasing bony complications
due to bone metastases in prostate cancer, breast cancer, and other solid
tumors, can cause extensive side effects.54
Highly selective matrix metalloproteinase inhibitors inhibit osteoclastic
and bone tumor cell lines but not osteoblasts. They are also more effective
in promoting tumor apoptosis compared with the standard-of-care
bisphosphonate, zoledronate.55
Bisphosphonates are now a routine part of therapeutic regimen for
metastatic bone pain, and at least 50% of patients report clinically relevant
analgesic effect. Placebo-controlled trials with oral or IV bisphosphonates
have shown that prolonged administration can reduce the frequency of
skeletal-related events by 30% to 40%. The superiority of zoledronic acid
compared with pamidronate has been shown by a multiple-event analysis
in a large randomized trial. The short infusion time of zoledronic acid also
constitutes a convenient therapy. Flu-like symptoms, which are

2391
manageable with standard treatment, do occur. Renal monitoring is
recommended, with dose reductions for patients with renal dysfunction.
Osteonecrosis of the mandible has been reported in patients receiving
bisphosphonates and might be avoidable with appropriate dental care.56

CALCITONIN
The hormone calcitonin has the potential to relieve pain and also retain
bone density, leading to a decreased risk of fractures. However, there is
limited evidence to support the routine use of calcitonin for pain secondary
to bony metastases.57 Data suggests that calcitonin offers adjuvant
analgesia in the treatment of bone pain related to metastatic disease.58,59
A human clinical trial prospectively entered 22 patients to evaluate the
efficacy of salmon calcitonin in controlling pain related to bone
metastasis.60 Other controlled clinical trials of salmon calcitonin in the
treatment of cancer-related bone pain have shown equivocal analgesic
results without evidence of reducing complications due to bone metastasis
or improving quality of life or survival.57,61 Like many pain-relieving
strategies, there is considerable interpatient variability in responses. In
those patients who are not responding well to other first-line approaches, a
trial of calcitonin may be reasonable, but close follow-up should ensure
that benefits outweigh risks.

OPIOIDS/OPIATE ANTAGONISTS
Opioids continue to be an important means of treating metastatic bone
pain, but new research offers a challenge as to which treatment plan may
be most appropriate. In a murine sarcoma model of bone cancer pain, the
effects of sustained morphine found that morphine-enhanced, rather than
diminished, spontaneous and evoked pain, and that the effects were dose
dependent and naloxone sensitive.62 Morphine increased ATF-3
expression only in DRG cells of sarcoma mice. Morphine did not alter
tumor growth in vitro or tumor burden in vivo but accelerated sarcoma-
induced bone destruction and doubled the incidence of spontaneous
fracture in a dose- and naloxone-sensitive manner. Furthermore, morphine
increased osteoclast activity and upregulated interleukin-1β within the
femurs of sarcoma-treated mice suggesting enhancement of sarcoma-

2392
induced osteolysis.
These results suggest morphine may increase pain, osteolysis, bone loss,
and spontaneous fracture as well as markers of neuronal damage and
expression of proinflammatory cytokines. The data from this study suggest
the need to understand the long-term effects of chronic opioid therapy for
cancer pain.

ADJUVANT ANALGESICS
The pain of bone cancer can be refractory to traditional treatment
modalities. This may be the result of neuropathic changes in involved bone
tissues. In animal models of bone-invading malignancies, evidence for
peripheral nerve injury provides the pathophysiologic rationale for the use
of agents typically used to control neuropathic pain in the control of bone
cancer pain.63

N-METHYL-D-ASPARTATE ANTAGONISM AND α2

AGONISTS
Administration of α2 agonists (dexmedetomidine and clonidine), N-
methyl-D-aspartate (NMDA) antagonists (MK-801 and ketamine), and
morphine were examined in a mouse sarcoma bone cancer pain model.64
As expected, morphine produced a significant analgesic effect, and the α2
agonists produced analgesic effects with an efficacy similar to that of
morphine but only at doses that produced severe sedation. MK-801
demonstrated little analgesic effects, whereas ketamine yielded an
analgesic effect with the same efficacy as morphine. The authors
concluded that α2 agonists produce an analgesic effect only at a sedative
dose. Ketamine, but not MK-801, is associated with an analgesic response
without overt side effects, suggesting that non-NMDA effects may be
responsible for ketamine’s analgesic efficacy in this model. Applicability
of these findings to humans remains untested.

HORMONAL THERAPY
Progression of metastasis from breast, prostate, and uterine malignancies is
hormone dependent.65,66 Antihormonal treatment reduces an important
stimulus for growth and is a common form of adjunctive therapy in breast,

2393
prostate, and endometrial cancers.67
Estrogen and estrogen analogue therapy in patients with breast cancer
controls symptoms in 25% to 50% of patients temporarily.68 Antihormonal
therapy improved pain in 70% of patients with widespread bone
metastases from prostate cancer.69 Therapy with estrogens is efficacious
but may take 30 to 60 days before complete palliation. However, serious
adverse effects may exceed overall benefits. Although hormone therapy
with androgen receptor antagonists (e.g., flutamide) or antigrowth factor
agents (e.g., luteinizing hormone-releasing hormone analogs of
somatostatin and 5-reductase inhibitor) can be used to induce tumor
regression, the palliative effect may not offer long-term benefit as
hormone-refractory elements continue to proliferate.70

RADIONUCLEOTIDES
Analgesic effects from radionucleotides are not dependent on tumor
destruction per se but are thought to result from inhibition of pain
mediators from normal bone cells. Therapeutic responsiveness is greatest
in osteoblastic lesions. Multiple different agents have been used for
palliative treatment of cancer-related bone pain, including phosphorus-32,
strontium-89, yttrium-90, samarium-153, and rhenium-186.
Phosphorus-32 has been used for more than 30 years and relieves the
pain from osteoblastic metastases in approximately 80% of treated
patients.71 Myelosuppression caused by this agent has led to the
development of newer agents. Strontium-89 is a bone-seeking
radionuclide, whereas samarium-153 is a bone-seeking tetraphosphonate.
Both agents have been shown to have efficacy in the treatment of painful
osseous metastases from prostate cancer, breast cancer, and, perhaps, from
non–small-cell lung cancer. As many as 80% of selected patients72 with
painful osteoblastic bony metastases from prostate or breast cancer
experience some pain relief following strontium-89 administration.73
Additionally, 10% or more may become pain free, and the average
duration of clinical response typically ranges from 3 to 6 months with
minimal myelosuppression as compared to phosphorus-32.74

PROCEDURAL INTERVENTIONS

2394
In addition to pharmacotherapy, interventional therapies can be used to
relieve the pain associated with bone cancer. Examples include procedures
such as intralesional injections, nerve blocks, intraarticular injections,
radiofrequency rhizotomy, and vertebroplasty.

Intralesional Injection
In a study of patients with rib metastases or involvement of the ribs by
multiple myeloma, infiltration of tender areas with methylprednisolone
provided significant reduction in pain-related symptoms in over half the
cases.75 Of 20 assessable patients, 11 became pain free within 10 days
with recurrence of pain in only 1 of these patients; in 8 others, the pain was
considerably improved. The procedure was well tolerated, and there were
no complications.75 This technique has also been used to treat mandibular
lesions in which surgical excision of tumor would risk destabilizing the
affected bone.76 This technique may be applicable to other areas of
metastasis.77 Additionally, localized injection of corticosteroid, local
anesthetic, and even baclofen have been reported to offer clinically
meaningful relief in areas of secondary muscular spasm.78

Percutaneous Vertebroplasty/Kyphoplasty
Vertebral bony metastases are seen in 30% to 70% of all bony lesions.
These metastases compromise the strength of involved bone leading to
pathologic vertebral fractures even in the absence of trauma. Additional
causes of fractures include osteoporosis, malnutrition, radiation, and
steroid administration. Vertebroplasty offers the potential of pain relief. In
comparison, patients who have a nonmalignant basis for pathology of the
bone such as osteoporosis, reports of analgesic benefit in cancer patients
are not as high but are still significant with ranges reported between 50%
and 80%.79 This may be explained by the widespread nature of metastatic
disease and the multifactorial origins of pain. The mechanism by which
vertebroplasty provides pain relief is not completely understood but could
be secondary to fixation of mobile bone fragments and/or thermal
neurolysis secondary to the exothermic reaction of methylmethacrylate
cement yielding temperatures in excess of 70° C.80

2395
Rhizotomy
Minimally invasive neurodestructive techniques have been demonstrated
to be effective in a number of malignancies, specifically of visceral and
neuropathic nature. Techniques involve radiofrequency lesioning,
cryotherapy, and chemical neurolysis using phenol, alcohol, and
hypertonic saline. Because pain from bony metastasis has a neuropathic
component, these techniques offer an option in the control of cancer-
related bone pain. Other diagnoses where this approached can be applied
to include chordoma, osteoid osteoma, and osseous metastasis. Studies of
radiofrequency lesioning of bony and soft tissue malignancy have reported
significant palliation of pain.81–84

ASSOCIATED PROCESSES
Avascular Necrosis
Avascular necrosis can be found in survivors of cancer who have been
exposed to corticosteroid therapy. Pain is the result of weight bearing on
the affected joint. In an MRI study of patients having survived childhood
cancer, 67% of patients demonstrated osteonecrosis at the ankle.85

Postoperative Frozen Shoulder

In postthoracotomy or postmastectomy patients, pain leads to an increased
risk for the development of frozen shoulder. The site may become an
independent locus of pain and can be complicated by complex regional
pain syndrome. Adequate mobilization of the joint with sufficient
analgesia should be implemented soon following surgery to prevent this
chronic, painful, and debilitating complication.86

GRANULOCYTE COLONY-STIMULATING FACTOR

RELATED PAIN
Granulocyte colony-stimulating factor (G-CSF) is used to stimulate the
production of granulocytes in immunocompromised patients following
chemotherapy and radiation. Bone and generalized muscle pain is a
common complication, which can last for 10 or more days.87 Effective
analgesia can require opioids.88 G-CSF also induces an inflammatory
reaction through undefined cellular signaling and histamine release.89

2396
Increased histamine levels cause nociceptive C-fiber–mediated pain and
edema formation within bone leading to pain.90 Antihistamines such as
terfenadine and astemizole have anti-inflammatory properties in addition
to their potency as histamine-1 antagonist and can be used to treat bone
pain secondary to G-CSF therapy.

Conclusion
The bony skeleton is the most common location for metastatic cancer and
leads to a very high incidence of morbidity including severe pain
(spontaneous and provoked), hypercalcemia, pathologic fracture, and
spinal cord and or nerve root compression. Bone pain is frequently
undertreated. Approximately 80% of patients experienced pain before
palliative therapy. Progress in understanding the prevention and treatment
of cancer-related bone pain is being made. There are many therapies
available to treat pain caused by infiltration of cancer into bone.91
Major skeletal-related events occur in cancer patients on average every
3 to 6 months. The prognosis of metastatic bone disease is dependent on
the primary site. Breast and prostate cancer survival is measured in years;
in lung cancer, survival may be measured in months. Severity and duration
of tumor involvement in bone cancer are predictors of outcome and can be
measured by bone-specific markers. Studies have demonstrated a
significant correlation between the rate of bone resorption, clinical
outcomes, skeletal morbidity, and overall life expectancy. Improved
understanding and treatment will not only improve the quality of life of
cancer patients but also improve long-term outcomes.7

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18. Clines GA, Guise TA. Mechanisms and treatment for bone metastases. Clin Adv Hematol
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19. Chung LW, Baseman A, Assikis V, et al. Molecular insights into prostate cancer progression:
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21. Bjurholm A. Neuroendocrine peptides in bone. Int Orthop 1991;15:325–329.
22. Lipton A. Management of bone metastases in breast cancer. Curr Treat Options Oncol
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23. Peters CM, Ghilardi JR, Keyser CP, et al. Tumor-induced injury of primary afferent sensory
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25. Lipton A. Pathophysiology of bone metastases: how this knowledge may lead to therapeutic
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27. Mantyh P. Pain due to bone metastases: new research issues and their clinical implications. In:
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31. Beheshti M, Vali R, Waldenberger P, et al. The use of F-18 choline PET in the assessment of
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32. James SL, Davies AM. Post-operative imaging of soft tissue sarcomas. Cancer Imaging
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33. Jayr C. Analgesic effects of cyclooxygenase 2 inhibitors. Bull Cancer 2004;91(suppl 2):S125–
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34. Sabino MA, Ghilardi JR, Jongen JL, et al. Simultaneous reduction in cancer pain, bone
destruction, and tumor growth by selective inhibition of cyclooxygenase-2. Cancer Res
2002;62(24):7343–7349.
35. Singh B, Berry JA, Shoher A, et al. COX-2 involvement in breast cancer metastasis to bone.
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36. Singh B, Berry JA, Shoher A, et al. COX-2 induces IL-11 production in human breast cancer
cells. J Surg Res 2006;131(2):267–275.
37. Farooqui M, Li Y, Rogers T, et al. COX-2 inhibitor celecoxib prevents chronic morphine-
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38. Zhou X, Shi X, Ren K, et al. Celecoxib inhibits cell growth and modulates the expression of
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39. Clezardin P, Teti A. Bone metastasis: pathogenesis and therapeutic implications. Clin Exp
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40. Mercadante S. Malignant bone pain: pathophysiology and treatment. Pain 1997;69:1–18.
41. MacDonald N. Principles governing the use of cancer chemotherapy in palliative medicine.
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42. Tannock I, Gospodarowicz M, Meakin W, et al. Treatment of metastatic prostatic cancer with
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43. Vitté C, Fleisch H, Guenther HL. Bisphosphonates induce osteoblasts to secrete an inhibitor
of osteoclast-mediated resorption. Endocrinology 1996;137:2324–2333.
44. Body JJ, Mancini I. Bisphosphonates for cancer patients: why, how, and when? Support Care
Cancer 2002;10(5):399–407.
45. Costa L. Biphosphonates: reducing the risk of skeletal complications from bone metastasis.
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46. Coleman RE. Optimising treatment of bone metastases by ArediaTM and ZometaTM. Breast
Cancer 2000;7(4):361–369.
47. Santini D, Fratto ME, Vincenzi B, et al. Zoledronic acid in the management of metastatic bone
disease. Expert Opin Biol Ther 2006;6(12):1333–1348.
48. Rosen L, Gordon D, Kaminski M. Zoledronic acid versus pamidronate in the treatment of
skeletal metastases in patients with breast cancer or osteolytic lesions of multiple myeloma: a
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50. Ellis GK, Bone HG, Chlebowski R, et al. Effect of denosumab on bone mineral density in

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analyses of a phase 3 study. Breast Cancer Res Treat 2009;118(1):81–87.
51. Gnant M, Pfeiler G, Dubsky PC, et al. Adjuvant denosumab in breast cancer (ABCSG-18): a
multicentre, randomised, double-blind, placebo-controlled trial. Lancet 2015;386(9992):433–
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52. McGreevy C, Williams D. Safety of drugs used in the treatment of osteoporosis. Ther Adv
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54. Smith MR, McGovern FJ, Zietman AL, et al. Pamidronate to prevent bone loss during
androgen-deprivation therapy for prostate cancer. N Engl J Med 2001;345(13):948–955.
55. Tauro M, Shay G, Sansil SS, et al. Bone-seeking matrix metalloproteinase-2 inhibitors prevent
bone metastatic breast cancer growth. Mol Cancer Ther 2017;16(3):494–505.
56. Lipton A. Efficacy and safety of intravenous bisphosphonates in patients with bone metastases
caused by metastatic breast cancer. Clin Breast Cancer 2007;7(suppl 1):S14–S20.
57. Martinez-Sapata MJ, Roqué M, Alonso-Coello P, et al. Calcitonin for metastatic bone pain.
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58. Gennari C. Analgesic effect of calcitonin in osteoporosis. Bone 2002;30(suppl 5):67S–70S.
59. Visser E. A review of calcitonin and its use in the treatment of acute pain. Acute Pain
2005;7(4):185–189.
60. Mystakidou K, Befon S, Hondros K, et al. Continuous subcutaneous administration of high-
dose salmon calcitonin in bone metastasis: pain control and beta-endorphin plasma levels. J
Pain Symptom Manage 1999;18(5):323–330.
61. Tsavaris N, Kopterides P, Kosmas C, et al. Analgesic activity of high-dose intravenous
calcitonin in cancer patients with bone metastases. Oncol Rep 2006;16(4):871–875.
62. King T, Vardanyan A, Majuta L, et al. Morphine treatment accelerates sarcoma-induced bone
pain, bone loss, and spontaneous fracture in a murine model of bone cancer. Pain 2007;132(1–
2):154–168.
63. Donovan-Rodriguez T, Dickenson AH, Urch CE. Gabapentin normalizes spinal neuronal
responses that correlate with behavior in a rat model of cancer-induced bone pain.
Anesthesiology 2005;102(1):132–140.
64. Saito O, Aoe T, Kozikowski A, et al. Ketamine and N-acetylaspartylglutamate peptidase
inhibitor exert analgesia in bone cancer pain. Can J Anaesth 2006;53(9):891–898.
65. Sant’Agnese PA. The prostatic endocrine-paracrine regulation system and neuroendocrine
differentiation in prostatic carcinoma: a review and future direction in basic research. J Urol
1992;152:2.
66. Wood BC. Hormone treatments in the common hormone-dependent carcinomas. Palliat Med
1993;7:257–272.
67. Mike S, Harrison C, Coles B, et al. Chemotherapy for hormone-refractory prostate cancer.
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68. Reale C, Turkiewicz AM, Reale CA. Antalgic treatment of pain associated with bone
metastases. Crit Rev Oncol Hematol 2001;37:1–11.
69. Lattouf JB, Saad F. Preservation of bone health in prostate cancer. Curr Opin Support Palliat
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70. Pelger RC, Soerdjbalie-Maikoe V, Hamdy NA. Strategies for management of prostate cancer-
related bone pain. Drugs Aging 2001;18(12):899–911.
71. Silberstein EB. The treatment of painful osseous metastases with phosphorus-32-labeled
phosphates. Semin Oncol 1993;20(3 suppl 2):10–21.
72. Oosterhof GO, Roberts JT, de Reijke SA, et al. Strontium(89) chloride versus palliative local

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European Organisation for Research and Treatment of Cancer, Genitourinary Group. Eur Urol
2003;44(5):519–526.
73. Robinson K. Strontium 89 therapy for the palliation of pain due to osseous metastases. JAMA
1995;274(5):420–424.
74. Kraeber-Bodéré F, Campion L, Rousseau, et al. Treatment of bone metastases of prostate
cancer with strontium-89 chloride: efficacy in relation to the degree of bone involvement. Eur
J Nucl Med 2000;27(10):1487–1493.
75. Rowell NP. Intralesional methylprednisolone for rib metastases: an alternative to
radiotherapy? Palliat Med 1988;2(2):153–155.
76. Adornato M, Paticoff KA. Intralesional corticosteroid injection for treatment of central giant-
cell granuloma. J Am Dent Assoc 2001;132(2):186–190.
77. Lin P, Frink SJ. Intralesional treatment of bone tumors. Operative Techniques in Orthopaedics
2004;14(4):251–258.
78. Sis T, Wong C. Difficult problems and their solutions in patients with cancer pain of the head
and neck areas. Curr Rev Pain 2000;4(3):206–214.
79. Alberico R, Ahmed AH, Husain SH. Vertebroplasty and kyphoplasty. In: de Leon Casseola O,
ed. Cancer Pain Management: Pharmacologic, Interventional, and Palliative Approaches.
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80. Fourney D, Schomer DF, Nader R, et al. Percutaneous vertebroplasty and kyphoplasty for
painful vertebral body fractures in cancer patients. J Neurosurg 2003;98(suppl 1):21–30.
81. Dupuy D, Ahmed M, Rodrigues B, et al. Percutaneous radiofrequency ablation of painful
osseous metastases: a phase II trial. Proc Am Soc Clin Oncol 2001;20:385a.
82. Locklin MA, Mannes A, Berger A, et al. Palliation of soft tissue cancer pain with
radiofrequency ablation. J Support Oncol 2004;2:439–445.
83. Wood B, Fojo A, Levy EB, et al. Radiofrequency ablation of painful neoplasms as a palliative
therapy: early experience. J Vasc Interv Radiol 2000;11S:207.
84. Goetz M, Callstrom MR, Charboneau JW, et al. Percutaneous image-guided radiofrequency
ablation of painful metastases involving bone: a multicenter study. J Clin Oncol
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care. In: Fisch M, Burton A, eds. Cancer Pain Management. New York: McGraw-Hill;
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Melzack’s Textbook of Pain. 6th ed. London: Elsevier; 2006:1039–1060.
87. Kubista E, Glaspy J, Holmes FA, et al. Bone pain associated with once-per-cycle
pegfilgrastim is similar to daily filgrastim in patients with breast cancer. Clin Breast Cancer
2003;6:391–398.
88. Gudi R, Krishnamurthy M, Patcher BR. Astemizole in the treatment of granulocyte colony-
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Surv 1988;7:55–67.
91. Slatkin N. Cancer-related pain and its pharmacologic management in the patient with bone
metastasis. J Support Oncol 2006;4(2 suppl 1):15–21.

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CHAPTER 47
Cancer-Related Visceral Pain
MARY ALICE VIJJESWARAPU, LALITHA SUNDARARAMAN,
and EDGAR ROSS

Epidemiology Review
In 2004, 1.4 million Americans were diagnosed with cancer. This number
equals approximately 4,000 new diagnoses per day. In the same year, over
500,000 American deaths were attributed to cancer, accounting for 22%
overall mortality.1 Currently, more than 10 million individuals in the
United States carry the burden of a cancer diagnosis, which is 3% of the
population.2 Approximately 50% of patients who carry a diagnosis of
cancer report pain as a symptom of the disease process. This percentage
increases to 75% of patients reporting pain in the advanced stages of
disease.3,4
In 2016, it is estimated that there are 1,685,210 new cases of cancer in
the United States, and 595,690 people will die from the disease. The
number of people living beyond a cancer diagnosis reached nearly 14.5
million in 2014 and is expected to rise to almost 19 million by 2024.
Approximately 39.6% of men and women will be diagnosed with cancer at
some point during their lifetimes (based on 2010 to 2012 data).5 The
prevalence of pain in cancer varies widely depending on the stage of
cancer, type of cancer, and treatment received. The pooled prevalence is
about 50% with the highest prevalence in head and neck cancer patients
(70% 95% CI, 55% to 80%).6
With competent management, cancer pain can be eliminated or well
controlled in 80% to 90% of cases, but nearly 1 in 2 patients in the
developed world receives less than optimal care. Worldwide, nearly 80%
of people with cancer receive little or no pain medication.7 Trends in death
rates for all cancer sites combined from 2000 to 2014 showed a decrease.
Death rates decreased statistically, significantly from 2000 to 2014 by

2402
1.8% (95% CI = −1.8% to −1.8%) on average per year among men and by
1.4% (95% CI = −1.4% to −1.3%) per year among women.8
After patients come to terms with the diagnosis of cancer and the
implications of their disease, most patients and their families will express
concern about the pain and suffering they will experience as their disease
progresses. Commonly asked questions include how much pain will there
be and can it be controlled?4 Unfortunately, despite evidence that cancer
pain can be controlled, it is managed poorly in many cases. Multiple
factors limit adequate treatment of cancer pain, including misperceptions
of disease processes, misconceptions regarding pain medications and
procedures, professionals inadequately trained in pain management, failure
to consult specialists trained in contemporary pain management methods,
and social stigma around opioid use, including fears of addiction by
patients, family members, and professional health care providers.9 Also,
many common cancers in the advanced stages of disease when pain is
highly prevalent are incurable, and survival may be measured in months,
not years. Whereas health care professionals may only measure survival
duration as a meaningful treatment outcome, patients and families may
measure outcomes in terms of improvement in quality of life, alleviation of
pain, and relief of other associated symptoms related to cancer and
treatment.10
Because pain syndromes arise from cancer therapies (including
chemotherapy, radiation therapy, or surgery), patients who survive their
primary malignancy may be left with pain secondary to an iatrogenic
process. Chemotherapy may induce a painful peripheral neuropathy.
Neuropathy is well described with vincristine, platinum, taxanes,
thalidomide, bortezomib, and other agents. Pain secondary to radiation
may appear years to decades after completion of radiotherapy. Pain
syndromes following surgery may present after mastectomy, amputation,
thoracotomy, or other surgical approaches to malignancies (see Chapters
41, 42, 45, and 48).11

Characteristics of Visceral Pain

ANATOMY AND PHYSIOLOGY

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Visceral pain is caused by disorders of internal organs such as the
stomach, kidney, gallbladder, urinary bladder, and intestines as well as
changes in the central nervous system. Pain can result from distension,
impaction, ischemia, inflammation, or traction on the mesentery and can
be associated with symptoms such as nausea, fever, malaise, and pain.12
Growth of visceral tumors disrupts normal physiologic processes
secondary to compression and invasion of adjacent structures. Progression
of disease may be asymptomatic until a critical event manifests (e.g.,
obstruction of a hollow viscus). Under these conditions, the first symptom
a patient may experience is pain.13–15
Visceral pain is unique in quality of presentation when compared to pain
that arises from musculoskeletal structures of the body. Visceral pain is
usually vague in its presentation and may be confused by referral to a
variety of somatic locations secondary to viscerosomatic convergence.16
The phenomenon of viscerosomatic convergence refers to the diffuse
nature of visceral pain and its referral to superficial structures due to the
convergence of visceral and somatic afferents on the same dorsal horn
neurons and secondary hyperalgesia. Symptoms may seem out of
proportion to physical examination and imaging.17 Additionally, visceral
pain may be attributable both to the malignancy itself and to
chemotherapeutic and radiation therapies. Increased pain following
symptomatic relief may suggest the local recurrence of disease or a new
locus of disease requiring repeat evaluation of the patient.18
Some features of visceral nociception may offer a better understanding
of the experience of patients with visceral pain. Visceral pain is more
frequently accompanied by an autonomic response than is somatic pain or
pain from skin injury, unless the pain is referred visceral pain mimicking
somatic pain.16 There is a poor correlation between the extent of visceral
tissue damage and the severity of pain experienced. Visceral pain is poorly
localized because of poor representation within the primary somatosensory
cortex. The majority of visceral afferents are specific to motor or reflex
responses with few neural afferents that are specialized for pain
transmission. Those afferents that are specialized for pain are sparsely
distributed throughout the viscera; both high-threshold nociceptors and
low-threshold “silent” nociceptors are invoked in the pain experience.15

2404
 Studies have demonstrated multiple visceral pain mechanisms as well as
the mechanisms by which one class of visceral pain may relate to other
sources of malignant pain. There are four primary classes of visceral pain:
1. Mechanical: caused by stretch of visceral structures (bowel lumen or
hepatic capsule)
2. Ischemic: caused by tumor invasion or compression of visceral blood
supply
3. Inflammatory: humoral mediators of inflammation released
secondary to tumor infiltration of visceral structures
4. Neuropathic: compression or invasion of neural structures supplying
the viscera18
Surgery, chemotherapy, or radiation therapy of cancer can also be
responsible for iatrogenic damage of the viscera, associated visceral
structures, or nerves. Applying a stimulus that causes tissue damage (e.g.,
cutting, burning, or pinching) to skin or muscle reliably produces the
perception of pain, but these stimuli do not reliably evoke reports of pain
when applied to visceral structures. Pain secondary to distension of a
hollow viscous, such as in the case of bowel obstruction, does not
necessarily produce a similar perception when applied to surface
structures. In controlled studies, visceral pain can be consistently
demonstrated by mechanical distension of hollow organs using distending
fluids or balloon devices.19 These modalities of inducing pain most closely
reproduce the natural or pathophysiologic processes causing pain.
Mechanical distension can be specifically applied to a given organ
structure in isolation of other structures, mimicking processes involving
the gastrointestinal, biliary, and urinary tracts which may occur from
tumor obstruction (or adhesions) in these sites. Distension of organ
capsules, such as the splenic, renal, or hepatic capsule, has also been
demonstrated to produce profound pain. On the other hand, gentle or slow
but progressive distension or obstruction may not produce pain until a
critical point in which ischemia or rupture results. Torsion or stretch on
mesenteric structures or omentum may produce states of ischemia, infarct,
and inflammatory response producing reports of severe pain.20
Inflammatory processes in visceral structures may produce pain as a
result of ischemic response, but some tumors may produce inflammatory

2405
mediators with no inciting ischemic event. Both prostaglandin E2 and
serotonin have been demonstrated as independent chemical stimuli in the
production of pain as malignancy invades adjacent structures.21–23
Experimental studies have demonstrated that the application of
inflammatory chemical stimuli can evoke pain behaviors, yet specific
mechanical means of eliciting pain have been limited in their translation to
studies of other visceral structures.24
Ischemic pain has also been described as occurring secondary to
occlusion of visceral vasculature or by compression of visceral structures
by tumor growth. When tumor growth exceeds vascular supply, necrosis
may result, inducing a variety of inflammatory processes.23 Inflammatory
mediators, such as hydrogen ions, kinins, prostanoids, leukotrienes, or
other cytokines, are initiators of visceral pain. These chemical agents also
sensitize neurologic afferents of organ structures amplifying nociception
associated with mechanical stimuli. In general, healthy viscera are
typically insensate to pain, whereas superficial structures are continually
sensate.24 When diseased, however, visceral organs produce pain severe
enough to be incapacitating to other physical activity. Pain from surface
structures of the body evokes reflexive motion in the classic “fight or
flight” response, whereas the sensation of visceral pain discourages motion
or physical activity. Anecdotal evidence supports an association between
pain of visceral origin and emotional response and is commonly held to be
more anxiety-provoking than pain from somatic structures. Some argue
that this anxiety comes from a patient’s inability to visualize the cause of
the pain.25 Anxiety scales are reported higher in patients with visceral pain
ratings of 2 on a scale of 10 when compared to a higher rated pain
experience with visible cause on a superficial structure.26 Furthermore,
some symptomatology is more common in patients with visceral pain.
Perception of both nausea and dyspnea are more commonly associated
with pain of a visceral organ. An autonomic response to visceral pain is far
more common than to pain of superficial structures.27,28
Psychological processing of visceral pain is distinct from that related to
somatic pain. There are a low number of visceral nociceptors compared
with somatic nociceptors. There is a lack of specialization of visceral
afferents. Many visceral afferents are polymodal nociceptors. Viscera have

2406
unique ascending tracts through the dorsal column and poor representation
within the primary somatosensory cortex.29,30 Viscera have significant
input through the medial thalamus to the limbic cortex, amygdala, anterior
cingulate, and insular cortex, which influence the affective aspect of pain
perception.31 Viscera also have a close association with autonomic nerves.
The perception of visceral pain may be disproportionate to pathology
exhibited by physical examination or imaging. As an example, a small
nephrolith may offer some of the most severe pain states, whereas
extensive cancer metastasis may evoke little or no discomfort. Disorders
such as chronic pancreatitis demonstrate very little correlation between
laboratory studies and flares in pain perception. Disorders such as irritable
bowel syndrome and noncardiac chest pain syndrome appear to lack a
definitive histopathologic basis for the discomfort and pain.32,33
Many models exist for visceral pain including intraperitoneal injection
of a chemical, distension of hollow organs (cecum, colon, rectum),
distension of the gallbladder and associated biliary system, and distention
or chemical stimulation of the bladder and other urinary tract structures, as
well as distension, compression, or traction on reproductive organs.
However, lesions studied in one organ are limited in that they are specific
to a given stimulus and do not necessarily translate to application in other
visceral structures.34

SENSITIZATION
Sensitization occurring secondary to the repeated presentation of visceral
stimuli has been noted in human psychophysical studies as well as in
animal studies. Repeated presentation of the same visceral stimuli
produces increasing strength of response in neuronal, cardiovascular, and
visceromotor reflex responses. Inflammation of visceral structures
increases the magnitude of response to a given mechanical stimulus and
decreases the stimulation thresholds for the evocation of nociceptive
responses.35 Inflammation of visceral structures significantly modifies
behavioral, neuronal, autonomic, and motor responses to visceral
stimulation in experimental models. This model mirrors clinical
circumstances because inflammation in visceral structures frequently leads
to reports of pain.36

2407
 Painful conditions such as mucositis, esophagitis, gastritis, pancreatitis,
and colitis all exhibit mucosal inflammatory changes. The inflammatory
sensitization may take place at primary afferents. These afferents are
normally nonreactive to most stimuli and have been described as “silent”
in nonpathologic states. However, in the context of an inflammatory tissue
response, they become spontaneously active and highly reactive to
mechanical stimuli. Silent afferents may comprise 50% of the neuronal
sample in a visceral organ but are infrequently noted in superficial or
cutaneous structures. Lack of baseline sensitivity in normal viscera may be
secondary to sparsity of visceral afferentation. There are fewer afferents
per unit area than similar measures of cutaneous afferents. Because of this
sparse innervation, increased activity may be necessary to cross a
threshold for perception. Spinal neurons responsive to visceral stimuli also
change their responsiveness to visceral stimuli in the presence of
inflammation. The cause of this behavior is unknown, although voltage-
gated sensitization by the transient receptor potential vanilloid 1 (TRPV-1)
and tetrodotoxin-resistant (TTX-R) receptors may play a role.37,38
Increased afferent activity, altered intrinsic properties of dorsal horn
neurons, and altered modulatory influences or some combination may all
serve a role in the process. Dorsal column pathways have been
demonstrated to play a role in visceral nociception but not in cutaneous
nociception. The results of multiple studies suggest that visceral pain
requires a sensitization process both in the periphery and the spinal cord.39

LOCALIZATION
Visceral pain is classically thought of as deep and diffuse in presentation.
Localization of the pain generator can be difficult to identify by physical
examination. Superficial pain, in contrast, can be elicited by examination
with precise localization and with consideration to the site of the body
examined; pain locus can be identified within millimeters. Moreover,
surface pain loci reliably localize to the same site, never migrating to other
body areas, in the absence of neural injury.
Visceral pain is characterized as migratory in its presentation, often
perceived in several loci simultaneously or migrating regionally in spite of
localization of pathology. This is evident in the presentation of

2408
appendicitis. Furthermore, the perception of pain associated with visceral
pathology is not normally localized to the organ itself but to somatic
structures that receive afferent inputs at the same spinal segments as the
visceral afferent entry. For this reason, visceral pain is classically
described as either unlocalized pain or as referred pain that may have two
separate features. Sensation of the diseased viscera is transferred to a
surface site (e.g., an ischemic myocardium can be felt in neck and arms) or
additional sites may become hypersensitive to inputs applied directly to
those other sites (e.g., flank muscle becomes sensitive to palpation with
urolithiasis). This latter phenomenon is referred to as secondary somatic
hyperalgesia.
Psychophysical studies of internal organ sensation have focused on a
given organ using simple stimuli, correlating the given stimuli to a given
organ with perception at the respective site of stimulus. Other
psychophysical studies using visceral stimuli have examined the referred
sensations described by subjects. These studies have often failed to
contrast referred pain to a body surface with cutaneous sensations at the
same surface. Patient illustrations of referred sensations tend to extend
over large surface areas, whereas studies using cutaneous stimuli generate
pinpoint localization to highly precise sites.
The phenomenon of secondary somatic hyperalgesia produced by
visceral pathology has been compared to sites of sensitivity with lesions
produced by herpes zoster. These initial studies were fundamental to the
development of dermatomal mapping. In visceral disease processes,
multiple dermatomes have been identified suggesting that secondary
somatic hyperalgesia is widely distributed (i.e., poorly localized).
Recent psychophysical studies have attempted to compare visceral with
nonvisceral pain. In one study, the sensation produced with balloon
distension of the esophagus was compared to thermal stimulation of the
mid-chest skin. Subjects perceived larger areas of sensation for esophageal
distension than for intensity-matched, heat-evoked sensation on body
maps. Temporally, there was also a difference. A rapid response was noted
with heat stimulus, whereas there was poor correlation with the esophageal
stimulus and the perception of the sensation. Intense visceral discomfort
remained after discontinuation of the distending apparatus but not after

2409
discontinuation of the cutaneous stimulation. Visceral sensation was
concluded to be diffuse both spatially and temporally. Corollary
observation of cerebral blood flow identified that similar cerebral areas
were activated by both stimuli.
When evaluating the patient in visceral pain with malignancy, the early
presentation may be misleading with vague midline discomfort. It may be
poorly localized and accompanied by both an emotional response and
autonomic event. Later in the evolution of disease process, patients may
complain of somatic or referred pain hypersensitivity at the spinal level of
the visceral nociceptor terminus. Referred pain is sharp and localized. It is
often associated with allodynia and muscle spasm. Furthermore, visceral
hypersensitivity may induce the perception of pain in another organ
receiving innervation from the same spinal segment.

VISCERAL AFFERENTATION
Visceral primary afferents differ significantly from cutaneous primary
afferents in both number and pattern of distribution. Visceral sensory
pathways are organized into nerve fascicles and cell body groupings
extending from prevertebral regions to contact viscera predominately via
perivascular pathways. Cell bodies of visceral primary afferent nerve
fibers are located in the visceral dorsal root ganglia of the thoracic and
upper lumbar spine, but the peripheral axons of these neurons follow a
circuitous path to visceral organs passing via the paravertebral sympathetic
chain and ganglia as well as nerve fascicles that are termed the cardiac and
splanchnic nerves. The splanchnic nerves are divided into the greater,
lesser, least, thoracic, and lumbar divisions. The pelvic nerves arise from
dorsal root ganglia at sacral levels, accepting sympathetic chain input
before innervating urogenital structures.
Visceral sensory processing also differs from cutaneous sensory
processing because visceral neuronal synapses exist at cell bodies of
prevertebral ganglia such as the celiac ganglion, superior mesenteric
ganglion, and pelvic ganglion, producing changes in local visceral function
outside central control. The gastrointestinal tract is also supplied by an
independent enteric nervous system relating to functions of digestion and
absorption. In the pelvis, structures receive dual innervation with afferents

2410
from lower thoracic to upper lumbar segments and from sacral segments.
Testicle and ovary embryologically originate in the superior aspect of the
abdomen and, therefore, receive thoracic innervation. The urinary bladder
has a similar thoracolumbar innervation with sensory inputs extending up
to the T10 level but also receives sacral inputs (the pelvic nerve) with
other tissues originating from sacral dermatomes (rectum, genital
structures).
Pelvic organs also receive efferent and afferent connections from the
vagus nerve and local ganglionic circuitry, resulting in a complex and
diffuse neuroanatomy. Afferents with endings in a focal visceral site may
have cell bodies in the dorsal root ganglia of 10 or more spinal levels in a
bilaterally distributed fashion. In contrast, cutaneous afferents from a
particular body surface arise from only 3 to 5 unilaterally located dorsal
root ganglia.
Visceral receptors are located in mucosa, serosa, and muscle of hollow
organs as well as visceral mesentery. They are not reported in parenchyma
of solid organs. The specialized receptors that discriminate a variety of
stimuli in somatic structures are absent in viscera. The mesentery,
however, does contain Pacinian corpuscles. Hollow organs contain
specialized low-threshold and high-threshold mechanoreceptors. Low-
threshold receptors serve a basic regulatory function, whereas high-
threshold receptors are activated only with noxious mechanical stimuli.
Visceral nociception results from summation of nociceptive input to
regulatory low-threshold receptors and noxious high-threshold and silent
nociceptors rather than activation of stimulus-specific nociceptors.40

ASCENDING PATHWAYS
Visceral afferent fiber activation causes an increase in nitric oxide
synthase in the dorsal horn of the spinal cord, causing expression of the
oncogene c-Fos in laminae I, V, VII, X of the dorsal horn within the
thoracolumbar spine. Similar upregulation is seen in the amygdala and
paraventricular hypothalamic nuclei and consequent elevation in
norepinephrine production within the locus ceruleus.
Features of visceral pain processing differing from somatic processing
include dorsal column ascending secondary sensory afferents, the spinal

2411
trigeminal to parabrachioamygdaloid tract, and the spinohypothalamic
pathway. In the visceral system, both ventrolateral and dorsal column
postsynaptic neurons have a role in nociception. Ascending tracts synapse
at the lateral thalamus first, then limbic centers, and then somatosensory
cortex. Whereas somatic nociception is represented somatotopically within
the primary somatosensory cortex, visceral pain is represented in the
secondary somatosensory cortex and poorly represented within the primary
somatosensory cortex. Visceral pain is well represented in the limbic
system, including anterior cingulate gyrus, insular cortex, and amygdala,
suggesting a basis for the strong emotional component of visceral pain.
Whereas visceral pain elicits decreased patient activity, nausea, and
hypotension, somatic pain elicits agitation, reactive activity, and
hypertension. Nociceptive activity within the gastrointestinal tract induces
inhibition of dorsal motor neurons of the vagus within the medulla leading
to gastroparesis and nausea.

Visceral Pain Syndromes

Although most pain associated with malignancy is diffuse and chronic,
most acute pain syndromes in cancer are secondary to diagnostic or
therapeutic interventions. Some tumors generate an acute onset of pain,
which may be the result of a perforation of a hollow viscus or rupture of a
visceral capsule. Any sudden onset of pain warrants a comprehensive pain
assessment. Following is a list of possible pain syndromes that may be
encountered by the health care provider.

ORAL MUCOSA
Paraneoplastic Pemphigus
Paraneoplastic pemphigus is a mucocutaneous disorder accompanying
non-Hodgkin lymphoma and chronic lymphocytic leukemia. It is
characterized by widespread shallow ulcers, hemorrhagic crusting of the
lips, conjunctival bullae, and may be accompanied by pulmonary lesions,
occurring secondary to autoantibodies directed against desmoplakins and
desmogleins.41

2412
Oropharyngeal Mucositis and Stomatitis
Mucositis and stomatitis should be distinguished as two separate processes
(also see Chapter 45). Oral mucositis is an inflammation of oral mucosa
resulting from chemotherapeutic agents or ionizing radiation, manifesting
as erythema or ulcerations. Stomatitis is any inflammatory condition of
oral tissue, including mucosa, dentition, periapices, and periodontium,
including inflammation secondary to infection of oral tissues. Mucositis
appears 7 to 10 days after initiation of high-dose cancer therapy and is
generally self-limited when uncomplicated by infection, resolving 2 to 4
weeks after completion of chemotherapy. In order to standardize
assessment, a variety of scales have been created to grade the level of
stomatitis by characterizing alterations in lips, tongue, mucous
membranes, gingiva, teeth, pharynx, quality of saliva, and voice. The
clinical syndrome usually involves the oropharynx but may involve other
gastrointestinal mucosal surfaces such as the esophagus, stomach, or
intestine, producing such symptoms as odynophagia, dyspepsia, or
diarrhea. Any mucosal damage may become superinfected with
microorganisms, most commonly Candida albicans and herpes simplex.42
Radiotherapy may also induce mucositis. Doses of radiation in excess of
4,000 cGy frequently cause ulceration with pain lasting several weeks
following treatment.43 Acute pain associated with radiotherapy can be
caused by acute radiation toxicity causing inflammation and ulceration of
skin or mucous membranes. The syndrome produced is dependent on the
exposed field.44,45

MEDIASTINUM
5-Fluorouracil-Induced Anginal Chest Pain
In patients receiving 5-fluorouracil (5-FU) infusions, ischemic chest pain
may develop. Painful events are more common in patients with a history of
coronary artery disease and are likely secondary to coronary vasospasm.

Pleura
Lung tumors, with or without chest wall involvement, may produce
visceral pain. In a large case series of patients with lung malignancies, pain
was found to be unilateral in 80% of patients and bilateral in 20% of

2413
patients. Patients with hilar tumors reported sternal or scapular pain.
Patients with tumors involving the upper and lower lobe experienced
referral of pain into the shoulder and lower chest, respectively.46,47
Additionally, some lung malignancies generate ipsilateral facial pain,
thought to be secondary to noxious stimulation of vagal afferent
neurons.48–51

Pancoast Syndrome
Pancoast syndrome is caused by malignant neoplasms of the superior
sulcus of the lung with destructive lesions of the thoracic inlet and
involvement of the brachial plexus and cervical sympathetic nerves
(stellate ganglion).52,53 Patients report severe pain in the shoulder region
radiating toward the axilla and scapula along the ulnar aspect of the
muscles of the hand, and patients may also develop atrophy of hand and
arm muscles, Horner syndrome (ptosis, miosis, hemianhidrosis,
enophthalmos), and compression of the blood vessels with edema.54
Ninety-five percent of patients have either squamous cell or
adenocarcinomas. Small cell carcinoma is found in fewer than 5% of cases
in most series. Along with these symptoms and signs, additional predictors
of poor prognosis are weight loss, supraclavicular fossa or vertebral body
involvement, disease stage, and surgical treatment.55,56
These bronchopulmonary tumors may invade the bony structures of the
chest. The first or second thoracic vertebra or the first, second, or third ribs
may be invaded. One review has described rib erosion in 50% of patients.
The tumor may invade the first or second thoracic vertebral bodies or
intervertebral foramina, extending to the spinal cord, and resulting in cord
compression. The subclavian vein or artery may also be invaded.
Advanced tumors may involve the recurrent laryngeal nerve, phrenic
nerve, or superior vena cava (SVC).

PANCREAS
Midline Retroperitoneal Syndrome
The most common cancer-related causes of upper abdominal
retroperitoneal pain are pancreatic cancer and retroperitoneal
lymphadenopathy, particularly celiac lymphadenopathy. These disease

2414
processes elicit afferent activity via injury to deep somatic structures of the
posterior abdominal wall, distortion of pain-sensitive connective tissue,
vascular and ductal structures, as well as local inflammation and direct
infiltration of the celiac plexus. Patients report pain in the epigastrium, in
the low thoracic region of the back, or both. Pain is described as diffuse
and dull, exacerbated with recumbency, and improved by sitting forward.
Computed tomography (CT), magnetic resonance imaging, or ultrasound
scanning of the abdomen may reveal the disease process.

Pancreatic Cancer
Patients with pain secondary to unresectable pancreatic cancer report
severe abdominal pain radiating into the back. This pain is often refractory
to analgesics, even strong opioids. Pain may be accompanied by
obstructive jaundice (yellowing of the skin and eyes, itching, dark urine,
clay-colored stool) and occurs more frequently when the cancer is located
at the head of the pancreas. Other associated symptoms may include
weight loss, anorexia, fatigue, and a change in bowel habits (constipation
or diarrhea). Controlled trials support the use of neurolytic celiac plexus
block with superior results in terms of pain relief over analgesics alone
(see Chapter 44 and discussion of celiac plexus block in the following
discussion).57

LIVER PAIN
Hepatic Distension Syndrome
The liver has many nociceptive structures including the liver capsule,
blood vessels, and biliary tract. Afferents from these structures travel via
the celiac plexus, the phrenic nerve, and the lower right intercostal nerves.
Hepatic metastasis typically causes pain when the tumor stretches the
capsule. Patients with intrahepatic metastases or hepatomegaly secondary
to cholestasis may report discomfort in the right subcostal region or right
midback or flank.58 Patients may experience referred pain to the right
neck, shoulder, or scapula.59 Patients describe the pain as a dull ache
exacerbated by movement, pressure in the abdomen, and deep inspiration.
Associated symptoms include anorexia and nausea. Physical examination
reveals a hard, irregular subcostal mass, which is dull to percussion, and

2415
descends with inspiration. Diagnostic ultrasound or CT may reveal a
space-occupying lesion.
Analgesics are the first line of therapy for pain control with drug
selection and titration a function of the extent of hepatic compromise.
Corticosteroids reduce hepatic edema and liver pain. If a tumor is
chemosensitive, chemotherapy may be the treatment of choice. Hormone
therapy may decrease hepatomegaly from liver metastasis but may take
several months to accomplish a goal of pain relief. As with pancreatic
cancer, celiac plexus block may provide definitive relief. Two randomized
controlled trials (RCTs) have demonstrated hepatic irradiation to be
effective in palliation of hepatic pain in 80% of patients with a reduction
of systemic symptoms in half as many patients.60

INTESTINAL PAIN
Chronic Intestinal Obstruction
In patients with abdominal or pelvic cancers, intestinal obstruction causes
diffuse abdominal pain. Pain may be secondary to smooth muscle
contraction, mesenteric tension, and ischemia of the bowel wall.
Obstruction may be due to tumor, autonomic neuropathy, ileus, metabolic
abnormality, or medication. Pain may be continuous or intermittent
(colicky) and may be associated with vomiting, anorexia, and constipation.

Peritoneal Carcinomatosis
The peritoneal cavity, enclosed by visceral and parietal peritoneum, is the
largest potential space in the body. Any pathologic process involving the
peritoneal cavity can easily disseminate throughout this space by means of
unrestricted movement of fluid and cells. Primary malignant diseases
arising from the peritoneal cavity include malignant mesothelioma, cystic
mesothelioma, and primary peritoneal carcinoma. Carcinomatosis can
cause peritoneal inflammation, mesenteric tethering, and malignant
adhesions and ascites, all of which can trigger nociceptive activity.
Patients most commonly report abdominal pain and distension. Mesenteric
tethering and tension appear to cause a diffuse abdominal or low back
pain. Tense malignant ascites can produce diffuse abdominal discomfort
and a distinct stretching pain in the anterior abdominal wall. Adhesions

2416
can also cause obstruction of a hollow viscus, with intermittent colicky
pain.61 CT scanning may demonstrate evidence of ascites, omental
infiltration, and peritoneal nodules.

Radiation Enteritis
Acute radiation enteritis may develop in as many as 50% of patients
receiving pelvic or abdominal radiotherapy. Patients with small intestinal
involvement complain of cramping abdominal pain and have associated
nausea and diarrhea. Patients receiving pelvic radiotherapy may develop
proctocolitis, associated with pain, tenesmus, diarrhea, mucous discharge,
and bleeding. These symptoms may resolve shortly after completion of
therapy or may last as long as 6 months.

Intraperitoneal Chemotherapy Pain

Approximately 25% of patients receiving intraperitoneal chemotherapy
may develop transient mild to moderate abdominal pain and complain of
fullness or bloating.62 A second group of patients (approximately 25%)
may experience pain severe enough to require opioid analgesia or
discontinuation of therapy. Pain is secondary to chemical serositis or
infection. Infectious peritonitis is accompanied by fever and leukocytosis
in blood and peritoneal fluid.

PELVIC PAIN
Malignancy-related pelvic pain not due to bone metastases is most often
secondary to presacral recurrence of rectal carcinoma or secondary to
pelvic recurrence of cervical cancer. Lumbosacral plexus infiltration is
common, resulting in severe pain with a significant neuropathic
contribution. Analgesics or interventional therapies should be implemented
according to protocols and guidelines (see Chapter 43).

Malignant Perineal Pain

Perineal pain may be secondary to tumors of the colon or rectum, female
reproductive tract, and distal genitourinary system. A report of perineal
pain following therapeutic resolution of malignancy may be a precursor of
recurrence and should prompt complete evaluation.63 Pain preceding

2417
evidence of disease may be secondary to microscopic perineural invasion
of an insidious malignant process. Patients report pain to be constant and
aching, exacerbated with sitting or standing. Associated symptoms may
include tenesmus or bladder spasm.64 If tumor invades musculature of the
pelvis, patients may complain of a constant aching in the pelvis, which is
exacerbated with standing. Examination of the pelvic floor may
demonstrate tumor.

Ureteral Obstruction
Patients with tumor involving the pelvis may have pain due to tumor
compression or infiltration of the distal ureter.10 Obstruction of the
proximal ureter is less common and is associated with retroperitoneal
lymphadenopathy, an isolated retroperitoneal metastasis, mural metastases,
or intraluminal metastases. Cancers of the cervix, ovary, prostate, and
rectum are most commonly associated with this complication. Other rare
causes of ureteral obstruction include retroperitoneal fibrosis resulting
from radiotherapy or graft-versus-host disease. Pain is described as dull,
chronic discomfort in the flank often with associated radiation into the
inguinal region or genitalia.10 However, patients may have obstruction
without evidence of pain.

Ovarian Cancer Pain

Patients experiencing severe chronic abdominal or pelvic pain may be
experiencing the harbinger of ovarian cancer. It is the most common
presenting symptom and most common symptom of recurrence.10 Two-
thirds of patients experience pain in the 2 weeks prior to the onset or
recurrence of the disease. In patients who have been previously treated, it
is an important symptom of potential recurrence.10

Tumor-Related Gynecomastia
In patients complaining of breast pain or tenderness, there is a risk of
occult tumor of the testes or lung. Human chorionic gonadotrophin
(HCG)-secreting tumors of testis, including malignant and benign types as
well as other HCG-secreting tumors, may produce breast tenderness or
gynecomastia.65 Approximately 10% of patients diagnosed with testicular

2418
cancer complain of gynecomastia or breast tenderness.66

Intravesical Chemotherapy or Immunotherapy

Patients receiving intravesical Bacillus Calmette-Guérin (BCG) therapy
for urinary bladder transitional cell carcinoma experience a syndrome of
bladder irritability. Patients report urinary frequency and painful
micturition. In rare cases, patients receiving BCG therapy may develop a
painful polyarthritis.67 Other intravesical chemotherapies, such as
doxorubicin, may also cause a painful chemical cystitis.68

Corticosteroid-Induced Perineal Discomfort

In patients receiving high-dose corticosteroid therapy, some may report an
uncomfortable sensation of burning perineal pain.69

ADRENAL PAIN SYNDROME

Patients with adrenal metastases of considerable size, common in lung
cancer, may develop unilateral flank pain or abdominal pain. Patients
report pain from this condition as highly variable, describing it as dull and
aching to severe in presentation.70

Vascular Obstruction
Hypercoagulability with thrombosis is the most frequent complication
associated with malignancy and the second most frequent cause of
mortality in malignant disease. A thrombotic event may occur in advance
of the diagnosis of cancer by months or years; therefore, thrombosis
should be considered as a marker for occult malignancy. Chemotherapy
and hormone therapy are associated with an increased thrombotic risk.
Additionally, deep vein thrombosis (DVT) is a more common
postoperative complication in patients with malignancies than in other
postoperative populations.
Hypercoagulability in malignancy is secondary to tumor cell expression
of tissue factor and cancer procoagulant. Apoptosis of malignant cells or
penumbra of nonmalignant cells affected by invading malignant tissue
activates normally dormant tissue factor, initiating a coagulation cascade
and formation of thrombus. Tumor proliferation, chemotherapy, hormonal

2419
therapy, radiation therapy, and hematopoietic growth factors all increase
apoptotic activity and increase the risk of thrombus. Factors contributing
to the formation of thrombus include cytokine release, acute phase
reaction, and neovascularization. Tumors associated with higher risk of
hypercoagulability include tumors of the pelvis, pancreas, stomach, breast,
and brain.

Venous Thrombosis
Patients with DVT most often present with pain and swelling of the lower
extremity. Patients often report that pain is mild, dull and crampy, or a
diffuse perception of pressure or heaviness. The calf is most often
involved, but the sole of the foot, heel, thigh, groin, or pelvis may be the
site of thrombus and pain. Exacerbating factors include standing or
walking. Physical examination may reveal signs of DVT, including
swelling, warmth, dilation of superficial veins, tenderness along venous
tracts, and pain with stretching of the affected limb. Rarely, a patient may
present with ischemia of the lower extremity or in worse cases, a
gangrenous limb. This presentation may occur in the absence of arterial or
capillary occlusion (phlegmasia cerulea dolens). Signs include severe pain,
extensive edema, and cyanosis of the affected leg. Mortality varies but
may be as high as 40% secondary to ischemia of the affected extremity or
progression of thrombus to cause pulmonary emboli.
Only 2% of DVT cases involve the upper extremity with a low rate of
associated pulmonary embolism. On physical examination, upper
extremity DVT most often presents with edema, dilated collateral
circulation, and pain.69 In patients with malignancy, central venous
catheterization is the most frequent cause along with extrinsic compression
by tumor.71,72

Superior Vena Cava Obstruction

For patients with lung cancer and lymphoma, SVC obstruction develops
with extrinsic compression of the SVC by tumor expansion or by enlarged
mediastinal lymph nodes.71 Intravascular catheters are an iatrogenic cause,
especially with left-sided ports where the catheter tip rests in the upper
portion of the vessel.73 Physical examination reveals facial swelling,

2420
dilated neck veins, and dilated chest wall veins. Less common patient
reports of symptoms associated with SVC obstruction include chest pain,
headache, and mastalgia.74

Acute Mesenteric Vein Thrombosis

Acute thrombosis of the mesenteric veins is most commonly associated
with hypercoagulability secondary to malignancy and more rarely
secondary to venous compression by lymphadenopathy, extension of
venous thrombosis, or iatrogenic hypercoagulable states.

PAIN SYNDROMES RELATED TO INTRAVENOUS

CHEMOTHERAPEUTIC AGENTS
Chemotherapeutic agents may cause vascular pain secondary to venous
spasm, chemical phlebitis, vesicant extravasation, and anthracycline-
associated flare. Venospasm pain is not secondary to inflammation or
phlebitis. Attenuation of symptoms may come from application of a warm
compress or reduction of chemotherapeutic infusion rate.
Agents causing chemical phlebitis include amsacrine, dacarbazine,
carmustine and vinorelbine, potassium chloride, and hyperosmolar
solutions. The pain and erythema associated with chemical phlebitis
should be monitored closely because it shares many of the early features of
vesicant cytotoxic extravasation that in later stages presents as
desquamation and ulceration of cutaneous structures. Venous flare reaction
is often associated with the use of anthracycline or doxorubicin and
presents with local urticaria, pain, or stinging.

Hepatic Artery Infusion Pain

Patients receiving cytotoxic infusions directly into the hepatic artery often
report diffuse abdominal pain.73 Pain is attributed to gastric ulceration,
gastric erosion, or cholangitis. With no persistence of complications,
resolution of pain occurs with completion of therapy.

COMPLEX VISCERAL PAIN SYNDROMES

Nontraumatic rupture of a visceral tumor may cause sudden, severe
abdominal or pelvic pain and is most commonly associated with

2421
hepatocellular carcinoma.75 Metastases from other tumors also cause
visceral ruptures (e.g., kidney rupture from a metastasis from
adenocarcinoma of the colon or metastasis-induced perforated
appendicitis).76,77 Torsion of pedunculated visceral tumors may cause
cramping abdominal pain.78

POSTRADIATION VISCERAL PAIN

Postradiation therapy pain syndromes often involve both somatic and
visceral structures, regardless of the target organ. Late effects, including
connective tissue fibrosis, neural damage, and secondary malignancies,
can occur long after completion of radiotherapy. A recent large
retrospective cohort study revealed an association between previous pelvic
radiation and hip fractures, with an increase in lifetime fracture rate from
17% (control) to 27% (radiation group). Pelvic pain after radiotherapy may
be due to pelvic insufficiency fracture, enteritis, visceral dysfunction, or
neural damage. Chronic pelvic pain has been reported as a consequence of
prostate brachytherapy. Twenty percent of patients receiving
brachytherapy have been reported to complain of dysuria 1 year after
treatment.

Radiation Enteritis and Proctitis

In 2% to 10% of patients receiving pelvic or abdominal radiation therapy,
chronic enteritis and proctocolitis may occur.79 The rectum and distal
colon are more frequently sites of involvement. Onset may be as early as 3
months or as late as 30 years.80 Presentations may include proctitis
(bloody diarrhea, tenesmus, and cramping pain), obstruction due to
stricture formation, or fistulae to the bladder or vagina.10 Small bowel
radiation damage typically causes colicky abdominal pain, which can be
associated with chronic nausea or malabsorption. Barium studies may
demonstrate a narrow tubular bowel segment resembling Crohn’s disease
or ischemic colitis. Endoscopy and biopsy may be needed to identify
recurrent cancer.

Burning Perineum Syndrome

Perineal discomfort may develop 6 to 18 months following pelvic

2422
radiotherapy. Patients complain of burning pain in the perianal region and
may involve the vagina or scrotum. For those patients with
postabdominoperineal resection, phantom anus pain and recurrent tumor
should be considered.

Radiation Cystitis
Radiation therapy used in the treatment of tumors of the pelvic organs
(prostate, bladder, colon/rectum, uterus, ovary, and vagina/vulva) may
produce chronic radiation cystitis.10 Symptoms of radiation injury to the
bladder may be as minor as temporary irritation with voiding or
asymptomatic hematuria, or as severe as gross hematuria, a contracted
nonfunctional bladder, persistent incontinence, and fistula formation.
Other signs and symptoms may include frequency, urgency, dysuria,
hematuria, incontinence, hydronephrosis, pneumaturia, and fecaluria.10

POSTCHEMOTHERAPY VISCERAL PAIN

Painful peripheral neuropathy is frequently a dose-limiting side effect of
some chemotherapeutic regimens. Once the therapy is stopped, the
neuropathic pain will resolve with or without symptomatic treatment.
However, in a small number of patients, the neuropathy does not resolve
and may continue to be intensely painful. Prevalence during treatment
varies from agent to agent, with the intensity of treatment (dose intensity
and cumulative dose), with other concurrent therapies such as surgery and
radiotherapy, and with the use of combination chemotherapy. Estimates of
prevalence range from 4% to 76% during chemotherapy treatment.

Treatment
In general, treatment for cancer-related visceral pain syndromes should
adhere to standard cancer pain treatment guidelines (e.g., World Health
Organization (WHO) Analgesic Ladder; American Pain Society
Guidelines). The reader is referred to Chapters 43, 44, and 48 for details of
various pharmacotherapeutic, radiotherapeutic, and interventional
treatment modalities. Therapies that target visceral pain mechanisms with
some specificity that are not covered in detail in other chapters are

2423
elaborated in the following discussion.

N-METHYL-D-ASPARTATE RECEPTOR
ANTAGONISTS
Ketamine, which blocks N-methyl-D-aspartate (NMDA) receptors, can
influence visceral hypersensitivity. Primary visceral hypersensitivity is
attributed to a reduction in peripheral nociceptive thresholds. Two central
processes mediate secondary visceral hypersensitivity: (1) plasticity of
activated C fibers and (2) convergence of afferents at multiple levels and
maintained by glutamate release that binds to NMDA receptors. NMDA
receptor activation results in nitric oxide synthase expression, nitric oxide
production, and prostaglandin production.
Through these mechanisms (and perhaps others), ketamine has been
found to be useful in the management of pain states that are either poorly
responsive to opioids and other analgesics or when there are dose-limiting
adverse effects to other pain treatments. Ketamine use has been described,
with variable success, in adults, pediatric patients, via intrathecal,
parenteral, and oral routes, and in inpatient as well as outpatient
settings.81–90

CORTICOSTEROIDS
Dexamethasone inhibits neuronal nitric oxide synthase gene expression. It
has been effective in treating visceral pain and bowel obstruction.91

GABAPENTIN
Gabapentin has been demonstrated to reduce glutamate levels and reduces
hypersensitivity associated with celiac pain.92

SHORT INTERFERING RNA THERAPEUTICS

The discovery that short double-stranded RNA molecules can be used to
induce RNA interference (RNAi) in mammalian systems has opened up
several possible new avenues in treatment of pain. Gene silencing by small
interfering RNAs (siRNAs) has been demonstrated in neurons, and several
targets involved in pain perception have been identified can be modulated
by these siRNAs. In the past decade, hundreds of molecular targets have

2424
been identified for their roles in pain modulation, but most molecular
targets are not readily amenable to drugs with small molecules. In the past
years, RNAi has become the most widely used technology to suppress
gene expression. Effective delivery of nucleic acid-based therapeutic
molecules to the central nervous system remains a limiting step for RNAi,
and currently, transfection agents are being used via the intrathecal route to
deliver siRNA into spinal cord cells as well as dorsal root ganglion cells
and hence act on many possible targets for gene expression and
modulation including nerves and spinal cord regions affected by cancer
pain.93–95

T-TYPE CALCIUM CHANNEL ANTAGONISTS

T-type calcium channels are expressed in many diverse tissues, including
neuronal, cardiovascular, and endocrine. T-type calcium channels are
known to play roles in the development, maintenance, and repair of these
tissues but have also been implicated in disease when not properly
regulated. T-type calcium channels found on peripheral and central
endings of primary afferent neurons are involved in nociception. Voltage-
gated calcium channels can be divided into two groups: high-voltage
activated calcium channels (L, N, P/Q, and R types) and low-voltage
activated calcium channels (T types).96 Li et al.97 showed that paclitaxel-
induced neuropathy causes hyperexcitability in dorsal root ganglion
neurons that is paralleled by increased expression of low voltage–activated
calcium channels or namely the T-type channels. Hence, there was great
excitement that antagonism of these channels could be of great promise in
the treatment of neuropathic pain. Additionally, Le Blanc et al.98 proved
that these T-type calcium channel blocker (CCB) antagonists restore
synchrony in thalamic burst firing and possibly alter the affective pathway
of pain.
Preclinical studies with ABT-639, a peripherally acting highly selective
T-type Cav3.2 CCB, showed dose-dependent reduction of pain in multiple
pain models including arthritic, neuropathic, cancer- and capsaicin-
induced pain. However, the initial study results are still to be validated
through repeat studies. Wallace et al.99 compared the pharmacodynamic
effects of a single 100-mg dose of ABT-639, a peripherally active,

2425
selective T-type Cav3.2 channel blocker, with pregabalin. They used an
intradermal capsaicin model to assess drug efficacy and demonstrated that
a single 100-mg dose of ABT-639 had no effect on experimental pain
induced by intradermal capsaicin injection. Hence, the jury remains out on
T-type calcium channel antagonists.

AMPA/KAINATE ANTAGONISTS
Glutamate activates three subtypes of ligand-gated ion channel: the
NMDA, (S)-2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl) propionic acid
(AMPA), and kainate receptors. Animal studies suggest that AMPA and
kainate receptors are involved in epilepsy, pain, and psychiatric disorders.
Kainic acid activates nociceptors, and consequently, kainate receptor
antagonists have a potential as analgesics. Receptors for AMPA (GluR1-4)
are found throughout all superficial laminae of the dorsal horn pre- and
postsynaptically. AMPA agonists augment responses of spinal neurons to
noxious and nonnoxious stimuli. Kainate receptors (Glu 5-7; KA2) are
expressed diffusely in the dorsal horn, mostly in lamina.100,101
Gormsen et al.102 investigated the efficacy of NS1209, a test AMPA
receptor antagonist and lidocaine in nerve injury pain. In a three-way RCT
involving 13 patients comparing lidocaine, NS1209, and placebo, the
authors found that like lidocaine, NS1209 was superior to placebo in
alleviating some key symptoms of neuropathic pain (i.e., evoked types of
pain, including mechanical and cold allodynia but not superior in
alleviating spontaneous current pain). Possibly, more work is needed to
delineate the disease mechanisms influenced by AMPA/kainate receptors
before antagonists can be developed for the treatment of pain.

P38 KINASE INHIBITORS

p38 mitogen-activated protein kinases (MAPK) are serine/threonine
protein kinases involved in the regulation and synthesis of inflammatory
mediators and show great potential for the development of cytokine-
targeted anti-inflammatory drugs. p38 inhibitors have been shown in
preclinical models to decrease neuropathic pain, particularly where there is
a substantial inflammatory component.103
In a randomized control trial involving 43 patients with carpal tunnel

2426
syndrome, radiculopathy or other causes of nerve trauma, Anand et al.104
demonstrated lower pain scores with acceptable side effects for the new
drug dilmapimod. However, other clinical trials of these medications have
found prolongation of QT intervals by these agents and have largely been
unsuccessful. Further studies require results to be ratified for use in cancer
neurogenic pain.

CHEMOKINE RECEPTOR TYPE 2 ANTAGONISTS

Chemokine receptor type 2 (CCR2) is a chemokine receptor that mediates
monocyte chemotaxis and hence is thought to play a crucial role in
inflammatory and neuropathic pain states. Abbadie et al.105 proved that
mice with chronic pain showed activated CCR2-positive microglia in the
spinal cord. They suggested that the recruitment and activation of
macrophages and microglia peripherally and in neural tissue may
contribute to both inflammatory and neuropathic pain states. Accordingly,
blockade of the CCR2 receptor may provide a novel therapeutic modality
for the treatment of chronic pain.
However, many trials including a recent one by AstraZeneca have
failed. Newer emerging evidence suggests that alternate applications for
CCR2 antagonists are possible. It has been shown that spinal CCR2 is
upregulated in several neuropathic pain models and expressed by neuronal
and glial cells in the spinal cord. Hu et al.106 investigated the expression
changes and cellular localization of spinal CCR2 in a rat model of bone
cancer induced by Walker 256 cell inoculation. The results indicated that
mechanical allodynia progressively increased in bone cancer pain rats with
increased CCR2 expressed by both microglia and neurons in the spinal
cord. These results suggest that CCR2 may be involved in the development
of cancer pain, and that targeting CCR2 may be a new strategy for the
treatment of cancer pain.

P2X PURINOCEPTOR 3 ANTAGONISTS

P2X purinoceptor 3 (P2X3) receptor subunits are expressed prominently
and relatively selectively in so-called C- and Aδ-fiber primary afferent
neurons in most tissues and organ systems, including skin, joints, and
hollow organs, suggesting a high degree of specificity to the pain sensing

2427
system in the human body. P2X3 antagonists block the activation of these
fibers by adenosine triphosphate (ATP) and reduce ATP sensitization of
peripheral pain neurons. In addition, P2X3 is expressed presynaptically at
the central terminals of C-fiber afferent neurons, where upregulation and
sensitization of pain signals by ATP occurs. This is also potentially
blocked by P2X3 receptor antagonists. Another exciting prospect offered
by these agents is the potential of decreased side effects due to the
selective expression of P2X3, with a lesser risk of affecting the
gastrointestinal and renal systems that remain limiting factors for many
other existing medications.107 Gilchrist et al.108 also suggested in their
murine model study that there is increased expression of P2X3 receptors in
tumor growth in rats with hence increased potential for ATP activation and
bone cancer pain. This study opens avenues for possible use of P2X3
antagonists in bone cancer pain.
Newer research has suggested that a potentially significant pathway for
the transmission of cancer visceral pain would be the highly specific
postsynaptic dorsal column, which have been shown to express neurokinin
receptors (neurokinin-1 [NK-1]) in the event of visceral stimulation that
help propagate cancer visceral pain. Surgical lesioning of the dorsal
column is potentially difficult, and hence, pharmacologic lesion of the
pathway may be an alternate choice. Evidence has shown that spinal dorsal
column neurons start to express NK-1 receptors after visceral stimulation,
suggesting new targets for the development of pharmacologic strategies
for the control of visceral pain. Wang et al.109 suggested that targeted
cytoxin composed of substance P coupled to the cytotoxic ribosome
inactivating protein, saporin, might selectively destroy spinal postsynaptic
dorsal column neurons expressing NK-1 receptors, to help improve
intractable visceral pain of cancer origin.
Gillespie et al.110 also demonstrated that there is increased NK-1
receptor signaling in colitis associated with cancer further suggesting that
there is potential in antagonizing this transmission in the treatment of
visceral cancer pain. However, this therapeutics is still in its infancy, and
many more studies are needed for further ratification before this group of
drugs can be of clinical significance.

2428
NEWER OPIOID DERIVATIVES FOR THE
TREATMENT OF CHRONIC PAIN
Opioid agonists act on the µ, κ, and δ receptors. Of the µ, δ, and κ
subtypes of opioid receptors, most analgesia is thought to derive from mu
activation.

Cebranopadol
Cebranopadol is a new opioid agonist that is under development by the
Grünenthal company in collaboration with Depomed of United States. It is
a full agonist at the nociceptin/orphanin pathway (NOP) and at µ and δ
receptors, whereas being a partial agonist at the κ receptor. Conventional
opioids are currently the mainstay of visceral cancer pain treatment.
However, their efficacy is limited by potential side effects due to effects
on the gastrointestinal, respiratory, and central nervous systems as well as
the potential of addiction and tolerance.111,112
In animal studies, drugs acting at the nociceptin/orphanin receptors do
not generate typical opioid-like side effects and may even ameliorate
supraspinal opioid-related side effects when administered concurrently
with an opioid. Hence, an agonist at the NOP and the opioid receptors
would be particularly useful in the treatment of visceral pain with a more
favorable side effect profile.113
In a bone cancer pain murine model, Linz et al.114 demonstrated that
cebranopadol caused dose-dependent increased pain withdrawal thresholds
that reached statistical significance after 30- and 60-minute intervals.
However, there is evidence to suggest that cebranopadol is more
effective in neuropathic rather than nociceptive bone cancer pain. Animal
studies indicate that cebranopadol is more effective in experimental
models of chronic neuropathic pain (e.g., streptozotocin-induced diabetic
polyneuropathy and spinal nerve ligation models) compared to acute
nociceptive pain (bone cancer pain and tail-flick test).115 In the rat, there
are strong indications that cebranopadol shows limited depression of
breathing also which has been shown to be significant in comparison to
conventional opioids.116 Moreover, tolerance and addiction are less likely
with cebranopadol than with conventional opioids due to slower
metabolism and pharmacokinetic profile.117

2429
 In the rat, tolerance to morphine develops quickly, and in a study by
Lambert et al.,117 rats were completely tolerant to morphine (8.8 mg/kg
intraperitoneal [IP] daily) in 11 days. In contrast, an equianalgesic dose of
cebranopadol (only 0.8 µg/kg IP daily) was still effective for a further 15
days, or 26 days in total.118 Hence, cebranopadol presents great potential
in the treatment of cancer pain with a better side effect, tolerance, and
dependence profile.

PROCEDURAL INTERVENTIONS
Ganglion Impar Block
The ganglion impar is a solitary retroperitoneal structure located at the
level of the sacrococcygeal junction. This unpaired ganglion marks the end
of two sympathetic chains. The ganglion receives sympathetic and
parasympathetic fibers at the lumbar and sacral levels, providing
sympathetic innervation to portions of the pelvic viscera and genitalia.119
Visceral pain in the perineal area associated with malignancies may be
effectively treated with neurolysis of the ganglion impar (also known as
Walther ganglion).120 Patients who will benefit from this block frequently
present with a vague poorly localized pain that is frequently accompanied
by sensations of burning and urgency. The ganglion impar block is useful
to the management of sympathetically mediated pain in the perineum,
rectum, and genitalia. It has been primarily used for malignancy; however,
it has been used for treatment of associated syndromes such as radiation
enteritis, proctalgia fugax, and reflex sympathetic dystrophy.
The ganglion impar is close in proximity to the rectum. There is
increased risk of contamination through the needle track as the needle is
removed. Infection and fistula are possible complications in patients who
are already immunocompromised or have received radiation to the
perineum.

Thoracic Sympathetic Ganglion Block

Preganglionic fibers of the thoracic sympathetics exit with respective
thoracic paravertebral nerves from the intervertebral foramen. After
exiting the intervertebral foramen, thoracic paravertebral nerves branch
looping dorsal through the same foramen to provide innervation to the

2430
spinal ligaments, meninges, and respective vertebra. The paravertebral
nerve at this level also affects the thoracic sympathetic chain through
myelinated preganglionic fibers of the white rami communicantes.
Preganglionic and postganglionic fibers synapse at the level of thoracic
sympathetic ganglia. Postganglionic fibers provide sympathetic
innervation to the vasculature, sweat glands, and pilomotor muscles of the
skin as well as the cardiac plexus and terminate in distal ganglia as they
course up and down the thoracic sympathetic trunk.121
Block of the thoracic sympathetic ganglion is useful for evaluation of
sympathetically mediated pain to the thoracic and upper abdominal
viscera, the thorax, and the chest wall. Differential blockade may serve as
a prognostic indicator of the benefit to be expected from lesioning of the
thoracic sympathetic ganglion. The block has been used in the past to treat
intractable abdominal pain as well as intractable cardiac pain. It has also
been demonstrated to be effective in the treatment of acute herpes zoster,
postherpetic neuralgia, and phantom breast pain following mastectomy.
Thoracic sympathetic chain destruction may be used to relieve pain in pain
syndromes that have been improved by local anesthetic block.122
Because of the close proximity to the pleural space of the exiting nerve
roots at the thoracic level from sympathetic ganglion, pneumothorax is a
possible complication. The pleural space lies lateral and anterior to the
thoracic sympathetic chain. The lower cervical ganglion fuses with the
first thoracic ganglion to make the stellate ganglion. Caudad in the thoracic
chain, thoracic ganglia move further anterior resting along the
posterolateral surface of the vertebral body. Other possible complications
include accidental injection of the epidural, subdural, and subarachnoid
space. Infection is of greater concern in patients with malignancy because
of their immunocompromised state.

Interpleural Catheters
The role of interpleural analgesia (IPA) in both acute and chronic pain
management is still undergoing clinical scrutiny. Original work with this
technique showed that IPA could provide analgesia in patients with
subcostal incisions and fractured ribs.
The technique for insertion of an interpleural catheter is relatively easy,

2431
and an epidural tray can be utilized. Local anesthetics (0.5% bupivacaine
or 2% lidocaine) have been traditionally utilized via intermittent bolus or a
continuous infusion. Interpleural phenol has been described as an
alternative for the treatment of visceral pain associated with esophageal
cancer. This may be an effective technique to treat visceral pain associated
with cancer of the esophagus, liver, biliary tree, stomach, and pancreas.
For analgesia associated with cancer, continuous infusions of
bupivacaine or intermittent bolus doses of bupivacaine may also provide
adequate analgesia. Higher concentrations of bupivacaine increase the risk
of toxicity.
Complications are secondary to needle or catheter injury or are
secondary to the neurolytic agent injected in the interpleural space.
Pneumothorax may occur in 2% of patients, and lung injury has been
reported when a rigid catheter is used. Phrenic nerve palsy may occur
following this block resulting in respiratory failure. Thus, bilateral blocks
should be avoided. Doses of phenol should be limited; systemic effects
from drug absorption may occur because the pleural membranes are highly
vascularized.

Surgery
Referral for surgical options should be pursued with diagnosis and
treatment of pain in malignancy at any time during the course of care.
Surgical objectives in the palliation of cancer include staging of disease,
control of disease, control of pain and associated symptoms,
reconstruction, and rehabilitation.123 Patients interested in and capable of
tolerating surgical options should be referred to a surgeon for
consideration of options, even if there are nonsurgical options available. If
no intervention is recommended, the patient will have an understanding for
the surgical referral and have a sense of closure with regard to the variety
of options available for palliation. Surgical consult is particularly valuable
in the areas of wound management, complicated issues with regard to
nutrition, and discussion of progression of disease.122
There is no standard set of procedures for the palliation of malignant
visceral pain. The operations available are a reflection of the subjective
pain experience of the patient, the specific stage of the disease, and the

2432
anatomic effects of the disease. Often, other distressing symptoms may be
the reason for surgical management as well as the complaints of pain. The
given surgical option should palliate as many symptoms as possible
without altering benefit–risk ratios.122 The most important preoperative
measure involves reassurance to the patient that preparation is complete
and that postoperative analgesia has been considered. This is best achieved
with close coordination with the partnering anesthesia team and
preoperative consultation regarding analgesic options. Furthermore, the
operative encounter may be the foundation for continued postoperative
pain management options.
Malignancy presenting with pain is likely to be advanced in nature.
Resection of an organ or portion of an organ for management of pain is
reasonable even in the case of uncontrollable disease, especially if the
disease is resectable or partially resectable. There is little data, however,
comparing the efficacy of resection with nonoperative approaches.
In visceral disease, surgical resection has proven effective for the relief
of dysphagia, odynophagia, and chest pain in patients with esophageal
carcinoma; the relief of painful ulceration in those with gastric carcinoma;
and the preemptive control of jaundice, pain, and duodenal obstruction in
those with pancreatic carcinoma.122
Surgery can promote comfort as well as eliminate pain. Mechanical
bowel obstruction may be expected in as many as 15% of cancer patients.
Pain is a reflection of the severity of the distension, the nature of the
primary neoplasm, and the level of obstruction. Resection has also been
offered on occasion for relief of pain associated with carcinoma of the
kidney. In some situations, nephrectomy may be considered to prevent
pain, hematuria, and constitutional effects of the disease. In patients with
large bladder masses, total or partial organ resection may be a
consideration in cases where more conservative options have been
considered. Stent placement may relieve severe pain secondary to
malignant ureteral obstruction by tumors of the prostate, cervix, bladder,
and colon. If stent placement is not an option, percutaneous nephrostomy
may be effective.122
Debulking of functional tumors of the liver may be beneficial in patients
with carcinoid to decrease such symptoms as flushing and diarrhea.

2433
Debulking has also been used in patients with metastatic gastrinoma,
ovarian cancer, and large and small bowel malignancies.
Finally, drainage of ascites, which may develop in as many as half of
cancer patients, may relieve associated symptoms such as bloating, diffuse
abdominal pain, dyspnea, nausea, early satiety, and gastric reflux.

Dorsal Myelotomy for Treatment of Intractable Visceral

Cancer Pain
Neurosurgical interruption of midline visceral pain pathway can help
control severe visceral pain without causing significant adverse neurologic
sequelae in patients with advanced visceral cancer. However, surgery is
not without side effects, and often, this approach is used when
conventional pharmacologic treatment has failed. Hwang et al.122
demonstrated a technique of punctate midline myelotomy (PMM) for the
treatment of cancer pain refractory to opioids. In their study, a PMM at the
T3 level was performed in six patients who experienced severe visceral
pain caused by hepatobiliary or pancreatic cancer. In a small study
involving six patients, follow-up periods ranged from 2 to 18 weeks after
operation. All six patients had immediate pain relief after operation.
Although the pain recurred from 2 to 12 weeks later in three patients, the
severity of recurrent cancer pain was markedly decreased.122
Kim et al.124 also attempted a high thoracic myelotomy in their
palliation attempt in the treatment of severe pain due to stomach cancer.
Under general anesthesia, patients received high thoracic midline dorsal
column myelotomies after T1 or T2 laminectomy. In their study, they
demonstrated clinically significant decrease in pain scores after the
procedure, although one patient developed paresthesia and posterior
column signs below the level of myelotomy without analgesia and another
paresthesia responsive to corticosteroids. They concluded that dorsal
column myelotomy at a high thoracic cord level effectively controls severe
abdominal pain and should be considered as a new palliative operation for
patients with severe visceral pain.125

Hypophysectomy and Cancer Pain

Destruction of the pituitary stalk has been a long established palliative

2434
approach to the treatment of severe refractory cancer pain especially due to
widespread metastases and also in bone cancer pain in breast cancer.
Surgical, stereotactic instillation of alcohol in to the sella turcica and other
methods of chemical hypophysectomy have been long established in
cancer pain treatment. A proposed mechanism is that or its associated
neurophysins act as central pain transmitters. The production of these
transmitters is decreased or abolished by chemical or surgical
hypophysectomy through the destruction of hypothalamic nuclei.126–128

Conclusion
Failure to assess and treat cancer pain, whether of somatic, visceral,
neuropathic, or mixed types, is still a common problem among patients in
all stages of malignant disease. Barriers to adequate care have been
discussed in previous chapters. Notwithstanding needed improvements in
clinician education, access to pain and supportive care specialists, among
other needed systems improvements, and similar to other causes of cancer
pain, relief of pain in patients with visceral malignancies or treatment-
related visceral pain syndromes should be organized as part of a
comprehensive interdisciplinary approach to care. Visceral pain cannot be
exclusively managed with pharmacotherapy, and the resources of several
medical and supportive care disciplines should be considered with each
patient so that pain management can be tailored to the individual
requirements of each patient according to his or her unique constellation of
clinical and social circumstances.

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82. Finkel JC, Pestieau SR, Quezado ZM. Ketamine as an adjuvant for treatment of cancer pain in
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84. Chung WJ, Pharo GH. Successful use of ketamine infusion in the treatment of intractable
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85. Fitzgibbon EJ, Viola R. Parenteral ketamine as an analgesic adjuvant for severe pain:
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86. Fitzgibbon EJ, Hall P, Schroder C, et al. Low dose ketamine as an analgesic adjuvant in
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87. Mannion S, O’Brien T. Ketamine in the management of chronic pancreatic pain. J Pain
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88. Prommer E. Ketamine to control pain. J Palliat Med 2003;6(3):443–446.
89. Mercadante S, Arcuri E, Tirelli W, et al. Analgesic effect of intravenous ketamine in cancer
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90. Gordon DB, Sehgal N, Schroeder ME, et al. Treatment of pain crisis at end of life from severe
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91. Kotlińska–Lemieszek A, Luczak J. Subanesthetic ketamine: an essential adjuvant for
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92. Warr DG. Chemotherapy- and cancer-related nausea and vomiting. Curr Oncol 2008;15(suppl
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93. Tan PH, Yang LC, Shih HC, et al. Gene knockdown with intrathecal siRNA of NMDA
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96. Kopecky BJ, Liang R, Bao J. T-type calcium channel blockers as neuroprotective agents.
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98. LeBlanc BW, Lii TR, Huang JJ, et al. T-type calcium channel blocker Z944 restores cortical
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99. Wallace M, Duan R, Liu W, et al. A randomized, double-blind, placebo-controlled, crossover
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100. Tölle TR, Berthele A, Schadrack J, et al. Involvement of glutamatergic neurotransmission and
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102. Gormsen L, Finnerup NB, Almqvist PM, et al. The efficacy of the AMPA receptor antagonist
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103. Gangwal RP, Bhadauriya A, Damre MV, et al. p38 Mitogen-activated protein kinase
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110. Gillespie E, Leeman SE, Watts LA, et al. Truncated neurokinin-1 receptor is increased in
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CHAPTER 48
Radiotherapy and Chemotherapy
in Cancer Pain Management
NORA JANJAN

Introduction
“Cancer pain is best controlled by removing the cancer or causing it to
regress.”1 This succinct principle stated by palliative medicine specialist
Dr. Neil MacDonald is a useful framework from which to consider the role
of palliative chemotherapy and radiotherapy in the management of
symptomatic disease. In the year 2016, 1,685,210 new cancer cases were
diagnosed, and about 595,690 cancer-related deaths occurred. National
expenditures for cancer care in the United States totaled nearly $125
billion in 2010 and are projected to reach $156 billion in 2020.2
There has been substantial progress in cancer incidence and mortality.
The incidence of cancer from 2009 to 2013 was stable in women but
decreased by 2.3% per year in men. An overall 13% decrease in cancer
deaths occurred between the years 2004 and 2013.2,3 Death rates decreased
for 11 of the 16 most common cancer types in men and for 13 of the 18
most common cancer types in women; this decline in cancer death rates
included lung, colorectal, female breast, and prostate cancer. The 5-year
survival rate for breast cancer increased from 18.7% between 1975 and
1977 to 33.6% between 2006 and 2012. The improvements in 5-year
survival rates also included meaningful increases in survival with distant-
stage disease.3 Deaths due to breast cancer declined almost 40% between
1989 and 2015, averting 322,600 deaths.4,5 This trend can be attributed to
the persistent efforts in research, early detection of disease, and treatment
advances. Cancer and its treatment, however, still result in a significant
burden of symptoms like pain.
Cancer has a negative impact on almost all cancer patients’ domains of

2442
daily living. Quality-of-life measurements have been shown to predict
survival and add to the prognostic information derived from the Karnofsky
performance status (KPS) and extent of disease. Physical symptoms
including pain, dry mouth, constipation, change in taste, lack of appetite
and energy, feeling bloated, nausea, vomiting, weight loss, and feeling
drowsy or dizzy often portend a poorer prognosis.6 Palliative care is an
integral component of cancer treatment with a goal to effectively and
efficiently relieve symptoms and maintain the maximum functional and
emotional well-being for the duration of the patient’s life.7–13
Recognizing the value of the early integration of palliative care, an
American Society of Clinical Oncology clinical practice guideline states
that the standard for oncology care includes the control of the symptoms of
cancer and its treatment from diagnosis to death. Data supporting this
guideline includes nine randomized controlled trials and five secondary
analyses from these trials that demonstrate the effectiveness of dedicated
palliative care services early in the treatment of cancer. Essential
components of palliative care may include symptom management,
education about the cancer and its prognosis, clarification of treatment
goals and assistance with medical decision making, coping needs, and
coordination of care.14
Applying these principles, a prospective trial in 171 newly diagnosed
advanced lung or noncolorectal gastrointestinal cancer patients evaluated
the key elements of early palliative care from 2,921 clinic visits. The initial
cancer therapy was chemotherapy (80.7%) or radiotherapy (19.3%).
Patients randomly assigned to at least monthly visits in the palliative care
clinic had assessments performed at baseline and at 24 weeks. Most of
these palliative care visits addressed symptom management (74.5%) and
coping (64.2%). By 24 weeks, patients who more frequently addressed
treatment decisions were less likely to initiate chemotherapy (P = .02) or
be hospitalized (P = .005) in the 60 days before death. With a higher
proportion of visits addressing advanced care planning, hospice care was
more frequently used (P = .03) (Fig. 48.1).15

2443
FIGURE 48.1 Content of palliative care (PC) visits across the illness trajectory. PC clinicians
recorded the content they addressed after each visit. Reported proportions for the final three visits
are restricted to decedents. Reported proportions for the initial three visits exclude visits that were
also among the final three visits. Reported proportions for middle visits represent averages across
all available middle visits. Relative to the initial three visits, the final three visits increasingly
addressed treatment decisions (P < .001), advance care planning (P < .001), and disposition (P <
.001) but decreasingly addressed rapport (P < .001) and illness understanding (P < .001). (From
Hoerger M, Greer JA, Jackson VA, et al. Defining the elements of early palliative care that are
associated with patient-reported outcomes and the delivery of end-of-life care. J Clin Oncol
2018;36[11]:1096–1102. Reprinted with permission. Copyright © 2018 American Society of
Clinical Oncology. All rights reserved.)

Application of palliative care principles has a profound impact on the

physical and psychological comfort of the patient and their caregivers.
These palliative care principles also have a profound socioeconomic
impact given that the highest costs incurred in health care are at the end of
life. Referral to a specialty palliative care service only occurred in 298
(30%) of 978 patients. Of these 298 patients, only 94 (9.6% of the total)
had an early referral, whereas the remaining 204 patients (21% of the total)
had a late referral to the palliative care service. Early delivery of palliative
care resulted in lower rates of inpatient admission in the last month of life
(33% vs. 66%), lower rates of intensive care unit (ICU) stay in the last
month of life (5% vs. 20%), fewer emergency department visits in the last
month (34% vs. 54%), fewer instances of hospice service less than 3 days
(7% vs. 20%), and lower rate of inpatient death (15% vs. 34%). The direct

2444
cost of inpatient medical care in the last 6 months of life with early
palliative care was less than among those with late palliative care ($19,000
vs. $25,700).16
At the Johns Hopkins Medical Institutions, the palliative care unit and
palliative care consults had a positive financial impact of $3,488,863.10.
Palliative care consultations alone, with 60% of these involving cancer
patients, saved $2,765,218.00. The 30-day readmission rate was cut from
15% to 10%. Hospice care was arranged in 57% of palliative care
consultation patients as compared to only 27% if a palliative care consult
was not requested.17
The early integration of palliative care services significantly reduces
health care utilization during end-of-life care. Insurance claims during the
last month of life from 6,568 cancer patients from a Surveillance,
Epidemiology, and End Results (SEER) database between 2007 and 2015
were reviewed. At baseline, at least one imaging scan was performed in
48.9%, and 56.3% of patients were hospitalized; only 31.4% of patients
younger than 65 years were enrolled in hospice. With changes in health
care and reimbursement policies over this time frame, the administration
of chemotherapy and/or radiotherapy, diagnostic imaging, and
hospitalization rates declined (Fig. 48.2).18

2445
FIGURE 48.2 Trends in health care use in the last 30 days of life by year of death and percentage
of decedents. A: Chemotherapy or radiation use. B: Imaging use. C: Hospitalization and emergency
department (ED) visits. D: Hospice and opioid use. Overall, 963 patients died between 2007 and
2009, 2,628 between 2010 and 2012, and 2,977 between 2013 and 2015. aStatistically significant
trend over time. bFor people under 65 years of age: 426 died between 2007 and 2009, 1,088 died
between 2010 and 2012, and 1,064 died between 2013 and 2015. cUnder 65 years, not enrolled in
hospice. CT, computed tomography; MRI, magnetic resonance imaging; PET, positron emission
tomography. (From McDermott CL, Fedorenko C, Kreizenbeck K, et al. End-of-life services among
patients with cancer: evidence from cancer registry records linked with commercial health insurance
claims. J Oncol Pract 2017;13[11]:e889–e899. Reprinted with permission. Copyright © 2017
American Society of Clinical Oncology. All rights reserved.)

Palliative chemotherapy has been an ambiguous term and mostly refers

to chemotherapy given when the likelihood of cure was minimal. In the
true sense, palliative chemotherapy means that systemic therapy is
delivered to relieve symptoms and improve quality of life regardless of
stage of disease or the likelihood of remission or cure. The primary
outcomes of most studies involving disease-modifying systemic agents,
however, do not have symptom relief as a major endpoint. Although
virtually all systemic agents used in cancer have been surveyed for impact
on quality-of-life, the results of these quality-of-life surveys are rarely
reported. Reduction in the size of the tumor, which is the intended goal of

2446
chemotherapy, should intuitively decrease cancer pain. However, because
the therapeutic benefits of chemotherapy are limited by their own
toxicities, the risks versus benefits need to be weighed as part of treatment
planning and decision making on a case-by-case basis.
Palliative radiation often is used near the end of life to relieve pain and
obstruction from tumor. To achieve the most benefit, palliative radiation
should be administered to prevent or relieve symptoms before they become
severe. If referral for palliative radiation is delayed until the patient
becomes extremely debilitated and/or the lesion has progressed
significantly, often the possibility of any benefit from palliative radiation
is lost. Demonstrating this, a retrospective study of 1,424 patients with
metastatic cancer was conducted between 2010 and 2015 found that 11.3%
had received palliative radiation therapy before ICU admission. The in-
hospital mortality rate was 36.7% for palliative radiation patients
compared to 16.6% of other patients with metastatic cancer. After ICU
admission, only 21.1% of patients previously treated with palliative
radiation received additional cancer treatment.19
The median length of survival is critical to evaluating response to and
determining the appropriate recommendations for palliative therapy. The
most common application of palliative radiation is in management of pain
related to bone metastasis. Seventy percent of metastatic bone lesions are
painful and debilitating. The goal of treatment is to relieve pain, restore
functional ability, and prevent pathologic fractures. In prostate cancer, the
distribution of bone metastases has prognostic significance. Survival is
longer when the metastases are restricted to the pelvis and lumbar spine or
if there is a response to salvage hormone therapy, but lower if metastatic
involvement is outside the pelvis and lumbar spine irrespective of response
to salvage hormone therapy.20–22 Survival rapidly declines once visceral
metastases develop.23–25
The location of the metastasis can also be a limitation in the
effectiveness of a palliative radiation. Metastatic involvement of weight-
bearing bones and those used in functional activities are often less likely to
respond completely to palliative interventions due to applied mechanical
forces put on them. Pain relief is achieved in 73% of spine metastases,
88% of limb lesions, 67% of pelvic metastases, and 75% of metastases to

2447
other parts of the skeleton.26–28
Palliative therapy has become a recognized subspecialty within radiation
oncology.29 Despite the establishment of multiple palliative medicine
programs in the country and the proven efficacy of palliative radiotherapy
for symptoms, radiotherapy is often underutilized due to long radiation
treatment schedules.26 Even with a relatively short life expectancy,
palliative radiotherapy may be helpful, but less than 3% of the patients in
hospice care received radiation in one survey.30
Conducting randomized trials among large patient cohorts, shorter
radiation treatment regimens have enhanced quality of care by achieving
equivalent symptom reduction when compared to longer radiation
regimens and have significantly reduced the lengths of hospitalization (P =
.01).31 Among 181 patients hospitalized for bone metastases between 2010
and 2016, a palliative care radiation oncology consult service
recommended shorter palliative radiation schedules, increased palliative
care utilization, and reduced hospital stays by 8.5 days. Median total
hospitalization costs were $76,792 for patients with bone metastases
before a palliative radiation oncology consult service was available and
were reduced to $50,582 after the palliative radiation oncology consult
service was formed.32 Cost of outpatient radiation therapy was evaluated
from claims-linked data from 207 breast and 233 prostate cancer patients
in 98 cancer treatment centers in 16 US states between 2008 and 2010. The
mean total cost of radiation for bone metastases was $7,457 for breast
cancer and $7,553 for prostate cancer patients.33
More sophisticated and costly radiation techniques, like stereotactic and
proton radiation, are available to treat patients expected to have a longer
survival or those with complicated clinical presentations, like those near
critical structures and in/near previously irradiated sites. Stereotactic
radiation is not cost-effective for routine cases having an incremental cost-
effectiveness ratio of $124,552 per quality-adjusted life years. However,
stereotactic radiation does become cost-effective, with an incremental
cost-effectiveness ratio of less than $100,000 per quality-adjusted life
years, among patients with a median survival of over 10 months.34 More
abbreviated radiation courses result in cost savings for less complicated
clinical presentations. Ineffective therapy, however, incurs more personal

2448
and economic cost resulting from the continued need for analgesics and
the functional limitations caused by unrelieved pain and disability.35,36
The most common barriers to radiotherapy still relate to the costs of
radiation therapy and transportation difficulties. The selection of a
radiation course or technique, like that for a systemic therapy, is dependent
on the patient wishes, prognosis, and comorbidities.

BONE DISEASE
The annual prevalence of bone metastasis was determined to be 256,137 in
the years 2000 to 2004. The direct cost for patients with bone metastasis
was $75,329, and the incremental cost was $44,442 compared to patients
with cancer without bone metastasis. The national cost burden for patients
with skeletal metastasis was estimated at $12.6 billion which is 17% of the
$74 billion total direct medical cost estimated by National Institutes of
Health (NIH).37 The prevalence of metastatic bone disease totaled 279,679
as determined by claims-based data from 2004 to 2008, with breast,
prostate, and lung cancer accounting for 68% of these cases.38
Multidisciplinary evaluation of patients with metastatic disease to the
bone allows comprehensive management of the associated symptoms,
determines the risk for pathologic fracture, and helps coordinate
administration of a wide range of available antineoplastic therapies (also
see Chapter 46).39,40 Bone metastases can be treated with localized,
systemic, or both kinds of therapies. Because localized treatments, like
radiation and surgery, provide treatment only to a localized symptomatic
site of disease, it is frequently used in coordination with systemic therapies
such as chemotherapy, hormonal therapy, and bisphosphonates.
Radiopharmaceuticals provide another systemic option that treats diffuse
symptomatic bone metastases.39,41 Because the radiation is deposited
directly at the involved area in the bone, radiopharmaceuticals, such as
strontium 89 or samarium 153, can also be used to treat diffuse bone
metastases or when symptoms recur in a previously irradiated site.
Radiopharmaceuticals can also act as an adjuvant to localized external
beam irradiation and reduce the development of other symptomatic sites of
disease. A study was conducted among patients referred to a
multidisciplinary bone metastases clinic between 2007 and 2015.

2449
Independent of age, 62% of patients received palliative radiation, whereas
surgical stabilization was required in 30% over the age of 66 years and in
39% of patients 65 years of age or younger.42
Control of cancer-related pain with the use of analgesics is imperative to
allow comfort during and while awaiting response to therapeutic
interventions. Pain represents a sensitive measure of disease activity. Close
follow-up should be performed to ensure control of cancer and treatment-
related pain and to initiate diagnostic studies to identify progressive or
recurrent disease. Pain, risk for pathologic fracture, and spinal cord
compression are the most common indications to treat bone metastases
with localized therapy including radiation and surgery.

CLINICAL APPLICATIONS OF RADIATION THERAPY

Radiotherapy can be delivered with curative or palliative intent. Curative
treatment attempts to render the patient disease free of either primary or
metastatic disease. Treatment with palliative intent is intended to control
the symptoms of disease when the disease cannot be eradicated. A number
of clinical, prognostic, and therapeutic factors must be considered to
determine the most optimal treatment regimen for a course of palliative
radiotherapy. Although any site of disease can be effectively palliated,
treatment of bone metastases is one of the most common indications for
palliative irradiation with external beam therapy. During the last year of
life, one-third of patients receive radiation therapy, which decreased to
24.3% in the last 3 months of life and 8.5% during the last month of life.
Although radiation with curative intent was delivered at a constant rate in
25% of patients, palliative radiation was administered at a supralinear rate
over the last year of life in which the treatment of bone metastases and use
of single-fraction radiation increased closer to death.43
The limited radiation tolerances of normal tissues, such as the spinal
cord, make it impossible to administer a large enough dose of radiation to
completely eradicate most tumors. Palliative radiation should result in
sufficient tumor regression to relieve symptoms for the duration of the
patient’s life. Palliative radiotherapy is often combined with chemotherapy
and/or surgery to optimize therapeutic outcomes from tumor-related pain,
bleeding, visceral obstruction, or lymphatic and vascular obstruction.

2450
Common sites include respiratory system structures, pelvis, skin and
subcutaneous tissues, brain, and all bony structures. Potential relief of
symptoms is a more important determinant for palliative radiation than
whether lesions result from locally advanced or metastatic disease.
Symptoms that recur after palliative radiation most commonly result from
localized regrowth of tumor in the radiation field.44
The palliative interventions recommended depend on the patient’s
clinical status, burden of disease, and location of the symptomatic site. For
either locally advanced or metastatic disease, these factors are indexed to
the relative effectiveness, durability, and morbidity of each palliative
intervention. Each patient’s prognosis represents the single most important
factor in deciding the approach to palliative therapy.45
Because patients with metastatic disease have a limited life expectancy,
the number of radiation fractions prescribed for treatment with palliative
intent depends on prognosis and not primary histology, so a lower total
dose is given with palliative radiation over 1 to 2 weeks (hypofractionated
radiation schedule). Based on the radiation tolerance of normal tissues, a
low daily radiation dose (1.8 to 2.0 Gy) is given with conventional
radiation; in contrast, large daily radiation fractions are given with
hypofractionated radiation schedules. Hypofractionated radiation
schedules for palliative therapy can range from 2.5 Gy per fraction
administered over 3 weeks for a total dose of 35 Gy to a single 8-Gy dose
of radiation. Most frequently, 30 Gy is administered in 10 fractions over 2
weeks. Especially among patients with short life expectancies, many
centers administer 20 Gy in 1 week or a single fraction of radiation
because the rates of pain relief, mobility, and frequency of pathologic
fractures are similar to more protracted radiation schedules.46,47
Palliative interventions not only should be limited in time relative to the
patient’s life expectancy but should also be focused to limit toxicity.
Available radiation techniques that focus the radiation to the symptomatic
site should be applied to limit toxicity. Although the relative cost of more
advanced radiation planning and treatment may be higher, the tolerance to
palliative radiation is better, avoiding the costs of treating toxicities,
especially for radiation portals that include mucosal surfaces. Among the
radiation techniques that more precisely focus the delivery of radiation to

2451
the tumor are intensity-modulated radiation therapy (IMRT), proton
radiation therapy, and stereotactic radiation therapy (SRT).48

Response of Tumors to Radiotherapy

TRACHEA, BRONCHI, AND LUNGS
Locally advanced primary or metastatic involvement of the lung often
requires palliative intervention because cure is possible in only a few of
these cases. A variety of symptoms, some of them emergent, can manifest
because of tumor involvement of the lung. Pain can result from tumor
invasion of the ribs and nerve roots of the chest wall. Vertebral
involvement can be associated with spinal cord compression. Lower
respiratory tract obstruction, bleeding, and pneumonitis can result from
tracheobronchial tumor growth. Mediastinal infiltration can cause superior
vena cava syndrome.
All of these clinical presentations can be palliated with external beam
radiation that encompasses the disease that is evident on diagnostic images
and that treats pain referred along involved nerve roots. Radiation
schedules that administer 30 Gy in 10 fractions over 2 weeks, 20 Gy in 5
fractions, 2 fractions of 8.5 Gy 1 week apart, or 1 fraction of 10 Gy
(depending on the patient’s life expectancy and ability to tolerate
multifraction therapy) are typically prescribed to previously unirradiated
sites.48
Optimal palliation of patients with incurable lung cancer requires
coordinated interdisciplinary care. For patients with stage III non–small-
cell lung cancer who have a life expectancy of at least 3 months, have a
good performance status, and no comorbidities excluding the
administration of chemotherapy, administration of a platinum-containing
chemotherapy concurrent with hypofractionated palliative thoracic
radiation therapy is recommended over treatment with either modality
alone.49
Hemoptysis and chest pain can be effectively palliated with external
beam radiation, although dyspnea and dysphagia are not as effectively
relieved. If the area has been previously irradiated, techniques that exclude
critical anatomic structures, such as the spinal cord, are applied. Other

2452
approaches, like brachytherapy, stereotactic radiation, and proton therapy,
can be used when the symptomatic site is well localized and accessible.
Brachytherapy can be used to treat bronchial obstruction and bleeding by
placing a radioactive source directly against the tumor under
bronchoscopic guidance. In these cases, large doses of radiation can be
delivered over a few minutes by a high-dose rate brachytherapy unit.48,49

PANCREATIC CANCER
Palliative doses of radiation for unresectable pancreatic cancer have
minimal to no impact on survival. Randomized trials have not shown any
significant survival benefit when conventional radiation is used after
chemotherapy for unresectable pancreatic cancer. Results from
nonrandomized studies of 3 to 5 fractions that deliver a biologic equivalent
dose (BED) of 53 Gy of stereotactic radiation (SRT) not only have less
toxicity and a shorter treatment time but also a minimal impact on
survival. However, when 15 to 25 fractions of SRT, which deliver a BED
of 100 Gy, longer survival can be achieved with low toxicity. Based on the
anatomic disease extension and the patient’s performance status and
wishes, SRT can be tailored to effectively relieve cancer-related
symptoms, and in specific circumstances, extend life.50

PELVIS
Hemorrhage with or without obstruction or compression of viscera,
lymphatics, vascular structures, and nerves commonly occurs with locally
advanced or metastatic disease in the pelvis. Treatment may require
emergent radiotherapeutic, surgical interventions, or both. Hemorrhage is
commonly associated with tumors involving the rectum and genitourinary
tracts. As with tumors in the lung, radiation is an effective means of
stopping active bleeding. Colorectal cancers are often diagnosed among
patients with unexplained bleeding. In patients who have locally advanced
tumors with months to years of life expectancy, 40 Gy in 2.5 Gy fractions
to 50 Gy in 2 Gy fractions have been used with the intent to stop bleeding,
render the patient operable, and provide a chance for cure. With extensive
metastatic disease, 30 Gy in 10 fractions or 20 Gy in 5 fractions is used to
palliate symptoms of bleeding and obstruction. Colorectal tumor

2453
involvement may also result in obstruction requiring stent placement to
maintain the integrity of the visceral lumen while administering radiation.
Diverting colostomy is occasionally required but is reported to have been
avoided after chemohypofractionated irradiation.51
Tumors involving the cervix can hemorrhage and require emergent
radiotherapeutic intervention. Superficial radiographs are applied directly
to the bleeding cervix through a cone to treat the bleeding site and do not
compromise later radiation of other pelvic structures. Usually, radiation
doses between 5 and 10 Gy are administered in one to three applications of
cone therapy. Brachytherapy also can be used to treat gynecologic tumors,
especially in the vagina, cervix, and endometrium.51
Bladder cancers or tumors that secondarily invade the bladder can also
result in significant bleeding that can be palliated by external beam
radiation. Urinary obstruction commonly occurs with locally advanced
pelvic cancers, especially with bladder, rectum, prostate, and cervical
cancers. Occasionally, placement of a urinary stent, urostomy, or
nephrostomy is required until sufficient tumor regression can be
accomplished by radiation to reestablish integrity of the urinary tract. As
with the bowel and gynecologic tracts, a bladder fistula, resulting from
either the tumor itself or from tumor regression, is a concern.
The pelvic lymph nodes and major blood vessels may become
obstructed by tumor. This is most frequently seen when tumors arise in
pelvic structures but can also occur with pelvic metastases from breast and
other cancers. Lymph-vascular obstruction results in painful edema that is
refractory to diuretic and other therapies. Other than pain and functional
interference, when severe, fluid and electrolyte imbalances can occur.
Pelvic radiation can relieve lymph-vascular obstruction through tumor
regression.51
Pelvic tumors can also invade the sacral plexus and result in intractable
pain. Tumor can track along nerve roots and can be associated with bony
invasion of the sacrum. Pain caused by visceral, lymph-vascular, or both
kinds of obstructions often respond more rapidly to palliative radiation
than the more refractory neuropathic pain seen with sacral plexus
involvement. Other radiotherapeutic approaches, such as brachytherapy,
are extremely limited when the cancer persists or recurs after external

2454
beam radiation. Interventional pain management techniques are frequently
required to control pain associated with sacral plexus involvement (see
Chapter 44).
The use of palliative radiation in colorectal, prostate, and breast cancer
is common. Using SEER data of 39,619 patients between 2004 and 2011,
half of the patients received radiation in the last 6 months of life, defined
as the last 6 months of life. Of the patients who received radiation during
the end of life (19,586), only 46% had not previously been treated with
radiation. Surgery was performed at the end of life in 35% of the patients,
with proportionately more patients undergoing both surgery and radiation.
Radiation was administered during the last 14 days of life, in 5,723
patients (14%). Administration of radiation during the end of life strongly
correlated with end-of-life chemotherapy use, including the last 14 days of
life (36% of chemotherapy patients); by comparison, only 15% of patients
were treated with radiation in the group that did not receive chemotherapy
during the last 14 days of life. Especially during the last 14 days of life,
treatment may cause increased burden without improving quality of life.52

SKIN AND SUBCUTANEOUS TISSUES

Tumors can cause ulceration of the skin and subcutaneous tissues that are
often painful and distressing because of constant drainage. Representing a
source for the development of sepsis in immunocompromised patients,
localized radiation can be applied to destroy tumor and allow
reepithelialization of the skin. Radiation that treats only the skin and
subcutaneous tissues (electron beam therapy) is generally used to avoid
radiation side effects to underlying uninvolved normal structures.
Although usually 10 radiation treatments are given, the course of radiation
can be abbreviated further, ranging from 1 to 5 days. Occasionally, these
lesions are treated with brachytherapy. The radioactive sources can be
placed in a mold that sits on top of the tumor and delivers treatment over a
few minutes (high-dose rate) or a few days (low-dose rate).

BRAIN METASTASES
Radiation is used to relieve the symptoms of headache, seizure, nausea and
vomiting, and neurologic dysfunction associated with brain metastases. In

2455
patients with good performance status, surgery or radiosurgery followed
by postoperative whole brain radiation is commonly administered.
Radiation is generally with a total of 30 Gy in 10 fractions or 20 Gy in 5
fractions.53
Management of newly diagnosed single or multiple brain metastases,
however, depends on the estimated prognosis and the aims of treatment,
including survival, local treated lesion control, distant brain control, and
neurocognitive preservation. Prognostic systems, such as recursive
partitioning analysis and diagnosis-specific graded prognostic assessment,
may assist in predicting prognosis. Single brain metastasis greater than 3 to
4 cm in size with a good prognosis (expected survival of 3 months or
more), the lesion should be surgically resected followed by whole brain
radiotherapy (WBRT) or surgical resection followed by intraoperative
radiation or an SRT boost to the resection cavity. For a single metastasis
less than 3 to 4 cm in size, multiple options exist including SRT alone,
WBRT and SRT, WBRT and surgery, surgical resection, and SRT or
intraoperative radiation boost. For anatomically unresectable or
incompletely resected single brain metastases less than 3 to 4 cm in size,
WBRT and SRT or SRT alone should be considered. With an unresected
brain metastasis larger than 3 to 4 cm, WBRT should be considered.54
Multiple brain metastases, all of which are less than 3 to 4 cm in size
with a good prognosis SRT alone if the multiple lesions are limited in
number and location, WBRT and SRT, or WBRT alone are options. Other
alternatives include WBRT alone or resection of large brain metastasis or
metastases if it can be accomplished without causing significant mass
effect or morbidity followed by postoperative WBRT.
With poor prognosis, patients with either a single or multiple brain
metastases should be considered for palliative care with or without WBRT.

Bone Metastases
There are two major historical sets of experience with palliative radiation
for bone metastases. The Radiation Therapy Oncology Group (RTOG)
conducted a prospective trial that included a variety of treatment schedules
(Table 48.1). To account for prognosis, patients were stratified on the basis

2456
of whether they had a solitary or multiple sites of bony metastases. The
initial analysis of the study concluded that low-dose, short-course
treatment schedules were as effective as high-dose protracted treatment
programs.55 For solitary bone metastases, no difference existed in the
relief of pain when 20 Gy using 4-Gy fractions was compared with 40.5
Gy delivered as 2.7 Gy fractions. Relapse of pain occurred in 57% of
patients at a median of 15 weeks after completion of therapy for each dose
level. In patients with multiple bone metastases, the following dose
schedules were compared: 30 Gy at 3 Gy per fraction, 15 Gy given as 3 Gy
per fraction, 20 Gy using 4 Gy per fraction, and 25 Gy using 5 Gy per
fraction. No difference was identified in the rates of pain relief among
these treatment schedules. Partial relief of pain was achieved in 83%, and
complete relief occurred in 53% of the patients studied. More than 50% of
these patients developed recurrent pain, the fracture rate equaled 8%, and
the median duration of pain control was 12 weeks for all the radiation
schedules used for multiple bony metastases. Prognostic factors for
response included the initial pain score and site of the primary cancer.

TABLE 48.1 Dose–Response Evaluation from the Reanalysis of the

Radiation Therapy Oncology Group Bone Metastases Protocol55
Tumor Dose at Complete
Dose per 2 Gy per Response Rate
Fraction (Gy) Total Dose (Gy) Fractiona (%)b P Value
Solitary Bone Metastases P < .0003
2.7 40.5 42.9 55
4 20 23.3 37
Multiple Bone Metastases P < .0003
3 30 32.5 46
3 15 16.2 36
4 20 23.3 40
5 25 31.25 28
a
The radiobiologic equivalent dose if administered at 2 Gy per fraction.
bThecomplete response rate using the definition that excludes the use of analgesics and that
accounts for retreatment.

In a reanalysis of the data, a different definition for complete pain relief

was used and excluded the continued administration of analgesics. Using
this definition, the relief of pain was significantly related to the number of

2457
fractions and the total dose of radiation that was administered.56 Complete
relief of pain was achieved in 55% of patients with solitary bone
metastases who received 40.5 Gy at 2.7 Gy per fraction as compared with
37% of patients who received a total dose of 20 Gy given as 4 Gy per
fraction. A similar relationship was observed in the reanalysis of patients
who had multiple bone metastases. Complete relief of pain was achieved
in 46% of patients who received 30 Gy at 3 Gy per fraction versus 28% of
patients treated to 25 Gy using 5-Gy fractions. In most cases, the interval
to response was 4 weeks for both complete and minimal relief of
symptoms.
Three important issues are identified from the RTOG experience. First,
the results of the reanalysis demonstrate the importance of defining what
represents a response to therapy. Second, this revised definition of
response showed that the total radiation dose did influence the degree that
pain was relieved.55,56 The response rates and the radiobiologically
equivalent doses are listed from the reanalysis in Figure 48.1 for each of
the treatment schedules used. Patients treated with total doses of 40 Gy or
more had a 75% rate of complete pain relief versus a 62% rate of complete
pain relief for patients treated with total doses of less than 40 Gy.27,57
Third, the RTOG experience identified the amount of time that was needed
to experience relief of pain after radiation for bone metastases (Table
48.2). It is important to note that only one-half of the patients who were
going to respond had relief of symptoms at 2 to 4 weeks after
radiation.55,56 This underscores the need for continued analgesic support
after completing radiation. Consistently, it took 12 to 20 weeks after
radiation to accomplish the maximal level of relief. That period of time
may reflect the time needed for reossification. Radiographic evidence of
recalcification is observed in approximately one-fourth of cases, and in
70% of cases, recalcification is seen within 6 months of completing
radiation treatments.60–63 Recalcification is the basis of stabilization and
prevention of fractures in the future. For pain relief, a short course of
radiation is adequate; however, a longer schedule is recommended for
adequate recalcification.58,59 Again, clinical context, with a focus on life
expectancy, is a key determinant of radiation type, dose, and fractionation
schedule.

2458
 TABLE 48.2 Percentage of Patients Who Responded to Radiation
Relative to Time, Designated in Weeks after Completion of
Radiation Therapy
Weeks after Radiation
Tumor Dose
Total Dose Dose per at 2 Gy per 4–12 12–20
(Gy) Fraction (Gy) Fraction <2 (%) 2–4 (%) (%) (%)
Solitary Metastases
40.5 2.7 42.9 7 29 53 77
20 4 23.3 16 50 66 82
Multiple Metastases
30 3 32.5 19 48 73 84
15 3 16.2 34 70 84 93
20 4 23.3 28 53 75 88
25 5 31.25 22 41 72 80
NOTE: This prospective trial, conducted by the Radiation Therapy Oncology Group, randomized
radiation dose and number of fractions and stratified the randomization on the basis of solitary or
multiple bone metastases.58,59 Also listed is the radiobiologic equivalent dose if administered at 2
Gy per fraction.

Single-Fraction Radiation
A single large radiation fraction has demonstrated, in large multiple
prospective randomized clinical trials, as effective in relieving pain as
other radiation schedules that have more treatments. Radiobiologically, a
single 8-Gy fraction would give the same side effects to late reacting
tissues (i.e., tissues such as the spinal cord that do not regenerate) as if 18
Gy were given over nine treatments at 2 Gy per fraction.64 Because tumors
and acute reacting tissues, such as the esophagus and other mucosal
structures, respond differently than the late-reacting tissues, the
radiobiologically equivalent dose to the tumor for a single 8-Gy fraction
would be 12 Gy if 2 Gy fractions were used. The most common dose
fractionation schedule used for palliative radiation in the United States is
30 Gy over 10 fractions. Radiobiologically, this is equivalent to 36 Gy at 2
Gy per fraction for late-reacting tissues and 32.5 Gy to the tumor. When a
single dose of radiation was compared with a radiation schedule with
multiple radiation fractions, no difference was reported in either how
quickly symptoms resolved or the duration of pain relief.57,65–77 Pain relief

2459
was achieved in 80% after treatment and 50% of patients at 6 months
irrespective of the number of fractions. Complete response (CR) rates after
a single 8-Gy fraction total 15% at 2 weeks, 23% at 4 weeks, 28% at 8
weeks, and 9% at 12 weeks postradiation.
Despite the radiobiologic differences in the dose administered, the
similarities in response may be caused by tumor regression and
reossification that occurs at 3 months. The RTOG experience showed that
the maximum response to therapy was seen consistently at 3 months and
was independent of dose administered.55,56 The disparity in the
relationship between radiation dose and clinical response may also be
attributed to limited follow-up in the single-fraction study because a
significant proportion of patients in the study were lost to follow-up after 3
months.67–70 With longer follow-up, the response to a single radiation
fraction may not prove to be as durable as multiple fractions that give high
total radiation doses.76–78 These data demonstrate that prognosis needs to
be linked to variables such as site irradiated, total radiation dose, and
reirradiation.79
A shorter radiation schedule, such as a single fraction, is advantageous
for patients with poor prognostic factors. First, it is easier for patients with
a poor KPS to complete therapy. Second, response rates are equal to single
and multifraction therapy at 3 months because median survival is less than
6 months among patients with poor prognostic factors.67–75 The option of
retreatment after a single fraction of radiation may also provide an
advantage among patients with good prognostic factors as a means to
periodically reduce tumor burden and control symptoms in noncritical
anatomic sites. Higher radiation doses that provide more durable pain
relief are considered warranted for patients with good prognostic factors
who require treatment over the spine and other critical sites.80–86
The projected length of survival is the critical issue to determine the
optimal radiation dose and schedule for palliative radiation. In one study,
only 12 of 243 patients were alive at the time of analysis, with
approximately 50% alive at 6 months, 25% at 1 year, 8% at 2 years, and
3% at 3 years after palliative radiation. For breast cancer patients, the
survival rates at these time points after palliative radiation were 60%, 44%,
20%, and 7%, respectively. For prostate cancer, the survival rates were

2460
60% at 6 months and 24% at 1 year, and there were no patients who
survived 2 years.87 This survival difference may be an important
observation because unrelieved pain and the resultant sequelae of
immobility may contribute to mortality as well as morbidity.
The number of fractions used during a course of palliative radiation was
found to correlate directly with survival in a cohort of 1,292 patients.
Median survival was 13.4 months, 9.8 months, 7.0 months, and 6.9 months
for 15, 10, 5, and single-fraction palliative radiation regimens,
respectively. Performance status and insurance status also directly
correlated with median survival in this study. From this retrospective
study, radiation oncologists appropriately selected palliative treatment
schedules based on prognostic factors.88
These findings were confirmed in a retrospective analysis of 297
patients who began palliative radiotherapy. Of this patient cohort, factors
associated with 60 of these patients discontinuing palliative radiotherapy
included low KPS, high number of fractions prescribed, and treatment site
other than bone metastasis. However, the odds of discontinuing palliative
radiotherapy decreased for every 10-point increase in KPS. Independent of
all other factors, patients who discontinued treatment were more likely to
die. Factors associated with a shorter survival also included low KPS,
community practice location, multiple comorbidities, and treatment of
brain metastasis (Fig. 48.3).89

2461
FIGURE 48.3 Association of Karnofsky performance status (KPS) with overall survival. (From
Puckett LL, Luitweiler E, Potters L, et al. Preventing discontinuation of radiation therapy:
predictive factors to improve patient selection for palliative treatment. J Oncol Practice
2017;13[9]:e782–e791.)

Between 2004 and 2007, only 17% of external beam palliative radiation
courses were given in one to five radiation fractions, whereas from 2012 to
2016, 80% of patients received one to five radiation fractions. SRT was
administered in 9.7% of patients and 5.8% with radiopharmaceutical
therapy.90 At another institution between 2007 and 2012, less than 10
radiation fractions were administered in 83% of 339 patients during their
final course of radiation.91
With expanding evidence from multicenter prospective randomized
clinical trials and changes in insurance reimbursement policies, the
paradigm of palliative radiation for bone metastases has shifted.

Stereotactic Radiation for Nonspine Bone Metastases

Despite changes in insurance reimbursement policies, bone metastases

2462
located in anatomic areas other than the spine also have been treated with
SRT. The indications for SRT over conventional palliative radiation
included an oligometastasis (63%), progression of an oligometastasis
(17.3%), retreatment (2.4%), and other reasons such as anatomic location
(17.3%). The most common prescriptions were 30 Gy per five fractions
(30.2%) and 35 Gy per five fractions (42.5%). The median age of the
patients was 66.4 years (range 36 to 86 years); most of the patients were
male (60.5%), and prostate cancer was the predominant primary tumor.
Bone metastases were most commonly located in the pelvis (41.5%), and
almost half of the metastases were sclerotic. With a 13-month mean
follow-up, an association was found between local recurrence and the
tumor volume. Local recurrence rates were 4.7% at 6 months, 8.3% at 18
months, and 13.3% at 24 months. Radiographic evidence of a pathologic
fracture was documented in 8.5% of treated metastases, with lytic lesions
and female gender being a predictor for pathologic fracture.92

Reirradiation
Many factors influence response to palliative radiation for bone
metastases. Primary tumor site, performance status, and baseline pain
score are among the factors predictive for pain response. The predicted
response rates to palliative radiation range from 37.5% for patients with
multiple adverse factors to 79.8% for patients with the fewest adverse
factors.93 Genetic factors may also help to identify the patients who will
respond to palliative radiation and improve resource utilization. Single-
nucleotide variants involved in DNA repair, inflammation, cellular
adhesion, and cell signaling have significant association with radiation
response.94
The radiation schedule used for palliative radiation is influenced by the
radiation tolerance of adjacent normal tissues as well as prognosis. Acute
radiation toxicities are a function of the dose per fraction, total dose, and
the area and volume of tissue irradiated. If mucosal surfaces, such as the
upper respiratory and digestive tract, bowel, and bladder, can be excluded
from the radiation portals, acute radiation side effects can be significantly
reduced. This principle of minimizing radiation to uninvolved adjacent

2463
tissues applies to the radiation given with curative intent (multiple small
radiation doses over multiple weeks), palliative radiation, and reirradiation
(few to one large radiation dose). Reirradiation is generally possible
because the radiobiologic dose is relatively low after a single fraction of
radiation, especially to a previously unirradiation site remote from critical
structures like the small bowel or spinal cord.57,64–70,77–79 If high total
radiation doses had been previously administered, reirradiation for
persistent or recurrent pain is often challenging or precluded based on the
limitations of normal tissue tolerance, especially near the spinal cord.
For bone metastases, reirradiation was necessary in 25% of patients who
initially received a single 8-Gy radiation fraction, but all of these patients
responded to the second dose of radiation for bone metastases. Pain relief
in reirradiated patients was better in patients who had a longer pain-free
interval after the initial single 8-Gy dose of radiation (≥4 months), a better
performance status, and a single bone metastasis.95 There also was no
significant difference in pain relief at 2 months or overall survival based
on gender or age.96 Using an intention-to-treat analysis for the treatment of
bone metastases with palliative radiation, similar response rates were
found for single fraction (61%; 1,867/3,059 patients) and multiple
fractions (62%; 1,890/3,040 patients). Ten randomized trials were reported
since 2010, resulting in a total of 29 trials for analysis. Retreatment was
more frequent in the single-fraction arm with 20% receiving additional
treatment to the same site versus 8% in the multiple fraction arm.
However, no significant difference was seen in the risk for pathologic
fracture, the rate of spinal cord compression or acute toxicity rates at the
treatment site.97
Using SRT, reirradiation to a vertebral body can be safely accomplished
with palliation of symptoms. When SRT is given at least 5 months after
conventional palliative radiotherapy, and if the radiation dose to the thecal
sac does not exceed a biologically equivalent radiation dose of 70 Gy
normalized to a 2 Gy equivalent dose. Reirradiation with SRT can achieve
favorable response rates if spinal cord radiation dose restraints (10 Gy to
10% of the spinal cord) are followed.98
The results of reirradiation of vertebral metastases are favorable. Having
no other therapeutic option, tumor recurrence in the spinal and paraspinal

2464
areas in 372 spinal lesions were reirradiated using SRT. The time between
the initial radiation course and the reirradiated course was a median of 9.8
months. The median survival was 6.9 months after the last radiation
treatment (reirradiation), and median follow-up was 3.4 months (average
of 21 months). Relief of pain and neurologic improvement was
accomplished in 81%, and radiographic tumor control was evident in 71%.
Adverse effects occurred in 11 patients, with radionecrosis and
myelomalacia each occurring in 1 patient; 6% of patients had radiation
associated vertebral compression fractures.99
The specimens of 30 patients who underwent surgery after salvage SRT
(sSRT) and primary SRT (pSRT) to the spine were compared. This 30
patient cohort (69.6% sSRT, 30.4% pSRT) were identified from 704
patients treated with SRT for vertebral metastases between 2006 and 2012.
The mean time to surgery was 8.3 months for sSRT and 10.3 months for
pSRT. The most common reasons for surgery were pain (12.5% sSRT,
71.4% pSRT), fracture (37.5% sSRT, 28.6% pSRT), and neurologic
symptoms (68.8% sSRT, 42.9% pSRT). Neurologic symptoms were
common with radiologic tumor progression but not with fractures.
Radiologic tumor progression was seen in 71.4% sSRT and 42.9% pSRT,
and it significantly correlated with pathologic evidence of viable tumor
and tumor bed necrosis. Viable tumor was pathologically documented in
62.5% sSRT and 71.4% pSRT, although tumor bed necrosis was more
common after sSRT (81.3% in sSRT, 42.9% pSRT). Sequelae of radiation
included soft tissue necrosis (20.0% in sSRT, 28.6% pSRT), osteonecrosis
(14.3% in sSRT, 16.7% pSRT), or bone marrow fibrosis (42.9% in sSRT,
33.3% pSRT). Pathologic fractures were increased with bone marrow
fibrosis but not with either soft tissue necrosis or osteonecrosis.100

Pathologic Fracture
The most significant complications of bone metastases relate to pathologic
fracture and spinal cord compression. Pain that persists or that recurs after
palliative radiation should be evaluated to exclude progression of disease,
possible extension of disease outside the radiation portal that results in
referred pain, and bone fracture. Although pure osteolytic metastases are

2465
more likely to fracture than osteoblastic lesions, osteoblastic lesions, by
definition, have an osteolytic component so that new bone can be
formed.93 Reduced cortical strength can result in compression, stress, or
microfractures associated with reduced cortical strength.
Serial radiography is useful in following postradiation disease
progression and fractures. Pathologic fractures occur in 8% to 30% of
patients with bone metastases.101 Proximal long bones are more commonly
involved than distal bones. Consequently, pathologic fractures occur 50%
of the time in the femur and 15% in the humerus (Fig. 48.4). The femoral
neck and head are the most frequent locations for pathologic fracture
because of the propensity for metastases to involve proximal bones and the
stress of weight placed on this part of the femur. More than 80% of
pathologic fractures occur in breast (50%), kidney, lung, and thyroid
cancers.

2466
FIGURE 48.4 A: An extensive lytic lesion in the proximal humerus. B: Prophylactic internal
fixation performed to prevent pathologic fracture. This patient, who complained primarily of pain in
the hip, would have been placed on crutches to reduce stress on the involved femur. A bone scan
and radiography, obtained to exclude other sites of metastatic involvement, identified this lesion in
the humerus. The humerus would have certainly fractured if all the patient’s weight had been
displaced to the upper extremities with crutches.

Computed tomography (CT) was performed in femurs with bone

metastases to determine risk for pathologic fracture. No difference in the
CT scan was identified between femurs that fractured and did not fracture.
However, when only the cortical bone was evaluated, the pathologic
fracture group had a lower cumulative Hounsfield value compared to the
no fracture and no fixation groups.102
Approximately 10% to 30% of metastatic lesions in long bones develop
a pathologic fracture that requires surgical intervention. Patients with
pathologic fracture caused by bone metastases have clinical outcomes after
surgical repair that are comparable with patients sustaining a traumatic
fracture.103–106 Surgical management was performed in 184 patients with
bone metastases to relieve severe pain, avoid impending or stabilize
pathologic fractures between 2008 and 2016. Radiotherapy was previously
administered in 77% of the patients. Surgical management substantially
improved functional outcomes and relieved pain as early as 2 weeks after
surgery.107 However, poor prognosis is associated with hypercalcemia and
ongoing severe pain from other metastatic bone lesions. Therefore, in
those cases, the decision for surgical intervention should be weighed
carefully based on a relative benefit to burden analysis.103
Treatment of pathologic fracture or impending fracture depends on the
bone involved and the clinical status of the patient. Indications for surgical
intervention of pathologic fracture or impending fracture include these
factors: (1) an expected survival of more than 6 weeks, (2) an ability to
accomplish internal stability of the fracture site, (3) no coexistent medical
conditions that preclude early mobilization, (4) metastases involving
weight-bearing bones, and (5) lytic lesions more than 2 to 3 cm in size or
metastases that destroy more than 50% of the cortex.103–106 Intramedullary
stabilization without resection of metastases using locking nails meets the
requirements of palliative therapy. This procedure is less invasive and
allows early weight bearing.106 Postoperative radiation is often given after

2467
surgical fixation of a pathologic fracture to reduce risk of progressive
disease in the bone that could result in instability of the internal
fixation.104
Significant technologic advances in interventional radiology also
provide additional options for the treatment of bone metastases. These
options include thermal ablation (destroy the tumor with heat) and
endovascular therapies (destroy the tumor through devascularization).
Additionally, interventional radiology can stabilize pathologic fractures or
impending pathologic fractures.108

Spinal Cord Compression

Metastatic spinal cord compression (MSCC) is the most dreaded
complication of cancer. Pain is the initial symptom in approximately 90%
of patients with spinal cord compression.109 Paraparesis or paraplegia
occurs in more than 60%; sensory loss is noted in 70% to 80%; and 14% to
77% have bladder, bowel, or both kinds of disturbances.80,81,110 Six
predictive risk factors are associated with MSCC: the inability to walk,
increased deep tendon reflexes, compression fractures on radiographs of
spine, bone metastases present, bone metastases diagnosed more than 1
year earlier, and age less than 60 years. Patients with no risk factors had a
4% chance of developing cord compressions, and a patient with all six risk
factors present had an 87% chance of developing cord compression.103,104
Breast, lung, and prostate cancer comprised 21% to 24% risk of
developing cord compression.111–113
The clinical course of spinal cord compression resulting from malignant
melanoma is similar to that resulting from breast or prostate cancer. The
time from the original diagnosis of melanoma to the development of
metastatic spinal disease averages 32 months, and the average time is
reported to be 27 months from diagnosis of skeletal metastases to spinal
cord compression. The extent of the epidural mass influences prognosis
because a complete spinal block results in greater residual neurologic
impairment than a partial block. Median survival among patients with
spinal cord compression is 7 months, with a 36% probability for a 1-year
survival. For specific types of cancers, the mean survival time is 14

2468
months for breast cancer, 12 months in prostate cancer, 6 months in
malignant melanoma, and 3 months in lung cancer once epidural spinal
cord compression is diagnosed.14,82,94 After the diagnosis of epidural
spinal cord compression, the overall survival time averages 12 months,
with a median survival time of 5 months. The vertebral column is involved
by metastatic tumor in 40% of patients who die of cancer. Approximately
70% of vertebral metastases involve the thoracic spine, 20% the
lumbosacral region, and 10% the cervical spine.
Using the Tokuhashi prognostic scoring system, 119 patients with
epidural spinal cord compression were evaluated. Survival was 49 days in
group 1, compared to 108 days in group 2. On multivariate analysis, better
survival was also associated with breast, prostate cancer or lung cancers,
nonvisceral metastases, and subsequent systemic chemotherapy.114,115 A
total of 43 different prognostic factors were investigated in 142 articles to
determine whether models could be develop to predict survival in patients
with vertebral metastases. Only two prognostic factors, primary tumor and
performance status, were found to be associated with survival. Survival
was not influenced by age, gender, pathologic fracture, or the number and
location of the vertebral metastases.116
Weakness can signal the rapid progression of symptoms, and 30% of
patients with weakness become paraplegic within 1 week. Rapid
development of weakness, defined as occurring in less than 2 months,
most commonly occurs in lung cancer, whereas breast and prostate cancers
can progress more slowly. Neurologic deficits can develop within a few
hours in up to 20% of patients with spinal cord compression.80–86,117,118
The severity of weakness at presentation is the most significant factor for
recovery of function. The slower the rate of development of motor deficits,
the better the functional outcome.110,119 If no neurologic deficits are
present in a magnetic resonance imaging (MRI) scan proven spinal
carcinoma, then radiation can preserve function. Patients with neurologic
symptoms should be treated within 24 hours.120,121 Ninety percent of
patients who are ambulatory at presentation are ambulatory after treatment.
Only 13% of paraplegic patients regain function, particularly if paraplegia
is present for more than 24 hours before the initiation of therapy.
Notwithstanding the high mortality associated with MSCC, more than 30%

2469
of patients who develop spinal cord compression are alive 1 year later, and
50% of these patients remain ambulatory if the syndrome is recognized
and treated appropriately.
Pain can be present for months to just days prior to the onset of other
neurologic dysfunction. Unlike degenerative joint disease, which primarily
occurs in the low cervical and low lumbar regions, pain caused by epidural
spinal cord compression can occur anywhere in the spinal axis and is
aggravated by recumbency. Any cancer patient with back pain, especially
with known metastatic involvement of the vertebral bodies, should be
assessed for spinal cord compression. The risk of spinal cord compression
exceeds 60% among patients with back pain and plain film evidence of
vertebral collapse caused by metastatic cancer.122–126
Radiographic determination of the involved spinal levels is critical to
radiation treatment planning. Plain film radiography shows involvement of
more than one spinal level in approximately one-third of patients. If the
results of MRI, tomographic studies, and surgical findings are included,
more than 85% of patients have multiple sites of vertebral
involvement.80,81,122–126 For patients with known malignancy, a whole
spine MRI is recommended as the preferred diagnostic modality.110,127,128
With plain radiography, the destruction of the pedicles is the most
common finding that identifies spine metastases. In contrast, CT shows
that the initial anatomic location of metastases is in the posterior portion of
the vertebral body and that destruction of the pedicles occurs only in
combination with involvement of the vertebral body (Fig. 48.5).125
Symptomatic patients with a normal vertebral contour and osteoblastic
changes on plain film and bone scan should also be evaluated for spinal
cord compression (Fig. 48.6). Osteoblastic bony expansion, commonly
seen in both prostate and breast cancers, can result in spinal cord
compromise as well as osteolytic vertebral compression fractures.124

2470
FIGURE 48.5 A: Computed tomographic scan showing involvement of the posterior aspect of the
vertebral body resulting in partial spinal cord compression. B: Magnetic resonance imaging
showing involvement of the posterior aspect of the vertebral body resulting in partial spinal cord
compression.

2471
FIGURE 48.6 Bone scan that demonstrates multifocal disease involvement. Metastatic
involvement in weight-bearing areas such as the pelvis and lower lumbar area significantly affects
mobility.

Treatment of vertebral metastases has benefitted from less invasive

surgical strategies, systemic therapy with checkpoint inhibitors, and
advances in radiation therapy. Administered alone or postoperatively, SRT
has allowed the delivery of tumoricidal radiation doses while sparing
adjacent critical structures. A high-dose single (16 to 24 Gy) or
hypofractionated (24 to 30 Gy in two to three fractions) SRT administers a
significantly higher biologic effective dose over a shorter period of time
than traditional external beam radiation. Radiation-induced spinal cord

2472
injury from SRT is rare, with only 6 cases of radiation-induced
myelopathy out of 1,075 cases in one study.129
Emergency treatment of spinal cord compression includes
corticosteroids, radiotherapy, neurosurgical intervention, or combinations
of these three therapies. Radiotherapy is the treatment of choice for most
cases of spinal cord compression and is a radiotherapeutic emergency (Fig.
48.7). Spinal cord compression resulting from metastatic tumor can be
prevented or effectively treated when diagnosed early.80,81,122–126
Radiotherapy with shorter courses (e.g., 1 fraction with 8 Gy or 5 fractions
with 4 Gy) is as effective as a longer course (e.g., 30 Gy in 10 fractions),
but the longer courses have lower recurrence rates. A scoring system for
survival based on prognostic factors can guide the type of radiation
course.130 Patients with longer estimated survival time may benefit from
the longer course of radiation. Pretreatment of lytic vertebral body disease,
independent of the blastic component, predicts for subsequent SRT-
induced vertebral compression fracture.131

2473
FIGURE 48.7 Typical radiation portal to treat multifocal areas of disease involvement in the
vertebral bodies and epidural region.

Neurosurgical intervention for MSCC involves spinal cord

decompression accomplished by a laminectomy and is indicated in a
variety of clinical presentations.80,81,121–128,132,133 These situations include
rapid neurologic deterioration in the setting of tumor progression in a
previously irradiated area in order to provide stabilization of the spine,
tumor-induced paraplegia in patients with otherwise limited disease and
good probability of survival, and to establish a diagnosis.
Prognostic factors for survival after surgery for spine metastases were
evaluated in over 1,266 patients. Patients who survived less than 3 months
after surgery for spine metastases were in significantly worse condition

2474
preoperatively with more emergency cases and lower performance status,
more severe neurologic deficits, worse American Society of
Anesthesiologists (ASA) scores, unfavorable tumor histology, and
extraspinal and visceral metastases. By comparison, patients who survived
more than 2 years after surgery had a better performance status, less severe
neurologic deficits, better ASA scores, a more favorable tumor histology
and less extraspinal extension, and fewer visceral metastases. Patients with
one spinal level involved had a 34.9% 2-year survival compared to a
22.7% survival when two or more spinal levels were involved.134
Adjuvant radiotherapy is often given to treat microscopic residual
disease after neurosurgical intervention. A statistically significant
improvement in functional outcome has been reported with laminectomy
and radiotherapy in treatment of epidural spinal cord compression over
either modality alone. In paraparetic patients who undergo laminectomy
and radiation, 82% regain the ability to walk, 68% have improved
sphincter function, and 88% have relief of pain. With radiation alone, 65%
regained ambulation, 26% had improved sphincter function, and 70% had
improvement of pain.121,132,134–136 Laminectomy, however, carries risks
associated with surgery and anesthesia. Pain may worsen after
laminectomy if operative procedures fail to stabilize the spine. Vertebral
collapse may occur because of cancer or vertebral instability after cancer
therapy (Fig. 48.8).

2475
FIGURE 48.8 Compression fracture of the 12th thoracic vertebral body following an initial pain-
free interval after palliative radiation. Vertebral weakness with rapid tumor regression resulted in a
compression fracture that caused recurrent back pain because of spinal instability.

A total of 6,651 courses of radiation were prescribed to 3,782 patients

with a median age of 66 years. The most commonly treated skeletal sites
were the spine (56.8%) followed by the pelvis (18.2%). The primary sites
of most bone metastases were genitourinary (26.5%), lung (23.8%), and
breast cancers (21.9%). However, complicated bone metastases were
associated with hematolymphoid malignancies (39.1%), lung cancer
(34.2%), gastrointestinal (32.5%), breast (28.4%), and genitourinary
(28.4%) cancers. Factors that complicated 32.1% bone metastases were
neurologic compromise (18.7%), soft tissue mass (18.3%), and pathologic
fracture (6.5%). The most common sites of bone metastases with
complicating factors included the extremity (43.6%), skull (42.7%), and
spine (39.2%). Although single-fraction radiation may be effective for
uncomplicated bone metastases, more aggressive therapy is usually

2476
warranted for bone metastases with complicating factors.137,138
Paravertebral masses are most commonly associated with lung cancer
and are rare in prostate cancer. Overall, approximately 20% of patients
with epidural cord compression have an associated paravertebral mass.
Surgical resection combined with radiation therapy has been suggested to
improve functional outcome when a paravertebral mass is associated with
spinal cord compression. The overall survival is worse with lung cancer
and sarcoma than with breast and renal cancer.136,139,140

RADIATION TOLERANCE OF THE SPINAL CORD

Radiation tolerance is based on the dose per fraction, total dose, and the
volume of tissue treated. The dose per fraction is the most important factor
in the tolerance of tissues to radiation. Clinical and experimental
experience has failed to demonstrate any difference in radiosensitivity in
different segments of the spinal cord.141 The risk of radiation myelitis in
the cervicothoracic spine is less than 5% when 6,000 cGy is administered
at 172 cGy per fraction or 5,000 cGy is given with daily fractions of 200
cGy per fraction. Especially among patients who have received
chemotherapy, the total dose to the spinal cord is generally limited to
4,000 cGy administered at 200 cGy per fraction to minimize any risk of
irreversible radiation injury to the spinal cord. The total dose is also an
extremely important factor defining the radiation tolerance of the spinal
cord. A steep curve based on total radiation dose predicts the risk of
developing radiation myelopathy; a small increase in total radiation dose
can result in a large increased risk for radiation myelopathy.141–143
Retreatment of a previously irradiated segment of spinal cord results in
high risk for radiation-induced myelopathy because other neurologic
pathways cannot compensate for an injury to a specific level of the spinal
cord.
The radiation tolerance of the spinal cord can be compromised by prior
injury. Difficulty arises in differentiating pathologic and radiotherapeutic
injury when there has been spinal cord compression. Vasogenic edema of
the spinal cord and nerve roots can be caused by compression injury.
Metastatic epidural compression results in vasogenic spinal cord edema,
venous hemorrhage, loss of myelin, and ischemia. Vasogenic edema

2477
results in an increased synthesis of prostaglandin E, which can be
myelotoxic. Inhibition of this inflammatory pathway is one of the putative
benefits of corticosteroids or nonsteroidal anti-inflammatory therapy.
Other consequences of pathologic compression include hemorrhage, loss
of myelin, and ischemia.141–143
Two separate mechanisms of radiation injury result from white matter
damage and vasculopathies. White matter damage is associated with
diffuse demyelination and swollen axons that can be focally necrotic and
have associated glial reaction. Vascular damage has been shown
experimentally to be age dependent and can result in hemorrhage,
telangiectasia, and vascular necrosis.141–143 Six major types of injuries
have been shown experimentally to result from radiation to the spinal
column. Five of these occur in the spinal cord and one in the dorsal root
ganglia. The most severe spinal lesions, all of which are caused by
vascular damage and result in neurologic dysfunction, include white matter
necrosis, hemorrhage, and segmental parenchymal atrophy. The two less
severe spinal lesions included focal fiber loss and scattered white matter
vacuolization caused by damage to glial cells, axons, the vasculature, or all
three; these less severe sequelae are seen with lower total doses of
radiation and are less likely to result in neurologic dysfunction. In dorsal
root ganglia, radiation damage included intracytoplasmic vacuoles and loss
of neurons and satellite cells that could affect sensory function. These
findings are distinct from the demyelination of the posterior columns
associated with the self-limiting Lhermitte’s syndrome.144 Meningeal
thickening and fibrosis can also be observed after radiation, but the clinical
significance of this is unknown. Ependymal and nerve root damage from
radiation is rare.

CLINICAL MANAGEMENT
Persistent pain after radiotherapy for vertebral metastases should be
investigated to exclude the possibility of progressive disease inside or
outside the radiation portal or mechanical spinal instability because of a
vertebral compression fracture. Changes seen in the bone marrow on MRI
after palliative radiotherapy initially include decreased cellularity, edema,
and hemorrhage, followed by fatty replacement and fibrosis. These well-

2478
defined changes on MRI after radiotherapy can be distinguished from
those seen with progressive malignant disease.145–150
SRT is increasingly used to treat vertebral metastases as it provides
focused radiation to the involved vertebrae while limiting radiation injury
to nearby mucosal structures. A retrospective study of 1,905 vertebral
bodies treated by SRT in 791 patients between 2001 and 2013 resulted in a
low rate of vertebral compression fractures. Radiation doses ranged from
10 Gy in 1 fraction to 60 Gy in 5 fractions. Although lytic lesions had a
significantly increased risk for vertebral compression fractions, the overall
rate was 8.4% including a single-fraction dose of 16 to 18 Gy.151
The outcomes of spine SRT were evaluated in 127 patients with 148
metastatic lesions between 2003 and 2013. The 1- and 2-year actuarial
rates for local control were 82.6% and 75.8%, respectively; for overall
survival, these rates were 72.9% and 51.5%, respectively. When evaluated
by histology, the 1-year local failure rates were 8.7% for thyroid cancer,
7.0% for breast, 26.6% for lung, and 39.6% for colon cancer. Non–small-
cell lung cancer and colorectal cancer was a significant predictor of local
failure when SRT was used to treat spine metastases.152
Prior radiation portals may affect the ability to radiate spine metastases,
especially in breast and lung cancer patients. Standard radiation portals
currently used for breast cancer therapy infrequently treat the spinal axis.
The upper thoracic and lower cervical region, however, may be irradiated
in a field encompassing the supraclavicular nodes and axillary apex if
significant axillary node involvement is documented. With techniques
used in the past for breast cancer, the thoracic spine would receive a
significant dose of radiation from a field that treated the internal mammary
lymph nodes. Treatment of the mediastinum in lung cancer generally
includes the majority of the thoracic spine treated to the maximum dose
tolerated by the spinal cord.136 Unfortunately, previous radiation of the
spine as part of definitive therapy does not reduce the risk for subsequent
spinal cord compression as a consequence of persistent or recurrent
disease. As spinal metastases occur in up to 40% of cancer patients, and
median survival is less than 1 year, other options are available in
previously irradiated patients. In select patients, including those with
disease recurrence in a previously radiated area, interventional radiology

2479
techniques such as vertebral augmentation and radiofrequency ablation
have been effective in relieving debilitating pain and providing mechanical
stability.153
Surgical decompression is often the only available option for therapy
because previously administered radiation may preclude further
radiotherapy in the region of the malignant spinal cord compression. This
is often the case in lung cancer because metastases are located in the
thoracic spine in over 70% of cases, and many of these patients have
received mediastinal irradiation.140 Early involvement by the
radiotherapist in the management of patients with suspected spinal cord
involvement is important to allow time to obtain prior radiotherapy
records; determine if further radiation is possible; and expedite the safest,
most efficacious clinical decision-making process.
Based on clinical and radiographic grounds, leptomeningeal
carcinomatosis must also be considered in the diagnostic evaluation.
Leptomeningeal carcinomatosis occurs more commonly than clinically
diagnosed. For example, only one-half of breast cancer patients with
leptomeningeal carcinomatosis are diagnosed before death.154,155
Performing a lumbar puncture is a relative barrier to the diagnosis; at least
three cerebrospinal fluid samples are necessary to cytologically exclude
the diagnosis of leptomeningeal disease because in 10% to 40% of
patients, the initial cerebrospinal fluid sample fails to document tumor
cells.154 MRI can identify leptomeningeal disease among patients with
normal cerebrospinal fluid cytology and is sensitive and specific in
locating regions of nodular leptomeningeal involvement. Except in the
case of nodular leptomeningeal involvement, in which localized
radiotherapy may be of benefit as an adjuvant, intrathecal chemotherapy is
generally the treatment of choice.155

Treatment of Diffuse Bone Metastases

Wide-field radiotherapy, systemic radionuclides, and bisphosphonates
have been used to treat patients with disseminated bone metastases. These
approaches are useful in augmenting the therapeutic effect of localized
radiation and in preventing asymptomatic bony lesions from progressing.

2480
Although usually not a significant consideration in localized irradiation,
adequate bone marrow reserve is required for wide-field radiotherapy and
systemic radionuclides. Bone marrow scans can be performed to determine
the volume of functioning marrow and assess the feasibility of delivering
wide-field radiotherapy or radionuclides.

WIDE-FIELD RADIOTHERAPY
Hemibody irradiation was previously used to treat diffuse bone metastases
by administering one fraction of about 6 to 10 Gy or fractions of 3 Gy for
2 to 5 consecutive days to the upper, mid, or lower body. Fractionation
reduces the need for premedication and allows for higher total doses to be
delivered, but the effect on pain is equivalent to single-dose
radiation.156–158 Response rates are consistently reported to be greater than
70%, and more than 20% of patients have complete relief of pain. In
prostate and breast cancer patients, the overall response rate is 80%, and
complete relief of pain is 30%, respectively.156–161 Approximately one-
half of patients experience relief of pain within 48 hours of treatment, and
the overall response rates equal 80% for all types of primary tumors.
About 70% of the patients treated did not require further palliative
irradiation for recurrent bone pain over the duration of their lives.157
An RTOG study demonstrated that hemibody radiation reduced the time
to disease progression and decreased the need for subsequent palliative
radiation of bone metastases at 1 year of follow-up when compared with
local field irradiation alone. These results from the RTOG study are
consistent with other reported experience using hemibody
irradiation.159–161 Median survival after hemibody irradiation was
significantly better among patients who present with a good performance
status. Approximately 90% of patients with a CR and 70% of patients with
a partial response (PR) had a good to excellent performance status before
radiotherapy. Prior systemic therapy does not influence response to wide-
field radiotherapy. Symptomatic bone metastases that are refractory to
chemotherapy or hormonal therapy are reported to have CR rates of 70%
and PR rates of 24% with hemibody radiation. Symptoms are palliated in
88% of cases when a previously treated area is reirradiated. Premedication
prevents nausea, and partial shielding minimizes lung dose and the risk for

2481
radiation pneumonitis. Hematologic depression is limited. Toxicity is
observed in less than 10% of patients, whereas 50% experience
stabilization of disease at 1 year.
Hemibody radiation is currently rarely used for the treatment of
metastases due to the potential toxicity to the visceral structures and the
difficulties in treatment setup. Concerns regarding the permanent effects
on bone marrow reserve also exist relative to the subsequent need for
chemotherapy.

RADIOPHARMACEUTICALS
An alternative to hemibody irradiation for the treatment of widely
disseminated bone metastases is the use of systemic radioisotopes. The
most commonly used radiopharmaceutical in the treatment of bone
metastases is strontium 89. Strontium 89 combines with the calcium
component of hydroxyapatite in osteoblastic lesions. Many studies report
effective palliation of pain lasting more than 6 months in 60% to 80% of
patients with breast and prostate cancers.162–176 Improvements in
functional status and quality of life have been observed, and approximately
20% of patients have complete resolution of pain. Pain control has been
reported to be superior among patients with disseminated prostate cancer
treated both with strontium 89 and local radiotherapy as compared with
localized irradiation alone.165 Myelotoxicity resulting in 25% reduction of
platelet and white blood cell counts represents the only significant toxicity
associated with strontium 89, which is usually transient and reversible
within 12 weeks.177,178 Hematotoxicity is more pronounced in patients
with pretreatment platelet counts of less than or equal to 60 × 103, white
blood cell counts of less than or equal to 2.5 × 103, or greater than or equal
to 30% involvement of the red marrow–bearing bone. The radiation dose
absorbed by the bone marrow is 2 to 50 times less than the dose
administered by strontium 89 to the osteoblastic lesion. Radiation doses to
metastatic bony lesions with strontium 89 can range from 3 to more than
300 Gy.
Clinical response to strontium 89 is comparable with wide-field
radiotherapy. Response to strontium 89 therapy has been documented both
subjectively and objectively. Subjective response, manifested as

2482
symptomatic improvement, was reported by more than 80% of prostate
cancer patients using a validated self-reporting tool. Objective evidence of
response was documented by reductions in alkaline and acid phosphatase
levels that corresponded with a decrease in evidence of active metastatic
disease on sequential bone scans.179 Prior therapies for prostate cancer,
including local radiation therapy and systemic chemotherapy or hormone
therapy, do not influence toxicity or affect clinical response to strontium
89. Administered as an adjuvant to localized external beam radiotherapy in
metastatic prostate cancer, strontium 89 has been shown to improve pain
relief, reduce analgesic requirements, and delay progression of disease in
prospective randomized clinical trials. Quality-of-life assessments
demonstrated increased physical activity along with improved pain relief
after strontium 89 was administered in conjunction with localized external
beam radiation therapy.180,181 Cost–benefit analysis has also suggested an
advantage to the administration of strontium 89 with reductions in costs of
hospitalization for tertiary care.
Several other radiopharmaceuticals are available for clinical application
including samarium 153, gallium nitrate, phosphorus 32, and rhenium
186.182–184 The therapeutic mechanism of action relates to the physical and
biologic half-life in the bony lesion, the mean energy, and the delivered
dose of the radiopharmaceutical. Table 48.3 summarizes some of the
physical characteristics and clinical data for various radionuclides.
Phosphorus 32 and strontium 89 emit pure β-rays (little penetration in
tissue), whereas rhenium 186 and samarium 153 emit both β-rays and
relatively high-energy γ-ray photons that penetrate tissue for some distance
(103 to 159 keV).

TABLE 48.3 Physical Characteristics and Clinical Data for

Radionuclides
Duration
of
Half-life β-Energy γ-Energy Response Response
Radionuclide (Days) (MeV) (keV) Rate (%) (mo) Toxicity
32P 14.26 1.7 0 77 5.1 Moderate
89Sr 50.53 1.5 0 80 3–6 Low
117mSn 13.61 0.16 159 NR NR NR

2483
 1.1 1.3
186Re 3.78 0.9 137 77 — Low
0.8
153Sm 1.95 0.7 103 65 4 Low
0.6
32P,
phosphorus 32; 83Sr, strontium-89 chloride; 117mSn, 117mSn(4+)diethylenetriaminepentaacetic
acid; 186Re, rhenium 186; 153Sm, samarium 153; NR, no response.
Data from Lam MG, de Klerk JM, van Rijk PP, et al. Bone seeking radiopharmaceuticals for
palliation of pain in cancer patients with osseous metastases. Anticancer Agents Med Chem
2007;7(4):381–397; Liepe K, Kotzerke J. A comparative study of 188Re-HEDP, 186Re-HEDP,
153Sm-EDTMP, and 89Sr in the treatment of painful skeletal metastases. Nucl Med Commun
2007;28(8):623–630; and Bouchet LG, Bolch WE, Goddu SM, et al. Considerations in the
selection of radiopharmaceuticals for palliation of bone pain from metastatic osseous lesions. J
Nucl Med 2000;41(4):682–687.

Because samarium 153 has a γ-ray component, it is possible to directly

image the distribution of the radiation dose. The scans after injection of
samarium 153 are comparable to diagnostic scans obtained with
technetium 99m. The mean skeletal uptake is over 50% of the dose.175
Nonskeletal sites receive negligible radiation doses, and complete
clearance of radionuclide other than that absorbed by bone occurs within 6
to 8 hours of administration.174 In a double-blind placebo-controlled
clinical trial, samarium 153 has been shown to be an effective agent in
palliating painful bone metastases in breast cancer patients. Pain relief
occurred within 1 week and lasted at least 16 weeks after
administration.181,184 Approximately 65% of patients responded within the
first 4 weeks, and 43% to 72% had relief of pain of at least 16 weeks’
duration. No significant bone marrow toxicities have been observed.
Recommended doses range between 1.0 and 1.5 mCi/kg. In more than one-
third of patients, multiple administrations are possible.182 These
observations suggest potential suitability of this form of palliative therapy
for patients with both intermediate and limited life expectancies who are
not tolerating or responding favorably to other pain-relieving treatments.
Selectively concentrating in bone, the mechanism of action of rhenium
186 is similar to that of technetium diphosphonate 99m, which is used in
diagnostic bone scans. This characteristic allows direct imaging of the
deposition of rhenium 186 in bony metastases. The metastatic lesion
receives a highly concentrated dose of radiation after the administration of
rhenium 186, whereas the radiation dose to the marrow is limited to 0.75

2484
Gy. Thrombocytopenia appears to be the dose-limiting toxicity but is mild,
allowing therapy to be repeated.177 Phosphorus 32 has 77% of patients
experiencing significant relief of pain.179 The response rates and duration
of response with phosphorus 32 are similar to wide-field radiation and
strontium 89. However, the main disadvantage of phosphorus 32 is severe
hematologic toxicity.
Clinical trials are ongoing to compare the conventional
radiopharmaceuticals with newer radiopharmaceuticals and their effect in
combination with bisphosphonates and chemotherapy. There is prolonged
survival benefit in patients with hormone refractory prostate cancer if
radiopharmaceuticals and chemotherapy are used in combination.185
Although bone marrow toxicity is relatively limited in the doses of
radiopharmaceuticals currently administered either alone or in
combination with other agents, future dose intensity studies may require
hematologic support with colony-stimulating factors.
Sequential radiography and bone scans after hormonal and
radiopharmaceutical therapy for breast and prostate cancers demonstrate
an osteoblastic response that reflects remodeling of the bone in osteolytic
osseous metastases.61,62 Approximately one-third of patients have
evidence of increased tracer uptake on bone scans (flare) obtained 8 to 16
weeks after treatment. Of these patients with a flare response on bone scan,
72% experience a response to the treatment. By comparison, only 36%
have a response to treatment when a limited response or no flare response
is observed.
Relapse of disease has been associated with an increase in the osteolytic
component. Osteoclast resorption in bone metastases is associated with the
release of acid and acid-dependent proteases that dissolve the organic
matrix of the bone. Gallium nitrate has been shown to inhibit accelerated
bone turnover among patients with widespread bone metastases and has
been clinically applied in the treatment of hypercalcemia. Preferentially
accumulating in the cortical surface, which is the most metabolically
active region of the bone, gallium nitrate acts to inhibit osteoclast
resorption. Additionally, gallium nitrate increases the absorption of
calcium and phosphorus and the incorporation of collagen into the bone.

2485
Role of Palliative Chemotherapy
Chemotherapy can be used as an adjuvant to radiotherapy and/or surgery
or as part of a combined antineoplastic regimen for primary treatment.
Systemic chemotherapy has the advantage of ubiquitous distribution
throughout the body, wherever the bloodstream might take a cancer cell.
Thus, adjuvant chemotherapy is used in patients who appear cured after
surgery but are suspected of having residual disease or micrometastasis.
Adjuvant chemotherapy has proven effective in node-positive breast
cancer, Dukes’ B2 and C colorectal carcinoma, stage III ovarian
carcinoma, testicular carcinoma, non–small-cell lung cancer, Wilms’
tumor, osteogenic sarcoma, and anaplastic astrocytoma.186
Neoadjunct chemotherapy is used as initial chemotherapy in cancers
that would be only partially curable by surgery or radiation. It is often
administered with anal cancer, bladder cancer, esophageal cancer,
laryngeal cancer, locally advanced non–small-cell lung cancer, and
osteogenic sarcoma. The goals of this therapy are to (1) decrease the size
of the tumor to be removed or radiated, (2) increase the likelihood that the
tumor will be surgically extricable, and (3) decrease the likelihood of
micrometastatic spread/seeding at the time of surgery.186 Systemic
chemotherapy is the primary treatment for disseminated/metastatic
malignant disease.
Based on the mechanisms mentioned earlier, the goal of systemic
chemotherapy is to interrupt the division of rapidly dividing cancer cells. It
is usually administered in multiple (usually 4 to 6) cycles every 3 to 4
weeks. The timing and dosing of chemotherapy are established to
maximize malignant cell kill while at the same time not exceeding the
body’s ability to regenerate the normally rapidly dividing cells that are
“innocent bystanders” of the cytotoxic effects of chemotherapy, namely,
the bone marrow progenitors, gastrointestinal epithelial cells, and hair
follicles. The predominant effect of chemotherapy on the intestinal tract
occurs in the first few days to a week after administration, whereas the
peak effect on the blood progenitor cells occurs 10 to 14 days posttherapy.
Thus, patients only require prophylactic antiemetics for the days around
therapy, but they “nadir” their blood counts, with variable risks of

2486
infection and bleeding, approximately 2 weeks after receiving treatment.
Regardless of the setting of administration (primary, adjuvant,
neoadjuvant, or combined modality), substantial evidence suggests that
combination chemotherapy with agents that have different mechanisms of
action as well as different (noncumulative) toxicities yields significantly
higher efficacy than single-agent chemotherapy. On the basis of an
extensive review of in vivo and in vitro laboratory research and clinical
experiences acquired during the 1950s and 1960s, DeVita and Schein187
developed a set of basic principles of combination chemotherapy for
cancer patients, and these are still the guiding principles today. Among the
most important of these principles are the following: (1) All of the
component drugs in a combination must have activity against the neoplasm
being treated; (2) drugs must be administered at dosages close to the
minimum effective dosage for each drug as a single agent or beyond, if
possible; (3) drugs that interrupt the synthesis of cellular macromolecules
at several sites can be combined for additive or synergistic effects on the
various synthetic pathways; (4) drugs in combination should have as little
cross-toxicity as possible; and (5) mechanisms of tumor cell resistance to
two agents in combination must not be similar.
Since 2006, the U.S. Food and Drug Administration (FDA) has
approved more than 110 new cancer drugs. Advances in therapeutic
regimens include a reduction in the risk of breast cancer recurrence with
more prolonged hormonal therapy and a regimen that significantly extends
survival in recurrent ovarian cancer. Other strategies have focused on
reducing adverse effects from cancer therapy without compromising
cancer control. Among these are shortening the duration of adjuvant
chemotherapy for stage III colorectal cancer. With improvements in cancer
therapy, a 25% decline in cancer death rate has been achieved since its
peak in 1991.188–190
For all tumor sites, a high prevalence of moderate to severe symptoms
was experienced by 120,745 cancer patients during the first year after
cancer diagnosis. In the 729,861 symptom surveys conducted between
2007 and 2014 in patients who survived at least 1 full year after cancer
diagnosis, the most symptoms were documented in the first month,
whereas elevated scores for nausea persisted up to 6 months after

2487
diagnosis. On multivariable analysis, cancer site, younger age, higher
comorbidities, female gender, lower income, and urban residence were
significantly associated with a higher symptom burden. Consistent with
other studies, greater symptom burden occurred in patients with respiratory
and oropharyngeal cancers. Younger patients have a greater likelihood of
receiving more aggressive therapies, an increased prevalence of advanced-
stage cancers, and/or higher expectations for functioning and the
resumption of their roles prior to the cancer diagnosis.191
Also in the first year after diagnosis, a 71% hospitalization rate was
documented for 25,032 patients who were treated for advanced cancer
between 2009 and 2012. Hospital admission was prompted through the
emergency department in 64% of cases, and 16% of patients were
hospitalized three or more times during the first year after cancer
diagnosis. Readmission rates were significantly associated with minority
status (race/ethnicity); public or no insurance; lower socioeconomic status;
comorbidities; and pancreatic, non–small-cell lung, or colorectal
cancers.192
The goal of personalized medicine is to have systemic therapies
selectively target tumor cells located in any site while sparing normal
tissues/organs from the toxicity of antineoplastic therapy. Significant
advances have been accomplished in systemic therapies within the realm
of precision medicine. These advances have resulted in two out of three
cancer patients living at least 5 years after diagnosis, and an increased 10-
year cancer survival rates to 64% in 2005 from 35% in 1975. From
November 2016 through October 2017, the FDA approved 31 new
therapies for more than 16 types of cancer. Adoptive cell immunotherapy
allows genetic reprogramming of a patient’s own immune cells to find and
attack cancer cells throughout the body. Chimeric antigen receptor (CAR)
T-cell therapy has resulted in significant advances in pediatric acute
lymphoblastic leukemia (ALL), and adult lymphoma and multiple
myeloma.188–190
The FDA approved the first adoptive cell immunotherapy in August
2017 for ALL. In May 2016, the FDA gave accelerated approval to a
second CAR T-cell therapy, an immune checkpoint inhibitor for
previously treated urothelial cancer that progressed despite platinum-based

2488
chemotherapy. Throughout 2017, the FDA approved four other immune
checkpoint inhibitors. One checkpoint inhibitor, pembrolizumab, resulted
in a 3-month survival improvement while the adverse effects were three
times lower for pembrolizumab than the chemotherapy group (15% vs.
49%) in a major clinical trial. Based on these results, especially because
two-thirds of patients are not eligible for cisplatin-based chemotherapy due
to physical frailty, immunotherapy is now being considered as an initial
treatment for advanced bladder cancer. In October 2017, an immune
checkpoint inhibitor became the first cancer treatment to receive a tumor-
agnostic indication. This accelerated FDA approval allows treatment of
any type of solid tumor that has mismatch repair deficiency a defect that
undermines the cell’s ability to repair DNA damage.188–190 Biomarkers
ideally should temper the socioeconomic cost for administration of
checkpoint inhibitors and other adoptive cell immunotherapies. Tumors
with a large number of mutations are generally more susceptible to
checkpoint inhibitors as mutations make more abnormal proteins
(antigens) that the immune system recognizes as foreign.193
Although more traditional systemic therapies continue to be routinely
administered, advances continue within personalized medicine. More
traditional chemotherapy administered for palliative effect is then
displaced by a novel agent that not only may be less toxic but also offers
hope to reverse the course of disease from palliative back to curative
intent. The two issues that exist in palliative chemotherapy involve
whether a meaningful improvement in quality and the length of life can be
achieved and the socioeconomic cost.
Breakthrough designated cancer drugs receive faster FDA approval.
Between 2012 and 2017, the FDA approved 58 new cancer drugs; 25
(43%) of these drugs were approved through breakthrough therapy
designation. Breakthrough therapy-designated drugs were not more likely
to act via a novel mechanism of action. The median time to first FDA
approval was 5.2 years for breakthrough designation versus 7.1 years for
the routine approval process. Rates of death and serious adverse events
were also similar in FDA approval through breakthrough designation and
routine process. Additionally, no statistically significant difference in
median progression free survival was found between drugs approved

2489
through the routine and the breakthrough designation (4 months vs. 8.6
months; P = .11).194
The issues of survival and quality of life will be borne out of expanded
clinical experience with these novel agents. Although greater clinical
experience may better define the indications for the agent, the same
unwillingness to abandon hope for a cure will invariably be encountered.
As was the experience when novel chemotherapeutic agents became
available, patients would seek the hope offered by a newer
chemotherapeutic regimen. The American Society of Clinical Oncology
Value Framework and the European Society of Medical Oncology
Magnitude of Clinical Benefit Scale evaluated the clinical benefits of
novel anticancer drugs relative to increasing costs. Anticancer drugs from
42 phase III randomized controlled trials cited for clinical efficacy
evidence in drug approvals between January 2006 and December 2015
were scored according to this value framework. Both monthly prices and
incremental anticancer drug costs increased and were significantly
associated with the year of approval, 9% and 21%, respectively. The mean
incremental anticancer drug cost increased fivefold from $30,447 in 2006
to $161,141 in 2015; however, the clinical benefits of these drugs did not
correlate with a proportional positive change.195
There are many factors responsible for the limited efficacy of
chemotherapy in these tumors. First, the cellular biology of these solid
tumors that often produce pain is such that they have limited response to
current drug regimens. Second, the size of the tumor is inversely related to
the incidence of satisfactory drug penetration into the mass. As a general
principle, the larger the mass, the poorer the cytotoxic response.
Furthermore, given that these tumors generally do not exhibit long-term
responses to first-line therapy, additional therapy with second- or third-line
drug treatments often yields a minimal (usually less than primary therapy)
response rate. Finally, in certain target sites (e.g., head and neck, pelvis),
prior radical surgery and/or prior radiation therapy impair the vascular
supply to the tumor bed, thus interfering with delivery of an effective drug
concentration to the target site.
Because this group represents the most challenging to demonstrate
objective response rates to chemotherapy, it is the ideal patient population

2490
in which to demonstrate a purely palliative benefit of chemotherapy,
represented by decreases in pain, dyspnea, and fatigue and increases in
performance status, appetite, and weight gain. A few investigators have
pursued these outcome measures with meaningful results. The initial FDA
approval of gemcitabine was granted not by data showing its benefits on
overall survival or objective response rate, but by improvements in pain
control, weight gain, and performance status in patients with pancreatic
cancer.

CLINICAL APPLICATIONS
Conventionally, efficacy of chemotherapy is defined by an objective
decrease in the radiographic size of the tumor (usually by CT). A CR
represents total disappearance of all observable disease for a minimum of
1 to 3 months, depending on the criteria used, whereas a PR represents a
decrease in measurable tumor size by at least 50%. Overall response rate
for a given regimen is the combination of CR + PR, and a significant
response rate translates into an improved survival of responders compared
with nonresponders. It also translates into relief of pain related to the
tumor mass—although pain relief from chemotherapy has rarely been the
endpoint of clinical trials.

PALLIATIVE CHEMOTHERAPY
The category that falls between an objective response and progressive
disease, in which the tumor neither shrinks nor grows in the face of active
anticancer therapy, is referred to as stable disease. Whether or not there is
any pain-relieving benefit to the administration of chemotherapy in the
setting of stable disease is undetermined. Although there is speculation
about the role of chemotherapy in altering peripheral sensory nerve
function, thereby producing analgesia as well as relieving pain by altering
the “tumor-host milieu,” these hypotheses have been tested in limited
trials.196–199 In the absence of empirically proven outcomes, clinical
observations suggest that “systemically administered cytotoxic drugs do
not relieve cancer pain in the absence of tumor regression.”196 Tumor
regression is a function of responsiveness to a given chemotherapeutic
regimen. Tumor variables that determine the course of chemotherapy and

2491
prognosis for response rate include histologic type (squamous cell
carcinoma, adenocarcinoma, germ cell, lymphoma, etc.), grade (high,
intermediate, low), and the degree of differentiation (well differentiated,
poorly differentiated).
In general, the more rapidly growing the tumor, the more frequent its
cellular division; therefore, the cells are more potentially responsive to
cytotoxic therapy: In these cases, intervention can lead to increased pain
control, long-term survival, and, potentially, cure. Those rapidly growing
tumors that are chemotherapy-resistant tend to be imminently fatal.

LYMPHOMA
Compared with other solid tumor types, Hodgkin and non-Hodgkin
lymphomas (NHLs) tend to respond better than most to combination
chemotherapy. For Hodgkin lymphoma, there are several active regimens,
but the preferred treatment regimen of doxorubicin, bleomycin,
vinblastine, and dacarbazine is highly active and produces a complete
remission rate that varies from 98% for early-stage disease (overall
survival of more than 93% at 6 years) to 82% for advanced stage disease
(overall survival of 73% at 6 years).200 The therapeutic effect of this
combination regimen is rapid, even in advanced cases, providing prompt
pain relief in those patients who have pain (although this has never been a
primary endpoint of clinical trials), with observed resolution of other
symptoms and signs as well. In NHL, there is a larger variability based on
histology, with high-grade NHL being significantly more responsive to
therapy than low-grade types. For high-grade NHL, treatment with a
variety of combination chemotherapy regimens (e.g., bleomycin,
doxorubicin, cyclophosphamide, vincristine, and prednisone;
cyclophosphamide, doxorubicin, vincristine, and prednisone; or others
with antibody therapies with rituximab) produces a 79% event-free
survival.201–203 Again, no studies of NHL have examined pain as a
primary endpoint, although pain remits in concert with active disease.

BREAST CANCER
In moderately chemosensitive tumors, the results obtained with the various
chemotherapeutic combinations are less favorable (30% to 60% response

2492
rates), and in general, the therapeutic effect is slower in onset. Small-cell
lung cancer, for example, tends to be quite aggressive, and combination
chemotherapy regimens with cisplatin and etoposide or cyclophosphamide,
doxorubicin, and vincristine can induce an objective response in
approximately 60% of cases, with CR occurring in approximately 10%.
Again, this and other studies have not attempted to quantify relief from
pain or dyspnea in small-cell lung cancer.
The course of recurrent or metastatic breast cancer follows two
dominant pathways. The hormone receptor–positive tumors tend to occur
in older (postmenopausal) women and follow a more indolent course when
treated with hormone therapy, with bone as the most common metastatic
site. The hormone receptor–negative tumors tend to occur in younger
(premenopausal) women and follow a more aggressive course, with
visceral and soft tissue involvement that is usually responsive to
chemotherapy. Conventional chemotherapy includes cyclophosphamide,
methotrexate, and prednisone and has been shown to improve quality of
life. Anthracycline-containing regimens have been shown to be superior to
cyclophosphamide, methotrexate, and prednisone. Single agents that
contain taxanes (docetaxel, paclitaxel, and protein-bound paclitaxel),
capecitabine, gemcitabine, or vinorelbine have been shown to be as
effective in improving survival and quality of life as combination
chemotherapy in metastatic breast cancer.204–206 Trastuzumab, alone or in
combination in human epidermal growth factor receptor 2 (HER2)/neu–
positive patients, has been shown to increase survival. Yet again, it is
noteworthy that given the prevalence of recurrent breast cancer, few
studies have specifically addressed quality-of-life issues and that even
fewer address symptomatic benefits of therapy.
A British study evaluating patients with advanced breast cancer who
received first-line palliative chemotherapy (a variety of regimens) did have
primary palliative (subjective patient-centered) outcomes that were
assessed by using the Rotterdam Symptom Checklist. In this study, one-
fourth of the patients (26%) felt better after having received chemotherapy,
with statistically significant decreases in psychological distress, pain, and
improvement in lack of energy and sense of tiredness. As might be
expected, feeling better correlated with disease response (P = .03).206

2493
HEAD AND NECK CANCER
Head and neck cancer is one of the most challenging disease sites to treat.
Cisplatin and 5-fluorouracil (5-FU) make the tumor more responsive to
radiotherapy, and this is the standard accepted multimodal regimen that
has been shown to increase survival. In fact, studies have shown that
combination chemotherapy with cisplatin and 5-FU, hydroxyurea and 5-
FU, and taxanes like pacletaxel and cisplatin followed by radiation have all
increased survival by 50% to 60%.207,208 Chemotherapy with a single
agent like cisplatin or carboplatin followed by radiation is also being
investigated.209 These aggressive regimens have potential toxicities and
twice-a-day radiotherapy with concomitant chemotherapy have shown
improved regional control, survival, and improved quality of life.210

OVARIAN CANCER
Finally, ovarian cancer is one of the more sensitive malignancies to
cytotoxic chemotherapy. Combination regimens in which a platinum-based
agent (cisplatin or carboplatin) is used achieve overall response rates of
60% to 80%. Newer agents, most notably the taxanes, also have significant
activity in ovarian cancer, with overall response rates of 20% to 40%. The
combination of carboplatin and paclitaxel has demonstrated superior
response rates and has become the standard of care for ovarian cancer
amenable to chemotherapy.211–212 Doyle et al.213 showed that although
objective responses are low with palliative chemotherapy, active palliation
with chemotherapy is associated with substantive improvement in patients’
emotional function and global quality of life.
In 2016, the FDA approved a regimen of bevacizumab to standard
platinum-based chemotherapy when the addition of bevacizumab
significantly extended median time to progression of disease to 13.8
months from 10.4 months with chemotherapy alone. Although not
statistically significant, overall survival was also longer with bevacizumab
being 42 months versus 37 months, respectively. Severe adverse effects
occurred in 96% of bevacizumab compared to 86% of the chemotherapy-
alone group.188–190 The FDA approved a maintenance treatment in 2017
for ovarian cancer based on a clinical trial in which olaparib, a poly
(adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitor,

2494
markedly slowed ovarian cancer progression of disease (19.1 months vs.
5.1 months).

LUNG CANCER
Non–small-cell lung cancer is the most prevalent cancer type, and
combinations of chemotherapeutic drugs like vinorelbine, gemcitabine,
docetaxel, and paclitaxel provide modest survival and probable quality-of-
life benefit in a significant number of patients when contrasted with best
supportive care.214–217 These agents show response rates in the 11% to
25% range when combined with platinum-based therapy. No study has
examined the effects of therapy on pain or dyspnea, although a few have
evaluated improvements in performance status and weight gain.217
However, oral topotecan has been shown to improve pain, dyspnea, sleep,
and fatigue, as well as increased survival, in patients with recurrent small-
cell lung cancer compared with best supportive care. Even when early
palliative care is performed, patients with metastatic non–small-cell lung
cancer receive similar number of chemotherapy regimens. The early
palliative care group, however, had half the odds of receiving
chemotherapy within 60 days of death. There was also a longer interval
between the last dose of intravenous chemotherapy and death in the early
palliative care group (median 64 days vs. 40.5 days) and a higher hospice
care enrollments for more than 1 week (60% vs. 33.3%; P = .004).218

GASTROINTESTINAL CANCERS
For gastrointestinal malignancies, the role of palliative chemotherapy is
limited. The fluoropyrimidines (5-FU and its derivatives) are the
conventional agents with demonstrated efficacy in gastrointestinal
malignancies. 5-FU has resulted in disappointingly low response rates of
approximately 20%.219 In a large study of more than 400 patients
conducted by the North Central Cancer Treatment Group,220 70% of
patients who received 5-FU/low-dose leucovorin had improvements in
performance status and weight gain; there was no assessment of pain as a
primary endpoint. The combination of 5-FU and leucovorin with agents
like oxaliplatin (FOLFOX) and irinotecan (FLOFIRI) have shown
improvement in quality of life.219–223

2495
 In pancreatic cancer, the approval of gemcitabine for pancreatic cancer
was based on the palliative endpoint of “clinical benefit” over the
conventional 5-FU therapy. In this study, clinical benefit was defined by a
composite of pain, performance status, and weight gain.177 This was one
of the first studies to directly assess the primary endpoint of pain via
patient report of pain intensity together with analgesic consumption.
Several recent systematic reviews have shown that gemcitabine-based
combinations have shown improved survival as well as quality of
life.224,225

PROSTATE CANCER
Prostate cancer is yet another prevalent disease that is poorly responsive to
conventional chemotherapy. There is more palliative endpoint evidence
supporting the use of chemotherapy in prostate cancer than any other
disease in part because it is a slow-growing tumor that tends to cause
significant pain and disability for a prolonged period of time. The most
widely discussed study is Tannock’s Canadian study that used
mitoxantrone and prednisone for hormone-refractory metastatic prostate
cancer where the primary endpoint was pain relief.226 In this study, pain
relief was again defined differently from previous studies as a “2-point
decrease in pain as assessed by a six-point pain scale . . . without an
increase in analgesic medication and maintained for two consecutive
evaluations at least 3 weeks apart.” They found that this chemotherapy
combination produced a positive effect above the benefit of prednisone
alone in 29% of patients, with a 50% decrease in analgesic requirements.
Other studies suggest the positive impact of docetaxel-based chemotherapy
in providing relief of pain in hormone-refractory metastatic prostate
cancer.227,228 Androgen deprivation therapy (ADT) for metastatic prostate
cancer plus docetaxel or abiraterone in newly diagnosed metastatic
noncastrate prostate cancer offers a survival benefit as compared to ADT
alone. The strongest evidence of benefit for docetaxel was for men with de
novo metastatic disease or high-volume disease (defined as four or more
bone metastases, one of more of which were outside the spine or pelvis
and/or the presence of any visceral disease).188–190,229

2496
DECISION MAKING ABOUT CHEMOTHERAPY
The diagnosis of cancer is often quite traumatic for both the patient and the
family. On the one hand, the administration of chemotherapy is, by
definition, cytotoxic—to malignant cells as well as normal host cells. On
the other hand, the risks of not treating the disease are also quite
significant. Given the fact that pain is a prevalent feature of both early- and
advanced-stage cancer—present in nearly 50% of patients with early-stage
disease and in 70% to 90% of cases of advanced cancer—the challenge is
to strike a balance between therapeutic and toxic (including fatal) effects
of chemotherapy. Thus, it is imperative that an interdisciplinary team of
clinicians with expertise in oncologic surgery, radiation therapy and
medical oncology, nursing, palliative medicine, and pharmacology
evaluate patients to determine the treatment plan that is likely to provide
the greatest cumulative benefit for the patient. If, as ought to be the ideal,
the patient is always to be kept at the center of the decision-making
process, then studies that assess patient-centered outcomes (pain, dyspnea,
fatigue, appetite, weight loss, performance status, anxiety, well-being, and
other quality-of-life measures) for chemotherapy merit a higher priority.
Newer targeted therapies need to be evaluated for benefits related to
reduction of symptom burden from neoplastic disease. Although it is
generally accepted that patients with a poor performance status do not
usually benefit from systemic chemotherapy, it is not known whether the
response to newer targeted agents will shift this paradigm.
An additional challenge for the medical oncologist is decision making if
first-line chemotherapy fails to control the tumor. For some disease types,
there is clear objective benefit from second-line therapy. For many,
however, second-line therapy is more likely to lead to enhanced
cumulative toxicities rather than objective tumor response.
Oncology patients have among the highest rates of hospitalization,
especially near the end of life. Changes in reimbursement policies result in
losses to hospital systems with unplanned readmissions within 60 days of
hospital discharge. In one cancer institute, 6% of all discharged patients
accounted for more than 40% of unplanned readmissions. The use of
hospital resources included ICU stay, emergency department visits,
overuse of chemotherapy, and under use of hospice care. Instituting an

2497
interdisciplinary care team (ICT) was created to evaluate patients, on a
bimonthly basis, with at least two unplanned hospital readmissions over
the last 60 days. Over a 6-month period, 36 patients had 226
hospitalizations and 163 emergency department visits, resulting in an
average number of hospitalizations of 1.08 per patient month (ppm);
hospitalizations dropped to 0.23 ppm after implementation of the ICT.
After the creation of the ICT, the average length of stay decreased from
7.17 to 4.06 days per admission, the average emergency department visits
decreased from 0.58 to 0.34 ppm, and the average number of unplanned
readmissions decreased from 0.43 to 0.13 ppm. Average time to death was
72 days, and time to death from the last exposure to chemotherapy was 58
days after institution of the ICT. Financial incentives for hospital systems
have made a major impact on the aggressiveness of care at the end of
life.230
A retrospective analysis of the hospital stay, lasting at least 3 days, was
conducted in 695 adult cancer patients who died in the hospital. Prior to
hospital admission, 21% had received outpatient palliative care (OPC),
46% inpatient palliative care (IPC), and 33% no palliative care (NPC).
Despite the differences in the care prior to hospital admission, no
differences were identified in the care administered during the final
admission; 11.2% of patients received radiation therapy, and 12.5%
received antineoplastic therapy. In the last 3 days of life, imaging tests
occurred in 50.1% patients; imaging tests were obtained in fewer palliative
care patients (43.5% OPC; 47.3% IPC) than the 58.1% who received NPC.
Radiation therapy was administered in 11.2%, and approximately 16% of
all patients received chemotherapy within 14 days of death among the
study groups. All patients received pain medications. Do-not-resuscitate
orders were in place within 6 months before the final admission at a
greater rate for OPC patients (22%) than for IPC (8%) and those with NPC
(12%).231
A sensitive and thoughtful discussion with the patient and the family
regarding the goals and priorities of care is needed. Emphasis must be
placed on the ability to successfully manage the symptoms of progressive
advanced disease with nonchemotherapeutic modalities when burdens are
likely to outweigh benefits.

2498
SIDE EFFECTS AND COMPLICATIONS
The toxicities and side effects of chemotherapeutic agents, such as nausea,
are commonly known. Perhaps the most common painful sequela of
chemotherapy administration is a toxic peripheral neuropathy manifested
as painful paresthesias, hyporeflexia, and, less frequently, sensory or
motor loss or autonomic dysfunction. The drugs most commonly
associated with this complication are the plant alkaloids, especially
vincristine; antimetabolites; the taxanes, especially paclitaxel; and
platinum-based compounds like cisplatin; vinorelbine, procarbazine, and
interferon.196–198,232,233 In some cases, the painful peripheral neuropathy
not only limits the dosing of anticancer therapy but also significantly
affects quality of life and can be more difficult to treat than the more
common nociceptive pain syndromes associated with the disease.
Dermatologic complications can occur from extravasation of
chemotherapeutic agents into the subcutaneous tissues. This is especially
problematic with drugs like vinca alkaloids, anthracyclines, and taxanes
that cause severe local pain and ulceration with progressive tissue
destruction.197
Another painful complication of cancer and its therapy is acute herpes
zoster and postherpetic neuralgia, which occur with increased frequency in
patients with cancer—especially in those receiving chemotherapy or
immunosuppressive drugs. Lastly, although the palliative benefits of
glucocorticoids on mood, pain (as an anti-inflammatory coanalgesic), and
appetite are well-known, chronic steroid therapy can cause myopathy, as
well as necrosis of the femoral and humeral heads.234 Furthermore, one
should be aware of the fact that withdrawal of glucocorticoids can cause a
sense of decreased well-being, with increased pain, decreased energy, and
apathy.235

Endocrine Therapy
Many types of tumors have been shown to respond to hormonal
manipulation, which is achieved either by ablating endocrine glands or by
administration of an exogenous hormone or hormone antagonist. The
mechanism of action of these agents has been clarified by the

2499
demonstration that receptors that bind with estrogen exist in the cytosol of
normal and malignant cells. Hormones bind to receptors in the cytoplasm
and sterically alter the shape of the receptive protein itself, which, after
transport to the cell nucleus, interacts with DNA, and results in altered
messenger RNA production and protein synthesis. After this interaction,
cytoplasmic receptor concentration is restored and the cycle can be
repeated. Estrogen receptors can be quantitated as 8S and 4S proteins.
Primary tumors in humans have estrogen receptor values that range from 0
to almost 1,000 fmol/mg cytosol protein. Receptors also exist for
progesterones and androgens, and receptors for corticosteroids have been
identified in the cytosol of leukemic cells.
Hormonal ablation can be achieved by surgical means, as occurs with
oophorectomy, adrenalectomy, and hypophysectomy; by irradiation of the
ovaries or ablating the pituitary gland with the various radioactive
compounds; by injecting alcohol; or by surgical extirpation. Medical
adrenalectomy can be achieved by administering aminoglutethimide, a
potent inhibitor of the conversion of cholesterol to pregnenolone in the
adrenal gland. Hormone additive therapy is achieved by the administration
of estrogens, progestins, androgens, antiestrogens, corticosteroids, and
thyroid hormones. Such hormone changes can cause complex endocrine
effects, such as pituitary inhibition of luteinizing hormone, follicle-
stimulating hormone, and prolactin, as well as changes in endogenous
steroid hormone production.199

ENDOCRINE THERAPY FOR RELIEF OF CANCER

PAIN
The first reports of the efficacy of hormonal therapy on relieving cancer
pain were correlated with tumor regression. A significant number of other
studies only reported the reduction in tumor volume without also assessing
pain relief.
Two large clinical trials were conducted in 2016 in hormone receptor–
positive early breast cancer patients with the aromatase inhibitor letrozole.
Compared to the recommended standard length of therapy was 5 years, the
clinical trials found that 10 years of letrozole reduced breast cancer
recurrences or a new cancer in the opposite breast by one-third. Despite

2500
these improvements in outcomes, longer hormonal therapy did not
improve overall or disease-free survival in these trials. In 2017, the 5-year
disease-free survival was improved to 83% when anastrozole was
prescribed for 6 years after tamoxifen therapy.188–190

Bisphosphonates
Bisphosphonates have significantly reduced skeletal-related events (SREs)
such as pathologic fracture, spinal cord compression, or the necessity of
radiation or surgery to reduce the morbidity of bone metastases.
Zoledronic acid (ZA), a third-generation aminobisphosphonate, reduces
the risk of SREs by 40%; after an initial 9 to 12 monthly doses, ZA is then
administered every 3 months. Denosumab, a human monoclonal antibody
that inhibits osteoclasts by binding to the receptor activator of kappa B
ligand, delays the onset of first and subsequent SREs more than ZA.236
The American Society of Clinical Oncology and Cancer Care Ontario
guidelines indicate that breast cancer patients with bone metastases should
be treated with bone modifying agents. Options include denosumab (120
mg subcutaneously every 4 weeks), pamidronate (90 mg intravenously
every 3 to 4 weeks), or ZA (4 mg intravenously every 12 weeks or every 3
to 4 weeks). These agents are most effective in reducing the incidence of
SRE and should not be used alone for bone pain.237

Summary
Sophisticated local and novel systemic therapeutic approaches are being
developed to better localize or personalize treatment. In palliative
radiotherapy, SRT (and to a lesser degree proton therapy) localizes
radiation to the tumor, often allowing for repeat radiation near critical
structures like the spinal cord. Novel systemic therapeutic approaches
include adoptive cell immunotherapy. Using few high-dose radiation
fractions, SRT is an accepted tool in palliative radiation therapy for
specific indications, and single-fraction radiation therapy is now an
accepted alternative to longer courses of palliative radiation. Although a
sophisticated radiation technique is used to address a difficult clinical
presentation, the palliative goals remain aligned. In contrast, novel

2501
systemic therapies, like adoptive cell immunotherapy, continue to provide
hope for curative intent even in advanced disease. Although the
therapeutic mechanisms of adoptive cell immunotherapy are novel, the
paradigm of curative intent for the patient, despite advanced disease,
remains unchanged. Furthermore, these therapeutic innovations have
substantial socioeconomic costs.
Despite the development of palliative care teams that become involved
early in the course of cancer care, much futile therapy continues to be
administered. Palliative care teams have had some success in reducing
chemotherapy administration in the last 14 days of life, increasing hospice
placement, and reducing hospital admissions and readmissions in the last
60 days of life. However, palliative care teams are not available within all
health systems, and decisions regarding antineoplastic therapy remain
largely unchanged.
Therapeutic decisions for cancer care become more difficult as the stage
of cancer advances. These therapeutic decisions are largely based on the
patient’s preferences and performance status, availability of novel
therapies, and the availability of supportive care.

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CHAPTER 49
Cancer Pain in Children
ROY L. KAO, LONNIE ZELTZER, and JACQUELINE CASILLAS

Overview of Childhood Cancer

EPIDEMIOLOGY
Worldwide, cancer is diagnosed in approximately 300,000 children under
age 20 years each year, and childhood cancer contributes to 80,000 deaths
per year.1 In the United States, almost 16,000 cases of cancer are
diagnosed each year in children aged birth to 19 years, contributing to
almost 2,000 deaths per year.2 As recently as the 1970s, a diagnosis of
cancer during childhood was considered a uniformly fatal disease.
However, through enrollment in clinical trials available through
cooperative pediatric oncology groups, as well as advances in supportive
care, 5-year overall survival rates in childhood cancer are now over 80% in
the United States.3 The 12 major diagnostic categories of childhood cancer
in The International Classification of Childhood Cancers, third edition
(ICCC-3) include (1) leukemias and myeloproliferative and
myelodysplastic diseases, (2) lymphomas, (3) central nervous system
(CNS) neoplasms, (4) neuroblastoma and other peripheral nervous cell
tumors, (5) retinoblastoma, (6) renal tumors, (7) hepatic tumors, (8)
malignant bone tumors, (9) soft tissue and other extraosseous sarcomas
(e.g., rhabdomyosarcoma), (10) germ cell tumors, (11) other malignant
epithelial neoplasms and malignant melanomas (e.g., thyroid and
nasopharyngeal carcinomas), and (12) other unspecified malignant
neoplasms.4 Certain types of cancer are more common in specific age
groups of children. For example, acute leukemias, neuroblastoma, and
renal tumors are more common in the younger age groups (ages 2 to 6
years), whereas the malignant bone tumors and lymphomas are more
common during the adolescent years.

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TREATMENT
The dramatic improvements in overall survival in childhood cancer are due
to better supportive care and use of aggressive, multimodal treatment
strategies combining chemotherapy, radiation, surgery, and/or
hematopoietic stem cell transplant (HSCT). In addition, protein kinase
inhibitors, monoclonal antibodies, and other targeted therapies have
become part of standard therapy in some diseases.5 Because the majority
of pediatric cancer centers are participants in cooperative group clinical
trials, children with cancer are often treated uniformly through the use of
internationally available, standardized treatment protocols. There are
“roadmaps” that are followed by the treating pediatric oncologists and
communicated to the family and patient so that they know when to expect
the next cycle of chemotherapy, including when the next invasive
procedure can be anticipated to occur. As a result, there may be certain
periods of higher anxiety, resulting in greater pain for pediatric cancer
patients during the cancer treatment continuum as they anticipate the
upcoming procedures. However, with careful planning, an effective pain
management regimen can be developed and implemented.

SURVIVORSHIP
The end result of these aggressive treatment regimens for pediatric cancer
patients is a success story for the 21st century. The current estimated
survival rate for a pediatric cancer patient is 80%. The current number of
survivors within the United States is over 370,000.2,3 However, despite
these advances, there continues to be a high risk for the development of
chronic health conditions (late effects) years after the cancer treatment is
completed. Complications of treatment include risk for second malignant
neoplasms, cardiac and/or pulmonary dysfunction, skeletal problems, and
neurocognitive deficits.6 There is nearly a 75% risk of childhood cancer
patients having a chronic health problem by 30 years postdiagnosis.7 As
the population of childhood cancer survivors continues to grow, it is
important to be familiar with the unique challenges faced both during and
after completion of treatment for cancer during childhood.

Pain in Children: How Does This Differ from That in

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Adults?
The model of pain for the adult population is a comprehensive one
consisting not only of a physical domain but also psychological and social
domains—the biopsychosocial model. In children, the biopsychosocial
model of pain is more complex because the developmental level of the
child needs to be considered. Childhood is a period in which there are
complex and rapid neurodevelopmental changes occurring from birth to
young adulthood. Children grow and develop through five stages of
development: (1) infancy, (2) toddlerhood, (3) preschool period, (4)
school-age period, and (5) adolescence. These levels of development are
important because they directly impact the assessment and management of
pain in children. For example, it was previously believed that newborns
and infants could not experience pain because of immature neurologic
systems and only as the child developed could pain be experienced.
However, ongoing basic research has dispelled this myth, and newborns
and infants can experience pain and mount a stress response to noxious
stimuli. Furthermore, a noxious stimulus transmitted through neural
afferent systems to a newborn brain may even be experienced as more
painful than for an adult because the pain inhibitory system is not fully
developed at birth.

INFANTS–PRESCHOOL
From birth through early childhood, a normal developmental assessment
evaluates five main areas: gross motor skills, fine motor skills, language
skills, personal/social skills, and cognitive skills. Changes occurring in
these areas impact the pain assessment and emotional response of the child
to the painful stimuli. For example, the language skills of a 2-year-old
include a 50-word vocabulary and 2-word sentences. During this period, if
the child is unable to effectively communicate his or her pain sensation
and his or her pain is inadequately treated, there can be more fear and
anxiety with each subsequent painful procedure. One year later, at 3 years
of age, there is an expected 250-word vocabulary, 3-word sentences, and
speech is intelligible to strangers 75% of the time. This child may be able
to more effectively communicate with his or her parents and doctors and
have a treatment for the pain initiated more promptly, a factor related to

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these enhanced communication skills that can serve to decrease anxiety for
future procedures.

SCHOOL AGE–ADOLESCENCE
A school-age child will have a progressive ability to effectively
communicate with the health care team. In turn, the providers must clearly
communicate with the child about their treatment plan in order to
minimize the anxiety children can experience from medical interventions.
During adolescence, normal development of increasing desire for
autonomy necessitates direct communication by the health care team, not
only with parents but also directly with the adolescent based on the
adolescent’s desire for independent decision making (when possible).
However, in all levels of normal development, the impact of illness can
cause a pediatric patient to regress and become more dependent on his or
her parents to support physical and emotional needs, with parents often
providing the primary input to the health care team about children’s pain
and effectiveness of pain management. When possible, it is always helpful
for the health care team to also attempt to get the child or adolescent’s self-
report of pain.

Pediatric Cancer Pain

The vast majority of children with cancer do not have a chronic medical
condition at the time of diagnosis and therefore have not experienced
chronic or recurrent episodic pain. Instead, they have mainly interfaced
with the health care system for well-child checks with the associated
immunization schedules and for acute, intermittent self-limiting infections
or minor injuries. Thus, it is not surprising that the diagnosis and rapid
initiation of treatment of cancer can overwhelm a child with fear and
anxiety because of the number of invasive, painful medical procedures that
are required, but for which the child is not psychologically prepared. In
addition, acute pain associated with the first medical procedure at the time
of diagnosis can set expectations of pain to be experienced by the child for
all future procedures. Studies have demonstrated that even posttraumatic
stress symptoms can be experienced by childhood cancer survivors due to
memory recall of invasive procedures during treatment and that these

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painful memories continue beyond the treatment into the survivorship
period.8

EPIDEMIOLOGY OF PEDIATRIC CANCER PAIN

Pain is a prevalent symptom accompanying pediatric cancer. Many
patients (49% to 62%) with pediatric cancer have pain as a presenting
symptom at diagnosis, with many of these patients having pain as the sole
presenting symptom of their cancer.9–11 Pain is often present for several
months prior to diagnosis.9 Using surveys during treatment, Miser et al.12
found nonprocedural pain was prevalent for 54% of inpatients and 26% of
outpatients in a single center. A national study in Germany by Zernikow et
al.13 found 15%, 28%, 50%, and 58% of patients diagnosed with cancer to
be in pain at time of, within 24 hours, within 7 days, or within 28 days of
interview, respectively. This is corroborated by Fortier et al.14 who used a
daily diary to show that 53.3% of children diagnosed with cancer had
chronic or recurrent pain, with 40% of children requiring at least one dose
of analgesic over the 14-day study period. Pain is more prevalent in
pediatric inpatients with cancer versus outpatients (84% vs. 35%) and most
prevalent in children with solid tumors (63%) versus leukemia (44%),
lymphoma (27%), or CNS tumors (50%).15
In contrast to findings in adults, pain in children undergoing treatment
for cancer was predominantly caused by antineoplastic treatments and
procedures, rather than from the disease itself.10,11,13,16–18 In one study,
49% of children stated that treatment-related pain was the most severe
problem, followed by 38% of children for procedure-related pain, and
finally 13% for disease-related pain.10 Disease-related pain generally
becomes less prevalent over time.9,11,12 The difference in etiology between
adult and pediatric cancer pain reflects differing cancer diagnoses and
treatment strategies for adult and pediatric cancers. Although pediatric
cancers are often rapidly proliferating mesenchymal tumors or leukemia
and thus cause pain at diagnosis, many are also responsive to an aggressive
combination of intravenous and intrathecal chemotherapeutic agents,
surgery, and/or radiation, which all can lead to painful therapy-related
pain. In contrast, adult cancers are often slow-growing epithelial tumors
which are often treated with less aggressive therapies.13

2520
 Increased pain prevalence is reported for certain groups of patients.
Among children with acute lymphoblastic leukemia (ALL), pain is
reported by the majority of patients throughout the first year of treatment,
improving somewhat over time.19,20 In children with progressive,
recurrent, or nonresponsive cancer, pain prevalence is 49%, rising to 62%
in the last 12 weeks of life. Furthermore, high-distress pain prevalence in
the same group of children is 39%, rising to 58% in the last 12 weeks of
life.21 By the last month of life, other studies show pain prevalence at
82%, with about half of all patients suffering “a great deal” or “a lot” from
the pain.22

UNDERTREATMENT AND IMPACT OF PEDIATRIC

CANCER PAIN
Undertreatment of pain continues to be a concern in pediatric cancer, both
in the inpatient setting23–25 and in the outpatient and home settings.14,19
Pain in these settings continues to be common, underrecognized, and
undertreated. At the end of life, treatment of pain is often unsuccessful.22
Barriers to adequate pain control in pediatrics include lack of pain
documentation and assessment18,25,26 and clinical staff reluctance to
prescribe or administer analgesics25 whether because of fear of addiction27
or inadequate pain management knowledge.27,28 Some clinicians hold the
mistaken belief that infants and children are less sensitive to pain.27
Physicians have been found to underestimate children’s pain as reported
by the patient or the parent.29 Other common misconceptions include
beliefs that a significant percentage of children overreport pain, that
increases in morphine dose beyond a certain amount will not produce
increased pain relief, and that respiratory depression is likely to happen in
patients who have received opioids for months.30–32 Breakthrough pain,
defined as episodes of medium to severe pain on a background of
otherwise controlled pain, can occur suddenly. It can last seconds to
minutes, often too fast for many “as-needed” medications to work
effectively.23
In the home setting, barriers to adequate analgesia may include
caregiver misconceptions regarding children’s pain, fears of side effects of
analgesic use, as well as avoidance of analgesic use.33,34 Two studies in

2521
different cultural contexts have found that many parents reported believing
that a child always tells his or her parent when he or she is in pain.32,35
In adolescents, patient attitudes may also act as barriers to effective
treatment of pain. Similarly to adults, adolescents are concerned about
addiction, development of tolerance, and analgesic side effects as well as
losing their ability to monitor health-related bodily changes. Some also
hold the fatalistic belief that cancer pain is unavoidable. Some attitudes are
more uniquely seen in this age group and stem from developmental needs
for autonomy and control, including concerns about how reporting pain
may lead to undesirable tests and restrictions in social activities. They are
also concerned about not being involved in treatment decisions. Thus,
active listening is important when reviewing adolescents’ pain
symptoms.36,37
Finally, system-based barriers exist, including limits to access to opioids
and accessibility of pain and palliative care specialists, especially for
pediatric populations and resource-poor areas.38–40
Pain, especially from medical procedures, leads to fear and anxiety.41
Younger children receiving medications to control pain prior to a
procedure experienced not only less pain with each procedure but also had
consistently lower pain scores for subsequent medical procedures.42
Procedure-related pain contributes to posttraumatic stress symptoms in
survivorship.43 Pain with moderate to severe distress was associated with a
significant worsening in total health-related quality of life (HRQOL)
scores as well as scores in specific domains related to physical, emotional,
and school HRQOL.44 Adolescents with cancer, especially those
experiencing severe pain, were significantly hindered in pursuing their
personal goals, which are important to adolescent needs and their normal
developmental trajectories.45

Evaluation of Pediatric Cancer Pain

Pain is a complex and subjective experience. Multiple components of the
nervous system are involved in pain transmission, processing, and
modulation, including sensory neurons, spinal cord, somatosensory cortex,
prefrontal cortex, insula, and anterior cingulate cortex.46 This is mirrored

2522
by the multidimensional nature of pain associated with cancer, where the
cancer pain experience is affected by the complex interplay of biologic,
psychological, and sociocultural domains of illness.47 For example, many
children with oral mucositis experience mouth and throat pain. This results
in severe emotional turmoil for the children, psychological distress for the
parents, cognitive dilemmas balancing eating and pain, oral care and
discomfort, and an increased need for distraction and psychological
support.48 Thus, we advocate for a biopsychosocial approach to the
evaluation of pain in children with cancer. In addition, because of the
complexities of the physical, psychological, sociocultural, and spiritual
contributors to pain in any one patient, a comprehensive pain evaluation is
ideally accomplished by a holistic evaluation and discussion among a
multidisciplinary team including a pediatric pain specialist, pediatric
oncologist, bedside nurse, social worker, psychologist, chaplain, child life
specialists, and other rehabilitative and expressive art therapists, with the
patient and family unit at the center.

HISTORY AND PHYSICAL EXAM

The importance of eliciting and listening to all details of the pain narrative
of the pediatric patient with cancer is critical. Again, what is asked of the
child and expected of the child is dependent on his or her developmental
level. For the school-age child or adolescent, the pain assessment should
occur early on, where there is the support of family, and in a
nonthreatening environment. At tertiary care centers that care for large
numbers of pediatric cancer patients, child life services are available and
can serve as another resource to help elucidate a clear description of the
pain narrative. For the infant or toddler, the health care provider is
dependent on the parents’ narratives of the painful experience because they
are the source of safety and communication for the young child.
Across the entire developmental continuum of pediatrics, the physical
examination, including close observation of the child and the family
dynamic, is critical to provide additional information about physical
factors that contribute to the experience of pain. During the history and
physical examination, it is also critical for the clinician to recognize and
identify psychosocial factors, such as parental fear or anxiety, which can

2523
also increase the suffering associated with pain for the pediatric patient
with cancer.

SENSORY EXPERIENCE—SELF-REPORT
The evaluation of pain often begins with assessment of its sensory
experience. The PQRST method is a useful method of assessing the
dimensions of the pain sensory experience in many children.49,50 PQRST
includes asking about Palliating/provoking factors, Quality descriptors of
the pain, Radiation of the pain to other parts of the body,
Site/symptoms/severity of the pain, and Timing/triggers. Different
characteristics may suggest neuropathic pain versus nociceptive pain and
may help narrow down sources of pain or may suggest different treatment
modalities.
The most commonly evaluated sensory dimension is pain intensity, and
several one-dimensional self-report scales are available. The Pieces of
Hurt/Poker Chip Tool,51 Oucher,52 Faces Pain Scale–Revised,53 and the
Visual Analogue Scale54 have been extensively validated and have been
recommended by several systematic reviews55–57 as the best measures for
clinical practice and research. These tools have been validated for a wide
range of pediatric age groups—Pieces of Hurt for 3 to 18 years, Oucher for
3 to 12 years, Faces Pain Scale–Revised for 4 to 16 years, and the Visual
Analogue Scale for at least 7 years and older. For children 8 years and
older, the 11-point numerical rating (0 to 10) is recommended, when
possible.58 Specific one-dimensional self-report tools are also available for
pain location59,60 and to describe the temporal dimension of pain.61

SENSORY EXPERIENCE—OBSERVATION
Observing a patient’s behaviors can be useful when self-report is not
available or unreliable. In young children, facial expressions, body
posture, cries, and inconsolability are commonly associated with acute
pain. Observations of physiologic indices such as heart rate, oxygen
saturation, or sweating can also be useful in acute pain and are sometimes
used in behavior scales for critically ill patients.
These observations are reflected in observational pain intensity scales
which can be employed in lieu or in addition to self-report scales. Patients

2524
whose pain might need to be measured with an observational (i.e.,
behavioral) scale might be too young (e.g., below 4 years of age); too
distressed; impaired in their cognitive or communication abilities; very
restricted by bandages, surgical tape, mechanical ventilation, or paralyzing
drugs; or whose self-report ratings are considered to be exaggerated,
minimized, or unrealistic due to cognitive, emotional, or situational
factors. A systematic review by von Baeyer and Spagrud62 recommends
two scales for brief pain events and procedural pain (Face, Legs, Arms,
Cry, and Consolability [FLACC]63 and Children’s Hospital of Eastern
Ontario Pain Scale [CHEOPS]64), one scale for postoperative pain in the
hospital (FLACC), one scale for postoperative pain at home (Parents’
Postoperative Pain Measure [PPPM]65), and one scale for critical care and
ventilator patients (COMFORT Scale66).
However, many of these behaviors and observations normalize as the
body adapts to persistent pain, and thus, different tools and observations
may need to be utilized for persistent pain. Verbal expressions of pain
continue to be an important indicator; however, lack of interest in
surroundings, assuming pain-relieving postures, slowness and paucity of
movement, and wariness at being moved become more prominent with
persisting pain in young toddlers.62 Recently, an observational scale
incorporating the aforementioned observations was developed and
validated specifically for persistent cancer pain in 2- to 6-year-olds (Hétero
Evaluation Douleur Enfant [HEDEN]).67
In adolescents, nonverbal cues to persistent pain can be more subtle. In
addition to decreased activity, adolescents with chronic pain have been
described as exhibiting irritability and moodiness, social withdrawal, and
sometimes uncooperativeness with treatments and medications, especially
as a way to rebel and exert some bodily control when in pain.50

EMOTIONAL AND COGNITIVE EXPERIENCE

It is important to include emotional (affective) and cognitive (evaluative)
measures when assessing children for pain. Affective measures reflect the
emotional experience of pain. Evaluative measures reflect the child’s
ability to cope with his or her pain.
Toddlers with cancer who experience pain display specific pain

2525
behaviors but can also display psychomotor inertia and anxiety
behaviors.68,69 Anxiety behaviors include tenseness, hostility, crying
easily, and wariness at being moved. On the opposite end of pain
expression is withdrawal or psychomotor inertia. Behaviors that suggest
this include resignation (lack of resistance), withdrawal, lack of
expression, lack of interest in surroundings, and slowness and paucity of
movement. This behavioral pattern is sometimes labeled “learned
helplessness,” “passive coping behavior,” and “sickness behavior, such as
fatigue and malaise.” These depressive symptoms can be confused with
actual depression, both for the observer as well as for the patient but may
improve once pain is addressed.69
There are several multidimensional tools that bring together both
questions about pain sensory experience as well as affective or evaluative
measures. One of these, the Adolescent and Pediatric Pain Tool
(APPT),70,71 itself derived from the McGill Pain Questionnaire, has been
validated in children 8 years and over and has been used in several studies
of children with cancer.18,19 It measures pain intensity, location, quality
descriptors, temporal descriptors, and the evaluative and affective
dimensions of pain. Affective words include words such as awful,
frightening, and suffocating. Evaluative words include words such as
uncontrollable, horrible, and annoying.

FUNCTIONAL AND QUALITY OF LIFE ASSESSMENT

Pain is but one of the symptoms that children experience while going
through cancer. Fatigue, nausea/vomiting, poor appetite, and depression
and anxiety are some of the most common, besides pain.15 Symptoms
often cluster and contribute toward overall decreases in HRQOL. For
example, pain in children with cancer can often lead to decreased
functioning and quality of life.72,73 As physical activity or play activities
can be exacerbated by pain from cancer, many patients instinctively avoid
activities, a factor that leads to deconditioning and loss of function. This
and the presence of pain itself can lead to depressive symptoms. Sleep is
also intuitively affected by pain, leading to fatigue.
The National Institutes of Health (NIH)-sponsored Patient-Reported
Outcomes Measurement Information System (PROMIS) initiative has

2526
developed a pain interference tool, evaluating the presence of
psychological, social, and physical dysfunction secondary to pain.74 The
questionnaire asks patients if pain has hindered their function in regard to
sleeping, attention, doing schoolwork, standing, walking, running, being
happy, or being angry. Data from PROMIS shows strong positive
correlations between pain interference and fatigue and pain interference
and depressive symptoms and a strong negative correlation between pain
interference and physical functioning-mobility.75 Symptom cluster
analyses show that pain in adolescents with cancer often co-occurs in the
same patients as fatigue, sleep disturbance, and depression76 or with
nausea and vomiting.77 Another cluster analysis study using PROMIS data
in children with cancer showed that patients with high pain interference
scores are more likely to also have high anxiety, depression, and fatigue
scores.78
Based on these data, clinicians should assess the effect of the child’s
pain on their function in several different domains, including physical
functioning and health; mood, coping, and psychological well-being;
social and family relationships; and fatigue and sleep.

PAST PAIN-DIRECTED THERAPIES

Treatments for pain along with patient pain relief, functional improvement,
and adverse effects should be noted in initial and ongoing evaluations of
the patient. Past pain treatments, especially when associated with less than
optimal control of pain, should be critically evaluated for appropriate
medication or modality, dosing, route of administration, and both
beneficial and adverse effects on pain and function. Common reasons for
pain treatment failure include intolerable adverse effects, too long of a
dosing interval, too small of a dose, or inappropriate route of
administration. In addition, not all pain treatments are equally effective for
each patient, and thus, it is helpful to know the history of what has been
attempted in the past.

CANCER HISTORY—DIAGNOSIS
Understanding the patient’s cancer diagnosis, extent of disease, treatments,
and prognosis is crucial to understanding the nature of pain that a patient

2527
with cancer might experience. Cancer, even in children, is a diverse set of
diagnoses affecting almost any organ system or part of the body, and even
each tumor type can present differently in each child. A cancer history for
the pain clinician should start with understanding the patient’s initial
presentation and diagnosis. Some patients present asymptomatically,
perhaps with a routine blood test, whereas some patients go for months or
years with symptoms, often painful, while undergoing different blood
tests, imaging studies, and even different surgical interventions before a
diagnosis of cancer is finally made. Some patients carry congenital
syndrome diagnoses or have undergone procedures, such as organ
transplant, which predispose to the development of different cancers. Each
of these situations brings a different set of pain experiences and pain
expectations for patients undergoing cancer treatments and survivors.
The location and extent of neoplastic disease is an important
consideration. Common solid tumor sites in children and adolescents
include the brain and spinal cord, peripheral nervous system, abdominal
organs (e.g., Wilms tumor, neuroblastoma, hepatoblastoma, germ cell
tumors, some rhabdomyosarcomas), the genitourinary systems (testicular
and ovarian germ cell tumors, rhabdomyosarcoma), the extremities (bone
and soft tissue sarcomas, Langerhans cell histiocytosis), mediastinum
(lymphomas, leukemia, teratoma), and the head and neck
(rhabdomyosarcoma, lymphomas, retinoblastoma, neuroblastoma,
Langerhans cell histiocytosis). By no means is this a comprehensive list,
and other rare diagnoses have been known to present in any organ system.
Although some patients will have been diagnosed with a tumor which is
localized to a specific organ or body part, other patients will have tumors
which have locally extended to adjacent organs and body regions. Some
common pediatric cancers are disseminated by nature, such as the
leukemias and many lymphomas. These hematologic malignancies can
involve not only bone marrow, lymph nodes, spleen, and mediastinum but
also extramedullary sites such as the brain and CNS, testes, bones, and
even skin. Other patients will have metastatic disease. Sites of metastasis
vary for each diagnosis, but common sites of metastasis include adjacent
lymph nodes, brain and CNS, lungs, liver, and bones. Each site of
involvement can result in a potentially different set of pain symptoms for

2528
the patient.

CANCER HISTORY—TREATMENTS
Treatments vary considerably depending on the cancer diagnosis, location,
extent, and other factors and bring along with them their own sets of pain
and symptom experiences for each patient. The most common treatment
plans for cancer in children include chemotherapy, surgery, and radiation.
Radiation therapy, including external beam radiation, brachytherapy, and
radioisotope therapy, and surgical resection have been mainstays of
treatment for various pediatric tumors. Chemotherapy, in common usage,
is often defined as any drug which works through the inhibition of mitosis
and cell division to induce tumor cell death. Chemotherapy is commonly
given orally, intravenously, intramuscularly, or intrathecally depending on
the agent and treatment regimen.
Other drugs have also become part of the cancer armamentarium but
work in other ways. Hormonal therapies, which are more common in adult
cancers such as breast and prostate cancer, are less often used in pediatric
cancers. Targeted therapies including monoclonal antibodies, small
molecule inhibitors, and other immunotherapy agents, which have largely
been developed for adult tumors, are becoming more and more frequently
used in pediatric cancers as well. In addition, autologous or allogeneic
hematopoietic stem cell infusions, sourced from bone marrow (“bone
marrow transplant”), peripheral blood, or umbilical cord blood, can be
used in different ways to replace a diseased hematopoietic system, rescue
it from high-dose chemotherapy, and/or induce an immune response to a
tumor (e.g., graft-versus-leukemia effect). Cellular therapies such as
chimeric antigen receptor–T cell therapy build on the concept of graft-
versus-tumor effect and have recently gained U.S. Food and Drug
Administration (FDA) approval.79
Besides cancer-directed treatments, different supportive therapies are
employed which can lead to pain. Stem cell factors such as granulocyte
and granulocyte/monocyte colony-stimulating factors are used to decrease
rates of febrile neutropenia and sepsis but can cause bone marrow
expansion leading to pain. Medical devices and catheters are often placed
to facilitate treatments. The most common of these include central venous

2529
access catheters such as tunneled catheters, peripherally inserted central
catheters, and implanted port catheters; feeding tubes such as nasogastric
tubes and percutaneous gastrostomy tubes; and intraventricular devices
such as ventriculoperitoneal shunts and Ommaya reservoirs. Even in the
presence of a central venous access catheter, peripheral intravenous
catheter placements are sometimes necessary for certain imaging
procedures and treatments.
Additionally, adverse effects of different cancer therapies are common
and important to help understand the patient’s cancer experience and
identify possible sources of pain. Because of the cyclical nature of many
treatment regimens, this knowledge can help the clinician anticipate
possible pain for the patient in later cycles and plan appropriate pain
preventive measures and treatments.
The patient’s prognosis and—critically—the patient and family’s
understanding of prognosis and goals of treatment are also important
considerations in evaluating pain in a patient with cancer. Treatment plans
can be curative or palliative in intent, and it is important to elicit this intent
in anticipating a patient’s pain experience. Whereas curative treatments
weigh the promise of long-term cure against possible short-term symptoms
and other adverse effects, palliative treatments prioritize the preservation
of a patient’s quality of life.

PAST MEDICAL, PSYCHIATRIC, SOCIAL, AND

SPIRITUAL HISTORY
Preexisting medical and psychiatric conditions are less common in
children but play a role in their ability to cope, physically or
psychologically, with cancer treatments. A patient and family’s social
situation and spirituality may also play a role in the support systems
available in coping with both disease diagnosis and pain and symptom
experience.

PROXY REPORTS
Whether or not a pediatric patient is able to provide a good history of his
or her pain, it can be helpful to elicit observations and history from parents
and other caretakers. Often, proxy report is the only source of information

2530
when patients are too young developmentally, in distress, or unwilling to
provide this history. In addition, pediatric oncology patients are sometimes
in the hospital so frequently, or for such an extended period of time,
bedside nurses in oncology units and infusion centers will also have a
longitudinal perspective on the patients and their current pain. On the other
hand, the clinician needs to be mindful that proxy reports from parents
sometimes differ from patient self-reports, especially when it comes to
internalizing symptoms such as pain, fatigue, and emotional distress.77,78
Parental anxiety can also affect their report of their child’s pain.79

INTEGRATING DATA IN EVALUATION OF THE

WHOLE CHILD
Some of the literature of pain evaluation focuses on pain intensity scales,
which have been necessary for quantitating pain for the purposes of
research and quality improvement efforts. In reality, however, each
clinician faced with a patient experiencing pain integrates multiple data
points from various sources in evaluating each patient. As an example,
although self-report pain scores have classically been the gold standard in
pain intensity assessment, recent observations and criticisms have led to a
reevaluation of this dogma.80 An isolated self-report pain score can have
wide variability in meaning from patient to patient and can even be biased
depending on situation, age, cognitive development, or experience. This
leads to difficulty in translating overly simplistic pain scores directly into
clinical decisions.
Instead, although pain is inherently a subjective experience and thus
self-report is an important piece of information, bundled81 or hierarchical82
pain assessment approaches hint at ways to include other factors to inform
clinical judgment. A bundled approach takes self-report, observation,
proxy report, and other factors into account before making a global
assessment of pain. One bundled approach, “CARES,” uses the following
factors: Context (evaluating for likely sources of pain), Assess pain
expression (including self-report and observation of pain behaviors and
functional limitations from pain), Risk (balancing adverse effects of
treatment with the clinical situation of the patient), Emotional factors
(considering developmental and psychological factors), and Sociocultural

2531
factors (understanding patient and family preferences).81
Hierarchical assessments take the bundled approach a step further, by
arranging pain-modifying factors into a specified order. An example of
this is a pain assessment guideline by Herr et al.,82 developed for patients
who cannot self-report pain reliably, including several groups which are
often encountered in pediatric oncology—preverbal infants and toddlers,
critically ill or unconscious patients, patients with intellectual disabilities,
and some patients at the end of life. This particular hierarchical approach
takes the following steps in order: (1) (attempt to) obtain self-report, (2)
search for potential causes of pain, (3) observe patient behavior, (4) obtain
proxy report, and (5) attempt an analgesic trial if pain behaviors continue
despite providing for basic needs and comfort.
After consideration of all these factors, and a discussion with the child,
caretakers, bedside providers, as well as the multidisciplinary team, a
targeted treatment plan can then be developed. Reassessment after any
analgesic trial is mandatory to further adjust the treatment plan to the
patients’ needs.

INCORPORATING TECHNOLOGY INTO ASSESSMENT

Finally, it is worth mentioning that there has been work done to develop
technologies to address barriers of inadequate assessment and
documentation of pain and patient reluctance to report pain. Phone text
messaging has been used to improve patient compliance with reporting
pain intensity, duration, and pain-related disability.83 A smartphone
application similarly has been shown to be feasible and perform
consistently compared to traditional interviewer-administered
questionnaires.81,82 The NIH PROMIS can be used on multiple platforms.
Studies have shown its feasibility and cross-cultural validity for measuring
functional mobility, pain interference, fatigue, depression, anxiety, peer
relationships, and anger.84,85 Tablet applications not only improve patient
reporting of pain and symptoms but can also incorporate basic cognitive
and behavioral skills training through electronic games.86

Etiologies of Cancer Pain

2532
Pain in children with cancer is often classified into one of four etiologies:
(1) cancer- or disease-related pain, (2) treatment-related pain, (3)
procedure-related pain, and (4) pain from other etiologies.87

DISEASE-RELATED PAIN
Bone Marrow Infiltration
The acute leukemias—ALL and acute myelogenous leukemia (AML)—are
the most common diagnostic category of pediatric cancer.88 The rapid
proliferation of leukemic blasts within the bone marrow commonly results
in the experience of diffuse bone pain. The clinical presentation of the
bone pain, however, is variable depending on the age of the patient.
Toddlers may present with a limp or inability to walk. A school-age child
who is able to provide a pain narrative may report diffuse, poorly
localized, total-body pain. An adolescent patient may have back pain that
he or she associates with a sports injury and may localize the pain to a
specific area in a long bone. Other pediatric leukemias include chronic
myeloid leukemia (CML) and juvenile myelomonocytic leukemia (JMML)
and in some situations can also present with bone pain. Some solid tumors,
such as neuroblastoma, can metastasize to the bone marrow and can also
present as a limp or, alternatively, as localized pain to a specific bony area.
Primary treatment of the underlying oncologic process is usually the
most effective way to alleviate the pain, sometimes working within days of
starting treatment. In the interim, standing or sometimes continuous
opioids may sometimes need to be used for pain control. Nonsteroidal anti-
inflammatory drugs (NSAIDs) should be avoided as they can exacerbate
the risk of bleeding in a patient whose bone marrow may not be able to
produce as many platelets, a condition which will soon be exacerbated by
undergoing myelosuppressive chemotherapy. Acetaminophen can be
helpful but may sometimes mask fever, which in a neutropenic or
functionally neutropenic child may signal septicemia.

Brain and Spinal Tumors

CNS tumors are the second most common cancer in children and the most
common group of solid tumors diagnosed during childhood. Headache is
one of the most common initial presenting signs of brain tumor in children.

2533
In recent studies, 31% to 40% of children with a brain tumor had headache
at symptom onset.89,90 At diagnosis, headache is a prominent feature in
33% to 62%.91,92 Headache is less common in children under the age of 3
years, likely because of both communication and expansile skull of the
infant, and sometimes is noted as ear, face, or neck pain. Most commonly,
headache is a result of mass effect of the brain tumor causing increased
intracranial pressure. Other times, headache may be the result of a
trigeminal or glossopharyngeal neuralgia caused by tumor compression of
cranial nerves. To decrease the intracranial pressure and thereby treat the
pain/headache for the child, different therapeutic approaches can be used.
For some brain tumors that are locally invasive without metastatic
potential, such as low-grade gliomas (astrocytomas), complete surgical
removal is the treatment of choice. For malignant brain tumors with
metastatic potential, such as medulloblastoma, chemotherapy and radiation
therapy are included in addition to the surgical treatment regimen. Not all
primary resections of malignant brain tumors result in complete surgical
removal of the tumor, so pain may persist due to residual disease. Often,
the child will be started on a corticosteroid pulse pre- or postoperatively to
decrease tumor- and surgery-associated cerebral edema. Temporary or
permanent ventricular shunts or ventriculostomies are often used to
alleviate intracranial pressure from the tumor and/or postoperative edema.
If the child continues to have headache after surgical intervention,
NSAIDs, such as ibuprofen, can be considered if there is no plan for
chemotherapy and/or radiation therapy. A histamine H2-receptor
antagonist is used to inhibit gastric acid production, especially with
concurrent corticosteroids. Otherwise, strong opioid therapy is the
treatment of choice.
Benzodiazepines, such as midazolam, can also be used indirectly for the
treatment of pain due to CNS tumors even though this class of medications
does not have direct analgesic effect. Their mechanism of action for the
treatment of pain in children includes decrease in anxiety, decrease in
muscle spasm that may occur postoperatively, and facilitation of night
sleep.93 Postoperatively after the resection of the CNS tumor, the child
may remain within the intensive care unit (ICU) because of the need for
monitoring intracranial pressure. In this setting, benzodiazepines may be

2534
used as a continuous infusion or with frequent bolus dosing so that
agitation is minimized.94 Benzodiazepines are often used concomitantly
with opioid analgesics in the ICU setting when significant postoperative
pain is reported, observed, or expected. Antipsychotics, such as quetiapine,
are also commonly used for agitation as are α-adrenergic agents such as
clonidine.

Visceral Pain
The four major etiologies of visceral pain include (1) organ invasion with
capsular wall stretching, (2) organ compression, (3) hollow organ
obstruction (e.g., ureter or bowel), and (4) tumor regrowth within the
organ or peritoneal cavity bleeding. In children, the abdominal tumors
which are most commonly implicated in visceral pain are Wilms tumor
(and other kidney tumors), neuroblastoma, abdominal germ cell tumors,
rhabdomyosarcoma and other soft tissue sarcomas, lymphoma, and hepatic
tumors (hepatoblastoma, hepatocellular carcinoma, sarcomas of the liver,
and metastatic lesions of the liver). Although pain is a common complaint,
many of these tumors may also present asymptomatically after incidental
palpation of a mass by the parent or pediatrician, or through other
symptoms, such as with Wilms tumor. As with bone pain in leukemia,
treatment with chemotherapy, radiation, or resection of the diseased organ
or part of the organ can eventually lead to a decrease in the child’s pain. In
the interim and in the postoperative period, opioids are the mainstay of
treatment.

Bone Tumors
Primary malignant bone tumors, such as osteosarcoma or Ewing sarcoma,
bone metastases from other malignancies, and Langerhans cell
histiocytosis, and some benign tumors, such as giant cell tumor of the
bone, can result in significant pain for the childhood cancer patient. Bone
pain in cancer is a complex pain state involving nociceptive, neuropathic,
and inflammatory elements.95 Bone pain from osteosarcoma, for example,
is due to both destruction of normal trabecular bone pattern from direct
tumor invasion in combination with intense soft tissue inflammation from
the periosteal new bone formation. Thus, the pain can often be very severe

2535
and often requires the use of opioids. NSAIDs could also be considered in
the prechemotherapy setting. After the start of chemotherapy, however,
NSAIDs should be used with caution as chemotherapy-related
myelosuppression, and resultant thrombocytopenia may put the patient at a
higher risk for bleeding.
Primary treatment of the tumor often provides the longest lasting effects
on tumor-related pain from bone tumors. For osteosarcoma and Ewing
sarcoma, neoadjuvant chemotherapy, followed by surgical resection and/or
radiation, are the common treatment approaches. A small reduction in the
size of the tumor may be enough to bring relief to the patient. Metastatic
bone lesions may sometimes be treated symptomatically with radiation
therapy, surgical decompression, or systemic chemotherapy depending on
the disease.
In adults, osteoclast inhibition—using a bisphosphonate96 or a receptor
activator of nuclear factor kappa B (RANK)-ligand inhibitor97—has been
shown to decrease fractures, spinal cord compression, and need for surgery
or radiation therapy in the setting of bone metastasis from solid tumors
such as breast and prostate cancer. Symptomatically, both treatments can
delay the progression of moderate-to-severe pain in these adult patients.
Studies in children are lacking. There are encouraging results for
bisphosphonates in pain control for benign cartilage tumors,98 unresectable
symptomatic benign bone tumors,99 and Langerhans cell histiocytosis.100
Newer agents, such as denosumab, a RANK-ligand inhibitor, have been
shown to be useful for treatment of bone pain in giant cell tumor of the
bone.101 Children’s Oncology Group studies on both zoledronic acid102
and denosumab (ClinicalTrials.gov identifier NCT20470091) in metastatic
or recurrent osteosarcoma have been undertaken, although effect on pain
was not an aim of either study. Bisphosphonates have also been well
tolerated in the treatment of children with hypercalcemia of
malignancy.103

PROCEDURE-RELATED PAIN
A child undergoing cancer treatment will undergo many invasive, painful
procedures. These include diagnostic or therapeutic procedures such as
bone marrow biopsies, lumbar punctures (LPs), and surgery for tissue

2536
biopsy or tumor removal; venipunctures and subcutaneous port access
(puncture) for diagnostic testing and/or treatment administration;
placement of feeding tubes and urinary catheters; and placement of
tunneled, peripherally inserted, or subcutaneous implanted “port” central
venous access catheters. Even dressing changes (for central lines, surgical
wounds) and suture and staple removal are a source of pain and distress for
patients.104
Not only does a child newly diagnosed with cancer face many repeated
painful stimuli but these pain-evoking procedures can also occur in a
relatively short period of time (within a few days, weeks, or months). In
addition to the physical pain that invasive procedures cause related to
tissue damage by insertion of a needle or device through the skin and/or
bone, the procedures themselves produce a great deal of psychological
distress, including fear and anxiety.105 This anxiety can result in a quick
recall of the procedure that will impact future pain management for all
future painful procedures. Children with ALL on current treatment
protocols, for example, undergo LPs on a regular basis ranging from once
or twice weekly during induction therapy to once every 3 months during
maintenance therapy. The initial LPs that are done at time of diagnosis and
for the initial induction treatment therefore set the stage for the pain
anticipated and experienced for children during their 2 to 3 years of
ongoing chemotherapy. Studies in leukemia patients have clearly
demonstrated that children have accurate memories of their painful
procedures. The more negative a memory a child had about a previous LP,
the higher the likelihood of increasing distress related to future LPs.106
Similar findings have been found for children undergoing other repeated
painful procedures.107,108
There may also be specific groups of pediatric cancer patients that are at
higher risk for distress due to painful, invasive procedures. Early studies
have suggested that differences in reactions to painful stimuli can be
attributed, at least in part, to a child’s temperament, including the
dimensions of distractibility and persistence.109–112 Having a higher level
of pain sensitivity (i.e., pain perception) is associated with greater anxiety
and pain both prior to and during an LP procedure.113 In addition, the
psychological stress and corresponding coping experienced by the parent

2537
can affect the child’s coping responses to the painful stressor. It has been
shown that mothers of childhood cancer survivors do experience
posttraumatic stress symptoms well into the survivorship period years after
their child was treated for cancer.114 Thus, given that a child is dependent
on parents for both physical and emotional support throughout the cancer
care continuum, a child can be at increased risk for distress due to pain if
his or her caretaker is not able to soothe or provide a safe, consistent
environment because of his or her own stress and maladaptive coping.
Topical and local therapies for pain control are important. More than
50% of children report pain during venipunctures or intravenous
cannulation,115 making these procedures an important target for pain
prevention and control. Topical anesthetics are attractive because of the
effectiveness without need for intravenous access and relative lack of
systemic side effects. Eutectic mixture of lidocaine and prilocaine (eutectic
mixture of local anesthetics [EMLA]) has been standard practice for
decreasing procedural pain in children, available both in cream116 and
patch117 forms. A warm lidocaine and tetracaine patch has also been
shown to be effective for facilitating first-time needle procedure
success.118 If insufficient time is available to allow topical anesthetic
creams to take effect, vapocoolant sprays may be helpful in decreasing
pain and decreasing intravenous cannulation failures in children.119 If
anxiety is a major factor, low-dose oral midazolam has been useful in
reducing fear and distress in younger children undergoing needle
procedures such as subcutaneous port access.120 High-dose
acetaminophen121 or morphine122 did not have the same effect.
EMLA may also be useful by itself for LPs but only with those patients
who undergo successful LP on their first attempt.123 When used along with
sedation, EMLA is useful in decreasing propofol use during LP.124 When
sedation is contraindicated, such as for patients with a large mediastinal
mass with risk for airway compromise, topical and local anesthetic may be
the only safe pain prevention strategy for these patients undergoing LP or
bone marrow biopsy.
More and more pediatric oncology centers have instituted sedation and
analgesia protocols for pediatric oncology procedures such as LPs and
bone marrow biopsies and aspirations. Guidelines for pediatric procedural

2538
sedation have been published.125,126 The desired level of sedation (e.g.,
anxiolysis vs. deep sedation vs. general anesthesia) depends on patient age
and cognitive development and painfulness of the procedure, balanced
with the risks of sedation (e.g., in setting of airway compression from a
mediastinal mass).127 Level of sedation also depends on the need for
immobility, as there is a risk of introducing leukemic cells from blood into
the spinal fluid with traumatic LP during induction therapy for ALL.128
The addition of intravenous fentanyl to intravenous propofol reduces
movement, propofol dose, recovery time, and hypotension129,130 and was
preferred by families.131 Intravenous ketamine had a superior effect on
procedural pain and hemodynamic stability in comparison with an opioid
alone132; however, ketamine/midazolam compared with propofol was
associated with a longer recovery period.133 Adding low-dose oral
midazolam does not affect pain, fear, or distress levels whether given with
or without intravenous ketamine prior to procedures for hematologic
disease.134
A combination of these two approaches may be considered. Two studies
showed the addition of ketamine (0.5 to 1 mg/kg) to fentanyl (1 µg/kg) and
propofol (0.5 to 2 mg/kg induction followed by 0.5 to 1 mg/kg as needed)
decreased propofol dose, rates of hypotension and hypoxia, and recovery
time.135,136 Ketamine may indeed replace the opioid, as a combination of
ketamine, and propofol may decrease incidence of respiratory compression
compared to propofol and alfentanil.137
Nitrous oxide (NO) may also be useful for pediatric procedural sedation,
especially in children who might be willing to accept a mask, and for
procedures which are not extremely painful. Delivery systems are being
improved and are more available for procedural applications. Randomized
controlled trials comparing other agents to NO are lacking,138 but a recent
study showed utility of NO in an outpatient setting for LPs.139

Postlumbar Puncture Headache

Even with adequate analgesia and sedation, LPs can sometimes be
associated with postlumbar puncture headaches (PLPHA). These are
characteristically postural headaches—worse with upright posture and
improved in the supine position—occur within 6 to 72 hours of a LP, and

2539
last 3 to 15 days.140 The mechanism is thought to be from ongoing leak of
cerebrospinal fluid through the puncture site resulting in low cerebrospinal
fluid pressure and volume. The incidence of PLPHA is rare in younger
children and peaks in the fourth or fifth decade of life.140,141 Preventive
measures are mandatory. The most well-studied and recommended
preventive measures include (1) using a needle no larger than 22 gauge,142
(2) using a pencil point rather than a cutting point needle, and (3) orienting
the needle bevel to be parallel, rather than perpendicular, to the long axis
of the spinal column. Position of the patient in bed rest for 6 to 24 hours
after LP does not appear to reduce the incidence of PLPHA compared to
lifting of activity limitations after 0 to 1 hour.143 Replacement of the
stylette before withdrawal of the needle has also been recommended,144
but application to pediatric cancer is limited because of the administration
of intrathecal chemotherapy.
Placement of an epidural blood patch is one of the few therapies for
PLPHA which has enough evidence to support its benefit.145 Autologous
blood is collected intravenously from the patient and injected into the
epidural space near the site of the prior LP, working to tamponade the area
of the previous dural puncture and facilitate sealing of the leak. Because
autologous blood is used, this should be avoided if the patient has
leukemia which is not yet in remission. Other therapies, such as
intravenous or oral caffeine, intravenous or oral hydration, tramadol,
acetaminophen, and ibuprofen, had either weak or no evidence supporting
their use or lack of pediatric data.143

Postoperative Pain
Surgical biopsy is often necessary for diagnosis, and resection of tumors is
a mainstay of therapy for most solid tumors. In addition, tunneled and
subcutaneous “port” central venous access catheters are often placed
surgically. These procedures, and the pain associated with them, are a
commonly distressing part of the cancer experience in children. For
abdominal surgery, an oncologic approach often precludes laparoscopic
resection, and this also increases pain and recovery time. Joint guidelines
from the American Pain Society, American Society of Regional
Anesthesia and Pain Medicine, and several committees within the

2540
American Society of Anesthesiologists are available.146 Recommendations
include the consideration of using multimodal analgesia, using
medications which target multiple mechanisms of action in the peripheral
and CNS; physical modalities such as transcutaneous electrical nerve
stimulation; cognitive behavioral modalities; nonopioid analgesics and
gabapentin, intravenous ketamine, and opioids including patient-controlled
analgesia (PCA); peripheral regional anesthesia; and neuraxial analgesia
for major thoracic and abdominal procedures. More about pediatric
postoperative pain management can be found in Chapter 50.

Phantom Limb Pain

Amputation and limb-salvage procedures may be used as surgical
approaches to achieve local control of a bone tumor, and each can result in
a chronic pain syndrome coined phantom limb pain. Phantom limb pain is
experienced when the pediatric patient continues to have pain appearing to
come from where the affected amputated limb used to be. There are
multiple possible etiologies for the occurrence of phantom limb pain that
include possible damage to the nerve endings in the surgical residual limb
with abnormal regrowth postoperatively leading to abnormal painful
discharges to spinal cord and brain. There may also be abnormalities in the
CNS response to the loss of limb in which there may be loss of inhibitory
sensory input from the amputated limb. Phantom limb pain is often severe
and very challenging to treat.
Systematic analyses of studies to effectively treat chronic postoperative
phantom limb pain have not clearly demonstrated an effective treatment
option in randomized controlled trials.147,148 Gabapentin and pregabalin,
amitriptyline, ketamine infusion, and lidocaine infusion are some of the
more commonly tested treatments. Central strategies, such as
hypnotherapy, biofeedback, and acupuncture, aimed at altering metabolic
activity in pain perception areas of the brain, such as the anterior cingulate
cortical area, may be more effective than peripheral strategies or opioids
(see Chapters 26 and 54). Mirror therapy, a nonpharmacologic therapy
which aims to reverse postamputation maladaptive reorganization of the
sensorimotor cortex, has been used to beneficial effect in the pediatric
oncology population149; however, systematic reviews including a broader

2541
population of adults and children with different reasons for amputation
show insufficient evidence of benefit for either mirror therapy or
movement representation techniques.150,151

TREATMENT-RELATED PAIN
Bone Marrow Expansion
Filgrastim and pegfilgrastim (versions of granulocyte colony-stimulating
factor), and sargramostim (granulocyte-macrophage colony-stimulating
factor) are often used subcutaneously during chemotherapy treatment to
raise neutrophil counts and reduce the number of episodes of febrile
neutropenia in between cycles of myelosuppressive chemotherapy or
during bone marrow engraftment after an HSCT. Alternatively, higher
doses can be used in patients to mobilize and boost recovery of
hematopoietic stem and progenitor cells for use later in autologous stem
cell rescue after high-dose chemotherapy. One major adverse effect of
these agents is bone pain secondary to a combination of bone marrow
expansion, peripheral nociceptor sensitization to nociceptive stimuli,
modulation of immune function, and a direct effect on bone
metabolism.152 A meta-analysis showed bone pain rates for filgrastim and
its long-acting version, pegfilgrastim, to be similar, at around 25% to
50%.153 As patients receiving colony-stimulating factors to prevent febrile
neutropenia are by definition at risk for neutropenia and
thrombocytopenia, NSAIDs should be avoided as well as around-the-clock
acetaminophen to prevent masking of fever. As-needed acetaminophen
and low-dose oral opioids are sometimes necessary to help patients
manage this pain.

Mucositis
Mucositis may occur when chemotherapy is given alone, but certain
treatments such as head and neck radiation, as well as high-dose
chemotherapy in the setting of HSCT, can worsen and prolong
mucositis.154 After HSCT, there is often a longer period for stem cell
recovery extending beyond the 7- to 10-day nadir occurring after
chemotherapy exposure. The grading scale for describing the severity of
oral mucositis established by the World Health Organization (WHO)

2542
ranges from mild, grade I mucositis, in which the oral mucosa is red and
tender, to severe, grade IV mucositis in which the patient is unable to eat
and maintain his or her own nutrition.155 The severity of the mucositis
often corresponds to the description of the severity of the pain by the
patient. Grade I mucositis may only require bolus dosing of an opioid
analgesic. In the high-dose chemotherapy and HSCT setting, however,
mucositis pain often requires use of an opioid PCA given the chronicity of
the pain (over a several week period) and the extensive tissue injury
involving the entire gastrointestinal tract. This often precludes enteral
analgesic therapies. An effective approach to PCA delivery of the opioid
analgesic is to have a low basal rate that is augmented with demand dosing
for breakthrough pain.23 If demand dosing usage is frequent, resulting in a
lockout of demand dose administration, then an increase in the basal rate is
warranted. These patients may require several weeks’ use of an opioid
PCA because the pain from mucositis can be severe and occur over a
prolonged time period while awaiting engraftment. However, when
engraftment occurs and counts recover, the PCA can often be weaned off
quickly. The caveat to this is that there may be withdrawal symptoms,
including agitation and/or diarrhea, and a methadone taper should be
considered.
Patients with head and neck cancers often will be treated with radiation
to the head and neck area or concurrent chemoradiation and are thus at
higher risk for severe oral mucositis in addition to other oral toxicities such
as trismus, xerostomia, and taste loss caused by inclusion of the jaw,
salivary glands, and tongue in radiation fields. These often present a major
challenge to oromotor function, enteral nutrition management, and
maintenance of quality of life. Mucosal erythema appears at around 10 Gy
of radiation, with associated burning sensation and sensitivity to spicy
foods. At 30 Gy, ulcers develop leading to opioid requirement and feeding
difficulties, and then mucositis remains at its peak for at least 2 weeks
following completion of radiation. Pain and symptoms of mucositis can
persist for 8 weeks.156
Guidelines for the prevention of mucositis in children have been
developed by the Pediatric Oncology Group of Ontario.157 A similar
guideline is available for adults and includes treatment options for

2543
mucositis.158 Preventive measures with sufficient supportive evidence for
both panel recommendations include oral cryotherapy, low-level light
therapy (LLLT), and keratinocyte growth factor. Oral cryotherapy involves
placing ice cubes or chips in the mouth continuously during a period of
cytotoxic treatment, typically 30 to 60 minutes at a time, resulting in
vasoconstriction in the oral mucosal surface and thus decreased exposure
to chemotherapy. Cryotherapy significantly reduced severe oral mucositis
in a pooled analysis of eight studies which reported on this outcome (RR
0.46, 95% confidence interval [CI] 0.30 to 0.71). There is, however, a lack
of positive studies in children, and feasibility is limited to only
chemotherapeutic agents with a short half-life given in a short infusion, as
well as by the concern that ice may pose a risk of choking hazard in young
children.
LLLT involves exposing oral mucosal tissues to a low-energy light
source, which may have anti-inflammatory, wound-healing, and analgesic
effects. Advantages include two studies which included children with
positive results. Limitations for hospitals include acquiring LLLT
machines and training. Overall severe mucositis was reduced (RR 0.37,
95% CI 0.20 to 0.67), as was severe pain (RR 0.26, 95% CI 0.18 to
0.37).157 Finally, keratinocyte growth factor (e.g., palifermin) is an
epithelial growth factor that works partly by thickening the oral mucosa.
Severe oral mucositis was reduced with keratinocyte growth factor as well
(RR 0.81, 95% CI 0.67 to 0.97), which is given for several days before and
after mucositis-inducing chemotherapy.157
Other interventions, including filgrastim, glutamine, Traumeel S, topical
vitamin E, chewing gum, oral chlorhexidine, sucralfate, and a preventive
oral care protocol, were not effective in reducing mucositis. Additional
recommendations from the adult guideline panel include PCA opioids for
oral mucositis and benzydamine mouthwash in patients with head and
neck cancer receiving moderate dose radiation therapy (up to 50 Gy)
without concomitant chemotherapy. They also suggest transdermal
fentanyl for oral mucositis due to high-dose chemotherapy, 2% morphine
mouthwash for mucositis in patients receiving head and neck
chemoradiation, 0.5% doxepin mouthwash for any oral mucositis, as well
as systemic zinc supplementation for prevention of mucositis.158 Again,

2544
studies in children are lacking so their use should be limited to selected
children and under expert guidance. Other topical treatments that have
been used include honey159 and aloe vera.160 Honey has been used in other
wound care settings to promote healing but requires irradiation to
neutralize botulinum toxin spores and other microbes which may
otherwise contraindicate their use in immunocompromised and very young
children,161 and further clinical trials would be needed to clarify its safety
in these populations.

Neuropathic Pain
Pediatric cancer patients can experience neuropathic pain for a variety of
reasons, including nerve invasion, inflammation of a nerve root due to the
malignancy or infectious process, and/or from cancer treatment side
effects. These etiologies include (1) chemotherapy-related peripheral
neuropathies, such as with vincristine neurotoxicity; (2) neural
compression or invasion by tumors, such as pelvic Ewing sarcomas; and
(3) infection related, such as herpes zoster reactivation due to immune
suppression. One common cause of chemotherapy-related peripheral
neuropathy is vincristine, a vinca alkaloid used as an effective cytotoxic
agent for many types of pediatric malignancies including leukemias,
lymphomas, and various solid tumors. Vincristine binds to tubulin and
inhibits microtubule formation and disrupts the formation of the mitotic
spindle, which is thought to be one of the mechanisms by which it causes
peripheral neuropathies, including jaw pain, leg pain, and abdominal
pain.162 In addition, direct injury of the nerve can occur with soft tissue
sarcomas arising in the pelvis, such as Ewing sarcoma or
rhabdomyosarcoma, and the child may present with complaints of
abdominal pain, lower extremity weakness, and/or bladder and bowel
dysfunction.
Assessment of chemotherapy-induced peripheral neuropathy is informed
not just by the painful aspect, or even the sensory symptoms, but also by
motor and autonomic symptoms; pin, vibration, and light touch sensation
by exam; motor exam; and deep tendon reflexes. These are included in the
pediatric Total Neuropathy Scale (TNS) and this can be included in the
pain assessment.163–165

2545
 Besides vincristine, peripheral neuropathy is also associated with
bortezomib, cisplatin, paclitaxel and other taxanes, and thalidomide.166
Calcineurin inhibitors, such as tacrolimus and cyclosporine, often used
after allogeneic HSCT, may also be associated with peripheral neuropathy.
Newer agents including dinutuximab (aka ch14.18), a chimeric,
monoclonal anti-GD2 antibody approved in the immunotherapy of
neuroblastoma, can also be associated with neuropathic pain, specifically
allodynia. In the phase 3 trial which led to its approval, grade 3 or 4
neuropathic pain was reported in 52% of patients receiving the drug,167
typically occurring during the infusion and reported as abdominal pain,
generalized pain, extremity pain, back pain, neuralgia, musculoskeletal
chest pain, and/or arthralgia. Opioid analgesic premedication is usually
given prior to start of the infusion, followed by continuous opioid infusion
until 2 hours following the completion of the medication.168 One study
describes the use of dexmedetomidine in combination with
hydromorphone for pain management during dinutuximab.169 The pain is
thought to be due to antibody binding to GD2 expressed on normal nerve
cells. Another immunotherapy agent against neuroblastoma is being
developed to avoid this adverse effect.170

PAIN FROM OTHER ETIOLOGIES

Infection
Patients undergoing immunosuppressive therapies such as chemotherapy,
or those with decreased immunologic reserve, such as patients with
leukemia, are susceptible to a myriad of infectious complications, many of
which can be painful and involve almost any part of the body. An
evaluation of pain in a patient with cancer must include evaluation for
bacterial, fungal, or viral infections based on the patient’s current level of
immunosuppression. Treatment of the primary infection and resolution of
neutropenia lead to improvement in pain. In the meantime, analgesic
therapy may be needed.
Of particular interest are herpes simplex viruses (HSV-1 and HSV-2)
and varicella zoster virus (VZV). Primary HSV-1 infection is often
asymptomatic in immunocompetent hosts but can commonly manifest as
painful vesicles in the mouth, throat, or other parts of the body. HSV-2 has

2546
a tropism for the genital area. After primary infection, these viruses
become latent in nerve cell nuclei. In immunocompromised hosts,
however, primary infection can be disseminated, and reactivation of HSV
and VZV infections is common and more severe, leading to substantial
morbidity and in some cases mortality. HSV-1 seropositivity is also a
strong risk factor for oral mucositis,171 with reactivation contributing to as
much as half of oral mucositis episodes172 and greater mucositis
severity173 in HSV-1–seropositive children undergoing myelosuppressive
chemotherapy.
VZV reactivation, also known as (herpes) zoster, often presents with
painful lesions within a dermatomal distribution and severe postherpetic
neuralgia, but immunocompromised patients are also at risk for cutaneous
or visceral dissemination, retinal necrosis, and mortality. Zoster affects
children with cancer at much higher rates than the general population, but
this is improving with varicella immunization.174,175
HSV infections, and thus, a proportion of oral mucositis, can be treated
and prevented with acyclovir.176 VZV reactivation in a patient with cancer
should also be treated with antivirals (e.g., acyclovir); however, additional
analgesic therapy with acetaminophen and/or opioids is often needed for
the acute neuritis associated with zoster, depending on severity.
Postherpetic neuralgia can nevertheless develop despite antiviral
therapy,177 and persistent pain despite healed lesions can be treated with
topical lidocaine or capsaicin on intact skin. Systemic therapy with
gabapentinoids and tricyclic antidepressants may be considered to treat or
attempt to prevent severe pain.178

Graft-versus-host Disease
Because of the intensity of treatment involved, pediatric cancer patients
requiring HSCT as part of their treatment are considered a high-risk group
of patients for the development of acute and chronic pain. Cancer
diagnoses that may require HSCT, either allogeneic or autologous, for
curative therapy include ALL, AML, myelodysplastic syndrome, and
neuroblastoma. Pediatric cancer patients who have received HSCT have
unique risk factors for the development of acute pain, including mucositis,
graft-versus-host disease (GVHD), and tissue erosive infectious

2547
complications.179 Thus, pain management is critical in the care of the
HSCT patient and, if not treated adequately, can result in decreased quality
of life.
GVHD is a unique complication of childhood cancer patients who
undergo HSCT. GVHD occurs due to the host (recipient) cells appearing
foreign to the engrafted hematopoietic stem cells. There are two forms of
GVHD, consisting of acute and chronic GVHD. Acute GVHD occurs
within the first 100 days of the HSCT, causing dermatitis, enteritis, and/or
hepatitis. Acute GVHD can be clinically manifested by skin rash, right
upper quadrant pain, and/or diarrhea and abdominal pain. The skin rash
can range from mild erythema of the palms and soles of the feet to bullous
desquamation in the severe form. Chronic GVHD typically occurs 100
days beyond the hematopoietic stem cell infusion and is thought to be an
autoimmune process. Chronic GVHD primarily has skin manifestations
that include scleroderma-type changes often accompanied by joint stiffness
and immobility.

Bone Complications of Therapy

Pediatric cancer patients are at risk for decreased bone mineral density and
painful and debilitating bone complications such as fractures and
osteonecrosis. Risk factors which are commonly seen in patients treated
for pediatric cancer include exposure to corticosteroids, methotrexate,
skeletal radiation, hypogonadism and growth hormone deficiency from
pituitary tumor or treatment, as well as long-term inactivity and
suboptimal nutrition during treatment.180,181 Severe osteonecrosis and
most fractures are treated with surgical intervention, but nonsurgical
treatments under investigation for osteonecrosis have included
bisphosphonates and hyperbaric oxygen therapy.182,183

PAIN IN SURVIVORSHIP
As more children, adolescents, and young adults become long-term
survivors of pediatric cancers, more is becoming known about their
physical and mental health. Adult survivors of pediatric cancers are more
likely to have chronic health conditions, some of them life threatening or
painful.7 A significant percentage of adult survivors of pediatric cancer

2548
also report poor physical or mental HRQOL.184 Thus, it is not surprising
that survivors of childhood cancers are much more likely to report pain
than their siblings185 and more likely to use prescription analgesics.186
Cancer-related or cancer treatment–related pain still affected 21% of
cancer survivors in the study. Predictors of recent pain attributed to
pediatric cancer or its treatment in these studies include lower household
income, divorced/separated/widowed status, lower educational attainment,
and primary cancer diagnosis of bone cancer or soft tissue sarcoma. Risk
factors for having been diagnosed with any pain condition, including
headache, included age less than 3 years at diagnosis, female gender,
minority race, single marital status, lower income, and unemployment.185
Pain contributes negatively to quality of life in survivors. Survivors with
pain were more likely to have comorbid internalizing and externalizing
symptoms.187 Thus, it is important to screen for and address pain in
childhood cancer survivors and also important to take measures during
initial treatment to prevent or moderate development of pain sensitization.

Management of Pain
Just as the assessment of pain in a pediatric patient with cancer ideally
involves a multidisciplinary team, a multidisciplinary approach is also
ideally employed in the management of pain in these patients. Anticipation
of expected painful effects of cancer and its treatment, education of the
parent and child, and prevention of procedural and therapy-related pain are
paramount to improving the patient’s cancer experience. A pain prevention
plan could involve critically evaluating potentially painful procedures for
their necessity.104 It is also important to consider procedural sedation if
indicated and consolidating painful procedures under one sedation if
possible. Similarly to the strategy of antiemetic prophylaxis for
emetogenic cancer treatments, the different interventions detailed in the
following text can also be used for prevention of pain when pain is
expected. A comprehensive approach incorporates this anticipatory
guidance and prevention as well as physical, psychological, and
pharmacologic approaches to treatment of the various pain syndromes in
children with cancer. Prevention of or minimizing pain will reduce the

2549
likelihood of distressing pain memories that can impact future pain
experiences.188

Pharmacologic Management of Cancer-Related Pain

in Children
In 2012, the WHO189 expanded guidelines on Cancer Pain Relief and
Palliative Care in Children, now covering pharmacologic treatment of
persisting pain in all children with medical illness with ongoing tissue
damage or inflammation. The WHO now recommends a two-step
approach to pharmacologic management of pain in this population. In this
approach, acetaminophen (paracetamol) or an NSAID, such as ibuprofen,
is given for mild pain, and strong opioids are given for moderate to severe
pain. In previous guidelines, the WHO had recommended an intermediate
step with weak opioids such as tramadol and codeine. However, because
tramadol is generally not labeled for patients under 12 years, and codeine
presents significant variability in response and toxicity related to CYP2D6
polymorphisms, this intermediate step has been removed from the
pediatric recommendation. Several studies in adults190,191 and the
European Association for Palliative Care guidelines for treatment of
cancer pain192 are also supportive of this strategy.
Treatment of cancer-related pain in children should follow this two-step
approach but with certain considerations. NSAIDs are known to cause
temporary platelet dysfunction which can lead to an increased risk for
bleeding. This may not be acceptable in the setting of bone marrow
infiltration (such as with newly diagnosed leukemia) nor in the setting of
bone marrow myelosuppression and resulting thrombocytopenia (such as
with ongoing chemotherapy). In addition, prolonged NSAID use can result
in renal injury, which can exacerbate cumulative renal insults from other
chemotherapy and supportive care medications such as aminoglycosides.
NSAIDs can also decrease renal clearance of toxic chemotherapy agents
such as methotrexate.193 Finally, NSAIDs are associated with gastric and
duodenal ulcers, especially in combination with corticosteroids.194 If given
in combination with corticosteroids, a histamine H2 receptor antagonist or
proton pump inhibitor may be required to prevent gastroduodenal

2550
ulcerations and stomach discomfort.
For these reasons, acetaminophen is more commonly used than NSAIDs
as a first-line treatment for mild pain in a child who has or is at risk of
thrombocytopenia. This includes patients newly diagnosed with leukemia
or other bone marrow infiltrating tumor as well as children undergoing
chemotherapy. Acetaminophen is most effective at doses of 15 mg/kg
every 6 hours.195 It is also now available in the intravenous formulation for
children not able to tolerate oral medications, but it can be costly.
Acetaminophen, however, has its own limits, especially in the setting of
liver dysfunction or failure.
Moreover, acetaminophen and ibuprofen are both used for their
antipyretic effects as well. This can complicate the treatment of pain in
patients with neutropenia (absolute neutrophil count <500 cells/µL).
Because fever may be the earliest and only sign of a severe infection in a
neutropenic patient, scheduled acetaminophen or NSAIDs may
theoretically pose a risk for delayed recognition of an infection which can
lead to sepsis or death. For this reason, these medications are usually dosed
as needed (“PRN”), and persisting pain is treated with scheduled opioids.
Lastly, it should be emphasized that the two-step strategy does not
necessarily preclude use of strong opioids as first-line therapy for
moderate to severe pain. A randomized trial testing nonopioid analgesics
against strong opioids as first-line therapy for moderate to severe pain in
“terminal” adult cancer patients showed that patients started on strong
opioids had better pain relief, fewer changes in therapy, greater reduction
in pain, and greater satisfaction with treatment, without serious adverse
events.196
The other principles advocated by WHO189 guidelines are to treat pain
“at regular intervals,” “by the appropriate route,” and “to the individual
child.”
• At regular intervals: Unless pain is truly intermittent or unpredictable,
persisting pain should be treated at regular intervals, while monitoring
for adverse effects, with the addition of “rescue doses” for intermittent
and breakthrough pain.
• By appropriate route: Analgesia should be administered by the
simplest, most effective, and least painful route. For most children,

2551
 oral analgesics are the route of choice; however, intravenous, rectal,
and subcutaneous routes may be needed depending on the clinical
situation. Of note, the rectal route is usually avoided in potentially
immunocompromised children, including those receiving
chemotherapy.
• To the individual child: Opioid analgesics should be titrated in
collaboration with the patient to achieve the best possible analgesic
effect with side effects acceptable to the patient.

Overview of Opioid Analgesia in Children

Strong opioids with the most evidence and clinical experience for pain in
pediatric patients with cancer include morphine,197 hydromorphone,198 and
fentanyl.199 Other important strong opioids with less data in pediatric
cancer patients include oxycodone, methadone, and buprenorphine.200,201
PCA with morphine, hydromorphone, or fentanyl is also an effective
option for pediatric patients as young as 5 years of age, depending on their
level of cognitive development.202–204
There are several unique delivery systems of opioid analgesics which
might prove useful in the pediatric cancer population to avoid the fear and
pain associated with injections. Options for oral transmucosal delivery of
fentanyl now include a lozenge/troche (Actiq), sublingual tablet (Abstral),
buccal tablet (Fentora), soluble film (Onsolis), and a sublingual spray
(Subsys). These preparations may even be more efficacious than oral
morphine for breakthrough cancer pain.205 Labeling, at this time, is limited
to opioid-tolerant adult patients.
Another noninvasive method of opioid drug delivery includes the use of
fentanyl or buprenorphine transdermal therapeutic systems (TTS). One
practical advantage is that when the oral route of tablet, capsule, or liquid
administration is contraindicated or not well tolerated by a child, the
transdermal drug delivery method allows for an alternative route. There
are emerging numbers of pharmacokinetic studies on the use of TTS in
children.206 The data supporting the transdermal route over traditional
morphine is minimal, but there are studies that demonstrate child and
parent satisfaction with the TTS delivery system of fentanyl and

2552
buprenorphine in both pain relief and quality of life in the pediatric
palliative care setting.207,208
It has been shown that in the pediatric cancer population, opioid
monotherapy is the most effective method for treating moderate to severe
pain.209 It is not effective, however, for all pediatric cancer patients due to
various etiologies including opioid-induced tolerance and opioid-induced
hyperalgesia.210 The analgesic response to any given opioid dose depends
on the tolerance of the patient. An opioid-tolerant patient will require a
higher dose for the same analgesic response when compared to the opioid-
naive patient.

ADVERSE EFFECTS
Adverse effects of opioid analgesics, for both the opioid-naive as well as
the opioid-tolerant patient, include somnolence, constipation, pruritus,
nausea, vomiting, urinary retention, and sweating. Management of opioid-
induced adverse effects is critical in pediatric patients with cancer.
Constipation may already be a significant problem for the child prior to the
use of opioids as certain types of chemotherapeutic agents, such as
vincristine, can cause severe impaired gut peristalsis. This, combined with
mucosal breakdown in an immunocompromised host, can lead to severe
infectious complications and sepsis. When using high dose or prolonged
courses of opioids for the treatment of CNS pain, the treatment plan must
also include a bowel regimen to reduce the likelihood of constipation.
There are several different classes of medications that can be used to treat
or prevent constipation including polyethylene glycol 3350 (often
preferable because it is a tasteless and odorless powder that can be mixed
with any liquid), senna (a stimulant laxative), docusate (a lubricating
laxative), milk of magnesia (which contains magnesium hydroxide, an
osmotic laxative), and/or mineral oil (a lubricant). Peripherally acting µ-
opioid receptor antagonists such as subcutaneous methylnaltrexone and
oral naloxegol211 are approved for opioid-induced constipation not
responsive to usual laxatives in adult noncancer patients, but they are often
used off-label for cancer patients without known or suspected lesions in
the intestinal wall.
Urinary retention may lead to hemorrhagic cystitis when combined with

2553
oxazaphosphorines such as ifosfamide and cyclophosphamide, and strict
intake and output parameters must be monitored while receiving these
medications. Patients with cancer are also at higher risk for nausea and
vomiting with concurrent chemotherapy. They are also at higher risk for
somnolence because of polypharmacy with potentially sedating
medications such as diphenhydramine and lorazepam used as antiemetic
therapy.
Opioid rotation is commonly used as a means of optimizing analgesia
while minimizing opioid-related adverse effects.

DEPENDENCE AND ADDICTION

There can also be barriers to the use of high dose or long-term use of
opioid analgesia in children due to parents’ and health care providers’
concerns regarding the risk of dependence or addiction.212 Some of the
more common symptoms of withdrawal in a child with physiologic opioid
dependence include severe dysphoria, diarrhea, anxiety, restlessness, and
chills and usually occur when the opioid analgesic is stopped abruptly. The
symptoms observed in pediatric patients can vary from those observed in
adults. For example, an infant can have a high-pitched cry and inability to
be soothed with a pacifier, bottle, or swaddling. A toddler’s signs of
withdrawal may include only diarrhea and temperature instability.
Conversely, addiction is a complex behavior characterized by the
compulsive use of a drug and psychological craving. Addiction is not
commonly seen in the pediatric population but may be observed in the
older adolescent who has complex psychosocial issues resulting in
maladaptive coping to pain.

TOLERANCE TO OPIOIDS
Given that tolerance to opioid analgesics can limit their clinical
effectiveness, various approaches can be used to prevent or reverse
tolerance in children who require prolonged exposure to high-dose opioids.
One proposed approach to prevent tolerance includes the use of N-methyl-
D-aspartate (NMDA) antagonists concomitantly with the opioid.
Methadone is a synthetic, long-acting opioid that has often been used for
both its µ-opioid effect as well as its NMDA receptor antagonist effect,

2554
which is thought to help prevent opioid tolerance. When managed by
experienced clinicians, opioid rotation from other opioids to methadone in
the face of opioid tolerance or unacceptable side effects can be safe and
effective in cancer pain.213
Ketamine has been studied and shown to have a role in mitigating
opioid-induced tolerance in children and adolescents who experience
cancer pain.214 Finkel et al.215 have used ketamine at lower doses than
used for anesthetic purposes. Specifically, they used ketamine from 0.1 to
1.0 mg/kg/hour in patients who had signs of opioid tolerance or had severe
side effects such as profound sedation. With this regimen, they found that
adjuvant ketamine infusions used in combination with opioid analgesics
(including morphine, methadone, and hydromorphone) resulted in
improved pain control.

“WEAK” OPIOID
Tramadol is an atypical opioid that has a weak affinity for the µ-opioid
receptor as well as being a weak inhibitor of serotonin and noradrenaline
reuptake. The advantage of tramadol is that it has negligible respiratory
depression.216 It is hepatically metabolized and renally excreted, factors
that must be taken into consideration when using this medication in the
pediatric cancer patient because chemotherapy can result in both renal and
hepatotoxicity. The active metabolite is O-desmethyltramadol (M1), and
recent pharmacokinetic studies in children have demonstrated that it is
possible to produce enough of the active metabolite to achieve adequate
pain relief.217 Safe dosing regimens for children ≥12 months of age
include 1 to 2 mg/kg per oral route of administration every 4 to 6 hours
with a maximum dose of 8 mg/kg/day.218

ADJUVANT THERAPIES FOR NEUROPATHIC PAIN

A review by Friedrichsdorf and Nugent219 acknowledges a lack of
randomized clinical trial data about the management of neuropathic pain in
children. There is evidence that NSAIDs (when not contraindicated), weak
opioids, and strong opioids may be helpful in adults, and the authors
suggest a stepwise approach including treatment of the underlying disease
process, integrative/nonpharmacologic therapies, NSAIDs, and weak or

2555
strong opioids before considering a tricyclic antidepressant (such as
amitriptyline), a gabapentinoid (gabapentin or pregabalin), or a
combination of a tricyclic and gabapentinoid. Because these medications
often take time to reach therapeutic effect, the addition of ketamine or
methadone for NMDA-receptor-channel blockade may be considered, or
low-dose benzodiazepine, α-agonists such as dexmedetomidine or
clonidine, and/or intravenous lidocaine. Localized pain can also be treated
with a lidocaine 5% patch. Regional anesthesia can also be considered.
Duloxetine is also a consideration in some patients based on its modest
effectiveness in adult chemotherapy-induced peripheral neuropathic
pain.220

Physical and Psychological Therapies for Pain in the

Pediatric Cancer Patient
There are multiple nonpharmacologic therapies that can be employed for
pain management in the pediatric cancer patient (Table 49.1). These
include massage therapy, yoga, hypnotherapy, meditation, biofeedback,
relaxation, spirituality, acupuncture, botanicals, physical therapy (PT), and
energy therapies including the use of magnets. The definition of
complementary and alternative medicine (CAM) was those interventions
that are neither generally provided by US hospital clinics nor widely
taught in medical school.221 More recently, there has been a concerted
effort by the NIH and clinicians alike to consider these options as
“integrative therapy.”222–224

TABLE 49.1 Complementary and Alternative Medicine Therapies

to Be Considered in the Treatment of Pediatric Cancer Pain
Acupuncture
Hypnotherapy
Massage
Biofeedback
Botanicals
Magnets
Spirituality/religiosity
Therapeutic yoga

2556
 Thus, although these nontraditional pain treatments may not be familiar
territory for physicians trained within the United States, there is an
emerging body of literature discussing the state of the science of
integrative therapy use in both adult and pediatric populations.225 In
addition, the latest literature in medical education has documented a clear
trend of higher usage rates of integrative therapies by anesthesia training
programs across the United States.226 Thus, integrative interventions,
including pharmacologic, psychologic, physical, and other therapies,
should be considered in the treatment of pediatric cancer pain.

ACUPUNCTURE
Acupuncture consists of inserting fine needles into the skin’s surface, or
using heat, pressure, or other stimulation in areas that correspond to
specific points along “meridians” (i.e., energy channels within the body).
These meridians in which the body’s life forces (spiritual, emotional,
mental, and physical) flow can be out of balance and cause the physical
sensations of pain, imbalance, and sickness. Insertion of the needles into
specific points along meridians through the practice of acupuncture helps
to restore the balance of forces within the body and thereby eliminate the
pain by achieving a flow of energy or Qi (pronounced “chi”). Although the
practice of acupuncture is more widely accepted within East Asian
societies, the use of acupuncture for treatment of pain has been increasing
across the United States.227,228 Currently, 46 US states and the District of
Columbia require licensure for the practice of acupuncture. For those
states that do not regulate the practice, the health care provider should ask
for certification by the National Certification Commission for Acupuncture
and Oriental Medicine (see Chapter 94).
There is a growing body of literature evaluating its effectiveness for
alleviating pain.229,230 The available literature on the use and effectiveness
of acupuncture in the treatment of pain in the pediatric population suggests
it is an acceptable treatment modality for adolescents with chronic pain, as
well as an effective modality for other common symptoms experienced by
the childhood cancer patient, including headache, nausea, and
vomiting.231–233 Nonetheless, acupuncture has not been widely
disseminated into pain treatment regimens for the pediatric population.

2557
One reason is preexisting beliefs by health care practitioners in the United
States that children are afraid of needles, and thus, they do not make
referrals for acupuncture. On the contrary, it has been shown that for those
children who have been referred to acupuncture for various chronic pain
syndromes, over two-thirds report that it was a positive experience and an
effective modality for treatment of their pain.234 Acupuncture, therefore,
can be considered as a possible adjuvant treatment modality for
neuropathic pain in the pediatric cancer patient.

BEHAVIORAL INTERVENTIONS
A Cochrane review on psychological interventions in needle-related
procedural pain supports distraction as an effective modality for
decreasing self-reported pain.235 Distraction techniques include listening
to music, watching cartoons, playing with a toy, nonprocedural talk,
squeezing a rubber ball, using cards with questions on them, listening to
stories via earphones, parental soothing, or a combination. Virtual reality
is a specific type of distraction technique involving immersing the child in
a virtual world using visual and auditory stimuli, with some positive
results.236–238
Cognitive-behavior therapies (CBTs) have also been extensively studied
needle-related procedural pain and distress in children. Specific therapies
included procedural preparation and information, relaxation, guided
imagery, modeling, procedural rehearsal, coping skills teaching, parent
coaching, and memory alteration techniques. A Cochrane review in
2006239 found sufficient evidence supporting combined CBT; however, an
update in 2013235 had stricter inclusion criteria for included studies and no
longer had sufficient data to support the benefit of CBT.

HYPNOTHERAPY
Hypnosis is a cognitive strategy that helps the child achieve a narrowed
focus of attention, relax, and learn how to dissociate from the current
sensory environment. Several groups in randomized controlled studies of
children with cancer undergoing medical procedures have shown
hypnotherapy to be effective in reducing procedure-related pain and
anxiety.240–242 These are summarized in numerous reviews.243,244 Wood

2558
and Bioy245 provide a succinct review on the effectiveness of this
technique, an understanding of the physiologic effect of hypnosis, and the
practical application of its use to treat pain in children. For example,
Rainville and colleagues246 have demonstrated, through the use of positive
emission tomography (PET), changes in regional cerebral blood flow when
hypnosis is used. In hypnotic states, there is increased blood flow to the
occipital cortical areas. This increase in blood flow to the occipital region
is thought to result in a reduction of inhibitory processes that occur
normally during high levels of attention.247 Thus, hypnosis results in an
acceptance of specific, altered sensations, thereby mediating changes in
perception of the painful experience.
Several studies on the effect of hypnosis for symptom management in
children, including the effect on pain perception, anxiety, and
nausea/vomiting have been completed. Early studies demonstrated the
feasibility of being able to hypnotize children.248 Subsequent studies by
Zeltzer et al.249 have demonstrated the effectiveness of hypnosis in
decreasing other symptoms experienced by pediatric cancer patients,
including nausea. Studies have also demonstrated the effectiveness of
hypnosis in decreasing pain and anxiety in children undergoing the
invasive painful procedures of LPs and bone marrow biopsies.250 Thus,
there continues to be increasing evidence of both the feasibility of
administration and the effectiveness of hypnosis in the pediatric
population, and it should be considered when a pediatric cancer patient is
undergoing invasive, painful procedures. As the review paper by Wood
and Bioy245 discusses, practical considerations of using hypnosis include
the child’s age (as younger children are more responsive to the hypnosis
when compared to adolescents), cognitive development, and therapeutic
relationship with his or her provider.

EXPRESSIVE ARTS THERAPIES

Expressive or creative arts therapies include such disciplines as art
therapy, music therapy, dance/movement therapy, drama therapy, and
poetry therapy. Expressive arts therapists are trained, credentialed
specialists who use an expressive art form in the context of psychotherapy,
medicine, or rehabilitation. The therapist systematically assesses the

2559
patient and tailors an interactive expressive art experience to the patient’s
psychological needs through a therapeutic process. The expressive arts not
only help to distract from the patient’s current illness and normalize the
hospital or clinic environment but also use theoretical concepts to improve
coping and manage distress. For example, Robb et al.251 studied a
therapeutic music video intervention in adolescents and young adults
which was grounded in motivational and developmental coping therapy to
(1) provide predictability through clearly defined goals and structured,
preferred music; (2) autonomy support through patient-directed choices
about music, lyric writing, video content, and involvement of others; and
(3) relationship building through a nonthreatening, creative activity to help
patients explore, identify, and express what is important to them.
Expressive arts therapies, especially music therapy, have been shown to
improve symptoms, such as anxiety, pain, and need for analgesics; lower
heart rate, respiratory rate, and blood pressure; and improve quality of life
and perceived social support.252 A small art therapy study using different
techniques such as visual imagination, structured and free drawing, and
medical play to promote coping behaviors helped improve patient
cooperation with painful procedures.253 Integrating different creative arts
therapies together may also be beneficial. A randomized study in pediatric
brain tumor patients showed that creative arts therapies can help improve
pain as well as nausea, anxiety, and mood.254

MASSAGE
Massage is the practice of light body stroking or deep tissue stroking that
is thought to work by increasing serotonin and reducing cortisol. The basic
principle of massage is that when muscles are overworked, there is a
release of waste products that accumulate in the area that can be relieved
using the hands of the therapist to manipulate muscles and surrounding
tissues. Massage therapy has been used as an adjuvant therapy in pain
management with a number of studies demonstrating its effectiveness. For
example, it has been shown that when massage therapy was used in
addition to a standard pharmacologic regimen for postoperative pain
management, the experimental group demonstrated decreased pain
intensity, pain unpleasantness, and anxiety when compared to the control

2560
group.255 Massage therapy is also a CAM modality that can be easily
instituted at the bedside for the cancer patient.256 There are a few studies
to date completed in the pediatric population on the use and effectiveness
of massage therapy for cancer-related pain. For example, oncology and
hematology inpatients who received a standardized massage therapy
protocol experienced significant improvements in anxiety, emotional state,
muscle soreness, discomfort, respiratory rate, and overall progress
compared with a control group.257 Children assigned to massage therapy
for 20 minutes prior to an LP or bone marrow procedure, in addition to
topical EMLA and intravenous midazolam, had significantly decreased
levels of pain and anxiety after the massage therapy compared to patients
in a control group.258 In a study of children with ALL, a daily massage
over a 1-month period was found to have an impact on the immune system
as demonstrated by an increased white blood cell count as well as an
improvement in children’s negative affect.259 Given the promising
application of massage therapy to decrease pain in children, future
research is warranted to evaluate the effectiveness of the healing powers of
touch (i.e., massage) in a randomized controlled trial for pediatric cancer
patients.

BIOFEEDBACK
Biofeedback involves measuring physiologic parameters, including blood
pressure, heart rate, skin temperature, sweating, and muscle tension, and
conveying the changes that occur while the child is learning breathing and
imagery strategies to alter these bodily processes. This bodily feedback
information can be provided through the use of computer-generated,
audio-generated, or other forms of visual-generated systems with skin
temperature or muscle contraction being the most commonly measured
parameter. The basic concept of biofeedback is that by providing
physiologic information to a patient who is usually unaware of these
bodily processes, while also teaching the child cognitive and breathing
strategies that alter these processes, the child can learn to reduce muscle
tension and autonomic arousal, thereby reducing pain. For children, it
provides proof that the mind can affect the body by being able to gain
physiologic control of the part of the nervous system that is activated by

2561
pain or stress.
Studies on the use of biofeedback have primarily been focused on adult
patients, particularly those with headaches. Meta-analysis of this mind–
body approach for the treatment of headache pain indicates that it is
effective when used alone or in combination with other CAM
modalities.260 Studies completed in pediatric patients again are limited in
number, but those that have been completed also have focused on the
treatment of pediatric migraine headache. Similar to the adult literature,
meta-analysis on the use of biofeedback, as well as other behavioral
methodologies to treat headache in children, demonstrates that it can be
considered as an important adjunct to the pain treatment regimen.261 Given
that there are minimal side effects and there is data suggesting its
effectiveness, biofeedback can also be considered as another adjunctive
therapy to pain management in the pediatric cancer patient. There is no
license to practice biofeedback, although the majority of practitioners have
other medical licensures, such as registered nursing (RN), PT, or marriage
and family therapy (MFT). Hospitals and clinics with pediatric pain
programs can often provide referral lists of biofeedback therapists.

BOTANICALS
The use of herbal or alternative medicines requires discussion in the
treatment of cancer pain given the increasing frequency of use within the
US population with or without data suggesting its effectiveness.262 The
studies that have evaluated the use of herbal medicine in pediatric patients
have been for the treatment of otalgia and have been completed outside the
United States.263 One such study evaluating the use of the naturopathic ear
drop, Otikon, concluded that it was as effective as anesthetic ear drops for
acute otitis media associated with ear pain.264 Thus, given the paucity of
studies documenting effectiveness of botanicals, this CAM option cannot
be recommended in the treatment of pediatric cancer pain. The lesson that
must be taken away, however, is that it is important for practitioners to ask
if botanicals (including megavitamins and herbs) are being used by the
parent to help treat their child’s pain because there may be drug
interactions that may interfere with the cancer treatment regimen.

2562
CANNABIS
Because of legalization efforts in several US states, Canada, and other
countries, “medical” cannabis is becoming more available and in many
different forms. Cannabis, including marijuana, is a psychoactive
substance produced from the cannabis plant and often comprising multiple
compounds, including plant-derived cannabinoids like
tetrahydrocannabinol (THC) and cannabidiol (CBD). Synthetic
cannabinoids have also been produced such as dronabinol, nabilone, and
nabiximols spray. The use of cannabis, especially for pain, nausea, or even
antitumor effects has generated significant interest in the public and among
some patients with cancer and their families.265 In humans, cannabinoids
bind endocannabinoid receptors CB1, found in the brain and nervous
system, and CB2, found in the immune system. Some reviews have found
improvement in cancer-related or other pain with certain preparations of
cannabis.266,267 A review of medical cannabis in pediatric populations in
many ways parallels the findings in adults in regard to chemotherapy-
induced nausea/vomiting, seizures, and spasticity; however, data on pain,
even neuropathic pain, in children is lacking. 268 Short-term side effects
such as increased heart rate and blood pressure are common and may limit
its use in patients with heart disease. Side effects of THC include
drowsiness and dizziness. Side effects of CBD include somnolence,
diarrhea, and decreased appetite. Prolonged use in recreational users has
been associated with mood, anxiety, and psychotic symptoms and
disorders.
Because of the heterogeneity of its composition and the lack of
regulation, a great deal of caution must be used in extrapolating results
from controlled studies to what is available on the market.
Immunocompromised patients should be warned against use of
unregulated marijuana, especially smoked and vaporized forms, because of
potential infectious complications such as invasive pulmonary
aspergillosis.269 Data on effectiveness on pain in children with cancer are
lacking, and effects of chronic cannabis use on the developing brain are
concerning.270,271 Because of a lack of efficacy data and these safety
concerns, pediatric societies have advocated for further research and urged
caution in recommending cannabis to pediatric patients, acknowledging

2563
that there may be a role in certain exceptional cases such as for children
with life-limiting or severely debilitating conditions.272,273 Comprehensive
discussion of potential benefits and risks and robust monitoring of safety
and efficacy during treatment is necessary.

MAGNETS
The use of magnets to treat chronic pain is another modality that has been
under investigation in adult populations. Interestingly, despite the lack of
clear data documenting the effectiveness, one study documented that
magnet use was the second most common nontraditional modality used by
adult patients with arthritis, second only to the use of a chiropractor.274
The basic mechanism of magnet use is that they produce a type of energy
—a magnetic field—that can affect pain sensation, although the exact
mechanism by which pain reduction occurs has not been identified. There
are various magnet products for use in health care including shoe insoles,
shoe inserts, mattress pads, bandages, belts, pillows, bracelets, and
headwear. Despite all of these various health care products, there are
limited data documenting the effectiveness of this modality. A recent
systematic review and meta-analysis of randomized trials demonstrated no
significant difference in pain reduction.275 There may be a placebo effect
for the patient who places a magnet on the body in the form of a bracelet
or bandage.276 The only reports in the literature of magnets in pediatric
populations refer to the dangers of magnet ingestions resulting in
gastrointestinal injuries.277 Thus, the use of magnets to treat young
pediatric cancer patients is another treatment modality that cannot be
recommended at this point in time and may be associated with risk of
ingestion by a young child.

SPIRITUALITY/RELIGIOSITY
Spirituality (i.e., religiosity) is an important domain that must be
considered when conceptualizing the model of palliative care for children
with pain.278 Spirituality is commonly used by cancer patients to cope with
their diagnosis, aggressive treatment plans, and associated painful
experiences. Spirituality has been shown to be an important coping
mechanism for adult cancer patients. For example, it has been shown that

2564
breast cancer patients who rate their spirituality as high have lower rates of
depression, although no effect on pain ratings.279 Similarly, when mothers
of childhood cancer patients were asked to rate their religiosity
concomitantly with the measurement of depression using the Beck
Depression Inventory-II, it was shown that those mothers who reported
lower levels of religious beliefs and behaviors had higher rates of
depressive symptoms.280 It has therefore been recommended that health
care providers consider—when they have patients practicing prayer or
prayer-like behaviors—to include a discussion on the benefit of this
behavior at improving health through the mind–body connection.281 In
addition, given that most major medical centers caring for children with
cancer have access to a chaplain or spiritual support, consulting this
service should be considered (where appropriate) when developing a pain
management plan for the pediatric cancer patient.

THERAPEUTIC YOGA
Therapeutic yoga, including Iyengar yoga, has been used in children to
reduce pain, anxiety, and correct health problems. Iyengar yoga, for
example, uses poses (asanas) and breathing to correct body structure,
enhance internal organ function, facilitate mindful awareness, and achieve
a sense of mind–body–spiritual well-being. Studies conducted in
adolescents have demonstrated the practice of yoga results in improvement
of mood, a decrease in the stress hormones, and decreased pain and
disability.282,283 There are no published randomized controlled trials of
yoga therapy in pediatric oncology; however, several single-arm pilot
studies suggest improvement in physical function, quality of life,
functional mobility, flexibility, physical activity, energy, sleep, and mood
and decreases in anxiety, nausea, and pain medication, as summarized in a
recent review.284 In the practice of Iyengar yoga, a teacher who has
studied for a minimum of 5 years teaches various poses to a child that can
be beneficial in decreasing pain. For the pediatric cancer patient with
unique needs, including an impaired immune system, private yoga lessons
are preferred over group lessons, with therapeutic Iyengar yoga our
preferred method of yoga because of extensive teacher training, the use of
supportive props, and selection of specific poses based on the needs of the

2565
child.

Palliative Care for Children with Cancer

A chapter on pain management for children with cancer is not complete
without highlighting the important topic of palliative care given that
overall 20% of children will not be cured of their disease. The WHO’s
definition of palliative care is “the active total care of patients whose
disease is not responsive to curative treatment. Control of pain, other
symptoms, and psychological, social, and spiritual problems is of
paramount concern. The goal of palliative care is achievement of the best
possible quality of life for patients and their families.”285 The “other
symptoms” in addition to pain that can be experienced by the child without
the option of curative therapy include fatigue, dyspnea, poor appetite,
nausea, vomiting, constipation, and/or diarrhea.23 Thus, symptom control
for children facing end of life is imperative. Studies have demonstrated
that when the multidisciplinary approach of palliative care is employed,
families and patients report improved satisfaction with their care,
improved informed decision making, and a decrease in the number of
emergency room visits and inpatient admissions.286
The American Academy of Pediatrics (AAP) has put forth a policy
statement promoting the use of palliative care at the end of life for children
with life-limiting disease. Their statement highlights that palliative care
can improve the quality of life for terminal patients and their families
through the treatment of symptoms and by addressing the psychological,
social, or spiritual aspects of facing a noncurable disease.287 Despite this
policy statement on the importance of the provision of palliative care
services for children with life-threatening disease, there are barriers that
currently exist and thereby impede its implementation across the US health
care system. First, there can be differences in parents’ understanding of
prognosis of their child’s illness when compared to their health care
providers’ knowledge, a discrepancy that in turn can impact a parental-
informed decision for end-of-life care, including pain management.288
Secondly, parents whose children have an incurable cancer diagnosis rate
doctor–patient communication as the principal determinant of high-quality

2566
physician care. Conversely, physicians’ care ratings depend on biomedical
rather than doctor–patient relationship aspects of care.289 It is, therefore,
critical for physicians caring for the dying child to listen to the concerns of
the patient and the parent particularly for those related to descriptions of
pain. By listening to a patient’s description of pain and thereby classifying
the etiology of the pain one can determine the best therapeutic approach.
By being aggressive with symptom management, the pain and suffering at
the end of life for a terminal pediatric cancer can be minimized.290
Pediatric palliative care requires evaluation and reevaluation of
symptoms. In addition to the assessment of pain, the provider needs to
assess for symptoms of fatigue, dyspnea, anxiety, nausea, and sleep
patterns. There should also be the assessment of caretaker function and
support because fatigue or anxiety in the primary caretaker can in turn
affect the symptoms associated with pain manifested by the child.
Treatment of other end-of-life symptoms, such as dyspnea, can require the
use of opioids, especially morphine, to decrease the sensation of air
hunger. If the child is heavily sedated and the family or caretaker has
minimal awake time with the child, psychostimulants (e.g.,
methylphenidate, modafinil) can be used in the mornings to override some
of the sedative side effects of high-dose opioids needed for pain. In
addition, nondrug therapies, such as music therapy or hypnotherapy, can
be used concurrently with pain medications. The pediatric palliative care
model as described earlier can be delivered both in the inpatient setting as
well as in the home if pediatric hospice services are available. In either
setting, the goal of maximizing quality of life for the quantity of time that
remains for a child without curative therapy should be emphasized. It
should be noted that many clinicians now consider palliative care to begin
with a serious diagnosis, such as cancer, even if the likelihood for cure is
high, because even some children with lower risk cancers, like ALL in the
young child, will die. Thus, a focus on maximizing quality of life and
reducing distressing symptoms should be as important a focus in the child
with cancer as is the aim for cure.291,292

Summary

2567
Although pediatric cancer statistics are currently at an all time high with an
overall survival rate of 80%, cancer-related morbidity, including the risk
for the development of significant acute and chronic pain, persists. Thus, a
comprehensive approach to pain management in the pediatric cancer
patient, especially through empowerment of the child through a mind–
body therapeutic approach to their pain management, is critical. There are
several pharmacologic treatments that can be used to treat the various
types of pediatric cancer pain including opioid analgesia, NMDA
antagonist agents, atypical opioid medications, tricyclic antidepressants,
and anticonvulsants. Integration of nonpharmacologic modalities as an
adjuvant or alternative to pharmacologic interventions is also important
because there can be limitations in the traditional pharmacologic approach
to pain, particularly for chronic pain syndromes. Although not all
nonpharmacologic therapies have a long track record in the scientific
literature regarding their effectiveness, it does not mean these options
should be excluded from pain management consideration, but rather, a
discussion with families of the strengths and limitations of such
approaches is warranted.
In summary, the foundation to the pain evaluation and treatment plans
for children with cancer is a focus on the whole child. The importance of
eliciting and listening to all details of the pain narrative of the pediatric
cancer patient is critical. Child self-report will be dependent on the
developmental level of the child and child pain evaluation encompasses
the parental role in the pain experience, a proxy reporter of the pain
narrative. For both the child and the parents, the pain assessment should
occur early on, in a nonthreatening environment, where the strong triad
relationship between the pediatric cancer patient, the parent, and the health
care provider can be an effective one. In this family-centered care
approach, the common goal of alleviating the child’s pain can be achieved
through education, empowerment, and the provision of mind–body
therapeutics.

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 ACUTE PAIN

CHAPTER 50
Acute Pain Management in
Children
STACY J. PETERSON, KRISTEN LYNN LABOVSKY,
and STEVEN J. WEISMAN

Nociception alerts the organism to potential or actual sources of harm.

Nociceptive functions are active at birth, even in preterm neonates, and the
experience of pain or pleasure has a powerful impact on learning and
neurologic development.1 Fitzgerald and Walker,1 using neurobiologic
studies in infant rats and psychophysical studies in infant humans, showed
that the infant nervous system is in many respects hyperresponsive to
noxious stimuli compared to the mature nervous system. Infant rats and
humans withdraw their limbs from milder mechanical or thermal stimuli
compared to older rats or humans. Infant rats and humans develop
hyperalgesia following tissue injury, with evidence for spinal sensitization
even in preterm neonates.
In the 1980s, there was a growing acceptance that peripheral and spinal
mechanisms of nociception are active in preterm and term neonates.
Controversy persisted regarding maturation of supraspinal mechanisms
and regarding how to view pain as a conscious experience or suffering in
neonates. Recent studies have examined correlates of brain activation
using near-infrared spectroscopy, which is sensitive to regional changes in
blood flow. A noxious stimulus to the heel (performed for clinically
indicated blood sampling) evoked increased signal overlying the
contralateral, but not ipsilateral, cerebral cortex, which has been
interpreted as a specific pattern of activation not solely dependent on
global changes in autonomic arousal and blood pressure. These and other
lines of evidence suggest that “painful stimulation reaches the brain” in
neonates, although they do not per se establish the nature of pain viewed as

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conscious experience or suffering in neonates. Additional discussion
follows later in the chapter regarding potential consequences of either
untreated pain or pain treatment in critically ill neonates.1
Care of infants and children with acute pain has changed considerably
over the past several decades, and available evidence suggests that
undertreatment of acute pain has become less prevalent in economically
developed countries over this time period.2 Changes in practice appear to
be the combined result of a series of developments in basic research,
clinical trials, and advocacy by parents as well as by clinicians, as listed in
Table 50.1.

TABLE 50.1 Factors Possibly Contributing to Increased Awareness

of and Treatment of Pain in Infants and Children
1. Studies demonstrating maturation of nociceptive pathways in infant animals and in infant
humans
2. Clinical trials demonstrating improved outcomes of neonates undergoing surgery under
adequate anesthesia
3. Studies of pain assessment in infants, children, and adolescents
4. Pharmacologic studies examining pharmacokinetic, pharmacodynamic, and clinical outcomes
of analgesics in infants and children
5. Development of acute pain services in pediatric tertiary centers
6. Development of regional anesthesia skills and service for infants and children
7. Advocacy by parents

Pain Assessment in Infants and Children

Assessing pain in infants and children is a fundamental but challenging
aspect of pediatric care. Uniform assessment of pain should be part of the
standard of care for hospitals and clinics caring for children. Typical adult
pain measures are not applicable to preverbal and young children. Infants
and very young children are dependent on adult caregivers to adequately
interpret their behavior and other signs in determining whether they have
pain. Methods of measuring pain in preverbal patients and toddlers (ages 2
and 3 years) generally involve combinations of behavioral observation,
such as facial expression, crying, and physiologic parameters. Preschool-
age and early school-age children (ages 3 years or 4 to 8 years) are
generally able to give some degree of self-report and pain scales in this age

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group incorporate self-report measures. In the younger group (ages 3 to 4
years), pain may be only be expressed in a binary way (i.e., either present
or not present), but by early school age (ages 5 to 6 years), children are
generally able to communicate a variety of pain levels.3 Fear and anxiety
in children may complicate pain assessment and, in some cases, leads them
to either overrate or underrate pain. For this reason, many behavioral
scales are taken to be measures of “distress,” which combines pain, fear,
and anxiety. For example, a 2-year-old child fearful of having a relatively
painless ear examination may appear to have extreme pain based on
behavioral measures. A 7-year-old child may deny pain because of the fear
of having to receive a “shot” if he admits to having pain. Valid and reliable
pain measures have been developed for children based on developmental
levels reflecting a child’s ability to communicate and understand concepts
of pain. In general, behavioral measures tend to underrate persistent pain
relative to self-report.
Pain assessment in infants, neonates, and premature infants is especially
challenging. Previously, infants were not thought to be fully capable of
experiencing pain, which led in part to inadequate efforts to treat pain in
infants. Numerous studies have examined the response of neonates and
preterm infants to pain and have shown various response patterns
including changes in stress hormones levels; observed behavioral
responses; and alterations in heart rate, heart rate variability, oxygen
saturation, and other physiologic responses.4–7 Studies have shown that
neonates who are subjected to heel lancing for blood sampling consistently
swipe the foot being lanced with the unaffected foot, indicating that
neonates have the ability to localize to the site of pain.8,9 Other data have
shown that hospitalized infants display graded responses of heart rate,
oxygen saturation, mean arterial pressure, and behavioral state with
varying degrees of pain intensity, indicating that infants have the ability to
distinguish severity of pain.10 Pain assessment scales for infants are
typically composite pain scores consisting of behavioral parameters such
as facial grimacing, posture, and crying combined with more objective
data such as heart rate, blood pressure, and oxygen saturation. Pain ratings
may be erroneous in critically ill infants because sepsis, hypotension,
respiratory failure, and other conditions will change many of the

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physiologic and behavioral parameters in composite pain scales. The
CRIES; Face, Legs, Activity, Cry, and Consolability (FLACC) scales; and
the Premature Infant Pain Profile have been validated for infants and
premature infants.11–13
Concrete thinking and stages of cognitive and language development of
preschool-age children can present difficulties in pain assessment. Many
toddlers when ill, hospitalized, or confronted with strangers refuse to
cooperate with self-report or formal testing of pain. Involving parents or
other familiar caregivers in the assessment of pain for toddlers can provide
useful information. Studies comparing parents’ to clinicians’ pain ratings
are inconsistent with some showing good agreement but others showing
disparities.14
The Children’s Hospital of Eastern Ontario Pain Scale (CHEOPS) and
the Behavioral Observational Pain Scale (BOPS) have been validated for
assessing postoperative pain in toddlers and young children.15,16 The
FLACC scale is a very widely used scale involving five items, each scored
from 0 to 2 to give a composite score ranging from 0 to 10.17 The FLACC
scale has become widely used because it is quick and versatile and its
components appear reasonable for a wide range of patient groups,
including infants and older patients with developmental disabilities.13,17–21
A recent review does find evidence to support its use in children aged 2
months to 7 years for postoperative pain as well as in children from ages 4
to 10 years who have cognitive impairment.21
Several validated self-report pain scores have been developed for
children 4 years and older, including photos or drawings of faces where
numerical anchors signify gradations of pain and a slide rule device where
increasing color intensity indicates increasing pain intensity.22 Young
children are able to differentiate pain intensity when presented with facial
expressions, although more than five choices of facial expressions interfere
with the child’s ability to reliably indicate pain.23 Most older school-age
children and adolescents have the cognitive and emotional maturity to use
adult numerical visual analogue scales; nevertheless, pain, illness,
hospitalization, and separation from parents cause some older children and
teenagers to regress emotionally, making scales used for younger children,
such as faces scale, more applicable. There has been considerable dispute

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regarding relative merits of different presentations of face-type scales;
however, the most widely accepted and validated face-based scale is the
Bieri Faces Pain Scale-Revised.23,24

Analgesic Pharmacology in Infants and Children

Age-related differences in analgesic pharmacology are explained by a
combination of pharmacokinetic and pharmacodynamics factors that vary
with development. Neonates and young children have delayed maturation
of hepatic enzymes involved in the metabolism of analgesics such as
opioids and amide local anesthetics, increasing the risk of drug
accumulation and toxicity.25 For example, ester-type local anesthetics are
metabolized by pseudocholinesterase. Young infants have significantly
less of this enzyme compared to the adult population; therefore, clearance
can be decreased and the effect of the local anesthetic is prolonged. Most
neonates and young infants will have considerable maturation of the
hepatic enzyme systems involved in biotransformation and conjugation by
the age of 6 months, although enzyme maturation rates can vary
considerably.26 Neonates and young infants have decreased plasma
concentrations of albumin and α1 acid glycoprotein, which leads to
decreased protein binding and greater concentrations of unbound,
pharmacologically active drug.27 Neonates also have reduced glomerular
filtration rates in the first few weeks of life resulting in slower elimination
of many drugs and many active metabolites of drugs that have undergone
hepatic metabolism which are excreted via the kidneys. A number of
specific age-related differences in pharmacokinetics and in drug actions
and risks are detailed with each drug class in the following text.

Nonopioid Analgesics
Nonopioid analgesics traditionally refer to aspirin, acetaminophen,
nonsteroidal anti-inflammatory drugs (NSAIDs), and selective cyclo-
oxygenase (COX) inhibitors. More recently, evidence of analgesic efficacy
in adjuvant medications such as gabapentin and pregabalin have expanded
the choices of nonopioid analgesics. Several new entities, such as the G

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protein-related receptor agonists, will provide other nontraditional opioid
receptor mediated analgesic choices. Many of the NSAID analgesics were
thought of as primarily peripherally active agents; however, analgesia does
occur from a combination of peripheral as well as central actions,
involving mechanisms in the spinal cord and brain, especially with
activation of microglia. Nonopioid analgesics are often first-line drugs
used for mild to moderate pain in infants and children because they do not
produce respiratory effects and are generally nonsedating.

ONTOGENY OF PROSTANOID BIOSYNTHESIS AND

CYCLO-OXYGENASES
A variety of prostanoids are produced during fetal life, and COX inhibition
can alter essential functions, including patency of the ductus arteriosus.
Recent studies by Ririe and coworkers28 in infant rats suggest that COX-
mediated processes in spinal microglia are quite immature at birth. These
studies raise the question of whether commonly used analgesics acting on
COX isoforms might be ineffective in infants due to this delayed
maturation of a prominent site of action.

ASPIRIN AND OTHER SALICYLATES

The use of aspirin in children has diminished significantly, largely due to
its association with Reye syndrome. The elimination of aspirin is greatly
reduced in infants. In our practice, aspirin is almost never prescribed as an
analgesic; its use is confined to situations in which antiplatelet actions are
required.

ACETAMINOPHEN
Acetaminophen is the most commonly used analgesic in pediatrics and has
been safely used in children of all ages. It is typically used for mild to
moderate pain, fever, and can be combined with opioids to provide
additional analgesic effect and decreased opioid use. The mechanisms
underlying acetaminophen’s analgesic and antipyretic actions remain
controversial. Multiple central targets of acetaminophen’s actions have
been described, including COX isoenzyme (type 3 as well as type 2)
inhibition, endogenous cannabinoid receptors, and nitric oxide pathways.29

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Clinically, acetaminophen, by itself, appears to produce minimal
gastropathy, minimal effect on platelet function, and much milder anti-
inflammatory actions compared to NSAIDs. Acetaminophen, combined
with NSAIDs, can produce additional analgesic benefits, with synergism
in some models.30 The elimination of acetaminophen is primarily through
glucuronidation and sulfation and elimination rates are similar among
infants, children, and adults.31,32 Various formulations are available with
different concentrations in the United States, although there has been a
recent attempt at standardization of dose formulations.33 Inadvertent
dosing errors have led to reports of fulminant hepatic failure among infants
and children.34 Typical oral dosing is 10 to 15 mg/kg per dose. The
maximum daily dosing is 40 mg/kg/day for premature infants and 75
mg/kg/day for term infants and children. Rectal dosing can be used for
children who are unable to tolerate oral dosing, although absorption of
rectal dosing can be variable.35 Maximal concentration after rectal dosing
occurs at approximately 2 to 3 hours. Typical rectal dosing is 30 to 45
mg/kg initially, followed by 20 mg/kg every 6 hours.32,34 In 2010, the U.S.
Food and Drug Administration (FDA) approved the use of intravenous
acetaminophen. Peak plasma concentration is reached in 15 minutes
following infusion and data show improved pain control with use of the
intravenous, with opioid sparing effect.36–38 There is a role for use of the
intravenous form in children who are both nothing by mouth (NPO) and
nothing by rectum (NPR), as well as situations where children are NPO
alone, given that rectal dosing can lead to discomfort, fear, or anxiety in
children beyond infancy.

NONSTEROIDAL ANTI-INFLAMMATORY DRUGS

NSAIDs are commonly used for mild to moderate pain and for fever
control in children. They are often combined with opioids to augment
analgesic efficacy and potentially reduce opioid use and opioid side
effects. The use of several NSAIDs in postsurgical patients has been
shown to reduce opioid use by approximately 30% to 40%.39
NSAIDs produce their anti-inflammatory effect by reversibly inhibiting
COX-1 and COX-2 isoforms and inhibiting the conversion of arachidonic
acid to prostanoids.40 The clearance of ibuprofen, ketorolac, and several

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other NSAIDs is more rapid in toddlers and preschool children compared
to adults.41
Based on epidemiologic studies and pooled data from clinical trials,
NSAIDs have a generally good safety margin in children and infants from
roughly age 6 months onward, particularly with short-term use. There are
limited safety data on the use of NSAIDs among neonates and young
infants. In certain situations, one can consider NSAID use, such as
ketorolac, in infants under 6 months, if the risk of using alternate
analgesics is felt to be greater than use of an NSAID.42,43 Indomethacin
has been used for closure of patent ductus arteriosus in neonates.
Elimination of indomethacin is slower in neonates and has the associated
risk of hyponatremia and renal toxicity in this age group.44 The incidence
of NSAID side effects is quite low in children, when administered for
postoperative pain relief. A large-scale study in children administered
short-term use of ibuprofen showed a very low overall risk of severe side
effects.45 The risks of renal and hepatic toxicities are increased in states of
decreased renal and hepatic blood flow, such as with significant surgical
blood loss or shock. Much of the safety data for long-term use of NSAIDs
in children is based on experience in treating juvenile rheumatoid arthritis
(JRA).46 Long-term use is associated with a higher incidence of mild
gastrointestinal distress, but significant gastropathy and gastrointestinal
bleeding in children is less common when compared to adults.
Although NSAIDs inhibit platelet aggregation and can prolong bleeding
time, clinically significant bleeding is uncommon in healthy children. The
use of NSAIDS after tonsillectomy procedures remains somewhat
controversial. Children requiring tonsillectomy often have obstructive
sleep apnea and are at increased risk of hypoventilation and apnea with
opioids, making nonopioid analgesics an attractive alternative. Nausea and
vomiting are also common after tonsillectomy, and opioids exacerbate
these problems. Life-threatening bleeding can occur after tonsillectomy in
the immediate postoperative period and approximately 7 days
postoperatively after the patient has been discharged from the hospital.
Two meta-analyses came to different conclusions about the safety of
NSAIDs in tonsillectomy. One found no significant increase in bleeding,
whereas the other reported a threefold increase in bleeding episodes of

2590
sufficient severity to require reoperation.47,48 A more recent retrospective
chart review did support the findings that postoperative use of ibuprofen
did increase posttonsillectomy bleeding.49 It is less clear if single dosing of
ketorolac during the perioperative period increases the risk of
postoperative bleeding in this population. A recent meta-analysis does not
show increased risk of posttonsillectomy hemorrhage in children with
perioperative ketorolac use.50 Despite these concerns, NSAIDs remain
commonly used in the posttonsillectomy population worldwide at many
institutions both perioperatively and in the postoperative healing period.
An additional concern with NSAID use is impaired bone healing after
orthopedic surgeries that involve osteoclast activation and new bone
formation.51 In vitro studies, animal models, and some case-control studies
in adults suggest a higher incidence of impaired bone healing and
nonunion with NSAID use. However, compared to adults, children are less
likely to have impairment of bone formation with similar orthopedic
procedures. Even in major procedures such as posterior spinal fusion for
scoliosis, perioperative use of NSAIDS appears to be safe and not to result
in a higher incidence of nonunion.52 For surgeries with lower risk of
nonunion, or for selected patients with greater than average risks or side
effects from opioids, judicious use of NSAIDs for brief time periods
should be considered.
Selective COX-2 inhibitors have the advantage of lower incidence of
gastrointestinal symptoms and decreased effect on platelet function
compared to traditional NSAIDs in adult patients. The risk of nephropathy
with selective COX-2 inhibitors is similar to that of traditional NSAIDs.53
Anti-inflammatory and analgesic effects of COX-2 inhibitors are also
similar to those of traditional NSAIDs. COX-2 inhibitors have been
associated with cardiovascular complications in adults, with both short-
and long-term use. Rofecoxib and valdecoxib have been withdrawn from
the market in response to these reports of cardiovascular complications in
adults. The cardiovascular risk of COX-2 inhibitors in infants and children
remains unclear. The use of COX-2 inhibitors may be considered in
children with JRA who experience good analgesia with traditional
NSAIDs, but who have significant gastrointestinal symptoms, or in
children with bleeding disorders, such as hemophilia or thrombocytopenia,

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to achieve analgesia with less risk of bleeding than with traditional
NSAIDs. Studies of COX-2 inhibitors for analgesia after tonsillectomy are
mixed. One study found better analgesia with ibuprofen compared to
placebo.54 One double-blind randomized controlled trial (RCT) found
benefit to use of celecoxib in the posttonsillectomy population with a
modest decrease in pain scores in addition to decreased use of
acetaminophen.55 Some studies suggest that COX-2 inhibitors might be
less likely to interfere with active bone formation. Please see Table 50.2
for dosing guidelines of common nonopioid analgesics.

TABLE 50.2 Dosing Guidelines for Nonopioid Analgesics

Dose <60 kg Dose >60 kg
Acetaminophen 10–15 mg/kg q4h PO 650–1,000 mg q4h PO
Acetaminophen 15 mg/kg q6h IV 15 mg/kg q6h IV
Naproxen 5 mg/kg q12h PO 250–500 mg q12h PO
Ibuprofen 6–10 mg/kg q6–8h PO 400–600 q6h PO
Celecoxib 2–4 mg/kg q1h PO 100–200 mg q12h PO
Ketorolac 0.3–5 mg/kg q6–8h IV, not for 15–30 mg q6–8h IV, not for
>5 d >5 d
Ketamine 0.1 mg/kg/h IV infusion with 0.1 mg/kg/h IV infusion with
titration titration
Gabapentin 15 mg/kg PO preoperative 1 g PO preoperative
NOTE: Dosing guidelines listed herein refer to children > 1 year of age. Maximum dose
acetaminophen: 75 mg/kg/day. Further modifications in dosing are required for use of these
agents in term and preterm neonates and in infants. Modifications are detailed in the text.
IV, intravenous; PO, orally.

KETAMINE
Ketamine is increasingly used in both acute and chronic pain, especially in
the postoperative period. Ketamine has anti-N-methyl-D-aspartate
(NMDA) activity, which acts to decrease wind-up, central sensitization,
opioid-induced hyperalgesia, and opioid tolerance. Multiple studies in the
adult population have shown that ketamine has not only opioid-sparing
effects but also analgesic and antihyperalgesic effects.56 Literature
supporting the use of ketamine in the perioperative period in children is
not as clear. A 2016 meta-analysis of perioperative ketamine use in
children did not find that ketamine beneficial in decreasing the amount of
opioids used postoperatively.57 Although the meta-analysis was not

2592
favorable, individual studies favor the use of ketamine in the postoperative
period. This study showed decreased opioid use and lower pain scores
following Nuss procedure in the group that received ketamine in addition
to fentanyl.58 One study published in 2016 did not find that low-dose
ketamine postoperatively in posterior fusion spine surgery in children
decreased opioid use postoperatively.59 This particular study also did not
find benefit in preventing long-term postoperative pain, although the
incidence of persistent postoperative pain in this demographic is not
clearly known. It is reasonable to consider use of ketamine in children,
particularly in those with difficult to control pain or a history of chronic
opioid use. The data for use in adults is well-established and thus is an area
that can be further explored in pediatrics.

ANTICONVULSANTS
The use of anticonvulsants in chronic pain is well established; however,
their use in acute pain, especially in children, is not as well established.
There is evidence to support perioperative use of gabapentin for spine
surgery in children. A study published in 2010 did show benefit to
perioperative use of gabapentin 15 mg/kg prior to posterior spine fusion.60
Gabapentin (continued at 5 mg/kg three times a day for a total of 5 days)
decreased opioid requirements and postoperative pain scores only in the
first 48 hours after surgery. Therefore, some clinicians only provide a
preoperative oral loading dose. Valproic acid is another anticonvulsant that
finds limited use in the acute treatment of pediatric migraine with one
study finding approximately 50% of patients receiving significant relief
from their headache.61 There is some evidence to support its efficacy in the
treatment of acute migraine; however, the studies are few and also
complicated by the fact that valproic acid was not the first-line treatment;
thus, other medications, treatments, and factors likely played a role in the
reported relief.62

Opioids
Opioids are among the most widely used analgesics for treating moderate
to severe pain in infants and children. As with adults, they are extremely

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useful but require careful patient selection, titrated dosing, and active
treatment of side effects.

ONTOGENY OF OPIOID ACTIONS

The ontogeny of opioid actions has been studied in human clinical trials, in
case series, and in a number of infant animal models. Infant animal models
have provided useful information, although there are marked differences
among species in opioid actions. There are age-related differences in
analgesia and side effects involving pharmacokinetic and
pharmacodynamics differences. Opioids (except for remifentanil) have
prolonged actions in neonates and infants due to immature hepatic enzyme
systems and immature renal excretion of active metabolites. Effects of
hepatic and renal dysfunction on opioid clearance are discussed in a
separate section in the following text. Additional factors that influence
opioid pharmacokinetics include developmental changes in expression of
P-glycoproteins, both in the gastrointestinal tract and in the blood–brain
barrier, and changes in protein binding.
Pharmacodynamic studies of opioids in neonates and younger infants
have examined analgesia and side effects, with a major emphasis on
measures of respiratory depression. These studies are made difficult by a
number of factors, including the imprecision inherent in observational pain
measures in neonates, on the state dependence of behavioral responses, on
the confounding effects of critical illness on measures, and on the
variability of painful stimuli. Major sites of opioid actions, including the
periaqueductal grey matter and descending pathways of the dorsolateral
funiculus, appear immature in infant rats. Conversely, opioids
administered systemically or via the epidural route show strong analgesic
responses in infant rats at developmental stages corresponding to preterm
neonates. In human studies, there are mixed results with use of opioids in
studies of procedural pain in neonates, and studies randomly assigning
ventilated neonates to receive morphine infusions versus placebo infusions
(with both groups receiving morphine for painful procedures) have not
shown clear advantages in the morphine infusion groups.63,64
Children who are at particular risk for respiratory depressant effects of
opioids include those with tonsillar hypertrophy, obstructive sleep apnea,

2594
certain neurologic conditions, and craniofacial abnormalities as well as
neonates and young infants. Neonates and infants, particularly premature
infants, have an increased risk of apnea and hypoventilation in response to
opioids on a pharmacodynamic as well as pharmacokinetic basis. Careful
dosing, cardiorespiratory monitoring, and close nursing observation are
warranted for neonates and younger infants receiving opioids.

CODEINE
Codeine is an opioid previously used widely to treat mild to moderate
pain. It is available as an elixir in pill and parenteral forms. Although it has
seen a declining use for pain, it remains commonly used in cough
suppressant formulations. For reasons to be detailed in the following text,
our opinion is that codeine is in general a suboptimal choice as an
analgesic in children in most settings, and we recommend against its use.65
Codeine is a prodrug extensively metabolized in the liver. It is
demethylated to morphine, which accounts for the analgesic effect.66 A
study of children undergoing surgery, receiving a fairly large dose of
codeine, found that roughly one-third of the subjects generated
undetectable blood concentrations of morphine, which would result in no
discernible analgesic effect. Conversely, there are genotypes associated
with ultrarapid metabolism of codeine to morphine.67,68 In these subjects,
standard recommended codeine doses can produce apnea. Standard dosing
is 0.5 to 1 mg/kg every 4 hours. Dose escalation beyond this range appears
to generate a higher incidence of side effects, particularly nausea and
vomiting. In standard doses, codeine is a very weak analgesic. Studies in
adult patients comparing efficacy of codeine to ibuprofen have shown that
30 to 45 mg codeine has less analgesic effect than 600 mg of ibuprofen.
Because of the relatively high incidence of the impaired inability to
demethylate codeine and higher incidence of side effects, other oral
opioids such as oxycodone, morphine, hydromorphone, and hydrocodone
are preferred. Intramuscular (IM) codeine has the double disadvantage of
being a weak and inconsistent analgesic delivered by a noxious route.
Codeine is often dispensed in combination with acetaminophen to
increase efficacy. When prescribing codeine combined with
acetaminophen, care is required to avoid inadvertent administration of

2595
toxic doses of acetaminophen, particularly when increased dosages are
prescribed for pain or when patients are taking other over-the-counter
preparations containing acetaminophen. Codeine is also commonly
prescribed as an antitussive.
As of 2013, the FDA has issued a new contraindication for the use of
codeine to treat pain or cough in children younger than 12 years as well as
a warning against its use the 12- to 18-year-old age group of children who
have sleep apnea and/or are obese.69

TRAMADOL
Tramadol has both opioid and nonopioid properties. It exists in a racemic
mixture where the positive enantiomer has opioid and serotoninergic
properties and its negative enantiomer exerts noradrenergic reuptake
properties.70 Like codeine, it is metabolized to O-desmethyltramadol by
the P450 isoenzyme CYP2D6. It exerts its analgesic effect via the µ-opioid
as well as acting as a serotonin and norepinephrine reuptake inhibitor. In
the United States, it is available only in the oral form. In other countries, it
is also available in an intravenous preparation. Although not approved for
use in children under the age of 12 years, it is widely used for
postoperative pain as well as acute pain in children.71
Tramadol is also associated with many reports of toxicity in children.
Overall, the incidence of these adverse reactions is low, but they do occur.
Toxicity for tramadol, like opioids, not only can result in respiratory
depression but can also result in seizures.
As of 2017, the FDA has issued new black box contraindication for the
use of tramadol to treat pain or cough in children less than 12 years of age.
They have also included a contraindication to the use of tramadol in
children undergoing tonsillectomy and/or adenoidectomy in patients under
the age of 18 years. In addition to these contraindications, a new warning
against the of tramadol in the 12- to 18-year-old age group in children with
sleep apnea or who are obese is also in place. These were put in place after
the recognition of the implications of genetic variability in P450 2D6
metabolism and the potential for life-threatening reactions.72

OXYCODONE

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Oxycodone can be used for moderate pain in doses of 0.05 to 0.1 mg/kg
every 4 hours and for moderate to severe pain in starting doses of 0.1 to
0.2 mg/kg every 4 hours in infants and children >1 year of age. Less
information regarding the use of oxycodone in neonates and small infants
is available. Recent review and modeling suggests the use of lower doses
in preterm neonate and small infants starting as low as 0.035 mg/kg and
increasing to 0.065 mg/kg in term neonates.73,74 Although historically
prescribed in smaller doses, oxycodone dosing can be escalated as needed
much like any of the so-called strong opioids. Oxycodone is generally well
tolerated by children either alone or in combination with acetaminophen.
Our impression is that it is associated with fewer side effects than codeine
when used to treat moderate to severe pain. Oxycodone is metabolized in
the liver to oxymorphone, which is metabolically active.75 Because
oxymorphone is eliminated by the kidneys, it can accumulate in patients
with renal failure. Oxycodone is commonly used in children
postoperatively when transitioning from parenteral opioids to oral opioids
in preparation for discharge.
A sustained-release preparation of oxycodone (OxyContin) is available
for use in the treatment of chronic pain and was approved use in children
age 11 to 16 years in 2015. Recently, the trend at our institution is away
from the use of long-acting oxycodone for postoperative pain. It has a
bioavailability of approximately 60% and reaches peak analgesic effect
after 60 to 90 minutes.76

MORPHINE
Morphine is often the first-line opioid chosen for parenteral use in
children. It has a long track record in pediatrics; it has received extensive
pharmacologic study at all age groups; it is inexpensive; and it can be
administered via oral, sublingual, intravenous, subcutaneous, rectal, and
neuraxial routes.
The duration of morphine’s clinical effects are related in a complex
manner to distribution into and out of the central nervous system, hepatic
metabolism, and excretion of active metabolites, including morphine 6-
glucuronide. Morphine primarily undergoes glucuronidation by the UDP
glucuronosyltransferase (UGT) pathway in the liver to morphine-3-

2597
glucuronide, which has predominantly excitatory actions, and morphine-6-
glucuronide, which has analgesic, sedative, and respiratory depressant
actions more potent than morphine.77 Because morphine-6-glucuronide is
renally eliminated, it can accumulate in patients with renal failure,
producing delayed sedation and hypoventilation. In addition, accumulation
of morphine 3-glucuronide can contribute to delirium, agitation, and
seizures. The elimination half-life of morphine in older children and adults
is approximately 3 to 4 hours. The elimination half-life is approximately 7
hours in full-term newborns and even longer in premature infants.78,79
Long-acting preparations of morphine, such as MS Contin or KADIAN,
are typically used for children with sickle cell pain, cancer pain, and other
types of chronic pain.
Dosing of morphine in children, as with all opioids, should be titrated to
effect and individualized based on severity of pain, underlying medical
conditions, age, side effects, and weight. See Table 50.3 for dosing
guidelines for oral and parenteral morphine.

TABLE 50.3 Initial Dosing Guidelines for Opioids

Parenteral Dosing Oral Dosing
Equianalgesic Usual Starting
Doses and Intravenous or Usual Starting Oral Doses
Intervals Subcutaneous Doses and Intervals
Ratio
Child <50 Child >50 Parenteral
Drug Parenteral Oral kg kg to Oral Child <50 kg
Codeine 120 mg 200 NR NR 1:2 NR
mg
Morphine 10 mg 30 mg Bolus: 0.1 Bolus: 5–8 1:3 Immediate-
(long mg/kg mg (long term) release: 0.3
term) every 2– every 2– mg/kg
4h 4h every 3–4
h
Infusion: Infusion: 1:6 Sustained-
0.03 1.5 mg/h (single release:
mg/kg/h dose) 20–35 kg,
10–15 mg
every 12 h;
35–50 kg,
15–30 mg
every 12 h
Oxycodone NA 15–20 NA NA NA 0.1–0.2

2598
 mg mg/kg
every 3–4
h
Methadonea 10 mg 10–20 0.1 mg/kg 5–8 mg 1:2 0.1–0.2
mg every 4– every 4– mg/kg
8h 8h every 4–8
h
Fentanyl 100 mg NA NA NA
(0.1 mg)
Bolus: 0.5– Bolus: 25–
1.0 50 mg
mg/kg every 1–
every 1– 2h
2h Infusion:
Infusion: 25–100
0.5–2.0 mg/h
mg/kg/h
Hydromorphone 1.5–2 mg 7.5– Bolus: 0.02 Bolus: 1 1:5 0.05–0.1
10 mg mg mg mg/kg
every 2– every 2– every 3–4
4h 4h h
Infusion: Infusion:
0.006 0.3 mg/h
mg/kg/h
Meperidineb 75–100 mg 300 NR NR 1:4 NR
mg
NOTE: Doses are for patients over 6 months of age. In infants under 6 months, initial per kilogram
doses should begin at roughly 25% of the per kilogram doses recommended here. Higher doses
are often required for patients receiving mechanical ventilation. All doses are approximate and
should be adjusted according to clinical circumstances. Recommendations are adapted from
previous summary tables, including those of a consensus statement from the World Health
Organization and the International Association for the Study of Pain.
aMethadone requires additional vigilance because it can accumulate and produce delayed sedation.

If sedation occurs, doses should be withheld until sedation resolves. Thereafter, doses should be
substantially reduced, the interval between doses should be extended to 3 to 12 hours, or both.
Electrocardiogram (ECG) for QT interval required.
bThe use of meperidine should generally be avoided. Can consider use for postoperative shivering.

NA, not applicable; NR, not recommended.

Adapted from Berder CB, Sethna NF. Analgesics for the treatment of pain in children. N Engl J
Med 2002;347(14):1094–1103. Copyright © 2002 Massachusetts Medical Society. Reprinted
with permission from Massachusetts Medical Society.

HYDROMORPHONE
Hydromorphone is a commonly used opioid for acute pain management in
children for both parenteral and oral use. Like morphine, it is used in

2599
children for patient-controlled analgesia (PCA), continuous infusions, oral
dosing, intermittent intravenous boluses, and epidural analgesia.
Hydromorphone can provide effective analgesia in children with cancer
pain and mucositis. In steady-state dosing, hydromorphone is 5 to 6 times
more potent than morphine when given intravenously in children.80
Although hydromorphone is commonly prescribed to patients with renal
insufficiency, this practice is not evidence-based. Hydromorphone is
metabolized primarily to hydromorphone-3-glucuronide (H3G) and, to a
much lesser extent, hydromorphone-6-glucuronide (H6G) through UGT
pathways.81 These glucuronides can also accumulate in patients with renal
insufficiency. Information on metabolism of hydromorphone in neonates
and young infants is very sparse.

METHADONE
Methadone is a long-acting opioid with a slow elimination and prolonged
duration of analgesia.82,83 The elimination half-life is highly variable,
ranging from 6 to 30 hours. Methadone has a high oral bioavailability of
70% to 100%. Due to these unique properties, methadone is convenient to
use as a prolonged duration opioid. Intermittent intravenous dosing at
prolonged intervals (e.g., every 4, 6, or 8 hours) can provide a basal level
of analgesia similar to that achieved by continuous infusions or frequent
intravenous boluses of other opioids.84
Methadone is available as an elixir and is often used in place of
sustained-release opioid preparations to treat chronic pain in young
children or in children unable to swallow pills. Conversely, methadone
requires careful titration and vigilance to avoid overdosage, both because
of extreme pharmacokinetic variability and for pharmacodynamic reasons
detailed in the following text.
Methadone is prepared as a racemic mixture of levo (l-) and dextro (d-)
isomers. The l-isomer acts as a µ-receptor agonist; the d-isomer acts as an
antagonist at the NMDA receptor in the brain and spinal cord. Antagonism
at the NMDA receptors results in analgesia and reduced hyperalgesia as
well as partially reversing tolerance to opioids.85
The NMDA antagonism of methadone is also a rationale for its use in
the treatment of neuropathic pain. The combined µ-agonist and NMDA

2600
antagonist actions of methadone result in incomplete cross tolerance. Thus,
the dose conversion ratios between methadone and morphine and other µ-
opioids are different for opioid-naive versus opioid-tolerant patients. For
opioid-naive patients, the average daily intravenous methadone
requirement is roughly one-third of the corresponding intravenous
morphine requirement; however, average daily methadone requirements
for opioid-tolerant patients may be a little as 10% to 15% of the total daily
morphine dosing.86 This is particularly relevant when converting morphine
to methadone for children with advanced cancer and when weaning
nonventilated infants and children following prolonged opioid therapy,
especially following intensive care. Careful titration and frequent patient
assessment for respiratory depression is warranted in dosing methadone.
When anticipating long-term methadone use, either when weaning from a
long-term opioid infusion, the opioid-dependent infant, or in cancer-related
pain, care should be taken during initial titration of methadone given its
long and variable half-life. It is generally our practice to increase
methadone no more frequently than every 2 to 3 days. For patients
showing signs of oversedation or respiratory depression, it is often
necessary to hold multiple doses of methadone because of its prolonged
duration of action. In our practice, we also use methadone intraoperatively
during certain procedures such as posterior-spinal fusion or Nuss bar
placement.87,88 We do not routinely manage acute pain with methadone
given other available alternatives.

FENTANYL
Fentanyl has a rapid onset and brief duration of action after single-dose
administration, and it is often used for brief painful procedures in children,
such as lumbar punctures, bone marrow aspirations, fracture reductions,
and dressing changes. Fentanyl is also used for PCA in children with acute
and chronic pain and in highly selected situations as a transdermal patch
for children with cancer-related chronic pain.89
Fentanyl primarily undergoes glucuronidation in the liver to inactive
metabolites, making it a preferred opioid for patients with renal or liver
failure. Fentanyl is 50 to 100 times more potent than morphine with single-
dose administration and roughly 20 to 50 times more potent with

2601
continuous infusions. The action of fentanyl after single-dose
administration is terminated by rapid redistribution; however, after
prolonged infusion or repeated boluses, the termination of fentanyl effect
is determined more by elimination than redistribution and results in a
prolonged duration of action. In addition, pharmacokinetics of fentanyl are
easily altered in small infants, as hepatic blood flow is affected during
surgery.90 Continuous infusions or repeated boluses in neonates can cause
a particularly prolonged effect. Rapid administration is associated with
glottic and chest wall rigidity, which can be especially pronounced in
neonates and young infants. Neuromuscular blockade and assisted
ventilation are usually necessary for treatment, particularly in neonates and
young infants. Naloxone may sometimes be effective in reversing
fentanyl-induced rigidity, but this action is not reliable.
For brief painful procedures, incremental doses of fentanyl at 0.5 to 1
µg/kg every 1 to 3 minutes usually provide effective analgesia.
Cardiorespiratory monitoring and immediate availability of airway
equipment and personal skilled in airway management are necessary. Oral
transmucosal fentanyl has also been used for brief painful procedures in
children and for breakthrough cancer pain.91 The oral transmucosal dose is
partially absorbed across the buccal mucosa and partially swallowed;
overall, the bioavailability is approximately 50%. It is generally well
tolerated by children, although almost 90% of children experience facial
pruritus. Additionally, the peak analgesic effect after a standard 15 µg/kg
dose is 20 minutes, which may be limiting for some procedures. Another
option is the use of intranasal fentanyl, which is particularly beneficial in
patients who do not have established intravenous access.92 Dosing of
intranasal fentanyl is higher than intravenous, at 1.5 µg/kg. Intranasal
fentanyl may be used in a variety of acute pain situations including sickle
cell crisis, limb injuries, and during general anesthesia for myringotomy.93
Transdermal fentanyl is used in children with cancer pain and other
forms of chronic pain requiring regular opioid dosing. It is indicated in a
small subgroup of children who are unable to swallow pills, who have
limited intravenous access, or who have experienced side effects with a
number of other opioids. Approximately 12 to 24 hours are necessary to
achieve steady-state plasma levels after applying the transdermal fentanyl

2602
patch, and it is therefore not indicated for acute fluctuations in pain
intensity. Additional short-acting opioids are necessary to treat
breakthrough pain. Transdermal fentanyl is indicated for opioid-tolerant
patients who have relatively constant pain. Serious and lethal adverse
events have been reported among opioid-naive patients who were treated
with transdermal fentanyl for acute postsurgical pain.94 There has been a
series of manufacturing problems that have led to inconsistent delivery for
some batches of transdermal fentanyl. We emphasize here that transdermal
fentanyl is not recommended for opioid-naive patients under any
circumstances.

MEPERIDINE
Meperidine is a synthetic opioid roughly one-tenth the potency of
morphine when administered intravenously. It has some anticholinergic
actions and is metabolized to normeperidine, which can cause seizures,
hallucinations, and agitation, particularly with repeated dosing.
Metabolism in infants is quite variable.95 Life-threatening reactions can
occur with the use of meperidine in patients taking monoamine oxidase
inhibitors, leading to hyperreflexia, seizures, hemodynamic instability, and
death.
Meperidine does have the unique property in subanalgesic doses of
treating rigors associated with blood product transfusions or shivering
following general anesthesia. Because of the serious adverse effects of
meperidine and because it offers no particular advantage for pain control,
its use should be limited to the treatment of rigors or shivering.

Opioid Administration in Infants and Children

As in adult patients, there are several means for systemic opioid delivery
in pediatric patients. The choice of which method depends to a certain
extent on available resources, coexisting medical conditions, types of pain,
patients’ mobility, and other factors.
Regardless of method of opioid delivery, protocols for safe opioid
administration should be in place to detect excess sedation, signs of
respiratory depression, and impending respiratory failure. Protocols should

2603
include regular nursing assessments, documentation of vital signs and
levels sedation, and, where appropriate, use of electronic cardiorespiratory
monitoring that should include pulse oximetry. Patients who should be
considered for cardiorespiratory monitoring include infants who are
younger than 6 months, infants who have a history of apnea and
bradycardia, or prematurity, and opioid-naive children who require a
continuous opioid infusion. Children at increased risk for airway
obstruction while receiving opioids such as those with tonsillar
hypertrophy and obstructive sleep apnea or children with craniofacial
abnormalities should also be considered for cardiorespiratory monitoring.
There is considerable variation in practices regarding methods to detect
and prevent opioid-induced respiratory depression. It is our general
practice to use continuous pulse oximetry for children who are utilizing
continuous opioids, PCA, or parent-/nurse-controlled analgesia (PNCA).
Many recommendations are based on reasonable extrapolation from
physiologic considerations. Nevertheless, evidence to quantify the risk
reduction from specific forms of monitoring is quite sparse.

INTERMITTENT INTRAVENOUS BOLUS DOSING

In clinical care areas other than the intensive care units or the
postanesthesia care units, in our institution, most intermittent bolus dosing
of opioids are administered as an infusion over 20 minutes rather than
“intravenous push.” Although a slow administration is thought of as a
somewhat safer method of intermittent dosing, careful monitoring and
repeated patient assessments remain important during and after the opioid
infusion. Intermittent systemic boluses cause wide fluctuations in plasma
opioids concentrations. Patients therefore experience probably few side
effects but increased pain just prior to their next bolus opioid dose. After
the dose is administered, patients experience pain relief, but often with
excessive side effects, as the plasma opioid concentration reaches
supratherapeutic levels. Regular, intermittent dosing of opioids can result
in dose stacking, especially if the opioids are ordered around the clock. As
each next dose is administered, the prior dose has not fully cleared the
plasma and the remaining plasma concentration can ramp up with each
successive dose. At some point, the next bolus results in a toxic peak level,

2604
which in the frail opioid-naive patient can result in significant
cardiorespiratory compromise. To avoid wide variations in plasma
concentrations with resultant fluctuations in analgesia and side effects,
continuous infusions and PCA are commonly used.

CONTINUOUS OPIOID INFUSIONS

Continuous opioid infusions offer the advantage of providing steady-state
plasma levels and result in good analgesia in infants and children who
experience relatively constant levels of pain intensity. Additional
intermittent boluses are necessary for periods of increased pain, such as
endotracheal tube suctioning or chest physiotherapy. Recommended
starting infusion rates have been adjusted for age based on both
pharmacokinetic considerations, on studies of respiratory responses, and
on clinical outcome studies. Starting infusion rates for morphine have been
recommended as around 0.025 to 0.030 mg/kg/hour for children and
infants >6 months of age, with reductions to 0.015 mg/kg/hour from 1 to 6
months, ranging down to 0.005 mg/kg/hour for preterm neonates at 32
weeks postconception. These recommendations should be taken as
population averages; individual rates should be adjusted according to
clinical conditions, expected intensity of painful stimuli, and behavioral
and physiologic signs.

PATIENT-, NURSE-, AND PARENT-CONTROLLED

ANALGESIA
PCA is widely used among pediatric centers for variety of acute painful
conditions such as cancer pain, sickle cell pain from vasoocclusive crises,
trauma, and acute postoperative pain. Most children 8 years of age and
older have the cognitive ability to understand cause and effect
relationships of pushing the PCA button and obtaining pain relief. In rare
cases, experienced children younger than 6 to 8 years, who have had long-
standing pain, are able to use PCA. For most children younger than 6 to 8
years, PCA has a higher failure rate in part because of the inability to
understand the causal connection between button-pressing and delivery of
medication to provide pain relief. However, nurse-controlled analgesia
(NCA) or PNCA has been shown to provide effective analgesia with good

2605
patient, parent, and caregiver satisfaction in younger children. PNCA is
also used for children with cognitive and physical limitations who are
unable to use the PCA.96–98 In our hospital, PNCA is the most common
method of systemic opioid administration following major surgery in
infants and in children with cognitive or physical limitations to self-
administration.99,100 At our institution, we have also adopted the use of
PNCA in our neonatal population. In this population, we recommend
starting your opioid dose lower at 10 µg/kg.
Commonly used opioids for PCA/NCA are morphine, hydromorphone,
and fentanyl. Use of a basal infusion along with PCA boluses has been a
subject of controversy and some controlled studies in adults and children.
In some studies, a basal infusion improves pain scores, patient satisfaction,
and the quality of nighttime sleep. In other studies, a basal infusion
increased surrogate measures of hypoventilation, including brief
respiratory pauses. Our view is that the recommendations regarding
addition of a basal infusion depend on patient medical conditions and risk
factors, on psychological factors, on expected intensity of painful stimuli,
and on history of previous opioid use. For example, a basal infusion may
be omitted for children who have received a regional block
intraoperatively, for children with increased respiratory risks, or for those
undergoing surgical procedures expected to be only moderately, but not
severely, painful. Conversely, we generally include a basal infusion for
patients who are opioid-tolerant or for procedures expected to cause severe
pain. For those undergoing very painful operations, such as scoliosis
surgery, open lateral thoracotomy, or major hip surgery, we generally
maintain a basal infusion at least through the first postoperative night.
Parent-controlled analgesia is widely accepted for use among children
with advanced cancer or children in palliative care. There have been
several serious adverse events reported, including apnea and death with the
use of parent-controlled analgesia in children with risk factors and with
insufficient protocols for patient observation and education on proper use.
Our view is that parent-controlled analgesia for opioid-naive children
should be restricted to institutions which have formal programs for parent
education, protocols for frequent assessments by nurses, and protocols for
cardiorespiratory. Please see Tables 50.4 and 50.5 for PCA dosing.

2606
 TABLE 50.4 Typical Starting Doses for Patient-Controlled
Analgesia (for >10 kg)
Continuous Rate
Drug Bolus Dose (μg/kg) (μg/kg/h) Hourly Limit (μg/kg)
Morphine 10–30 4–20 120
Hydromorphone 2–6 1–4 24
Fentanyl 0.25–1 0.25 2–4
NOTE: The usual lockout interval is 6 to 10 minutes.

TABLE 50.5 Typical Starting Doses for Patient-Controlled

Analgesia (for <10 kg)
Continuous Rate Hourly Maximum
Drug Bolus Dose (μg/kg) (μg/kg/h) (μg/kg)
Morphine 10–30a 10–30 90b
a
We recommend starting at 10 µg/kg per dose and no basal in infants <10 kg.
bLowerhourly maximum reflects differences in metabolism discussed in text in neonates.

TREATMENT OF OPIOID SIDE EFFECTS

Opioids are alike in that all produce similar side effects including nausea,
vomiting, constipation, pruritus, urinary retention, respiratory depression,
and sedation. In some cases, severe side effects are as distressing to
children as pain. Although children may have particular side effects with
individual opioids, there are few data to suggest that side effects differ
greatly among the more commonly used opioids. Kehlet101 and others
have argued for multimodal approaches to postoperative analgesia that
emphasize opioid-sparing, in part because of the detrimental impact of
opioid side effects on the course of postoperative recovery.
There is an important role for standardized protocols for treatment of
opioid side effects and for rapid institution of therapy for many patients.
Nevertheless, along with prompt intervention, there is a role for clinical
assessment and for consideration of a differential diagnosis. Two examples
illustrate this point: (1) A patient may not only be itching due to opioids
but could also have itching as part of an allergic response to a variety of
other medications or physiologic processes and (2) a patient with advanced
cancer, worsening back pain, and increasing opioid dosing may have
urinary retention due to the opioid, but urinary retention could also be a

2607
harbinger of impending compression of the spinal cord or caudal equina.
Clinicians need to balance prompt intervention with consideration of
alternative diagnoses underlying these symptoms.
Opioid side effects occur by actions at both peripheral and central sites.
For example, opioid-induced nausea and vomiting involves activation of
receptors in the brainstem as well as in the gastrointestinal tract.102
Similarly, some opioids may produce itching by peripheral histamine
release, but the observation of profound itching with very small doses of
intrathecal morphine supports the view that a predominant mechanism of
opioid-induced itching is neurogenic and central, involving an imbalance
of afferent signaling and neurotransmission in the spinal dorsal horn and
nucleus caudalis. Local hives or itching at a site of opioid injection does
not imply an allergic response.
Traditionally, treatment of opioid side effects has emphasized
antagonists at nonopioid receptors; that is, use of antagonists of dopamine
or serotonin receptors for treatment of nausea and vomiting or
antihistamines for treatment of itching. These drugs may generate their
own side effects, including extra pyramidal reactions from dopamine
antagonists (phenothiazines, butyrophenones, metoclopramide); headache
from serotonin antagonists (ondansetron, granisetron); and sedation,
constipation, and urinary retention from antihistamines (diphenhydramine,
hydroxyzine). Extrapyramidal reactions from dopamine antagonists may
be treated prophylactically or as needed with antihistamines or central
muscarinic anticholinergics. In our experience, extrapyramidal reactions
may be misdiagnosed by some clinicians as seizures. Even among patients
who do not have overt extrapyramidal signs, occasional patients report
extreme dysphoria following administration of these agents. Dopamine
antagonists and serotonin antagonists are partially effective in treatment of
opioid-induced nausea and vomiting, but the numbers-needed-to-treat
(NNTs) are higher than commonly believed by clinicians. The evidence
for effectiveness of antihistamines in the treatment of opioid-induced
itching is quite weak.103
There is a growing body of evidence supporting treating opioid side
effects, especially nausea and vomiting and itching, at least in inpatients
postoperatively, by ultra-low-dose infusions of opioid antagonists such as

2608
naloxone.104 Low-dose naloxone infusions are not simply reversing opioid
actions altogether, rather they are exploiting a differential dose response
for reversing side effects versus reversing analgesia, in part due to
differential binding to opioid receptors coupled to G-stimulatory versus G-
inhibitory proteins. We could not identify studies that would guide low-
dose naloxone infusions for side effect treatment in highly opioid-tolerant
patients, although a preliminary report in patients with sickle cell disease
suggested that a slightly higher naloxone infusion rate of 1 µg/kg/hour
might be recommended.105 At our institution, we routinely use doses
between 0.5 and 2 µg/kg/hour with 1 µg/kg/hour being the most prevalent
dosing. Nalbuphine is widely used for treatment of opioid-induced itching
and nausea, although one pediatric study showed no benefit compared to
placebo.106
Methylnaltrexone is a quaternized opioid antagonist that has access to
the area postrema (which lacks a blood–brain barrier), but which is
excluded from prominent sites of central analgesic action, such as the
periaqueductal grey matter. Recent reports show methylnaltrexone to be
beneficial to children and adolescents with opioid-induced constipation.107
Alvimopan is an enterally constrained opioid antagonist that blocks opioid
actions in the gastrointestinal tract, with minimal uptake in the portal vein
and efficient first-pass hepatic clearance of the small quantities that do
reach the liver.108 Available evidence suggests that these two approaches
hold promise for more effective treatment of opioid side effects, including
nausea, vomiting, constipation, and other forms of postoperative
gastrointestinal dysfunction.
Constipation is commonly seen in patients requiring opioids even for
short-term use. It is such a prevalent side effect of opioids that one should
employ a proactive approach of prescribing laxatives (polypropylene
glycol, senna, bisacodyl, docusate) for patients expected to require more
than just few doses of opioids. Please see Table 50.6 for management of
common opioid side effects in children.

TABLE 50.6 Management of Common Opioid Side Effects

Side Effect Comments Drug Dosage
Nausea Consider switching to different opioid. Ondansetron 10–30 kg: 1–2 mg
intravenously q8h

2609
 Use antiemetics. >30 kg: 2–4 mg intravenously q8h
Exclude other processes (e.g., bowel Naloxone infusion 0.25–1 µg/kg/h
obstruction). Metoclopramide 0.1–0.2 mg/kg
PO/intravenously q6h
Pruritus Exclude other causes (e.g., drug Nalbuphine 0.1 mg/kg per dose
allergy). intravenously q6h
Consider switching to different opioid. Naloxone infusion 0.25–2 µg/kg/h
Use antipruritics. Diphenhydramine 0.25–0.5 mg/kg
PO/intravenously q6h
Sedation Add nonsedating analgesic (e.g., Methylphenidate 0.05–0.2 mg/kg PO
ketorolac, acetaminophen) and bid (morning and midday dosing)a
reduce opioid dose. Dextroamphetamine 5–10 mg every
Consider switching to different opioid.
daya
Constipation Regular use of stimulant and stool Naloxone infusion 0.25–2 µg/kg/h
softener laxatives Docusate
Child: 10–40 mg PO daily
Adults: 50–200 mg PO daily
Dulcolax
Child: 5 mg PO/PR daily
Adult: 10 mg PO/PR daily
Methylnaltrexone, alvimopan dosing is
extrapolated from adults
a
Generally, only for use when long-term opioids are appropriate such as in cancer pain.
bid, twice a day; PO, orally; PR, rectally.

LOCAL ANESTHETICS AND REGIONAL ANESTHESIA

IN INFANTS AND CHILDREN
Local anesthetics are widely used for a range of indications in infants and
children, including topical analgesia for needle procedures, cutaneous
infiltration for minor procedures, wound infiltration for surgery, peripheral
and plexus blocks, and epidural and spinal anesthesia and analgesia. Work
over the past 30 years has examined pharmacokinetics, safety, and clinical
outcomes of local anesthesia in infants and children.
Pharmacokinetic information is available for many of the commonly
used local anesthetics. Amino amides, including lidocaine, bupivacaine,
and ropivacaine, have reduced clearance in neonates and younger infants
due to immaturity of hepatic metabolism.109 In the case of lidocaine, the
predominant hepatic metabolite, MEGX, can accumulate in neonates, with
a resultant risk of seizures. The amino ester chloroprocaine is rapidly
metabolized by plasma esterases even in neonates and may be useful if
prolonged infusions are required in neonates.110

2610
CUTANEOUS ANALGESIA
Needle procedures are a prominent source of acute distress for infants and
children. A number of local anesthetic formulations can produce good
analgesia for superficial needle procedures. Several approaches can
accelerate transfer across the skin, including eutectic mixtures, heating
elements, iontophoresis, and jet injection. Selection among approaches
may depend, in part, on local availability, cost, desired onset time, and
impact of vasodilatation or vasoconstriction on the planned
procedures.111,112 A convenient jet injector device, the JTip has greatly
facilitated the placement of intravenous lines, blood sampling, and skin
preparation before a variety of procedures. It is easy to use, well-tolerated,
and fast acting.113,114

WOUND INFILTRATION
Infiltration of the layers of surgical wounds is a simple approach to
providing postoperative analgesia. This may be accomplished by one-time
infiltration before wound closure or by placement of wound catheters for
prolonged infusions of local anesthetics. Liposomal bupivacaine is now
available, making it possible to have analgesia for 24 to 48 hours
following infiltration. Although not approved for use in pediatrics at this
time, it is available at some major pediatric centers and can be considered
for use in older children and adults. Further study is needed before
recommending its use in infants and younger children.

Epidural Analgesia in Infants and Children

Epidural analgesia has widespread use in infants and children for
postoperative pain management and can be considered in selected cases for
children with cancer pain and for certain chronic pain conditions such as
complex regional pain syndrome. Although epidural infusions can provide
outstanding analgesia for children, they require specific expertise both in
the techniques of placement and in management, and in our view, they
should not be undertaken without a system of pediatric-specific
management protocols.
A unique difference between adults and children concerns the fact that

2611
most pediatric regional anesthesia, including epidural analgesia, is
performed after induction of general anesthesia or sedation because many
children will not tolerate having needle procedures while awake. Although
the safety track record of placement of epidural needles and catheters has
been good, there remained some controversy regarding the risk–benefit
ratio.115–117 However, recent large reports from the Pediatric Regional
Anesthesia Network (PRAN) have confirmed the safety and efficacy of a
sleep block placement.118
Placing a lumbar epidural catheter in an anesthetized child is generally
considered to be safe among experienced pediatric anesthesia providers.
As an alternative to direct thoracic needle placement in infants, a common
technique is to advance an epidural catheter from the caudal space to the
desired surgical dermatome. Several studies have shown success in placing
thoracic epidural catheters in infants using this technique.119 Because
neonates and infants have an increased risk of amide local anesthetic
toxicity, proper placement of the epidural catheter tip is crucial in order to
provide optimal analgesia while minimizing safe local anesthetic infusion
rates.
For anesthetized patients who are receiving direct thoracic placement or
for cephalad advancement of catheters to thoracic levels from the caudal
route, our own strong personal preference is to encourage some method of
objective confirmation of positioning whenever possible. Three methods
can be used in different situations: (1) electrical nerve stimulation using
Tsui’s technique120; (2) radiographic confirmation, especially using
fluoroscopy with radiopaque wire reinforced catheters and/or small
amounts of water-soluble contrast material; and (3) ultrasound.
Confirming the location of intended caudal-to-thoracic epidural catheter
tip placement is strongly recommended because failure rates as high as
30% have been reported using a “blind” technique. As described by Tsui,
electrical stimulation employs a saline-filled, wire-wrapped catheter, with
twitches seen at the myotomal level of the catheter tip in a current range
generally between 2 and 15 mA. This technique also confirms that a
catheter is not subarachnoid (in which case, bilateral twitches in a broad
distribution are seen at a current <0.5 to 1 mA) and not threaded out a
nerve root foramen (in which case, unilateral twitches in a narrow

2612
distribution may be seen at a current <1.5 mA).
Confirming location of the epidural catheter tip in infants can be
accomplished by obtaining a chest radiograph after injecting a small
volume of radiocontrast dye or through the use of a radiopaque epidural
catheter which can easily be seen on plain chest radiograph or fluoroscopy.
An additional method of confirming epidural catheter tip location is to
advance the catheter from the caudal space under direct visualization using
fluoroscopy.
Ultrasound guidance can be used in guiding and confirming placement
of epidural catheters in neonates and younger infants, although this
technique requires two operators and significant experience in ultrasound
techniques. Neuraxial structures such as ligamentum flavum, dura, and
epidural space as well as depth from skin to epidural space can be clearly
visualized using ultrasound in part because of incomplete ossification of
the vertebrae in neonates and younger infants.121

DRUGS AND DRUG DOSING USED FOR EPIDURAL

ANALGESIA
Continuous epidural analgesia in infants and children generally consists of
dilute solutions of local anesthetics combined with fentanyl, morphine,
hydromorphone, or an α2 agonists such as clonidine.
Bupivacaine and ropivacaine are the most commonly used amide local
anesthetics for epidural analgesia because they have long duration of
action with slightly greater selectivity of sensory block compared to motor
block. Pharmacokinetic studies of bupivacaine in children over the age of
6 months have reported good safety for infusion rates of bupivacaine of
below 0.4 mg/kg/hour with plasma bupivacaine levels in a safe range of <2
to 3 µg/mL.122 Neonates have reduced clearance of bupivacaine.
Pharmacokinetic studies in neonates receiving continuous bupivacaine
infusions have shown a continuous rise in plasma bupivacaine levels after
the first 48 hours.
As a result of various pharmacokinetic studies, we use a maximum dose
of 0.4 mg/kg/hour of bupivacaine for continuous epidural infusions in
children over the age of 6 months. For children less than 4 to 6 months of
age, we restrict the dose of bupivacaine to 0.2 mg/kg/hour. Because of the

2613
limitations in dosing of bupivacaine in young infants, it is reasonable to
use adjuvants to epidural infusions which will have a synergistic effect
with bupivacaine such as opioids and clonidine in order to maximize
analgesia.
Ropivacaine is a long-acting amide local anesthetic, shown in adults, to
have less central nervous system and cardiac toxicity and slightly more
sensory selectivity when compared to bupivacaine. Due to this increased
safety profile, ropivacaine is seeing increased use and becoming standard
at many institutions such as ours. Pharmacokinetic studies in infants and
children receiving single boluses of epidural ropivacaine show that, as
with bupivacaine, clearances for ropivacaine are reduced in infants. In
different studies, clearances for ropivacaine have ranged from around 4 to
8.5 mL/min/kg with generally lower values in younger infants. Data to
support a less extensive motor block for ropivacaine have been mixed.
Overall, infusion rates of 0.4 mg/kg/hour in older infants and children and
0.2 to 0.3 mg/kg/hour in neonates and younger infants appear quite safe. It
is plausible that slightly higher rates than these will be shown to be safe as
well.123–125
Chloroprocaine is used as an alternative to amide local anesthetics for
continuous epidural infusions in neonates and very young infants to avoid
the limitations of reduced clearance of amide local anesthetics and to
safely permit sufficient epidural infusion rates for optimal analgesia. Even
in neonates, chloroprocaine is rapidly metabolized with an elimination
half-life of less than 6 minutes, making it an attractive choice for
continuous epidural infusions in neonates. Studies of continuous epidural
chloroprocaine infusions in term and preterm infants have shown good
sensory blockade with no signs of neurotoxicity.110,126
Compared to infusions of ropivacaine or bupivacaine, higher weight-
scaled infusion rates of chloroprocaine are required to achieve similar
degrees of blockade. For preterm and term infants, 1.5% chloroprocaine
can be infused at about 0.5 mL/kg/hour for midthoracic epidural catheters
and 0.6 to 0.7 mL/kg/hour for lumbar and lower thoracic catheters. Even
for neonates, additives may improve analgesia, but at roughly one-tenth
the concentrations recommended earlier for infusions in older children
with bupivacaine or ropivacaine. For example, fentanyl at a concentration

2614
of 0.2 µg/mL and clonidine at a concentration of 0.04 µg/mL might be
considered as adjuvants.
Chloroprocaine may be used to test previously placed epidural catheters
as a second loading dose. The rationale for using chloroprocaine rather
than lidocaine or other amide local anesthetics for a second loading dose is
based on the concern that because most patients will have had
intraoperative infusions of amide local anesthetics, additional amide local
anesthetics as a bolus test dose may cause serum amide local anesthetic
levels to reach toxic levels. Injecting approximately 0.5 mL/kg of 3%
chloroprocaine (up to a maximum total dose of around 18 mL for patients
>50 kg) incrementally into the epidural catheter should result in some
evidence of sensory and motor block, thereby confirming position of the
catheter in the epidural space. Alternatively, lidocaine in the 0.75% to
1.5% range can also be employed. Both of these local anesthetics have
relatively rapid onset to facilitate diagnosis of a working or misplaced
catheter. If the patient is tachycardic or hypertensive due to pain, these
parameters generally improve within 5 to 10 minutes if the catheter is in an
epidural location covering the surgical field. Once proper position of the
epidural catheter has been confirmed, then good analgesia should be able
to be obtained through the adjustment of appropriate epidural solutions and
infusion rates.
Neuraxially administered opioids have a synergistic analgesic effect
when combined with local anesthetics. Due to the hydrophilic property of
hydromorphone, there is a slight preference to using hydromorphone for
postoperative analgesia for more extensive surgical procedures involving
several dermatomes. However, due to more rostral spread of
hydromorphone, the risk of respiratory depression is greater. Specific data
point to no better analgesia but slightly more pruritus when morphine or
hydromorphone are compared for epidural administration.127,128 All
neuraxially administered opioids can cause side effects including nausea,
vomiting, urinary retention, pruritus, sedation, respiratory depression, and
constipation. Nausea, vomiting, and other side effects from epidural
opioids are treated similarly to those seen from parenteral opioids. Low-
dose naloxone infusions significantly reduce opioid side effects without
reversing opioid-induced analgesia.

2615
 Clonidine is often added to epidural local anesthetic infusions to
enhance analgesia without increasing nausea, vomiting, pruritus, or
respiratory depression. Studies of combinations of epidural clonidine with
local anesthetics in children have shown a low side effect profile.129,130
Controlled trials of single-dose caudal administration of clonidine with
bupivacaine have shown variable prolongation of analgesia by
approximately 50% to 75% than epidural bupivacaine alone.
Pharmacokinetic studies of single-dose epidural clonidine in children show
wide variation in plasma concentration as well as wide variation in the
time for clonidine absorption from the epidural space. Other studies have
not shown significant prolongation of single-shot caudal analgesia with
clonidine doses as high as 2 µg/kg.131
Although some clinicians perform single-shot caudal blocks routinely
with clonidine doses in the range of 2 µg/kg, our view is that this dose
frequently results in prolonged sedation, especially if other sedatives or
systemic opioids are administered as well. Our practice for children 1 year
of age and older is to use 0.5 to 1 µg/kg, to a maximum of 15 µg as a
single bolus for caudal blocks and roughly 0.12 to 0.16 µg/kg/hour (0.3 to
0.4 mL/kg/hour of a solution containing 0.4 µg/mL) added to continuous
epidural local anesthetic infusions (except for neonates, where lower doses
and concentrations are used, as noted in the preceding text). Please see
Table 50.7 for recommended doses for epidural infusions.

TABLE 50.7 Recommended Epidural Infusion Rates

Rate (mL/kg/hour)a
Solution <1 mo 1–4 mo >4 mob
Bupivacaine 0.1% +/− Rarely used Rarely used 0.4
Fentanylc 1–2 µg/mL +/−
Clonidine 0.4 µg/mL
Ropivacaine 0.1% +/− Rarely used 0.1–0.3 0.4–0.5
Fentanyl 2 µg/mL +/−
Clonidine 0.4 µg/mL
Bupivacaine 0.1% + Rarely used Rarely used 0.3–0.4
hydromorphone 5 µg/mL
Ropivacaine 0.1% + Rarely used 0.1–0.3 0.3–0.4
hydromorphone 5 µg/mL
Chloroprocaine 1.5% + 0.5 0.5 Rarely used Rarely
Fentanyl 0.2 µg/mL +/− (midthoracic) (midthoracic) used

2616
 Clonidine 0.04 µg/mL 0.6–0.7 0.6–0.7
(lumbar and low (lumbar and low
thoracic) thoracic)
NOTE: Solutions containing hydrophilic opioids such as hydromorphone may pose a higher risk for
delayed respiratory depression, so appropriate frequency of observation and continuous
electronic monitoring is recommended. Higher concentrations of opioids may be considered for
selected patients who are opioid-tolerant. Patient-controlled epidural anesthesia (PCEA) doses if
used should be 1/4 to 1/6 the basal rate. Hourly maximums: opioid (µg/kg/h): morphine, 3–5;
hydromorphone, 1.5–2.5; fentanyl, 0.1–0.5; ropivacaine, 0.4 mg/kg/h, 0.2 mg/kg/h in
newborns/neonates.
aInfusion rates and solutions should be modified according to clinical circumstances. Little

information is available on how best to adjust these rates based on degrees of prematurity.
bWeight scaled infusion rates should plateau at values recommended for patients weighing around

45 kg, such as maximum infusion rates for larger patients should rarely exceed 15 mL/h.
c
In infants <6 months of age, we recommend using fentanyl at 1 µg/mL.

We recommend frequent (every 4 hour) assessment of the epidural site

by the nursing staff and twice-daily inspection by the pain management
team. Catheter depth should be noted with care, as the catheter can migrate
either inward or outward. A small study suggests that this movement is
more common in children <40 kg compared to large children and
adults.132 Assessing the site for potential signs of infection, such as
tenderness, erythema, or abnormal discharge, should also be part of
frequent monitoring. Care should also be taken when using adherence
substances such as Mastisol to secure the epidural occlusive dressing, as
there are reports of contact dermatitis with use of these agents.133

Peripheral Nerve Blocks in Children

Peripheral nerve blocks provide reliable and safe postoperative pain
management. A report by the French-Language Society of Pediatric
Anesthesiologists showed that among 24,000 regional blocks in children,
the complication rate for peripheral nerve block was 0 in 1,000.116 The
PRAN database also showed the safety of peripheral nerve blocks in a
cohort of 13,725 patients.134 In 455 upper extremity blocks, the
complication rate was 2%, no complications in 556 head and neck blocks,
and a complication rate of 1% in 2,307 lower extremity blocks. In a
retrospective review of 226 continuous peripheral nerve blocks in children
over a 4-year period, no major adverse events were noted.135 A recent

2617
study using the PRAN database also demonstrated the safety of 2,074
continuous peripheral nerve block catheters with a complication rate of
12.1% with no incidences of deep infection, persistent neurologic deficits
or systemic local anesthetic toxicity.136
A general trend in clinical trials of peripheral nerve blockade is the
observation of very good analgesia with a very low side effect profile that
compares favorably to either systemic opioids or epidural infusions. In a
randomized trial comparing popliteal block versus epidural analgesia for
foot and ankle surgery, popliteal block results in superior analgesia with
reduced incidences of nausea, vomiting, and urinary retention.137
A recent review shows that the use of ultrasound improves both the
success rate of the block and improves the duration of the block.138
Advantages of ultrasound guidance include direct visualization of nerves
and other structures such as arteries which may reduce the likelihood of
intraneural or intravascular injection and direct visualization of local
anesthetic spread. Combining the use of ultrasound with peripheral nerve
stimulation is sometimes used when advancing catheters for continuous
use to further confirm catheter placement. The addition of clonidine to
peripheral nerve blocks in children has been shown to significantly
increase duration of sensory blockade by approximately 4 hours; however,
the incidence of motor blockade was also significantly increased.139
Like epidural anesthesia, the placement of peripheral nerve block may
require general anesthesia or deep sedation for most younger children.
Motivated older children and adolescents will often require only minimal
sedation. It is often helpful to apply a topical anesthetic, such as via a JTip,
to the anticipated needle insertion site to minimize pain from needle
insertion. It is our practice to perform the majority of neuraxial and
peripheral nerve blocks under general sedation. Indications for using
peripheral nerve blocks as the sole anesthetic technique include risk of
malignant hyperthermia, risk of postoperative apnea, and patient
preference.
Recommendations regarding dosing of local anesthetics for peripheral
nerve block in children vary among authors. Where immediate onset is
required, one group has recommended 0.5 mL/kg of a mixture of 1%
lidocaine with 1:200,000 epinephrine and 0.5% ropivacaine. Several

2618
groups employ continuous perineural infusions with 0.1 to 0.15
mL/kg/hour of ropivacaine in a concentration range between 0.1% and
0.2%. As with epidural anesthesia, use of α2 adrenergic agonists (e.g.,
clonidine) as adjuncts can be considered. Clonidine has been found to
increase time to first use of supplemental analgesia as well as fewer doses
of analgesia needed in first 24 hours following surgery at least when lower
concentrations of ropivacaine or bupivacaine are used.140 It is unclear if
this remains true with higher concentrations, such as 0.2% or 0.25% of
ropivacaine and bupivacaine respectively.

SUPRACLAVICULAR
A supraclavicular block is applicable to all surgeries of the upper
extremity excluding shoulder surgery. Placement of a continuous catheter
technique can be used in the treatment of refractory complex regional pain
syndrome in children.141 Supraclavicular block has been successfully used
as the sole anesthetic for children younger than 12 years of age undergoing
closed reduction of arm fractures.142
The trunks of the brachial plexus are located between the anterior and
medial scalene muscles in the interscalene groove. Using ultrasound
guidance, the first rib and subclavian artery should be located, with the
pleura located just beneath the first rib. The anterior and middle scalene
muscles are then located as they insert onto the first rib cephalad to the
subclavian artery. The brachial plexus is located between the anterior and
middle scalene muscles and superficial and lateral to the subclavian artery.
Under direct ultrasound visualization, the needle is inserted from a lateral
to medial direction toward the plexus, with particular attention to avoiding
directing the needle medial to the anterior scalene muscles or caudally
beneath the first rib to prevent pneumothorax. Only a single injection is
required due to the close proximity of the trunks of the plexus in this
region. If using a continuous catheter technique, we typically recommend
tunneling supraclavicular catheters, particularly for patients requiring
aggressive postoperative physical therapy and for catheters of longer
duration such as in the treatment of complex regional pain syndrome.

INFRACLAVICULAR

2619
Infraclavicular block is indicated for all distal upper extremity surgeries
such as syndactyly repair and repairs of open forearm fractures. In the
infraclavicular region, the plexus is located posterior to the pectoralis
major and minor. The cords of the brachial plexus are located medial,
lateral, and posterior to the axillary artery. Under direct ultrasound
visualization, with the ultrasound probe medial and caudal to the coracoid
process, the pectoralis muscles and the axillary artery and vein should be
identified. The axillary vein is located caudal to the axillary artery. The
needle is inserted under direct ultrasound visualization and advanced
laterally; once the sheath surrounding the plexus is reached, spread of local
anesthetic should be visualized spreading to the cords of the plexus.

SCIATIC NERVE BLOCK

The sciatic nerve block is useful in providing analgesia for a variety of
surgical procedures of the lower leg or foot, for painful physical therapy
following surgery, and for treatment of complex regional pain syndrome
affecting the lower leg or foot. The latter study showed excellent pain
relief and excellent rehabilitation with no adverse events using a
continuous infusion of 0.2 % ropivacaine at 0.1 mL/kg/hour for 96
hours.143 In the study of foot and ankle surgery by Dadure et al.,143 the
children with continuous popliteal nerve blocks received a continuous
infusion of 0.2% ropivacaine at 0.1 mL/kg/hour, and a 100% satisfaction
rate was reported.
Studies in adult patients comparing continuous sciatic nerve block with
PCA have shown superior analgesia; reduced morphine use; and reduced
frequency of nausea, vomiting, and sedation for adult patients with
continuous popliteal sciatic catheters.144 Two commonly used approaches
for sciatic nerve block in children are the subgluteal approach and the
popliteal approach.145 A single-injection technique is indicated after
relatively minor surgery when postoperative pain is expected to be mild
and of short duration. A continuous catheter technique will provide
prolonged analgesia after more extensive surgical procedures.

Sciatic-Subgluteal Approach
Because patients will need to be positioned in the prone position for a

2620
subgluteal approach to a sciatic nerve block, younger children will require
general anesthesia for placement. Cooperative older children and
adolescents can often tolerate the procedure in a prone procedure with
sedation. The technique described in the following text uses ultrasound
guidance with peripheral nerve stimulation for further confirmation. With
the patient in a prone position, ultrasound is used to locate the sciatic
nerve; a line marking the midpoint between the ischial tuberosity and the
greater trochanter can be useful in estimating position of the sciatic nerve.
Under visualization, an insulated 17G stimulating needle is advanced
approximately 1 to 2 cm below the midpoint mark and is directed medially
and superiorly. Initially, twitching of the gluteal muscles can be observed
but will disappear as the needle advanced further. Dorsi- and plantar-
flexion of foot is observed with stimulation of the sciatic nerve. A 20G
stimulating catheter is advanced approximately 3 cm beyond the tip of the
needle; angling the needle slightly caudally may facilitate advancing the
catheter. Further nerve stimulation of the catheter confirms proper catheter
placement.146

Popliteal Approach
Block of the sciatic nerve can also be achieved at the level of the popliteal
fossa. The sciatic nerve divides into the tibial and common peroneal nerves
in the popliteal fossa; proximal to the popliteal fossa crease. For this block,
patients can be positioned either prone or supine with the hip and knee
flexed. Our general preference is to use the prone approach when catheter
placement is being considered because it makes it easier to maintain
sterility and to perform tunneling of the catheter. Ultrasound is used to
locate the structures in the popliteal fossa; the popliteal artery and vein are
located deep and proximal to the sciatic nerve. The course of the sciatic
nerve should be seen and the point at which the sciatic nerve bifurcates
should be located. The tendon of the biceps femoris is located laterally,
and the tendons of the semimembranosus and semitendinosus muscles are
located medially. Ultrasound viewing and needle advancement can be
performed using several approaches, including an in-plane approach, with
the needle advancing in a lateral-to-medial direction, or an out of plane
approach, with the needle advancing in a sagittal direction. Injection of

2621
local anesthetic should show local anesthetic spread around the tibial and
common peroneal nerves.146

FEMORAL BLOCK
A femoral nerve block provides effective analgesia for knee surgery, for
surgery on the anterior thigh such as a muscle biopsy, and for femur
surgery or fractures. It will also provide analgesia to the medial lower
extremity below the knee by blocking the saphenous nerve. Compared to
PCA morphine and epidural analgesia, continuous femoral nerve block
provides more effective analgesia with fewer side effects. Results indicate
that using ultrasound guidance produced prolonged duration of sensory
blockade with less volume of local anesthetic compared to using nerve
stimulation. The typical landmarks for a femoral nerve block are the
inguinal crease and the femoral arterial pulse. The femoral nerve is located
lateral and deep to the femoral artery as it courses below the inguinal
ligament. With the patient positioned in a supine position, ultrasound is
used to locate the position of the femoral vein, artery, and nerve in the
inguinal crease. Under ultrasound visualization, an insulated block needle
is inserted just lateral to the arterial pulse and directed slightly cephalad.
Proper placement of the needle should be seen on ultrasound, positioned
alongside the femoral nerve. Nerve stimulation is an alternative method to
confirm proper placement of the needle. With proper needle placement,
twitching of the quadriceps and patella should be seen. Quadriceps
movement alone without signs of patellar movement is due to stimulation
of the sartorius muscle and does not confirm proper needle placement. If
the femoral nerve is not readily located, it will be necessary to redirect the
needle slightly laterally. When placing a catheter for continuous femoral
block, the needle is angled slightly more cephalad and the catheter is
advanced. If using nerve stimulation, twitching of the quadriceps and
patella will indicate correct catheter placement. Infection rates for
continuous femoral catheters appear to be low when used for short-term
use. In a study examining bacterial colonization and infection rates in
continuous femoral catheters, 57% of catheters had positive bacterial
colonization with Staphylococcus epidermidis as the most common
organism. However, there were no septic complications or serious

2622
infections for catheters in place for 48 hours.147
Recent study of femoral nerve blocks in the pediatric population found
that use of ropivacaine 0.5% was superior to ropivacaine 0.2% or
bupivacaine 0.25%, leading to decreased opioid use and earlier hospital
discharge.148

TRANSVERSUS ABDOMINIS PLANE BLOCK

Transversus abdominis plane (TAP) block is a technique where local
anesthetic is injected between the transversus abdominis and the internal
oblique muscles. This is generally easily visualized with the use of
ultrasonography. Recently, it has been gaining increasing popularity for
use in pediatrics. The block may be performed as a single shot or as a
continuous infusion. Applications for use include procedures such as
inguinal hernia repair or other abdominal surgery.149 A study using the
PRAN database looked at the safety of 1,994 children receiving TAP
blocks and found the upper incidence of overall complications was 0.3%
and these complications did not require any further interventions and were
considered minor.150 Although caudal epidural blockade may provide
superior pain relief, the TAP can be considered as it is less invasive and
also does not cause lower extremity motor weakness.

Painful Conditions in Pediatric Hospital Care

CANCER PAIN
Infants and children with cancer experience pain from cancer treatment
such as painful mucositis, postamputation pain, and peripheral
neuropathies as well as from tumor spread causing bone pain, neuropathic
pain, or headaches from raised intracranial pressure. Repeated painful
needles procedures, such as bone marrow biopsies and lumbar punctures,
are a great source of pain and distress. Several surveys have shown that as
successful chemotherapeutic protocols, radiation therapy and surgical
techniques have advanced, cancer treatment and painful procedures
account for greater sources of cancer pain in infants and children.151
Frequent diagnostic and painful procedures are common for infants and
children with cancer. For minor needle procedures such as intravenous line

2623
insertions and assessing implanted vascular access ports, topical analgesia
should be routinely used. A number of approaches to cutaneous analgesia
have been used, including local anesthetic creams or patches, with or
without physical methods to accelerate transit of drug across the stratum
corneum. Cognitive-behavioral interventions such as hypnosis and other
relaxation techniques have also been shown to be effective for procedural
pain. Children can also apply these techniques to nausea, headaches, and
other symptoms. Conscious sedation or general anesthesia is typically used
for more invasive needle procedures such as bone marrow biopsies and
lumbar punctures. Safe sedation protocols have been developed by the
American Academy of Pediatrics and are widely used by pediatric
oncologists and other pediatric subspecialists for procedural sedation.
Pediatric anesthesiologists are consulted for patients with risk factors that
place them at increased risk for conscious sedation, for patients who fail
conscious sedation, or for more invasive procedures such as central line
insertions.
Mucositis is a common side effect in children receiving chemotherapy
or radiation; it is especially severe and prolonged with bone marrow
transplantation. Initially, pain from mucositis is often treated with topical
agents, although evidence for efficacy in the prevention and treatment of
mucositis has been mixed. Opioids are used for pain that persists despite
topical agents. Data supports the safety and efficacy of opioid infusions
and PCA for the treatment of mucositis.80,152 Because many children with
mucositis will require opioids for weeks, our practice is to eventually
administer approximately 60% of the total daily opioid dose as a basal rate
in order to provide sustained analgesia. NCA is used for young children.
Although a majority of children have resolution of the cancer pain after
initial chemotherapy induction protocols, some children will continue to
experience visceral, somatic, and neuropathic pain due to tumor invasion
of solid organs, bone, nerves, and plexuses. Opioids are provided by the
oral route whenever feasible. It is common practice to use a long-acting
opioid, either methadone elixir or tablets or capsules of a sustained-release
preparation of morphine, hydromorphone, or oxycodone, along with short-
acting opioids for rescue or breakthrough pain. Currently, methadone is the
most widely available long-acting opioid available as an elixir formulation.

2624
When using methadone in the cancer population, it is essential to be aware
of the risk of increased QTc from other agents or due to possibility of
increased serum methadone levels. Some patients with rapidly escalating
pain or patients unable to tolerate oral opioids may require opioids via
parenteral routes, including intravenous and subcutaneous routes. Some
acute breakthrough pain can be managed with transmucosal fentanyl.91,153
Continuous infusions and PCA or NCA allow rapid titration for escalating
pain as well. In the setting of neuropathic cancer pain, we frequently
prescribe anticonvulsants and antidepressants largely by extrapolation
from adult practice. Opioids and other sedating medications may
contribute to fatigue, somnolence, sleep disturbance, and depressed mood,
but they may exist even in children not receiving opioids or sedatives.
Along with treating specific or remediable causes of these symptoms, our
common practice, again extrapolated from adult clinical trials, is to
consider a trial of a stimulant such as methylphenidate.
A subgroup of children with cancer pain will have persistent pain
despite massive dose escalation. Many of these children will have
unremitting neuropathic pain associated with tumor extension to the
epidural space, onto a plexus or along the course of major nerves. One
approach to persistent pain in this setting is to add a low-dose ketamine
infusion. At rates below 0.2 mg/kg/hour, dysphoria and dissociation are
relatively uncommon.154
Oral ketamine has been used as well, with a provisional dose ratio of
about 3:1 compared to intravenous dosing in steady state. In selected cases
of refractory pain, our practice is to use regional anesthetic techniques, and
most commonly in this setting, we favor implanted intrathecal ports with
the catheter generally advanced to the dorsal horn level appropriate to the
patient’s location of greatest pain.155 Note that for tumors predominantly
in the pelvis, lumbar spine, or lower extremities, this implies having the
catheter tip advanced up to around T11. The choice of drugs for these
infusions must be individualized based on the nature of the patient’s pain
and quality of life issues, including considerations of weakness, bowel and
bladder dysfunction, and sedation. In the majority of cases, we have found
it necessary to include small doses of local anesthetics along with opioids,
and in some cases, we have included other additives such as clonidine or

2625
ketamine. There is a small subgroup of children for whom it appears that
the most feasible option for achieving relief of pain, distress, or terminal
dyspnea is to provide sedation, using a range of agents, including
benzodiazepines, barbiturates, or other drugs.156

PAIN ASSOCIATED WITH SICKLE CELL

VASOOCCLUSIVE EPISODES
Pain is a common consequence of sickle cell disease due to acute
vasoocclusive episodes as well as pain from compression fractures,
avascular necrosis, acute cholecystitis, splenic sequestration, and stroke.
Painful vasoocclusive episodes are the most common cause of pain in
children with sickle cell disease and can occur in children as young as 6
months of age as fetal hemoglobin and its protection against vasoocclusive
crises decreases. Children can demonstrate a range of severity and
frequency of vasoocclusive episodes, from occasional episodes managed at
home with oral analgesics to baseline daily pain with frequent
exacerbations requiring numerous hospitalizations and systemic opioids
administration. PCA is commonly used for severe pain in hospitalized
patients, along with NSAIDs, hydration, red blood cell transfusion, and
supplemental oxygen. Larger opioid boluses may be necessary than are
typically used for postoperative pain management for patients with
extreme pain or for patients who are opioid-tolerant.157 Often basal
infusions are necessary, particularly at night to permit periods of
uninterrupted sleep. Published case series indicate that even with generous
PCA parameters, pain scores remain high for a high percentage of
patients.158 Recent data has shown promising results for subanesthetic
dosing of ketamine in patients with sickle cell disease.

CHILDREN WITH TRAUMA

General sound principles of analgesic management should be applied to
the care of children with the vast variety of traumatic injuries. Application
of appropriate nerve blocks, central blocks, when possible, can facilitate
recovery from the child’s injuries. In addition, many injured children are
fully able to take oral analgesics, avoiding the necessity of intravenous
access or, even, continued stay in the hospital, once their pain is

2626
successfully managed.

CHILDREN WITH DEVELOPMENTAL DISABILITIES

Children with cognitive and developmental disabilities such as cerebral
palsy and neurodegenerative disorders present unique challenges in
assessing and managing pain. Many children with disabilities experience
daily pain associated with muscle spasms, hip dislocation, and other
musculoskeletal pains and undergo frequent painful invasive procedures
such as scoliosis repair, tendon releases, and surgical treatment of
gastroesophageal reflux. Children may have little or no cognitive deficits
but significant motor and communication impairments, making pain
assessment especially difficult. Often, parents and caretakers are able to
distinguish subtle behavioral signs indicating pain. A number of pain
assessment tools such as the FLACC tool and the Non-communicating
Children’s Pain Checklist have been used for children with cognitive and
developmental disabilities. In comparing several pain assessment tools for
children with cognitive limitations, physicians and nurses rated the
FLACC as having higher clinical utility.159
Other children with severe cognitive impairment will have persistent
agitation and screaming without a clear etiology and are admitted to the
hospital for diagnostic evaluation and therapeutic trials. Patients should be
evaluated for treatable causes of pain such as fractures, hip dislocations,
esophagitis, and constipation. In some cases where no underlying cause
can be eventually identified, therapeutic trials of anticonvulsants and
antispasmodics may provide relief.160

Conclusions
Evidence is available to support safe and effective treatment of acute pain
in infants, children, and adolescents in the majority of circumstances.
Analgesic pharmacology has received extensive study in pediatrics over
the past several decades. Individual analgesics often provide incomplete
relief in standard doses, and there is a rationale for analgesic combinations
and multimodal analgesia in many situations. Opioids can provide good
analgesia at all ages, but with a spectrum of side effects that require active

2627
treatment, and with specific requirements for observation and monitoring
according to age and patient condition–related risk factors. Techniques
have been developed for neuraxial and peripheral regional anesthesia at all
ages. There is a growing emphasis on ultrasound, nerve stimulation,
selective use of fluoroscopy, and other approaches to provide objective
confirmation of needle and/or catheter positioning. Pediatric acute pain
management, whether by an acute pain service or by other delivery
models, can be improved by system-wide approaches that emphasize
systematic assessment of pain and other symptoms, communication,
clinician education, clarification of responsibilities, and protocols for
analgesic administration, side effect management, and monitoring.

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peripheral nerve blocks in children: a Cochrane review. Anesth Analg 2017;124(3):948–958.
139. Cucchiaro G, Ganesh A. The effects of clonidine on postoperative analgesia after peripheral
nerve blockade in children. Anesth Analg 2007;104(3):532–537.
140. Lundblad M TM, Kaabach O, Khalifa SB, et al. Alpha-2 adrenoceptor agonists as adjuncts to
peripheral nerve blocks in children: a meta-analysis. Paediatr Anaesth 2016;26:232–238.
141. Franklin A, Austin T. The use of a continuous brachial plexus catheter to facilitate inpatient
rehabilitation in a pediatric patient with refractory upper extremity complex regional pain
syndrome. Pain Pract 2013;13(2):109–113.
142. Pande R, Pande M, Bhadani U, et al. Supraclavicular brachial plexus block as a sole
anaesthetic technique in children: an analysis of 200 cases. Anaesthesia 2000;55(8):798–802.
143. Dadure C, Motais F, Ricard C, et al. Continuous peripheral nerve blocks at home for treatment
of recurrent complex regional pain syndrome I in children. Anesthesiology 2005;102(2):387–
391.
144. di Benedetto P, Casati A, Bertini L, et al. Postoperative analgesia with continuous sciatic
nerve block after foot surgery: a prospective, randomized comparison between the popliteal
and subgluteal approaches. Anesth Analg 2002;94(4):996–1000.
145. van Geffen GJ, Gielen M. Ultrasound-guided subgluteal sciatic nerve blocks with stimulating
catheters in children: a descriptive study. Anesth Analg 2006;103(2):328–333.
146. Oberndorfer U, Marhofer P, Bosenberg A, et al. Ultrasonographic guidance for sciatic and
femoral nerve blocks in children. Br J Anaesth 2007;98(6):797–801.
147. Cuvillon P, Ripart J, Lalourcey L, et al. The continuous femoral nerve block catheter for
postoperative analgesia: bacterial colonization, infectious rate and adverse effects. Anesth
Analg 2001;93(4):1045–1049.
148. Veneziano G, Tripi J, Tumin D, et al. Femoral nerve blockade using various concentrations of
local anesthetic for knee arthroscopy in the pediatric population. J Pain Res 2016;9:1073–
1079.
149. Sahin L, Sahin M, Gul R, et al. Ultrasound-guided transversus abdominis plane block in
children: a randomised comparison with wound infiltration. Eur J Anaesthesiol
2013;30(7):409–414.

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150. Long JB, Birmingham PK, De Oliveira GS Jr, et al. Transversus abdominis plane block in
children: a multicenter safety analysis of 1994 cases from the PRAN (Pediatric Regional
Anesthesia Network) database. Anesth Analg 2014;119(2):395–399.
151. Oakes LL, Anghelescu DL, Windsor KB, et al. An institutional quality improvement initiative
for pain management for pediatric cancer inpatients. J Pain Symptom Manage
2008;35(6):656–669.
152. Ruggiero A, Barone G, Liotti L, et al. Safety and efficacy of fentanyl administered by patient
controlled analgesia in children with cancer pain. Support Care Cancer 2007;15(5):569–573.
153. Fine PG, Marcus M, De Boer AJ, et al. An open label study of oral transmucosal fentanyl
citrate (OTFC) for the treatment of breakthrough cancer pain. Pain 1991;45(2):149–153.
154. Finkel JC, Pestieau SR, Quezado ZM. Ketamine as an adjuvant for treatment of cancer pain in
children and adolescents. J Pain 2007;8(6):515–521.
155. Collins JJ, Grier HE, Sethna NF, et al. Regional anesthesia for pain associated with terminal
pediatric malignancy. Pain 1996;65(1):63–69.
156. Wolfe J, Grier HE, Klar N, et al. Symptoms and suffering at the end of life in children with
cancer. New Engl J Med 2000;342(5):326–333.
157. Shapiro BS, Cohen DE, Howe CJ. Patient-controlled analgesia for sickle-cell-related pain. J
Pain Symptom Manage 1993;8(1):22–28.
158. Jacob E, Miaskowski C, Savedra M, et al. Quantification of analgesic use in children with
sickle cell disease. Clin J Pain 2007;23(1):8–14.
159. von Baeyer CL, Spagrud LJ. Systematic review of observational (behavioral) measures of
pain for children and adolescents aged 3 to 18 years. Pain 2007;127(1–2):140–150.
160. Hauer JM, Wical BS, Charnas L. Gabapentin successfully manages chronic unexplained
irritability in children with severe neurologic impairment. Pediatrics 2007;119(2):e519–e522.

2636
CHAPTER 51
Acute Pain in Adults
ROBERT W. HURLEY, MICHAEL L. KENT,
and CHRISTOPHER L. WU

Acute pain is the normal and predicable neurophysiologic response to

noxious mechanical, thermal, or chemical stimuli; is generally time-
limited; and resolves with the cessation of the noxious stimuli. The
etiology, often, is known or understood. It is typically associated with
invasive procedures, trauma, or medical diseases. The pain sensation is
usually limited to the area of trauma or damage or the area that
immediately surrounds it. Perhaps most importantly, the painful sensations
associated with such an injury are expected to resolve over time when
adequate wound healing has occurred. In contrast, chronic pain persists
beyond either the course of an acute injury or illness or its expected time
for healing and repair. Acute pain states can then be further divided by
duration, etiology, mechanism, intensity, and/or symptoms. In this chapter,
acute pain is discussed using postsurgical or postprocedural and
posttraumatic pain as models.
A revolution in the management of acute pain has occurred over the past
few decades. Widespread recognition of the undertreatment of acute pain
by clinicians, economists, and health policy experts has led to the
development of a national clinical practice guideline for acute pain
management by the Agency for Healthcare Quality and Research
(formerly the Agency for Health Care Policy and Research) of the U.S.
Department of Health and Human Services. This landmark document
includes acknowledgment of the historic inadequacies in perioperative
pain management, importance of good pain control, need for
accountability for adequate provision of perioperative analgesia by health
care institutions, and a statement on the need for involvement of specialists
in appropriate cases. In addition, several professional societies and
regulatory agencies, including the American Society of

2637
Anesthesiologists1,2 and The Joint Commission (formerly the Joint
Commission on Accreditation of Healthcare Organizations [JCAHO]),
have developed acute pain management standards3 or clinical practice
guidelines for acute pain management in hospitalized patients.4 With the
recent surge of opioid misuse and abuse in the United States, there has
been increased focus on the influence of these pain assessment standards
on opioid prescribing.4 Although the incorrect interpretation of these
standards by prescribers likely has a role in the increased use of opioids in
the acute care setting, it is unlikely that it was a primary driver of the
escalation in outpatient opioid prescribing. More likely causes of the
increased use of opioid medications in the outpatient setting were the best
intentions and overly simplistic advice of prominent physicians,5 the
incorrect interpretation of medical literature,6 generalization from small
uncontrolled studies,7 and the intentional misuse of this same literature for
financial gain by the manufacturers of the medications8.
With their knowledge of and familiarity with pharmacology, various
regional techniques, and the neurobiology of nociception, perioperative
physicians such as anesthesiologists are continually on the forefront of
clinical and research advances in acute pain, especially acute postoperative
pain management, and have traditionally been leaders in the development
of acute postoperative pain services, application of evidence-based
practice to acute postoperative pain, and creation of innovative approaches
to acute pain management. The effective treatment of acute pain (including
postprocedural pain) needs to involve a multidisciplinary approach like
that which has evolved in the treatment of chronic pain. Programs such as
the enhanced recovery after surgery (ERAS) pathways that are evidence-
based and multidisciplinary have demonstrated great success in the
management of postoperative pain and overall patient recovery.

Acute and Chronic Effects of Acute Pain

Uncontrolled acute pain may produce a range of detrimental acute and
chronic effects. Attenuation of periprocedural pathophysiology that occurs
during a procedure or surgery through reduction of nociceptive input into
the central nervous system (CNS) and optimization of periprocedural

2638
analgesia may decrease complications, facilitate the patient’s recovery
during the immediate postprocedural period,9 reduce the length of stay,10
and after discharge from the hospital.
The perioperative period is associated with a variety of
pathophysiologic responses that may be initiated or maintained by
peripheral nociceptive input. Although these responses may have had a
beneficial purpose in nature, the same response to the modern-day surgery
may be harmful. Uncontrolled perioperative pain may therefore be
considered a major morbidity for the patient. Furthermore, attenuation of
postprocedural or acute medical pain may decrease perioperative
morbidity and mortality.11
The transmission of pain stimuli from the periphery to the spinal cord
and supraspinally results in the neuroendocrine stress response. The
dominant neuroendocrine response to pain involves hypothalamic–
pituitary–adrenocortical and sympathoadrenal interaction, resulting in
increased sympathetic tone; increased catecholamine and catabolic
hormone secretion including cortisol, adrenocorticotropic hormone,
antidiuretic hormone, glucagon, aldosterone, renin, and angiotensin II; and
decreased secretion of anabolic hormones. The outcome of these changes
includes sodium and water retention and increased levels of blood glucose,
free fatty acids, ketone bodies, and lactate. A hypermetabolic, catabolic
state results as metabolism and oxygen consumption are increased, and
metabolic substrates are mobilized from storage depots. The negative
nitrogen balance and protein catabolism may impede the patient’s recovery
and contribute to morbidity or mortality. Sympathetic activation may
increase myocardial oxygen consumption and decrease myocardial oxygen
supply, which may be important in the development of myocardial
ischemia and infarction.11,12 Sympathetic activation may also delay return
of postprocedural gastrointestinal motility that may develop into an ileus.
Postprocedural acute pain may initiate several detrimental spinal reflex
pathways. Respiratory function can be markedly diminished, especially
with acute pain involving the upper abdomen, flank, and/or thorax. Reflex
inhibition of phrenic nerve activity is an important component of this
decreased pulmonary function.11,12 However, control of acute pain is also
important because patients with poor pain control may have poor

2639
inspiratory effort, have an inadequate cough, and be more likely to develop
pulmonary complications.11

Neurobiology of Acute Pain

The neurobiology of pain is extremely complex, with redundancy and
plasticity such that there is no “final common pathway” for the process of
nociception. However, understanding the neurobiology of pain is crucial
when contemplating which nociceptive processes to target in the treatment
of acute pain. Identification of new molecular and cellular processes
involved in the process of nociception has increased the number of
potential targets for analgesic therapies.

PRIMARY AFFERENTS AND PERIPHERAL NERVE

NEUROTRANSMITTERS
A variety of mechanical, thermal, or chemical stimuli can result in the
sensation of pain. Information about these painful or noxious stimuli is
carried to higher brain centers by receptors and neurons that are distinct
from those that carry innocuous somatic sensory information. This topic is
covered at length in Chapters 3 and 4. In brief, small-diameter Aδ and C
fibers primarily transmit nociceptive information, but subsets of Aδ and C
fibers are thermo receptors that transmit nonpainful cold and warm
information, respectively.13 Neurotransmission by the Aδ and C fibers is
performed by numerous peptides and amino acids. Substance P (SP) was
the first peptide to be defined as specific to the small diameter primary
afferents and is released by noxious thermal, mechanical, and chemical
stimulation of the periphery.14–16 Exogenous application of SP into the
spinal cord of rats results in dorsal horn neuronal activation17 and
behavioral responses consistent with pain.18 Neurokinin-1 (NK-1), the
receptor for SP, is found on superficial and deep neurons in the dorsal horn
of the spinal cord consistent with their role in pain transmission.19 Other
peptides present in the small diameter afferents include calcitonin growth-
related protein (CGRP), galanin, vasoactive intestinal polypeptide (VIP),
and somatostatin (SST); however, their role in the modulation of
nociceptive transmission is less well understood. In addition to these

2640
peptides, the excitatory amino acid glutamate is also present within small
diameter primary afferents, released by noxious stimulation20 and activates
the second-order dorsal horn neurons.21 The effects of glutamate are
predominantly mediated by three receptor classes: alpha-amino-3-
hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate, N-methyl-
D-aspartate (NMDA), and metabotropic glutamate receptors (mGluR).
AMPA receptors are found on postsynaptic neurons predominantly within
the superficial dorsal horn.22 NMDA receptors are found both pre- and
postsynaptically (i.e., on nociceptive primary afferents and apposing
second-order neurons within the superficial and deep dorsal horn).23
mGluR are predominantly found postsynaptically on the cell body and
dendrites of dorsal horns neurons.
The primary afferent’s presynaptic nerve terminal in the dorsal horn of
the spinal cord represents a site for a therapeutic intervention. Primary
afferent fibers transmit the pain signal to the spinal cord and possess
numerous receptor systems that can reduce this transmission by reducing
transmitter release such as the α2-adrenergic, glycinergic, serotoninergic,
opioidergic, and GABAergic receptors24–26 as well as ion channels
sensitive to local anesthetics and anticonvulsants including voltage-gated
calcium, sodium, and potassium channels.

SPINAL CORD AND SUPRASPINAL STRUCTURES

Aδ and C fiber neurons synapse primarily within laminae I, II, and V of
the dorsal horn of the spinal cord. These primary afferents release
neurotransmitters and neuropeptides that activate the second-order
projection neurons of the spinal cord. Pain transmission through the spinal
cord may be modulated by an endogenous descending pain inhibitory
system and may be influenced by exogenously administered medications.
The primary components of this descending pain inhibition system are the
“triad” of the periaqueductal gray (PAG), the rostral ventromedial medulla
(RVM), and the dorsal lateral pontine tegmentum (DLPT), which includes
the locus coeruleus (LC) and the A7 nuclei. The PAG is an important site
to produce analgesia following systemic administration of opioids. The
endogenous opioid [Met5]enkephalin is present within this nucleus,27 and
opioid receptors of each subtype are present in this region.28 The PAG

2641
provides dense projections to the RVM29 and brainstem noradrenergic
nuclei LC and A7.30 Although each of these regions has direct projections
to the spinal cord, it has been proposed that their projections to the RVM
are important components in the modulation of pain by these regions.31
The RVM can function as a relay nucleus in the production of
antinociception by more rostral midbrain structures (PAG), but it also has
a primary role in the suppression of nociceptive transmission at the level of
the spinal cord. The suppression of nociceptive reflex behavior is thought
to be mediated by the axons of RVM neurons that descend within the
dorsolateral funiculus and terminate bilaterally in laminae I, II, V, VI, and
VII of the spinal cord. Anatomical studies have shown these axons
terminate coincident with spinothalamic tract cells and interneurons of the
dorsal horn that are related to pain transmission.32,33 Consistent with the
anatomical terminations of the RVM axons, physiologic studies have
shown that stimulation of the RVM results in the inhibition of a population
of pain-specific neurons within the dorsal horn.34,35 Spinally projecting
neurons of the RVM possess numerous neurotransmitters including
serotonin, enkephalin, γ-aminobutyric acid (GABA), glutamate, and
SP.36–38 The DLPT contains all of the noradrenergic neurons that project
to the RVM and the spinal cord.39,40 In animal models, electrical
stimulation of the DLPT sites produces analgesia41,42 and the analgesia
produced by the activation of these nuclei is mediated by the α2 adrenergic
receptor.42,43 The pain physician can pharmacologically manipulate each
of these neurotransmitter systems to modulate pain transmission
throughout the CNS.

Prevention
PREVENTIVE ANALGESIA
The development of central and/or peripheral sensitization after traumatic
injury or surgical incision can result in the amplification of acute pain.
Preventing the establishment of altered central processing by analgesic
treatment may, in the short term, result in the reduction of postprocedural
or traumatic pain and accelerated recovery. In the long term, the benefits
may include a reduction in the development of chronic pain and an

2642
improvement in the patient’s quality of recovery and satisfaction.
Although experimental animal studies convincingly confirm the ability of
preventive analgesia to decrease postinjury pain, the results of clinical
trials are mixed.44–46
The precise definition of preventive analgesia is a controversy in this
area of medicine and contributes to the question of whether preemptive
analgesia is clinically relevant. Definitions of “preventive analgesia”
include (1) any attempt to give medications prior to surgical incision, (2)
administration of medications during the intraoperative or intraprocedural
period, or (3) administration of medications during the intraoperative and
postoperative period.47 The first two definitions describe an exclusive
preemptive approach and are relatively narrow and may contribute to the
lack of a detectable effect of in clinical trials. For this text, preemptive
analgesia is defined as an analgesic intervention started before the noxious
stimulus arises to block peripheral and central pain transmission. This
preemptive intervention is possible, primarily, in the context of surgical
intervention; ideally, one in which the patient has no or minimal pain prior
to the intervention. “Preventive analgesia” encompasses all three. It
includes an attempt to block pain transmission prior to the injury
(incision), during the noxious insult (surgery itself), and following the
injury and throughout the recovery period. Unfortunately, few trials have
examined the concept of preventive analgesia in a rigorous fashion.
Preemptive analgesia abiding by the first one of the aforementioned three
definitions has been loosely examined, although some argue that the
timing of the intervention44–46 may not be as clinically important as other
aspects of preemptive analgesia including intensity and duration of the
intervention. In the purest definition of preemptive analgesia, an
intervention such as preoperative administration of gabapentin48 is not
necessarily preemptive if the blockade of nociceptive transmission from
the periphery to central sites is incomplete or insufficient such that the
development of peripheral or central sensitization would not be prevented.
Incisional and inflammatory injuries are important in initiating and
maintaining both peripheral and central sensitization. Confining the
definition of preemptive analgesia to only the immediately preoperative or
intraoperative (incisional) period may not be clinically relevant or

2643
appropriate because the inflammatory response may last well into the
postoperative period and continue to maintain this sensitization. Other
methodologic and study design issues also may complicate the question of
whether preemptive analgesia is clinically relevant. A variety of agents
and techniques44–46 have been used to study preemptive analgesia. Using
the broader definition of preventive analgesia that covers the preoperative,
the intraoperative, and postoperative periods, the combination of
experimental data and positive clinical trials strongly suggests that
preventive analgesia is a clinically relevant phenomenon. Maximal clinical
benefit is observed when there is complete blockade of noxious stimuli
with extension of this blockade into the postoperative period. Recent
preclinical and clinical studies provide substantial evidence that central
sensitization and persistent pain after surgical incision is predominantly
maintained by the incoming barrage of sensitized peripheral pain fibers
throughout the perioperative period.49 By preventing central sensitization
and the peripheral input maintaining it, preventive analgesia along with
intensive multimodal analgesic interventions could theoretically reduce
acute postprocedure pain/hyperalgesia and chronic pain after surgery or
trauma.50 In a systematic review of clinical trials examining preemptive or
preventive analgesic approaches, Katz and McCartney51 reported an
analgesic benefit of preventive analgesia but no such benefit with the
strictly preemptive strategy.

Treatment Methods
Many options are available for the treatment of acute pain, including
systemic (i.e., opioid and nonopioid adjuvant) analgesics and regional (i.e.,
neuraxial and peripheral) analgesic techniques. By considering patients’
preferences and an individualized assessment of the risks and benefits of
each treatment modality, the clinician can optimize the analgesic regimen
for each patient. Essential aspects for postoperative monitoring for patients
receiving various postoperative analgesic treatment methods are listed in
Table 51.1.

TABLE 51.1 Monitoring and Documentation of Postoperative

2644
 Analgesia
Analgesic Medicationa
Name, concentration, and dose of drug
Settings of PCA device: demand dose, lockout interval, continuous infusion
Limits set (e.g., 1-h limits on dose administered)
Supplemental or breakthrough analgesics
Routine Monitoring
Amount of drug administered including number of unsuccessful and successful doses
Vital signs: temperature, heart rate, blood pressure, respiratory rate, 0–10 pain score
Analgesia
Pain at rest and with activity, percent pain relief
Use of breakthrough medication
Common Side Effects
Cardiovascular: hypotension, bradycardia, or tachycardia
Pulmonary: respiratory rate
Gastrointestinal: nausea and vomiting, pruritus, urinary retention
Neurologic: motor and sensory function, level of sedation
Instructions Provided
Treatment of side effects
Parameters for triggering notification of covering physician
Contact information should be provided (24 h/7 d per week) if problems occur
Emergency analgesic treatment if PCA device fails
aPostoperativeanalgesia includes systemic opioids and regional analgesic techniques. This list
incorporates some of the important elements of preprinted orders, documentation, and
intravenous PCA and epidural analgesia daily care described in the American Society of
Anesthesiologists Practice Guidelines for Acute Pain Management.
CNS, central nervous system; PCA, patient-controlled analgesia.

SYSTEMIC ANALGESIC TECHNIQUES

Opioids
Opioid analgesics are the gold standard treatments for postprocedural,
traumatic and acute medical pain. These agents generally exert their
analgesic effects through µ-opioid receptors in the CNS and the periphery
following an inflammatory injury, including surgical incision.52 A
theoretical advantage of full agonist opioid analgesics is that there is no
analgesic ceiling. Another advantage is that opioids may be administered
multiple routes including subcutaneous, transcutaneous, transmucosal, and
intramuscular (IM) routes. Opioids also may be administered at specific
anatomic sites such as the intrathecal (subarachnoid) or epidural space (see

2645
“Single-Dose Neuraxial Opioids” and “Continuous Epidural Analgesia”
sections in the following text). Unfortunately, the effectiveness of opioids
is limited by side effects including nausea, vomiting, sedation, or, the most
concerning, respiratory depression. The repetitive use of opioids may
induce the development of tolerance.
The most common routes of systemic opioid analgesic administration in
the acute pain setting are oral, intravenous (IV), and IM. Commonly,
parenteral administration of medications is necessary in the acute pain
setting because the patient is unable to tolerate oral intake. Possible
parenteral routes of administration include IV, IM, transdermal, and
iontophoretic/transdermal (ITD). The treatment of moderate to severe
acute pain often requires rapid and reliable onset of analgesia. To achieve
this, the preferred medication route has traditionally been IV or IM. The
development of ITD fentanyl and the validation of its efficacy in
postoperative patients may expand the parenteral administration
possibilities53 but do pose a risk of misuse and diversion. Traditional
transdermal fentanyl is not ideal for the use in the acute pain setting
because of its slow onset of analgesia and less predictable absorption and
pharmacokinetics in the postoperative recovery period. The full analgesic
benefit of this medication can be up to 24 to 36 hours after application to
the skin. The other important criterion for acute pain management includes
reliable and predictable analgesia. Unfortunately, there is wide intersubject
and intrasubject variability in serum concentration and analgesic response
after systemically administered opioids in the treatment of postoperative
pain.54 The IM route of administration may result in a wider variability
than the IV route and therefore may be a less ideal alternative. However,
because it possesses a rapid onset time, it may be the best alternative to
those who do not have immediate IV access.
The transition from parenteral to oral administration of opioids usually
occurs after the patient can tolerate oral intake and his or her pain has been
stabilized with parenteral opioids. The conversion from IV or IM
medications can be performed by converting the parenteral opioid into the
24-hour “parenteral morphine equivalents” (PME) and converting this into
the oral equivalent of the short- and long-acting opioid of choice. The
division of long-acting versus short-acting medications is highly dependent

2646
on the patient, the nature of the pain, the diurnal variation of the pain, but a
general rule is 50% of the daily requirement can be provided as a sustained
preparation and 50% as an immediate release breakthrough preparation.
Numerous “standard” tables exist for these conversions that are based on
pharmacokinetic data and physician experience. Other sources of
conversion tables or calculators are available including Washington State
Agency Medical Directors’ Group Calculator,55 the Hopkins Opioid
Program,56 and on mobile applications from the Centers for Disease
Control and Prevention57 or in tabular form (Tables 51.2 and 51.3).

TABLE 51.2 Guidelines for Equianalgesic Dosing of Opioid

Agonists in Milligrams
Parenteral (IV, SC,
Medication IM) Oral Transdermal
Codeinea 125 200 NA
Fentanyl 12.5 µg/h NA 12.5 µg/hb
Hydrocodone NA 30–60 NA
Hydromorphone 0.5–1.5 3–6 NA
Levorphanol 2 4 NA
Methadone (opioid 1–10 2–20 NA
naive)c
Morphine 10 30 NA
Oxycodone NA 20 NA
Oxymorphone NA 10 NA
Tramadol NA 300 NA
NOTE: Equianalgesic doses are approximate and are intended to serve only as an estimate of opioid
requirements. Actual doses may vary, in part because of wide interpatient variability in response
to opioids. Doses should be individualized and gradually titrated to effect.
a
Not recommended due to allelic variation of CYP2D6 leading to unpredictable, slow to ultrarapid,
metabolism.
b
Not recommended for acute postoperative pain management.
c
Methadone conversion is dependent on starting dose of morphine equivalent secondary to atypical
pharmacokinetics and dynamics and is not recommended for acute pain management.
IM, intramuscular; IV, intravenous; NA, not applicable; SC, subcutaneous.

TABLE 51.3 Methadone Conversion Based on Patient History of

Opioid Consumption
Current Oral Morphine Equivalent (OME)
(mg) Methadone Equianalgesic Conversion (mg)

2647
 <100 OME / 4
101–300 OME / 8
301–600 OME / 10
601–800 OME / 12
801–1,000 OME / 15
>1,000 OME / 20

Tramadol
Tramadol is a synthetic opioid that exhibits weak µ-agonist activity and
inhibits reuptake of norepinephrine and serotonin. Although tramadol
exerts its analgesic effects primarily through central mechanisms, it may
exhibit peripheral local anesthetic properties.58 Tramadol is effective for
treating moderate postoperative pain and comparable in analgesic efficacy
to aspirin (650 mg) and acetaminophen (1,000 mg) (Table 51.4). The
advantages of tramadol for mild to moderate acute pain treatment include
the relative lack of respiratory depression, major organ toxicity, or
depression of gastrointestinal motility, and it has a low potential for
abuse.59 Common side effects with an overall incidence ranging from
1.6% to 6.1% include dizziness, drowsiness, sweating, nausea, vomiting,
dry mouth, and headache.60 It is metabolized in the cytochrome P450
system via CYP2D6 and CYP3A4. It is, therefore, subject to the same risk
of variable metabolism as codeine due to genetic differences in the
CYP2D6 alleles. As a result of the CYP3A4 metabolism, it should be used
with caution in patients with seizures or increased intracranial pressure and
in those taking monoamine oxidase inhibitors or serotonin reuptake
inhibitors, including most antidepressants.61

Nonsteroidal Anti-inflammatory Agents

Nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin,
ibuprofen, and naproxen exert their analgesic effect through the inhibition
of the cyclooxygenase (COX) and synthesis of prostaglandins (PG). COX
enzymes and PGs are important inflammatory mediators and may play an
important role in the generation and maintenance of peripheral and central
sensitization. Nonselective NSAIDs inhibit both COX-1 and COX-2
enzymes and thereby decrease the production of prostaglandin E2 (PGE2)
and other PGs derived from arachidonic acid. PGs act at peripheral as well

2648
as central sites to alter nociceptive thresholds.61 For example,
administration of PGE2 directly into the hind paw62 or onto the spinal
cord63 of animals produces peripheral edema and hyperalgesia. Several
studies have highlighted the importance of a peripheral site of action for
NSAIDs. Administration in the periphery of monoclonal antibodies to
PGE2 is associated with a decrease in paw edema and hyperalgesia.64
More recently, studies have highlighted a central component for NSAID
action. In the spinal cord, PGE2 can act presynaptically to increase the
release of glutamate from primary afferent C fibers63,65 and
postsynaptically to directly excite dorsal horn neurons by activation of
nonselective cation currents.66 Both effects promote the development and
maintenance of central sensitization and enhanced pain states. The
systemic administration of NSAIDs reduces inflammation and the
behavioral correlate of central/peripheral sensitization and hyperalgesia.67
NSAIDs provide effective analgesia for mild to moderate acute pain and
are a useful supplement to opioids for treatment of moderate to severe
pain. The NSAID may provide some opioid-sparing properties through an
additive or synergistic analgesic effect. NSAIDs such as ketorolac, which
can be administered either orally or parenterally, are considered an integral
part of a multimodal analgesic regimen by producing analgesia through
different mechanisms than opioids or local anesthetics. As with opioids,
NSAIDs by themselves do not appear to have a significant impact on
mortality or major morbidity when compared to other analgesic agents.
However, NSAIDs may improve analgesia and patient-oriented outcomes
(e.g., satisfaction and quality of life) in part by reducing opioid analgesic
requirements, decreasing opioid-related side effects, and facilitating
patient recovery.68,69 When given in addition to systemic opioids, NSAIDs
will improve postoperative analgesia and reduce opioid requirements by
up to 50%, which may reduce some opioid-related side effects including
nausea and sedation. However, not all studies note a decrease in opioid-
related side effects with concurrent NSAID use.70
An analgesic benefit of aspirin over placebo has been shown for the
650-mg and 1,000-mg doses (see Table 51.4). The number of patients
needed to treat for at least a 50% reduction in pain (number needed to treat
[NNT]) was 4.4 (4.0 to 4.9) and 4.0 (3.2 to 5.4), respectively. Single-dose

2649
aspirin (650 mg) produced significantly more drowsiness and gastric
irritation than placebo, with a number needed to harm (NNH) of 28 (19 to
51) and 38 (22 to 174), respectively. The authors also found that the type
of pain model, pain measurement, sample size, quality of study design, and
study duration had no significant impact on the results.71 Similar NNT
were obtained for naproxen 400 to 500 mg in postoperative patients.72,73
The COX-2 selective inhibitor, celecoxib, when given at 200 mg has an
NNT of 4.5 when compared to placebo in postoperative patients.74 Neither
naproxen nor celecoxib were associated with an increase in adverse events.

TABLE 51.4 Relative Efficacy of Single-Dose Oral Analgesics

Medication NNTa 95% CI
Aspirin (650 mg) 4.4 4.0–4.9
Aspirin (1,000 mg) 4.0 3.2–5.4
Ibuprofen (400 mg) 2.7 2.5–3.0
Ibuprofen (600 mg) 2.4 1.9–3.3
Diclofenac (50 mg) 2.3 2.0–2.7
Ketorolac (10 mg) 2.6 2.3–3.1
Celecoxib (200 mg) 3.5 2.9–4.4
Celecoxib (400 mg) 2.1 1.8–2.5
Acetaminophen (650 mg) 5.3 4.1–7.2
Acetaminophen (1,000 mg) 3.8 3.4–4.4
Tramadol (50 mg) 7.1 4.6–18.0
Tramadol (100 mg) 4.8 3.4–8.2
Codeine (60 mg) 9.1 6.0–23.4
Oxycodone (15 mg) 2.4 1.5–4.9
Codeine (60 mg) + acetaminophen (650 mg) 3.6 2.9–4.5
Codeine (60 mg) + acetaminophen (1,000 mg) 2.2 1.7–2.9
Oxycodone (5 mg) + acetaminophen (325 mg) 2.5 2.0–3.2
CI, confidence interval; NNT, number needed to treat.
a
NNT in this case refers to the number of patients who must be treated to obtain more than 50%
pain relief for moderate to severe postoperative pain. NNT conveys statistical and clinical
significance, is useful to compare treatment efficacy for different interventions, and summarizes
treatment effects in a clinically relevant way. A lower mean NNT implies greater analgesic
efficacy in this example.

NSAIDs will affect osteoblastic and clastic activity in animal studies,75

and whether NSAIDs inhibit bone healing clinically is not certain. The
quality of the available literature is suboptimal, but several systematic
reviews have been conducted. In one meta-analysis of case-control and

2650
cohort studies,76 a significant association between lower quality studies
and higher reported odds ratios for nonunion was observed; however, there
was no increased risk of nonunion with NSAIDs when only the highest
quality studies were utilized. In another meta-analysis,77 short-time (<14
days) exposure to NSAIDs in lower/normal doses were not associated with
disunion after spinal fusion but exposure to higher dose ketorolac was
associated with an increased risk of nonunion.
Acetaminophen is commonly used for acute pain management as an
alternative to NSAIDs, but its site of action at the molecular level is still
controversial and not well defined. There are, however, some lines of
evidence supporting its role in the inhibition of COX. Acetaminophen has
been demonstrated to inhibit a variant of COX-2 enzymes in vivo78 and be
similar to the COX-2 selective inhibitors: It inhibits prostaglandin
synthesis in intact cells at low concentrations of added arachidonic acid
further suggesting that it may inhibit COX-2 function.79 It has also been
suggested that the molecular target of acetaminophen is a splice variant of
COX-1, named as COX-3,80 but its low expression level and activity
suggests that this selective interaction is unlikely to be clinically
relevant.81 This suggests that acetaminophen inhibits COX-2 activity in
vivo and that its analgesic effect may be a function of decreased peripheral
PGE2 synthesis in addition to centrally mediated analgesic effects of
acetaminophen on descending serotoninergic pathways.82
Acetaminophen is very effective in the treatment of acute pain,
especially that of postprocedural pain. The number of patients needed to
treat for at least a 50% reduction in pain over 4 to 6 hours (NNT) for 1,000
mg of acetaminophen is 4.4, which is similar to that of 650 mg of aspirin
or 100 mg of ibuprofen.83 However, it was less effective than higher dose
ibuprofen (400 mg) or diclofenac (50 mg) with NNTs of 2.3 and 2.4,
respectively. Fortunately, acetaminophen is rarely associated with adverse
effects in the short term; however, it is associated with hepatotoxicity after
chronic use or overdose. In countries, outside of the United States, IV
propacetamol, the prodrug of acetaminophen or acetaminophen itself is
administered to postoperative patients who are not able to tolerate oral
analgesics. In clinical trials conducted in patients with moderate to severe
pain after orthopedic and gynecologic surgery, the analgesic efficacy of

2651
propacetamol was similar to that of NSAIDs.84,85 Although providing fast
and significant pain relief as well as a significant opioid-sparing
effect,84–86 it is not associated with the increased incidence of nausea,
vomiting, and respiratory depression observed with opioids or the
deleterious gastrointestinal, hematologic, cardiovascular, and renal effects
associated with NSAIDs and selective COX-2 inhibitors. Lack of
inhibition of COX-1 peripherally by acetaminophen may explain its
favorable safety effect.87 These results have been replicated with IV
acetaminophen in patients recovering from major orthopedic surgery.88 In
the patient who is able to tolerate oral acetaminophen and has normal
gastrointestinal absorption, there is likely minimal additional benefit of IV
acetaminophen over the oral equivalent.

Excitatory Amino Acids

The excitatory amino acid neurotransmitter, glutamate, has a central role in
the transmission of nociceptive signals from the periphery to the
supraspinal structures and in the modulation of those signals in brainstem
and spinal cord through descending bulbospinal tracts. The NMDA
receptor, in particular, has been shown to have a crucial role in the
development of persistent pain states including neuropathic pain.89
Although this receptor represents an obvious target to produce analgesia,
pharmacologic antagonism has met with little clinical success. IV
administration of the NMDA antagonist ketamine produced a reduction in
neuropathic pain; however, this came at the cost of high incidence of side
effects.90 Ketamine has had better results in the treatment of cancer pain as
both a direct analgesic and by improving opioid-based analgesia.91,92
Clinical trials of dextromethorphan and memantine have failed to show
any beneficial effect when compared to placebo.93,94 The role of NMDA
antagonists in acute postprocedural or posttraumatic pain has met with less
disappointing but somewhat mixed results. In one study, the addition of a
single low-dose ketamine (0.25 mg/kg) administration to postoperative
pain management with morphine was not found to be beneficial.95
However, the use of low-dose (subanesthetic doses) infusions of ketamine
has been successfully used to reduce morphine requirements, need for
rescue analgesia and pain scores in patients recovering from abdominal

2652
surgery, spine, orthopedic surgery, and trauma.96–100 In a recent meta-
analysis, the inclusion of ketamine to a postoperative analgesic regimen
improved pain relief and resulted in lower opioid requirement without
adding adverse events.101

Anticonvulsants
Anticonvulsants, including gabapentin, carbamazepine, lamotrigine, and
pregabalin, have traditionally used for the treatment of chronic neuropathic
conditions. Gabapentin is an anticonvulsant that was developed as a
spasmolytic and adjunct for the treatment of generalized or partial epileptic
seizures resistant to conventional therapies. Although it was originally
designed as a structural analog of the inhibitory neurotransmitter GABA, it
does not bind to GABA receptors, and the mechanism of action of this
class of drugs is not fully understood.102 It is likely that its analgesic
effects result from an action at the α2δ1 accessory unit of voltage-
dependent Ca2 channels for which it has substantial affinity103 and which
are upregulated in the dorsal root ganglia and spinal cord after peripheral
nerve injury104 as can be produced by surgical incision.105,106 Gabapentin
may produce analgesia by binding to and inhibiting presynaptic voltage-
dependent Ca2 channels, decreasing calcium influx and thereby inhibiting
the release of neurotransmitters including glutamate from the primary
afferent nerve fibers that synapse on and activate pain responsive neurons
in the spinal cord.107
In clinical studies, several open-label single-center and multicenter,
double-blind trials established that gabapentin was also effective for the
treatment of chronic pain conditions, including postherpetic neuralgia,
diabetic neuropathy, central pain, phantom pain, malignant pain,
trigeminal neuralgia, and HIV-related neuropathy, which may be difficult
to treat with more conventional therapies.108–113 The role of gabapentin in
the treatment of acute pain is more controversial. Although in animal and
human models of acute pain the administration of gabapentin or pregabalin
produces no analgesia, when it is administered prior to a variety of surgical
procedures, patients report decreased pain and decreased opioid use
postoperatively.48,114,115 Gilron et al.116 showed synergism between
gabapentin and morphine in patients suffering from neuropathic pain. This

2653
synergistic effect may have played a role in the decreased pain scores of
those receiving gabapentin because concomitant opioids were routinely
administered in the postoperative period. Pregabalin and gabapentin have
not been found to be effective in the treatment of acute chemotherapy-
induced pain.117 Pregabalin was not found to have a benefit in the
treatment of acute sciatica pain.118 Therefore, with the exception of the
well-documented effectiveness of carbamazepine in the treatment of the
acute exacerbation of trigeminal neuralgia, there is no evidence for the
effectiveness of anticonvulsants in the treatment of acute pain not related
to an operation or trauma.

α-Adrenergic Medications
α-Adrenergic receptors are widely distributed throughout the CNS and
peripheral nervous system (PNS). The α1 receptors play an essential role in
the regulation of vascular tone but no significant role in nociception.
Activation of α2 receptors produces analgesia. They are linked to an
inhibitory G protein on the presynaptic terminus of Aδ and C fibers and
are activated by descending noradrenergic tracts from the brainstem LC
and A7, which hyperpolarizes the primary afferent and reduces afferent
transmitter release and pain transmission. However, depending on the α2
receptor subtype 2a, 2b, or 2c, different physiologic consequences may
occur. The α2b subtype produces hemodynamic responses (hypotension),
whereas the α2a receptor is responsible analgesia.119,120 Clonidine is the
prototypic α2 agonist used for analgesia, although it has substantial
hemodynamic side effects because of its lack of absolute α subtype
selectivity. A newer agent, dexmedetomidine, is a more selective α2
receptor agonist that is analgesic and sedating with fewer cardiovascular
effects.121,122
In experimental models of acute transient pain, systemically
administered clonidine had no analgesic benefit.123 In studies of
postoperative patients, IV clonidine has been found to augment the local
anesthetic block of the psoas compartment for hip surgery.124 However,
the benefit was short lived and provided approximately 7 hours of
additional analgesia. Preoperative and perioperative administration of

2654
systemic clonidine has been found to have a very modest analgesic (and
anxiolytic) effect following abdominal hysterectomy.125,126 Perioperative
use of systemic clonidine has been found to reduce overall opioid
requirements following spinal surgery when given as a bolus of 3 µg/kg
and followed by an infusion of 0.3 µg/kg/hour; however, modest changes
in blood pressure and heart were also noted.127
Dexmedetomidine, although more selective for α2 receptors and more
subtype selective (α2a), does not produce significant analgesia in human
experimental models of acute heat or electrical pain at doses that produce
modest to severe sedation.128 In one study, dexmedetomidine infusion
reduced healthy volunteer’s cold pressor–induced pain by 30% at doses
that produced sedation and memory loss but did not produce hemodynamic
perturbations.121 Preoperative administration of dexmedetomidine reduced
postoperative opioid consumption but had no effect on postprocedure pain
scores or recovery time.129 Perioperative administration reduces opioid
requirements after thoracotomy130 and tubal ligation131 but resulted in
significant sedation and heart rate instability in some patients.

Steroids
Glucocorticoids are commonly used as prophylaxis for postoperative
nausea and vomiting, but these agents may also produce an analgesic
effect. Glucocorticoids may reduce acute pain in a variety of mechanisms
including a reduction in inflammation and tissue damage. A recent meta-
analysis examined the analgesic efficacy of a single perioperative dose of
dexamethasone. Patients who received dexamethasone had lower pain
scores, used less opioids, required less rescue analgesia for intolerable
pain, had longer time to first dose of analgesic, and had shorter stays in the
postanesthesia care unit.132 There was no increase in infection or delayed
wound healing with dexamethasone despite the finding that but blood
glucose levels were higher 24 hours postoperatively. On the other hand,
another meta-analysis in thyroidectomy patients133 found that a single
preoperative dose of dexamethasone did not decrease the incidence and
severity of pain postoperatively. A meta-analysis of studies examining the
addition of dexamethasone (4 to 10 mg) to local anesthetics for peripheral
nerve blocks noted a faster onset of action and significant increase in the

2655
duration of analgesia with the addition of dexamethasone compared with
local anesthetic solutions alone.134

Serotoninergic Medications
Serotoninergic receptors found in the spinal dorsal horn have a complex
relationship to the modulation of nociceptive transmission. Three of the
subtypes of serotoninergic receptors play a role in nociceptive
transmission, 5-HT1 and 5-HT2 hyperpolarize neurons within the dorsal
horn and inhibit pain transmission, whereas 5-HT4 receptors depolarize
dorsal horn neurons and augment the transmission of nociceptive
information.135 Presynaptic terminals of descending neurons from the
RVM appear to oppose 5-HT1 and 5-HT2 receptors of primary afferents
and interneurons in the spinal cord producing a reduction in pain like
behavior in animals following activation of the RVM. Unfortunately, no
subtype-specific serotoninergic agonists are available for human use for
analgesia. Interestingly, a recent study found that activation of the 5-HT4
receptor in the brainstem eliminates the respiratory depression associated
with administration the opioid fentanyl,136 thus having an indirect but very
beneficial effect on the treatment of pain.
The only clinically available serotonergic agonists or indirect
serotoninergic agonists consist of the selective serotonin reuptake
inhibitors (SSRIs) that are primarily used for the treatment of depression
and anxiety disorders. Unfortunately, the data regarding the use of SSRIs
in acute pain are lacking or negative. The lack of clinical studies assessing
the analgesic value of this class is likely due to the lack of analgesic
benefit of this class of drugs in the treatment of chronic pain.137

NONSELECTIVE NORADRENERGIC AND

SEROTONINERGIC MEDICATIONS
Although the group of nonselective noradrenergic and serotoninergic
reuptake inhibitor medications, the tricyclic antidepressants (TCAs), does
not carry a U.S. Food and Drug Administration indication for pain, they
are a mainstay of treatment of a variety of neuropathic and nonneuropathic
chronic pain states. TCAs suppress nociceptive transmission independent
of their effects on depressed affect in the psychological domain. The exact

2656
mechanism of analgesic action remains unclear. As a class of agents,
TCAs act to inhibit the reuptake and destruction or storage of biogenic
amines including norepinephrine and serotonin. One possible mechanism
is the accentuation of the descending serotoninergic and noradrenergic
bulbospinal pathways on the spinal cord dorsal horn, by acting locally on
5-HT1, 5-HT2, and α2 receptors. Interestingly, SSRIs have little if any
analgesic potential138; yet, the TCAs with the greatest pain relieving
effects have their greatest inhibition of serotonin reuptake.139 Alternate
mechanisms including histamine receptor blockade,140 calcium channel
blockade,141 antagonism of the NMDA receptor,142 anti-inflammatory
effects,143 and blockade of sodium channels144 have been suggested.
The results for TCAs in experimental models of acute pain are
somewhat mixed. The secondary amine, desipramine, which has the
greatest norepinephrine reuptake inhibitor selectivity, has no effect on pain
scores in a capsaicin-induced mechanical allodynia model.145 In contrast,
imipramine the tertiary amine precursor to desipramine produced a
reduction in pain resulting from noxious stimulation of the nasal
mucosa.146 A single study found that the administration of the tertiary
tricyclic amine, amitriptyline, during the acute stage of herpes zoster
decreased the prevalence of postherpetic neuralgia.147 TCAs have not been
found to be effective in the treatment of postoperative pain.148–150
The role of the selective serotonin and norepinephrine reuptake
inhibitors, duloxetine and venlafaxine, has not been fully elucidated. Like
the TCAs, these drugs have been used successfully to treat chronic pain
conditions. However, in the acute postoperative setting, the results are
mixed. A recent randomized controlled trial (RCT) examining the
perioperative administration of duloxetine found a decrease in
postoperative pain and opioid consumption following spine surgery151 and
hysterectomy,152 however was ineffective following knee arthroplasty.153
Another selective serotonin-norepinephrine reuptake inhibitor (SSNRI),
venlafaxine has similarly mixed results for postoperative pain.154 The
atypical antidepressant bupropion has not been investigated in trials of
acute pain; however, it is not effective in the treatment of mechanical
chronic back pain.155

2657
INTRAVENOUS PATIENT-CONTROLLED ANALGESIA
Various factors, including the interpatient and intrapatient variability in
analgesic needs, variability in serum drug levels (especially with IM
injections), and administrative delays, may contribute to inadequate
postoperative analgesia. There may be difficulty in compensating for these
factors with the use of a traditional PRN analgesic regimen. By
circumventing some of these issues, IV patient-controlled analgesia
(IVPCA) optimizes delivery of analgesic opioids and minimizes the effects
of pharmacokinetic variability among individual patients. IVPCA is based
on the premise that a negative feedback loop exists, when pain is
experienced, analgesic medication is self-administered, and when pain is
reduced, there are no further demands. When the negative feedback loop is
violated, excessive sedation or respiratory depression may occur.156
Although some equipment-related malfunctions have been reported, the
PCA device itself is relatively free of problems, and most problems related
to PCA use result from user or operator errors.156
A PCA device can be programmed for several variables, including the
demand (bolus) dose, lockout interval, and background infusion (Table
51.5). The optimal demand or bolus dose is integral to IVPCA analgesic
efficacy because an insufficient demand dose may result in inadequate
analgesia, whereas an excessive demand dose may result in a higher
incidence of undesirable side effects such as respiratory depression.157
Although the optimal demand dose is uncertain, available data suggest that
the optimal demand dose for morphine is 1 mg and that for fentanyl is 40
µg for opioid-naive patients; however, the actual dose for fentanyl is often
less in clinical practice.156,157 The lockout interval may also affect the
analgesic efficacy of IVPCA and is a safety feature of IVPCA. Although
the optimal lockout interval is unknown, most intervals range from 5 to 10
minutes, and varying the interval within this range appears to have no
effect on analgesia or side effects.156 Most PCA devices allow the addition
of a continuous or background infusion in addition to the demand dose.
Initially, routine use of a background infusion was thought to confer
certain advantages, including improved analgesia especially during sleep;
however, subsequent trials failed to demonstrate any analgesic benefits of
a background infusion in opioid-naive patients.158 Although the routine

2658
use of continuous or background infusions in IVPCA in adult opioid-naive
patients is not recommended, there may be a role for use of a background
infusion for opioid-tolerant or pediatric patients. A Cochrane database
meta-analysis revealed that IVPCA (compared to PRN opioids) provided
significantly greater analgesia and patient satisfaction; however, patients
who had IVPCA used more opioids with a higher incidence of pruritus but
no difference in the incidence of other adverse events compared to PRN
opioids.159

2659
 TABLE 51.5 Intravenous Patient-Controlled Analgesia Regimens
for Acute Pain
Lockout
Interval
Medication Pharmacodynamics Bolusa (min)
Morphine µ-Opioid receptor 0.5–2.5 mg 5–10
agonist
Fentanyl µ-Opioid receptor 10–20 µg 5–10
agonist
Hydromorphone µ-Opioid receptor 0.5–0.25 mg 5–10
agonist
Alfentanil µ-Opioid receptor 0.1–0.2 mg 5–8
agonist
Sufentanil µ-Opioid receptor 2–5 µg 4–10
agonist
Methadone µ-Opioid receptor 0.5–2.5 mg 8–20
agonist
NMDA receptor
antagonist
Meperidine µ-Opioid receptor 5–25 mg 5–10
agonist
Oxymorphone µ-Opioid receptor 0.2–0.4 mg 8–10
agonist
Buprenorphine µ-Opioid receptor partial 0.03–0.1 mg 8–20
agonist
κ-Opioid receptor
antagonist
Nalbuphine µ-Opioid receptor 1–5 mg 5–15
antagonist
κ-Opioid receptor
agonist
Pentazocine µ-Opioid receptor 5–15 mg 5–15
antagonist
κ-Opioid receptor
agonist
aAll
doses are for adult patients. The anesthesiologist should proceed with titrated intravenous
loading doses if necessary to establish initial analgesia. Individual patient’s requirements vary
widely, with smaller doses typically given for elderly or compromised patients. Continuous
infusions are not initially recommended for opioid-naive adult patients.
NMDA, N-methyl-D-aspartate.

The incidence of opioid-related adverse events from IVPCA does not

appear to differ significantly from that administered intravenously,

2660
intramuscularly, or subcutaneously. The rate of respiratory depression
associated with IVPCA is low (<0.5%) and does not appear to be higher
than that with systemic or neuraxial opioids.160,161 Factors that may be
associated with occurrence of respiratory depression with IVPCA include
use of a background infusion, advanced age, concomitant administration of
sedative or hypnotic agents, and coexisting pulmonary disease such as
sleep apnea.160,161

REGIONAL ANALGESIC TECHNIQUES

A variety of neuraxial and peripheral regional analgesic techniques may be
employed for the effective treatment of acute pain. Many these techniques
were initially developed for the management of acute postoperative pain;
however, their application is appropriate for the treatment of any severe
acute pain. In general, epidural and peripheral techniques when local
anesthetics are used can provide superior analgesia compared with
systemic opioids,162 and use of these techniques may even reduce
morbidity and mortality in the postoperative population.11,12 However,
there are risks associated with the use of these techniques, and a risk
versus benefit analysis of these techniques should be performed on an
individual basis to determine the appropriateness of neuraxial or peripheral
regional techniques for each patient, especially in light of some of the
controversies about the use of these techniques in the presence of
anticoagulation.

Single-Dose Neuraxial Opioids

A single dose of opioid may provide significant analgesia when
administered as a sole or adjuvant analgesic agent when administered
intrathecally or epidurally. One of the most important factors in
determining the clinical pharmacology for an opioid is its degree of lipid
solubility. Once inside the cerebrospinal fluid (CSF) through direct
intrathecal injection or gradual migration from the epidural space,
hydrophilic opioids (i.e., morphine and hydromorphone) tend to remain
within the CSF and produce a delayed but longer duration of analgesia
along with a generally higher incidence of side effects due to its cephalad
spread. Neuraxial administration of lipophilic opioids, such as fentanyl and

2661
sufentanil, tends to provide rapid onset of analgesia, and the rapid
clearance from the CSF may limit cephalad spread and development of
certain side effects such as delayed respiratory depression but not
pruritus.163 The site of analgesic action for hydrophilic opioids is
overwhelmingly spinal, but the primary site of action (spinal vs. systemic)
for single-dose neuraxial lipophilic opioids is not as certain.164
The differences in pharmacokinetics between lipophilic and hydrophilic
opioids may influence the choice of opioid to optimize analgesia and
minimize side effects for a clinical situation. Single-dose intrathecal
administration of a lipophilic opioid may be useful in situations (e.g.,
ambulatory surgical patients) in which rapid analgesic onset (minutes)
combined with a moderate duration of action (<4 hours) and minimal risk
of respiratory depression is needed.165 Single-dose hydrophilic opioid
administration provides effective postoperative analgesia and may be
useful in patients monitored on an inpatient basis for which a longer
duration of analgesia would be beneficial.
Single-dose epidural administration of lipophilic and hydrophilic
opioids is used to provide analgesia, with considerations generally like
those discussed with single-dose intrathecal administration of opioids. A
single bolus of epidural fentanyl may be administered to provide rapid
postoperative analgesia; however, diluting the epidural dose of fentanyl
(typically 50 to 100 µg) in at least 10 mL of preservative-free normal
saline is suggested to decrease the onset and prolong the duration of
analgesia, possibly as a result of an increase in the initial spread and
diffusion of the lipophilic opioid.166 Single-dose epidural morphine is
effective for postoperative analgesia and may decrease postoperative
patient morbidity in selected patients.167,168 Use of a single-dose
hydrophilic opioid may be especially helpful in providing postoperative
epidural analgesia when the epidural catheter’s location is not congruent
with the surgical incision (e.g., lumbar epidural catheter for thoracic
surgery). Lower doses of epidural morphine may be required for elderly
patients and thoracic catheter sites. Commonly used dosages for intrathecal
and epidural administration of neuraxial opioids are provided in Table
51.6.

2662
 TABLE 51.6 Recommended Dosage for Neuraxial Administration
of Opioids
Intrathecal Single Epidural Continuous
Medication Dose Epidural Single Dose Infusion
Fentanyl 5–25 µg 50–100 µg 25–100 µg/h
Morphine 0.1–0.3 mg 1–5 mg 0.1–1 mg/h
Morphine-extended Not recommended 5–15 mg Not recommended
release
Hydromorphone 0.005–0.1 mg 0.5–1 mg 0.1–0.2 mg/h
Sufentanil 2–10 µg 1–50 µg 10–20 µg/h
Alfentanil Not recommended 0.5–1 mg 0.2 mg/h
Methadone Not recommended 4–8 mg 0.3–0.5 mg/h
NOTE: Doses are approximate and based on the use of the neuraxial opioid alone. No continuous
intrathecal infusions are provided. Lower doses may be effective when administered to elderly
patients. Units vary across medications for single dose (µg vs. mg) and continuous infusions
(µg/h vs. mg/h).

An extended-release formulation of (single-dose) epidural morphine

(DepoDur) encapsulated within liposomes resulting in up to 48 hours of
analgesia is available.169 The greatest benefit of liposomal morphine is its
extended-release formulation and the prolonged duration of effect that may
be important with the increasing use of long-acting low molecular weight
heparin medications for postoperative patients for thrombosis prophylaxis.
Liposomal morphine exhibits not only a dose-dependent increase in
analgesia but, unfortunately, also a dose-dependent increase in adverse
events including respiratory depression. This formulation is used
infrequently, and therefore, no long-term data have been developed
looking at patient outcomes including overall adverse event rates or any
reduction in thrombosis rates as compared to traditional epidural catheter-
based long-term management. As with traditional single-dose neuraxial
opioids, clinicians should provide a lower dose of liposomal extended-
release morphine in the elderly or those with decreased physiologic reserve
or coexisting diseases, and liposomal extended-release morphine has not
been approved for use in pediatric patients.

Continuous Epidural Analgesia

Analgesia delivered through an indwelling epidural catheter is a generally
safe and effective method for management of acute pain.170 Postoperative

2663
epidural analgesia can provide superior analgesia compared with systemic
opioids.171

Epidural Medications
Epidural infusions of local anesthetic alone may be used for postoperative
analgesia, but in general, they are not as effective in controlling pain as
local anesthetic–opioid epidural analgesic combinations.171 The rationale
for using local anesthetic only epidural infusions has been to avoid the side
effects of epidural opioids. Traditionally, this practice has resulted in
inadequate analgesia and relatively high incidence of motor block and
hypotension although utilizing lower concentration of local anesthetics
may ameliorate some of the negative effects.
Opioids may be used alone for postoperative epidural infusions in order
to avoid the motor block or hypotension from local anesthetic–induced
sympathetic blockade.170 This advantage might be desirable in patients
following abdominal aortic aneurysm operations as well as surgery with
large fluid shifts in patients with significant cardiac or cerebrovascular
disease. There are differences between continuous epidural infusions
(CEIs) of lipophilic (e.g., fentanyl, sufentanil) and hydrophilic (e.g.,
morphine, hydromorphone) opioids. The analgesic site of action (spinal vs.
systemic) for CEIs of lipophilic opioids is not clear, although several
randomized clinical trials suggest that it is systemic172 because there were
no differences in plasma concentrations, side effects, or pain scores
between those who received IV or epidural infusions of fentanyl. Although
some data suggest a benefit from epidural of lipophilic opioids when
compared to IV administration,173 the overall advantage of administering
CEIs of lipophilic opioids alone is marginal at best. Hydrophilic opioids
are quite different because of their relative lack of diffusion into the
systemic circulation; the primary site of their analgesic action is spinal.172
Hydrophilic opioids can distribute throughout the CSF; therefore, the
continuous infusion of these opioids may be especially useful for
providing postoperative analgesia when the site of catheter insertion is not
congruent with the site of surgery. CEIs of hydrophilic opioids provide
superior analgesia compared with traditional PRN administration of
systemic opioids.174

2664
 The combination of local anesthetics and opioids in a CEI may have
advantages over infusions using a local anesthetic or opioid alone.
Compared with a local anesthetic or opioid alone, a local anesthetic–opioid
combination provides superior postoperative analgesia including improved
dynamic pain relief, limits regression of sensory block, and possibly
decreases the dose of local anesthetic administered,175 although the
incidence of side effects may or may not be diminished.170 CEI of a local
anesthetic–opioid combination also provides superior analgesia compared
with IVPCA with opioids.171 It is unclear whether the analgesic effect of
the local anesthetic and opioid in the epidural analgesia is additive or
synergistic. Experimental studies demonstrate a synergistic effect between
local anesthetics and opioids176; however, clinical trials suggest an
additive effect177 and the lack of improvement in side effects when used in
combination supports the clinical experimental data.
The choice of local anesthetic for CEIs varies. In general, bupivacaine
or ropivacaine over lidocaine is chosen because of the differential and
preferential clinical sensory blockade with minimal impairment of motor
function.178 The concentrations used for postoperative epidural analgesia
(≤0.125% bupivacaine or ≤0.2% ropivacaine) are lower than those used for
intraoperative anesthesia. The choice of opioid also varies, although many
clinicians choose to use a lipophilic opioid (fentanyl, 2 to 5 µg/mL, or
sufentanil, 0.5 to 1 µg/mL) to allow for rapid titration of analgesia.170,172
However, the use of the lipophilic opioid may just provide greater
analgesia than local anesthetics alone; it is not clear whether use of these
highly permeable medications does not simply provide a stable systemic
concentration of opioid. The use of a hydrophilic opioid (morphine, 0.05 to
0.1 mg/mL, or hydromorphone, 0.01 to 0.05 mg/mL) as part of a local
anesthetic–opioid epidural analgesic regimen is more consistent with the
goal of spinal delivery of opioid and also provides effective postoperative
analgesia.172
A variety of adjuvant medications may be added to epidural infusions to
enhance analgesia while minimizing side effects, but none has gained
widespread acceptance. Two of the more studied adjuvants are clonidine
and epinephrine. Clonidine mediates its analgesic effects primarily through
its action at α2 receptors in the spinal cord, and the epidural dose typically

2665
used ranges from 5 to 20 µg per hour.179,180 The clinical application of
clonidine is limited by its side effects: hypotension, bradycardia, and
sedation.179,180 Hypotension and bradycardia are both dose-dependent.
Epinephrine may improve epidural analgesia, can increase sensory block,
and is generally administered at a concentration of 2 to 5 µg/mL,181 but it
is also associated with a worsened motor block.182 Epidural epinephrine
added to local anesthetics is also associated with longer stage 2 labor and
decrease Apgar scores in parturient.182 Epidural administration of NMDA
antagonists, such as ketamine, has been performed on a limited basis.
Lauretti et al.183 found no analgesic benefit when ketamine was added to
the clonidine epidural infusion following orthopedic surgery. This
contrasts with another trial showing a preemptive analgesic benefit of
epidural ketamine prior to a thoracotomy incision.184 The theoretical
explanation for the latter result is that ketamine attenuates the development
of central sensitization and might potentiate the analgesic effect of epidural
opioids. The caveat to this is that the safety of neuraxial ketamine
infusions is controversial and may result in neuronal apoptosis185 and is
therefore should not be used. Further safety and analgesic data are needed
to justify its use.

Side Effects of Neuraxial Analgesic Drugs

Many medication-related (opioid and local anesthetic) side effects can
occur with use of postoperative epidural analgesia. However, before
automatically ascribing the cause to the epidural analgesic regimen, it is
important to first consider other causes of the most common adverse
effects of epidural analgesia; namely, hypotension, respiratory
insufficiency/depression. These can include low intravascular volume,
bleeding, and low cardiac output for hypotension and cerebrovascular
accident, pulmonary edema, and evolving sepsis. Standing orders and
nursing protocols for analgesic regimens, neurologic, hemodynamic, and
respiratory monitoring; treatment of side effects; and physician notification
about critical parameters should be standard for all patients receiving
neuraxial and other types of postoperative analgesia.
Local anesthetics used in an epidural analgesic regimen may block
sympathetic fibers and contribute to postoperative hypotension. Although

2666
the incidence of postoperative hypotension with postoperative epidural
analgesia may be as high as approximately 7%, the average is closer to
0.7% to 3%.186 Strategies to treat noncritical hypotension due to epidural
analgesia include decreasing the overall dose of local anesthetic
administered, or use of opioid-alone epidural because it is unlikely that
neuraxial opioid alone would contribute to postoperative hypotension.170
Use of local anesthetics for postoperative epidural analgesia may also
contribute to lower extremity motor block in approximately 2% to 3% of
patients,186 and this may contribute to development of pressure sores in the
heels.187 A lower concentration of local anesthetics and catheter-incision
congruent placement of epidural catheters for abdominal or thoracic
procedures may decrease the incidence of motor block.188 Although motor
block resolves in most cases after stopping the epidural infusion for
approximately 2 hours, persistent or increasing motor block needs to be
promptly evaluated, and spinal hematoma, spinal abscess, and intrathecal
catheter migration should be considered as part of the differential
diagnosis.
Nausea and vomiting associated with neuraxial administration of a
single-dose opioid occurs in approximately 20% to 50% of patients,189 and
the cumulative incidence among those receiving continuous infusions of
opioids may be as high as 45% to 80%.190 Clinical and experimental data
suggest that the incidence of neuraxial opioid–related nausea and vomiting
is dose-dependent.191 Nausea and vomiting from neuraxial opioids may be
related to the cephalad migration of opioid within the CSF to the area
postrema in the medulla.189 Use of fentanyl alone or in combination with a
local anesthetic in an epidural infusion is associated with a lower incidence
of nausea and vomiting compared with infusions using morphine.190,192 A
variety of agents have been successfully used to treat neuraxial opioid–
induced nausea and vomiting, including naloxone, droperidol,
metoclopramide, dexamethasone, and transdermal scopolamine.193,194
Pruritus is one of the most common side effects of epidural or
intrathecal administration of opioids, with an incidence of approximately
60% compared with about 15% to 18% for epidural local anesthetic
administration or systemic opioids.195 Although the cause of neuraxial
opioid–induced pruritus is uncertain, it does not appear to be associated

2667
with peripheral histamine release but may be related to central activation
of an “itch center” in the medulla or opioid receptors in the trigeminal
nucleus or nerve roots with cephalad migration of the opioid189 or through
the activation of a separate population of primary afferents that mediate
nonhistamine itch.196 It is unclear whether the incidence of neuraxial
opioid–related pruritus is dose-dependent because a quantitative
systematic review195 suggests no evidence of a relationship, whereas other
clinical and experimental studies indicate a significant correlation.197 Use
of an epidural infusion of fentanyl alone or as part of a local anesthetic–
opioid combination appears to be generally associated with a lower
incidence of pruritus compared with morphine.192 A variety of agents have
been evaluated for the prevention and treatment of opioid-induced pruritus.
IV naloxone, naltrexone, nalbuphine, and droperidol appear to be
efficacious for the pharmacologic control of opioid-induced pruritus.195
Although pruritus is a common side effect, it often mild, it is relatively
easy to treat.198
Neuraxial opioids used in appropriate doses are not associated with a
higher incidence of respiratory depression than that seen with systemic
administration of opioids. The incidence of respiratory depression
associated with neuraxial administration of opioids is dose-dependent and
typically ranges from 0.1% to 0.9%.199 The incidence of respiratory
depression with continuous infusions of epidural opioids appears to be no
greater than that seen after systemic opioid administration.199 Although
some institutions require patients with CEIs of hydrophilic opioids to
receive monitoring in an intensive care unit setting, many large-scale trials
have demonstrated the relative safety (incidence of respiratory depression
<0.9%) of this technique on regular hospital wards.200 Neuraxial lipophilic
opioids are thought to cause less delayed respiratory depression than
hydrophilic opioids, although administration of lipophilic opioids may be
associated with significant, early respiratory depression.201 Delayed
respiratory depression is primarily associated with the cephalad spread of
the hydrophilic opioids, which typically occurs within 12 hours after
injection.202 Risks factors for respiratory depression with neuraxial opioids
include increasing dose, increasing age, concomitant use of systemic
opioids or sedatives, and possibly prolonged or extensive surgery,

2668
presence of comorbidities, and thoracic surgery.202 Treatment with
naloxone and airway management, if necessary, is effective in 0.1- to 0.4-
mg increments; however, the clinical duration of action is relatively short
compared with the respiratory-depressant effect of neuraxial opioids, and a
continuous infusion of naloxone (0.5 to 5 µg/kg/hour) may be needed.203
Urinary retention associated with neuraxial administration of opioids is
the result of an interaction with the opioid receptors in the spinal cord that
decreases the detrusor muscle’s strength of contraction.189 The incidence
of urinary retention seems to be higher with neuraxially administered
opioids than that given systemically. Urinary retention does not appear to
depend on opioid dose and may be treated with the use of low-dose
naloxone, although at the risk of reversing the analgesic effects.203
Epidural administration of local anesthetics is also associated with urinary
retention, with a reported rate of approximately 10% to 30%.204 Higher
epidural infusion rates of local anesthetics (with a greater extent of sensory
block and higher incidence of motor block) may be associated with a
higher incidence of urinary retention.205

Patient-Controlled Epidural Analgesia

Epidural analgesia can be delivered as a fixed rate or continuous infusion
(CEI) or through a patient-controlled device (patient-controlled epidural
analgesia [PCEA]) has become more common. Like IVPCA, PCEA allows
for individualization of postoperative analgesic requirements and may
have several advantages over CEI, including lower drug use and greater
patient satisfaction.206 PCEA also provides superior analgesia compared
with IVPCA. PCEA is a safe and effective technique for acute analgesia in
hospitalized. Observational data from two series of more than 1,000
patients each reveal that more than 90% of patients with PCEA receive
adequate analgesia, with a median pain score of 1 (of a possible 10) at rest
and 4 with activity.186,207 Incidences of side effects are 1.8% to 16.7% for
pruritus, 3.8% to 14.8% for nausea, 13.2% for sedation, 4.3% to 6.8% for
hypotension, 0.1% to 2% for motor block, and 0.2% to 0.3% for
respiratory depression.186,207 These rates are comparable to those reported
with CEI, with an incidence of 10.2% to 22% for pruritus, 3.1% to 22% for
nausea, 7.4% for sedation, 0.7% to 6.6% for hypotension, 3% for motor

2669
block, and 0.1% to 1.6% for respiratory depression.200,208 The optimal
PCEA analgesic solution and delivery parameters are unclear. Use of a
continuous or background infusion in addition to the demand dose is more
common with PCEA than with IVPCA and may provide analgesia superior
to the use of a demand dose alone.209 In general, most acute pain
specialists are gravitating toward a variety of low-concentration local
anesthetic–opioid combinations (Table 51.7) in an attempt to improve
analgesia while minimizing side effects.

TABLE 51.7 Neuraxial Patient-Controlled Analgesia Regimens for

Acute Pain
Continuous Demand Lockout
Rate Dose Interval
Location of Incision Analgesic Solution (mL/h) (mL) (min)
General regimen
0.05% bupivacaine + 4 4–10 2–6 10
µg/mL fentanyl
0.0625% bupivacaine + 5 4–6 3–4 10–15
µg/mL fentanyl
0.1% bupivacaine + 5 6 2 10–15
µg/mL fentanyl
0.2% ropivacaine + 5 5 2 20
µg/mL fentanyl
Thoracic
0.0625%–0.125% 3–4 2–3 10–15
bupivacaine + 5 µg/mL
fentanyl
Abdominal
0.0625% bupivacaine + 5 4–6 3–4 10–15
µg/mL fentanyl
0.125% bupivacaine + 0.5 3–5 2–3 12
µg/mL sufentanil
0.1% to 0.2% ropivacaine + 3–5 2–5 10–15
2 µg/mL fentanyl
Lower extremity
0.0625%–0.125% 4 2 10
bupivacaine + 5 µg/mL
fentanyl
NOTE: Patient-controlled epidural analgesic regimens commonly used at the Johns Hopkins
Hospital.

Outcome Studies of Epidural Analgesia

2670
Use of perioperative epidural anesthesia and analgesia, especially with a
local anesthetic–based analgesic solution, can attenuate the
pathophysiologic response to surgery and may be associated with a
reduction in mortality and morbidity compared with analgesia with
systemic (opioid) agents.11,12 A meta-analysis of randomized data (141
trials enrolling 9,559 subjects) demonstrated that perioperative use of
neuraxial anesthesia and analgesia versus general anesthesia and systemic
opioids reduced overall mortality (primarily in orthopedic patients) by
approximately 30%.210 In a Medicare database analysis of 68,000 surgical
patients, postoperative epidural-based analgesia was associated with a
decrease in overall mortality.211 Furthermore, use of epidural analgesia can
decrease the incidence of postoperative gastrointestinal, pulmonary, and
possibly cardiac complications.11,12 By inhibiting sympathetic outflow,
decreasing the total opioid dose, and attenuating a spinal reflex inhibition
of the gastrointestinal tract,11 postoperative thoracic epidural analgesia can
facilitate return of gastrointestinal motility without contributing to bowel
dehiscence.212 Randomized clinical trials demonstrate that use of
postoperative thoracic epidural analgesia with a local anesthetic–based
analgesic solution allows earlier return of gastrointestinal function and
fulfillment of discharge criteria.
The benefits of perioperative epidural analgesia (compared with
systemic opioid analgesia) on morbidity and mortality is best summarized
in a meta-analysis in adults having surgery under general anesthesia.213 A
total of 125 trials (9,044 patients) were examined and patients who
received epidural analgesia had a significantly lower risk of death (3.1%
vs. 4.9%; odds ratio, 0.60; 95% confidence interval, 0.39 to 0.93) and also
decreased risk of atrial fibrillation, supraventricular tachycardia, deep vein
thrombosis, respiratory depression, atelectasis, pneumonia, gastrointestinal
ileus, and postoperative nausea and vomiting.
The ability of postoperative epidural analgesia to attenuate postoperative
pathophysiology and improve outcomes also depends on the type of drugs
used (opioids vs. local anesthetics). Maximal attenuation of perioperative
pathophysiology occurs with use of a local anesthetic–based epidural
analgesic solution. The use of a local anesthetic–based or local
anesthetic/opioid combination versus opioid-alone analgesic solution is

2671
associated with an earlier recovery of gastrointestinal motility after
abdominal surgery and less frequent occurrence of pulmonary
complications. Epidural analgesia is not a generic entity because different
catheter locations and analgesic regimens may differentially affect
perioperative morbidity.

Risks of Epidural Analgesia

The benefits of perioperative epidural anesthesia-analgesia must be
weighed against the risks of this technique. Risks and benefits should be
evaluated for each patient. There are complications associated with
placement of an epidural catheter, with several risks associated with
indwelling epidural catheters including epidural hematoma and abscess
should be discussed in the context of postprocedure and/or acute pain
management with epidural analgesia. The concurrent use of anticoagulants
and of neuraxial anesthesia and analgesia has always been a relatively
controversial issue but has been highlighted over the past decade with the
increased incidence of spinal hematomas after the introduction of low
molecular weight heparin in North America in 1993. Different types and
classes of anticoagulants have different pharmacokinetic properties that
affect the timing of neuraxial catheter or needle insertion and catheter
removal. Despite several observational and retrospective studies
investigating the incidence of spinal hematoma in the setting of various
anticoagulants and neuraxial techniques, there is no definitive conclusion
regarding the absolute safety of neuraxial anesthesia and anticoagulation.
The American Society of Regional Anesthesia and Pain Medicine (ASRA)
lists a series of consensus statements based on the available literature for
administration (insertion and removal) of neuraxial techniques in the
presence of various anticoagulants, including oral anticoagulants
(warfarin), antiplatelet agents, fibrinolytics-thrombolytics, standard
unfractionated heparin, and low molecular weight heparin.214 The ASRA
consensus statements include the concepts that the timing of neuraxial
needle or catheter insertion or removal should reflect the pharmacokinetic
properties of the specific anticoagulant, that frequent neurologic
monitoring is essential, that concurrent use of multiple anticoagulants may
increase the risk of bleeding, and that the analgesic regimen should be
tailored to facilitate neurologic monitoring, which may be continued in

2672
some cases for 24 hours after epidural catheter removal. An updated
version of the ASRA consensus statements on neuraxial anesthesia and
anticoagulation can be found on their Web site,215 and some of these
statements address the newer anticoagulants. Anticoagulation risk
associated with indwelling spinal cord stimulator leads, which could be
considered an approximation of indwelling epidural catheters, has been
addressed in a recent guideline.216
Infection associated with postoperative epidural analgesia may result
from exogenous or endogenous sources.170 Serious infections such as
epidural abscess and meningitis associated with epidural analgesic are rare
(<1 in 1,000, <1 in 50,000, respectively).217 Epidural infections are
associated with many sources of the bacteria including needle
contamination, catheter contamination, epidural medication contamination,
lack of the use of in-line bacterial filters, duration of catheter implantation,
and patient predisposing factors for infection.218 The use of epidural
analgesia in the general surgical population with a typical duration of
postoperative catheterization (approximately 2 to 4 days) is generally not
associated with epidural abscess formation.186 A trial of postoperative
epidural analgesia (mean catheterization of 6.3 days) in more than 4,000
surgical cancer patients did not reveal any abscesses. Even though serious
infectious complications appear to be rare after short-term (<4 days)
epidural infusions, there may be a relatively higher incidence of superficial
inflammation or cellulitis (4% to 14%) and even higher rate of catheter
colonization (20% to 35%), with the proportion of positive cultures
increasing with the duration of catheterization; however, catheter
colonization rate may not be a good predictor of epidural space
infection.219

PERIPHERAL REGIONAL ANALGESIA

The use of peripheral regional analgesic techniques as a single injection or
continuous infusion can provide superior analgesia for acute pain when
compared with systemic opioids and may even result in improvement in
various outcomes.220 A variety of wound infiltration and peripheral
regional techniques (e.g., brachial plexus, lumbar plexus, femoral, sciatic-
popliteal, and scalp nerve blocks) can be used to provide postprocedural

2673
and acute analgesia. Peripheral nerve regional analgesic techniques may
have several advantages over systemic opioids including superior
analgesia and decrease in opioid-related side effects and over neuraxial
techniques including decreased risk of epidural hematoma formation.221 A
one-time injection of local anesthetic for peripheral regional techniques
may be used primarily for intraoperative anesthesia or as an adjunct for
postprocedure analgesia but can be used for acute traumatic pain
management such as long bone fractures or rib fractures. Compared with
placebo, peripheral nerve blocks with local anesthetics provide superior
analgesia and are associated with decreased opioid use, decreased opioid-
related side effects, and improvement in patient satisfaction.220 The
duration of postoperative analgesia resulting from the local anesthetic in
the peripheral nerve block varies but may last up to 24 hours after
injection. Continuous infusions of local anesthetics can be administered
through peripheral nerve catheters. The use of continuous infusions or
patient-controlled peripheral analgesia results in superior analgesia
decreased opioid-related side effects, and greater patient satisfaction in
comparison with systemic opioids.221 Unfortunately, the optimal
parameters including the local anesthetic, the medication concentration,
the inclusion of opioid or other adjuvant medications, or continuous versus
PCA versus intermittent boluses for peripheral analgesia have not been
determined.
Several nonepidural regional analgesic techniques can be used for
management of postoperative thoracic pain, including paravertebral and
intercostal blocks, interpleural (intrapleural) analgesia, and cryoanalgesia.
The most promising technique appears to be the thoracic paravertebral
block, which has been used for thoracic, breast, and upper abdominal
surgery and for treatment of rib fracture pain.222 The possible sites of
analgesia for the thoracic paravertebral block include direct somatic nerve,
sympathetic nerve, and epidural blockade. The thoracic paravertebral
block can be administered as a single injection or continuous infusion
through a catheter may provide equal or superior analgesia compared with
thoracic epidural analgesia and is a valuable alternative to thoracic
epidural analgesia.223 The analgesic efficacy of interpleural analgesia is
controversial.224 In a meta-analysis of RCTs examining interpleural

2674
analgesia, no difference was observed between interpleural analgesia and
placebo injections. Interpleural analgesia appears to be inferior to epidural
and paravertebral analgesia for postoperative pain control, preservation of
lung function after thoracotomy, and reduction of postoperative pulmonary
complications.224 Intercostal blocks may provide short-term postoperative
analgesia and may be repeated postoperatively; however, the incidence of
pneumothorax increases with each intercostal nerve blocked (1.4% per
nerve, with an overall incidence of 8.7% per patient).225 Like interpleural
analgesia, intercostal blocks do not reduce the incidence of pulmonary
complications postoperatively compared to epidural analgesia.
Cryoanalgesia can be used for postoperative analgesia after thoracotomy
but, like interpleural analgesia and intercostal blocks, does not appear to
provide any analgesic advantage over epidural analgesia and is not
effective for other types of postoperative pain.226

Intra-articular Analgesia
Local peripheral administration of opioids including intra-articular
injections after knee procedures may provide analgesia for up to 24 hours
after surgery.227 Peripheral opioid receptors are found on the peripheral
terminals of primary afferent nerves and are upregulated during
inflammation of peripheral tissues.52 The results of the several randomized
clinical trials investigating this topic are summarized.227 Use of a higher
dose of intra-articular morphine (5 mg vs. 1 mg) results in superior
analgesia; however, there may be no advantage in the degree of analgesia
provided between intra-articular and systemic opioids. The systemic
absorption and action of intra-articular morphine injection have not yet
been excluded. Intra-articular injection of local anesthetics may provide a
limited duration of postoperative analgesia, but the clinical benefit from
intra-articular local anesthetics injections is unclear.228 Liposomal
bupivacaine, a new formulation, is now available and is approved for
surgical wound infiltration. This preparation has been promoted to
surgeons to reduce the need for regional anesthetic techniques, improve
postoperative ambulation, and recovery. Unfortunately, the evidence from
independent trials (nonmanufacturer supported trials) has not found
additional benefit of this preparation over nonliposomal (standard)

2675
bupivacaine.229 In an analysis of cost efficacy, liposomal bupivacaine was
found to be equally effective and significantly more expensive.230

ENHANCED RECOVERY AFTER SURGERY

PATHWAYS
ERAS pathways are perioperative care programs whose main goals are to
improve patient recovery through research, education, and implementation
of evidence-based practice. Compared to traditional care, ERAS pathways
have been associated with a decrease length of stay, decreased
pulmonary/cardiac complications and urinary tract infections, although
there may not be any improvement in mortality or readmission rate.231 Use
of ERAS pathways have also been associated with decreases in rate of
surgical site infections and even possibly cancer recurrence for oncologic
surgical patients.232 ERAS pathways have been established for many
surgical procedures including colon resection, cystectomy,
pancreatoduodenectomy, and liver surgery.231,233–235
The recent increased interest in these pathways provides many
opportunities for pain management clinicians, as one of the key
cornerstones of any ERAS pathway is the control of perioperative pain
while minimizing analgesic-related side effects. Uncontrolled
postoperative pain results in detrimental physiologic effects (e.g., delayed
gastrointestinal function, decreased respiratory activity), which may delay
patient recovery. The delivery of postoperative pain management in ERAS
patients’ needs to be tailored to facilitate patient recovery and clinicians
must carefully choose from a variety of analgesic agents/techniques for the
treatment of postoperative pain in ERAS patients such that the physiologic
and pharmacologic benefits are maximized and side effects minimized to
facilitate patient recovery and return to baseline function.
For any ERAS pathway, one of the primary pain management goals is to
deliver a multimodal analgesic regimen incorporating many nonopioid
analgesic agents/techniques to minimize the use of and side effects from
opioids.
Multimodal analgesia commonly generally refers to use of mostly
nonopioid analgesics/techniques to maximize analgesia while minimizing
opioid-related side effects and may include a combination of interventional

2676
analgesic techniques (e.g., epidural catheter or peripheral nerve catheter
analgesia) and systemic pharmacologic therapies (e.g., NSAID,
acetaminophen, gabapentinoids). Postprocedural or posttraumatic pain is
best managed through a multimodal approach.236 The use of regional
anesthesia and analgesia is an integral part of the multimodal strategy
because of the superior analgesia and physiologic benefits conferred by
these techniques.9,171

Analgesia in Special Populations

This chapter provides a general approach to the principles and practice of
acute pain management, but this approach may not be applicable to certain
populations that may have unique anatomic, physiologic, pharmacologic,
affective, and cognitive issues. The management of acute pain should be
tailored to the specific needs of a population. Although each topic by itself
could merit a separate chapter in some textbooks, the general principles
and essence of the issues associated with each population are outlined, and
references are made to other more extensive sources.

WAR TRAUMA
The treatment of traumatic battlefield pain is largely a function of the type
and acuity of injury, stability of the patient, level of treatment (Table 51.8),
availability of resources, and patient diagnosis. The chain of casualty
evacuation is built on levels or echelons of care, which were developed in
World War II to facilitate the rapid evacuation of wounded soldiers based
on their medical condition and needs. To maximize efficiency and ensure
the continued availability of resources, health care providers at each level
provide no more care than that which is necessary to either return the
soldier to duty or safely evacuate the casualty to the next highest level. For
first-level treatment, pain management consists of NSAIDs or
acetaminophen, which some units dispense to individual soldiers as part of
“wound packs.”237 COX-2 inhibitors possess the advantage of having
minimal inhibitory effects on platelet function, which can prolong
bleeding. One concern about NSAIDs is the possible increased incidence
of renal failure in dehydrated and hypovolemic soldiers,238 but this risk is

2677
mitigated by the young age, and lack of concomitant medical problems and
medication usage in most deployed soldiers. Acetaminophen may be
marginally safer than NSAIDs but is generally less effective as an
analgesic.239 Historically, morphine was the standard opioid analgesic
used for battlefield pain control, having been first administered orally in
the War of 1812 and parenterally in the US Civil War. During recent
conflicts, the US military has widely incorporated Tactical Combat
Casualty Care guidelines that include the suggested analgesic management
of battlefield wounded service members. Patients who are injured with
mild to moderate pain are administered acetaminophen and meloxicam.
However, patients with more severe injuries not suffering from
hemodynamic shock or respiratory depression may additionally receive
oral transmucosal fentanyl citrate (OTFC) 800 µg. The pharmacokinetics
of transmucosal delivery are comparable to that of IM administration, with
therapeutic blood levels being reached within 10 to 15 minutes, and peak
plasma concentration occurring about 20 minutes after administration.240
Approximately 25% of OTFC is absorbed via the oral mucosa, with
another 25% being slowly absorbed through the gastrointestinal tract.240
The pharmacokinetics of OTFC appears to be independent of age,
unaffected by multiple-dose regimens, and less prone to hemodynamic
variations,241,242 which may make it an ideal drug for battlefield analgesia.
In a study by Wedmore et al.,243 records of 286 battlefield wounded over a
7-year span who received OTFC were reviewed. Significant reductions in
numerical rating scores were reported with only one soldier experiencing
respiratory depression. For patients suffering from hemodynamic shock,
respiratory depression, or inadequate analgesia from OTFC, ketamine 20
mg IV/intraosseous (IO) may be administered every 20 minutes with
reassessment for benefit and untoward side effects. Morphine remains an
alternative to OTFC in patients where IV access has been established.
Other rapidly acting analgesics that may someday be used in lieu of
parenteral opioids include intranasal butorphanol, intranasal ketamine, and
fentanyl buccal tablets.

TABLE 51.8 Levels of Care in a War Zone

Type of Medical Primary

2678
 Level (Echelon) Location Unit Functions/Personnel
First Combat zone Battalion aid station Pain relief,
stabilization, and
preparation for medical
evacuation; self-
care/corpsmen
care/buddy care
Second Combat zone Mobile field surgical Resuscitation and
teams or forward surgical stabilization by
surgical teams surgeons, anesthetists,
and nurses
Third Controlled area of Combat support Medical and surgical
combat zone hospital or mobile care; broad array of
army surgical physicians and nurses
hospital
Fourth Communication zone Military medical Medical and surgical
centers in United care; may provide
States or overseas definitive treatment (in
United States) or
rehabilitation services
in retained active duty
personnel
Fifth United States VA hospitals Definitive long-term
treatment and
rehabilitation in
wounded or medically
boarded soldiers
VA, Veteran’s Affairs.

Second-level medical treatment facilities include mobile field surgical

teams and forward surgical teams (FST), whose providers include
surgeons, anesthetists, and nurses. The primary functions of FSTs are
resuscitation and stabilization, with the typical duration of stay being
measured in hours. Pain control at this echelon of care generally involves
oral opioid and nonopioid analgesics, and IV opioids, which can be safely
monitored by nurses and other personnel trained in postanesthesia
recovery. PCA may be used at these facilities as resources dictate but is
often unavailable. During recent conflicts, the capability to conduct
regional anesthetic techniques such as single injection peripheral nerve
blocks has tremendously grown with the increasing presence of ultrasound
technology with FSTs.
Care at third-level military treatment facilities includes intensive care

2679
units and medical wards, which may administer continuous infusions of
opioid and nonopioid (e.g., ketamine and epidural infusions of local
anesthetics) analgesics for acute and subacute injuries. When pain
management–trained anesthesiologists have been deployed to a combat
support hospitals (CSH), more advanced interventions such as sympathetic
and paravertebral blocks have been performed. Peripheral and neuraxial
catheters are aggressively pursued for intermediate-term pain control
directly following injury and during transport (Table 51.9).244–246 In
addition to providing safe and titratable pain relief, peripheral nerve
catheters can be used for anesthesia in patients requiring repeat surgery or
wound débridement. With proper maintenance and monitoring, tunneled
peripheral nerve catheters can be reliably used for up to 3 weeks after
placement. The limitations of peripheral nerve catheters at CSH include
shortage of personnel, speed of exodus, infection risk, and concerns about
compartment syndrome.

TABLE 51.9 Advantages of Peripheral Nerve Catheters for War

Injuries
Can provide anesthesia for repeat surgery or wound débridement
Can provide excellent, limb-specific analgesia
Stable hemodynamics
Minimal side effects
Reduced need for opioid and other analgesics
Improved alertness
Requires only simple, easily transportable equipment

In summary, pain management in the operational setting is fraught with

a unique set of challenges almost unimaginable in civilian pain treatment
facilities. Because of wide variations in medical resources and personnel,
there is no “optimal” pain treatment for war injuries. Instead, treatment
should be individually tailored based on a patient’s injury, hemodynamic
condition, available resources, and the ability to monitor treatment
response. In modern warfare, the most common cause of soldier attrition is
not battle-related injury but rather acute and recurrent non–battle-related
injuries like those encountered in civilian pain treatment facilities and
primary care offices. Recent evidence suggests that high return-to-unit
rates can be obtained by the deployment of aggressive pain management

2680
capabilities in mature theaters of operation.

AMBULATORY SURGICAL PATIENTS

The percentage of surgical procedures being performed on an outpatient
basis continues to increase. There is an increase in the number of
outpatient surgical procedures and in the complexity of operations being
performed and comorbidities of the surgical outpatients. Optimizing
treatment of postoperative and postdischarge pain is especially important
in patients undergoing outpatient surgery because inadequate control of
postoperative pain is one of the leading causes of prolonged stays or
readmission after outpatient surgery.247 Although there has been much
effort to minimize symptoms such as pain and nausea in the postanesthesia
care unit and subsequent (phase II) recovery area to facilitate discharge
after outpatient surgery, increasing data suggest that postdischarge pain is
common and may interfere with patients’ recovery and the overall health-
related costs of outpatient surgery.248,249 Despite the advances in surgical
techniques that minimize surgical trauma and postoperative pain, the
incidence of moderate to severe postdischarge pain is still approximately
25% to 35%250 and can be especially troublesome for certain patients,
such as those undergoing tubal ligation and orthopedic procedures.251
After discharge, poorly controlled nausea and vomiting may interfere with
the intake of oral analgesics. In light of these considerations, the traditional
reliance on opioid analgesia may not be appropriate for patients
undergoing ambulatory surgery because of the opioid-related side effects
that may delay hospital discharge and postdischarge recovery after
outpatient surgery. A multimodal or “balanced” analgesic approach using a
combination of opioid and nonopioid analgesic adjuvant medications
including NSAIDs or acetaminophen and local anesthetics wound
infiltration or regional anesthetic techniques may be more appropriate in
this surgical population. The use of local anesthetics has decreased
postoperative pain, and the drugs can be administered as peripheral nerve
blocks, tissue infiltration, wound instillation, or topical analgesics. Similar
results have been achieved using systemic NSAIDs and acetaminophen.
Although multimodal analgesia may be especially effective in the
immediate postoperative period, not all the options may be routinely

2681
available after the patient is discharged to home. For example, use of local
anesthetics in peripheral nerve blocks, tissue infiltration, or wound
instillation may be effective in the immediate postoperative period;
however, a single dose of local anesthetic rarely provides more than 24
hours of analgesia. Realistically, most outpatients rely on a combination of
short-acting analgesics including an opioid and acetaminophen or NSAID
for postoperative pain control after hospital discharge.58 Routine use of
acetaminophen, especially when an NSAID is added to the regimen, is
recommended to maximize postoperative analgesia,252 although it is
important to remember that when acetaminophen is used as a coanalgesic
agent in combination products this limits the number of combination
analgesic tablets that the patient may consume because of liver toxicity.
The future of postoperative pain control in ambulatory surgical patients
may include postdischarge (home) use of continuous infusion of local
anesthetic solutions or even use of long-acting, “sustained-release” local
anesthetics or opioids.

ELDERLY PATIENTS
The elderly population, which is expected to increase by 33% over the
next two decades, accounts for approximately 12.5% of the total US
population and 38% of all health care spending (approximately 5% of the
US gross domestic product). There are changes in the physiology,
pharmacodynamics, pharmacokinetics, and processing of nociceptive
information that may influence the effectiveness of postoperative pain
control in the elderly. There may be communication, affective, cognitive,
social, and ideologic barriers to effective postoperative pain control in this
group. The elderly generally have decreased physiologic reserves and
increased comorbidities compared with younger counterparts, which may
result in a higher incidence of postoperative complications such as
postoperative delirium, especially in the presence of severe or uncontrolled
postoperative pain.
There is a clinically significant reduction in the intensity of pain
perception or symptoms with increasing age.253,254 For instance, silent
myocardial ischemia is more common in the elderly, who may instead
present with other angina equivalents. Experimental studies demonstrate a

2682
decrease in Aδ and C fiber nociceptive function, delay in central
sensitization, increase in pain thresholds, and decrease in sensitivity to
low-intensity noxious stimuli.255,256 However, elderly patients may have
an increased response to higher intensity noxious stimuli, decreased pain
tolerance, and decreased descending modulation (i.e., serotonin and
noradrenergic), which may contribute to the relatively high incidence of
chronic pain in elderly patients.255,257 Despite the methodologic issues in
available studies evaluating age-related differences in the perception of
pain, there appears to be a clinically relevant decrease in pain perception
with increasing age. However, this should not be interpreted that elderly
patients experience less pain than younger patients when they do report the
presence of pain.
The physiologic and pharmacokinetic effects of aging on acute pain
management are complex, and the clinical implications include the slow
titration of opioids that produces longer circulation times, smaller total
doses because of increased sensitivity, and expectation of a longer duration
of action due to reduced clearance. In general, analgesic requirements
decrease with increasing age. Age has been shown to be the best predictor
for postoperative requirements of intravenously and neuraxially
administered morphine.258 Similar to that seen in younger patients, there is
large interpatient variability in postoperative analgesic requirements. Use
of IVPCA in the elderly is appropriate to compensate for the wide
interpatient variability, although postoperative titration of IV morphine can
also allow successful and safe administration to elderly patients. Age per
se is not an impediment to effective postprocedure or acute pain use of
IVPCA or PCEA.259 Use of postoperative epidural analgesia for elderly
patients, especially in those with decreased physiologic reserves, may
attenuate perioperative pathophysiology and is reported to improve
postoperative outcomes such as facilitating return of gastrointestinal
function after abdominal surgery, decreasing the incidence of myocardial
ischemia, lowering pain scores, and decreasing pulmonary complications.
Postoperative pain management in the elderly may be especially
challenging because of some of the affective, cognitive, social, and
ideologic barriers. Health care providers treating geriatric patients tend to
have an unfounded level of fear of complications associated with treating

2683
perioperative pain as reflected by the inadequate treatment of pain in
elderly patients, even relative to younger patients.257 Elderly patients may
also contribute to inadequate pain control by their own reluctance to report
pain or take opioid medications. Elderly patients have a higher incidence
of affective or cognitive impairments such as depression or dementia that
may interfere with effective pain management.257 One of the most
devastating complications in the elderly surgical patient is postoperative
delirium, which is associated with increased mortality rates and longer
hospital stays.260 The cause of postoperative delirium is unknown,
although it is believed to result from an imbalance of neurotransmitters,
particularly acetylcholine and serotonin, in the presence of decreased
neurophysiologic reserve and inflammatory mediators.261,262 Although the
cause of postoperative delirium is multifactorial, uncontrolled
postoperative pain may be an important contributor to its development.263
Higher pain scores predict a decline in mental status and an increased risk
of delirium.264 A multimodal analgesic approach may be useful in elderly
patients but must be used with caution because adverse drug reactions in
the elderly increase as the number of medications administered increases.
Although the benefits of intraoperative regional anesthetic techniques on
postoperative cognitive function are unclear, the postoperative or acute
pain use of epidural analgesia may diminish postoperative or pain-related
delirium in part through superior analgesia and a decrease in pulmonary
complications.

OPIOID-TOLERANT PATIENTS
Postprocedural or acute pain may be difficult to manage in the opioid-
tolerant patient because the standard approaches used for assessment and
therapy in opioid-naive patients is inadequate for opioid-tolerant patients.
Although opioid-tolerant patients typically require higher doses of
analgesic medications in the immediate postprocedure period, many health
care providers still do not provide adequate postprocedural pain relief, in
part because of the fear of addiction or medication-related side effects. In
dealing with patients with chronic opioid use, health care providers often
mistakenly interchange several pharmacologic terms (i.e., tolerance,
physical dependence, and addiction), a practice that may contribute to

2684
misunderstanding and inappropriate treatment decisions.
Tolerance refers to the pharmacologic property of an opioid in which an
increasing amount is needed to maintain a given level of analgesia.
Physical dependence is another pharmacologic property of opioids
characterized by the occurrence of a withdrawal syndrome on abrupt
discontinuation of the opioid or administration of an opioid antagonist.
Tolerance and physical dependence are pharmacologic properties of
opioids and not synonymous with the aberrant psychological state or
behaviors associated with substance use disorder (SUD, formerly
addiction), a chronic disorder characterized by the compulsive use of a
substance resulting in physical, psychological, or social harm to the user
and continued use despite that harm. The exaggerated fear of addiction
contributes to the undertreatment of postprocedural and acute pain by
health care providers; however, the data suggest that there is minimal risk
of iatrogenic addiction with in-hospital or brief use of opioids for pain
control in outpatients who do not have a prior history of addiction.265,266
Several principles for pain assessment and treatment can be applied in the
postprocedural or acute pain opioid-tolerant patient. The physician should
expect high self-reported pain scores;267 base treatment decisions on
objective pain assessment (e.g., ability to deep breathe, cough, ambulate)
in conjunction with patients’ self-reported pain scores; and recognize the
need to identify and treat two major problems, maintenance of a baseline
(home) opioid requirement and control of incisional/procedural/acute pain.
It is also appropriate to recognize that opioid detoxification is usually not
an appropriate goal in this period of acute postprocedural recovery.
Likewise, several general strategies can be employed for the treatment of
postprocedural or acute pain in the opioid-tolerant patient. The physician
can create a treatment plan early and discuss it with the patient, procedural
team, and nursing staff; replace the patient’s baseline opioid requirements;
anticipate an increase in postprocedural analgesic requirements; maximize
the use of adjuvant drugs; consider use of regional analgesic techniques;
and plan for the transition to an oral regimen.267 Although chronic pain
patients are not synonymous with opioid-tolerant patients, many of these
patients are opioid-tolerant, and the same general principles and strategies
may be applied to chronic pain patients who are opioid-tolerant.

2685
Recognizing and treating nonnociceptive sources of distress may be
especially important for chronic pain patients. Although there is no
specific threshold or time frame for when a patient becomes opioid-
tolerant, after an opioid-tolerant patient is identified, a strategy for acute
pain control should be created and discussed with the patient. This may
include anticipation or arrangement for a longer than normal length of
hospital stay, consultation with the anesthesiology or pain service, and
confirmation of the patient’s daily opioid intake to facilitate calculation of
the patient’s basal or maintenance opioid requirement in the hospitalized
period. Administration of a PRN analgesic regimen alone for opioid-
tolerant patients is highly discouraged because replacing the basal opioid
requirement in the acute period can optimize pain relief and possibly
prevent opioid withdrawal. Basal opioid requirements can be administered
systemically (typically intravenously or transdermally) until the patient can
tolerate an oral analgesic regimen.156 For example, 50% to 100% of the
patient’s baseline opioid requirement can be administered as a continuous
infusion as part of an IVPCA regimen, with a demand dose to cover the
additional incisional pain. Conversion tables (see Tables 51.2 and 51.3)
may facilitate equianalgesic conversion of opioids; however, these tables
provide only estimations to assist health care providers in initiating opioid
titration.268 Opioid-tolerant patients generally require increased
postoperative analgesic levels, including a larger demand dose.267 Patients
may require frequent adjustment (e.g., two to three times each day) of the
IVPCA demand dose or continuous infusion, depending on the analgesic
requirements. There is individual variability in response to different
opioids, and if a decision is made to switch opioids, the choice of opioid
may not as important as using an equianalgesic dose. Patients may
experience different side effects with different opioids, and rotating to
another opioid may be reasonable if the patient is not tolerating the first
opioid.269 Adjuvant agents such as NSAIDs should be administered on a
regularly scheduled basis to optimize analgesic efficacy and possibly
provide an opioid-sparing effect. Use of regional analgesic techniques with
neuraxial opioids may provide excellent analgesia in opioid-tolerant
patients while preventing withdrawal symptoms.270 After the patient is
tolerating oral intake, the conversion from IV opioids to a form of oral or

2686
transdermal administration that would be more suitable for discharge to
home may be initiated. Opioid-tolerant patients typically can be converted
to a combination of a regularly administered, controlled-release
formulation of opioid such as sustained-release morphine or transdermal
fentanyl and a short-acting, immediate-release opioid on a PRN basis.
Although the conversion of IV opioid to an oral or transdermal form can
be accomplished over a period of 1 to 2 days in opioid-tolerant patients,
this process may take several days in extremely difficult cases. Converting
from an IV to oral or transdermal form of opioid is not an exact science,
and available conversion tables can serve only as a rough guide because of
significant interpatient and intrapatient variability in the sensitivity to
opioids, lack of complete cross-tolerance between opioids which may lead
to greater than anticipated potency of a new opioid, and changes in the
levels of pain, which may rapidly decrease in the immediate postoperative
period.268 Opioid tolerance also takes a slightly different form in those
patients receiving the partial µ-opioid agonist, buprenorphine, for with
medication assisted SUD therapy or chronic pain. It has broad interpatient
variability in pharmacologic half-life that can range for 24 to 60 hours
while having a high affinity for but low intrinsic activity at the µ-opioid
receptor. Therefore, patients presenting for surgery who receive
buprenorphine may not have the expected analgesic response to full
agonist opioids such as morphine and the time to a usual response may be
unpredictable. It has been recommended that patients on buprenorphine
presenting on the day of surgery have their buprenorphine maintained
throughout the perioperative period. If advance notice is given (greater
than 3 days), patients can be weaned from buprenorphine prior to surgery.
It is recommended that these patients be considered high-risk for difficulty
in postoperative pain and recovery; therefore, all nonopioid techniques and
medications should be used as appropriate. Patients with an opioid use
disorder will also represent a unique challenge for the perspective of
opioid tolerance, venous access, infection risk, and patient expectation of
appropriate pain care. In these patients, a discussion with the surgeon
should stress the importance of nonopioid management including surgical
and anesthetic techniques associated with lower postoperative pain as well
as a postoperative management plan. Techniques including lidocaine or

2687
ketamine infusion can be considered as a component of the postoperative
pain management plan. There should also be a recognition that the
postoperative period may also coincide with opioid (or polysubstance)
withdrawal and may need to be addressed. An addiction medicine or
addiction psychiatry consultation, if available, is likely to be beneficial for
comanagement.
A more challenging, yet durable, approach to the opioid-tolerant patient
will involve a presurgical prehabilitation program in which the oral
morphine equivalent dosage is reduced prior to the surgical procedure.
This approach would involve the coordination of multiple clinicians
including anesthesiologists or pain physician/anesthesiologists in
perioperative clinics, pain physicians, and the primary surgeon. Recent
evidence has shown that preoperative use of moderate to high dose opioids
(above the opioid-tolerant threshold of 60 mg of morphine equivalents) is
associated with increased length of stay, higher readmission rates, and
greater health care expenditures.10 Therefore, this prehabilitative approach
to opioids could result in improved patient outcomes and reduction in
health care cost. This approach warrants future studies.

OBESITY, OBSTRUCTIVE SLEEP APNEA, AND SLEEP

Patients with obesity and obstructive sleep apnea (OSA) may be at higher
risk for postoperative complications. Obesity and OSA are separate disease
states, but there is some association between the two, because OSA occurs
in a relatively higher percentage of obese than nonobese patients.271
Although some data suggest that epidural analgesia may decrease
postoperative complications in the obese patient,272 the optimal
postoperative analgesic and monitoring regimen for patients with OSA is
not clear. Data suggest that sleep is disrupted in the immediate
postoperative period and may influence postoperative morbidity and
patient-oriented outcomes.
Obesity is defined as a body mass index (BMI) of more than 30 kg/m2,
with morbid and supermorbid obesity defined as a BMI of more than 35
kg/m2 and 55 kg/m2, respectively. The prevalence of obesity has increased
to include approximately 22.5% of the US population.273 Although obese
patients do not necessarily have OSA, obesity is the most important

2688
physical characteristic associated with OSA. Approximately 60% to 90%
of OSA patients are obese, and at least 5% of morbidly obese patients have
OSA, which is defined as more than five episodes per hour of cessation of
airflow for more than 10 seconds despite continued ventilatory effort.271 It
is estimated that approximately 4% of men and 2% of women (18 million
Americans overall) have OSA and that up to 95% of persons with OSA are
underdiagnosed.271 Patients with OSA are generally at higher risk for
chronic cognitive impairment, pulmonary hypertension, cardiomyopathy,
systemic hypertension, and possibly for myocardial infarction.274,275 The
pathophysiology of airflow obstruction is related primarily to upper airway
pharyngeal collapse, including the retropalatal, retroglossal, and
retroepiglottic pharynx, during sleep, especially during rapid eye
movement (REM) sleep.271 During these obstructive episodes, OSA
patients may exhibit hypoxia, bradyarrhythmias or tachyarrhythmias,
myocardial ischemia, abrupt decreases in left ventricular stroke volume
and cardiac output, or increases in pulmonary and systemic blood
pressure.275 Based on our understanding of the pathophysiology of OSA, it
is easy to see how acute pain management can be difficult in this
population. Patients with OSA are at higher risk for respiratory arrest.276
Use of sedative doses of benzodiazepines and opioids may result in
frequent hypoxemia and apnea, which may be especially dangerous in the
OSA patient.276 Avoiding respiratory depressants by optimizing use of
NSAIDs and epidural analgesia with a local anesthetic–based regimen may
attenuate the risk for respiratory depression and arrest because the use of
epidural and systemic opioids is associated with sudden postoperative
respiratory arrest.277
The American Society of Anesthesiologists Task Force on Perioperative
Management of Patients with Obstructive Sleep Apnea created guidelines
that include acute pain management in patients with OSA.278 Although the
consultants acknowledged that the conclusions regarding postoperative
analgesic options were based on insufficient literature evaluating the
effects of various analgesic techniques, the presence of equivocal literature
regarding the use of epidural opioids compared with IM or IV opioids in
reducing respiratory depression, and insufficient literature regarding the
addition of a basal infusion to systemic patient-controlled opioids, the

2689
consultants nevertheless recommended that regional techniques rather than
systemic opioids should be used in an attempt to reduce the likelihood of
adverse outcomes in patients at increased perioperative risk from OSA.278
In addition, the consultants recommended the exclusion of opioids from
neuraxial postoperative analgesia to reduce perioperative risk, and the use
of NSAIDs to reduce adverse outcomes through their opioid-sparing
effect. The consultants were equivocal regarding whether avoiding a basal
infusion of opioids in patients with OSA reduces the likelihood of adverse
outcomes.278 Unfortunately, there is a paucity of randomized clinical trial
data to provide definitive high-quality evidence-based recommendations in
the provision of postoperative analgesia for OSA patients.

Gender or Sex Differences in Analgesia

A large body of data has been collected in the past 20 years concerning
differences between the sexes in response to pain, including pain
thresholds, and in the tolerance and response to acute pain treatment.
However, the exact differences as well as their relevance are far from
clear. According to the International Association for the Study of Pain
(IASP), “Pain is an unpleasant sensory and emotional experience arising
from actual or potential tissue damage or described in terms of such
damage.” This definition does not differentiate between “pain” as a
woman experiences it from “pain” as a man experiences it, and thus,
fundamental questions remain.
Females report more severe pain, more frequent bouts of pain, more
anatomically diffuse, and longer lasting pain than males with similar
disease processes, even when male- and female-specific disorders
including male urologic and female gynecologic pain are excluded from
the analysis. Females have a higher prevalence of pain related to
musculoskeletal or to visceral origin as well as pain related to autoimmune
disease (Table 51.10).279 Substantial amounts of the accumulated data rely
heavily on the subjective signs of the pain experience. These are highly
influenced by sociocultural variables that have little to do with a biologic
difference of pain threshold or perception between women and men. An
inherent reporting bias exists in the epidemiologic research related to the

2690
incidence of pain in the sexes. Females are more likely to visit a physician
and are more likely to report pain as a symptom than males280,281 reviewed
in282 which can therefore lead to an overestimation of the differences
between the sexes.

TABLE 51.10 Sex Prevalence of Clinical Pain Syndromes or

Diseases
Prevalence
Bodily Area Female > Male Female < Male
Head Headache Chronic tension Cluster
Migraine with aura Migraine without
aura
Postdural puncture Posttraumatic
Cervicogenic War injury
Temporal arteritis
Occipital neuralgia
Oral Odontalgia Paratrigeminal
syndrome
Burning mouth Trigeminal
Temporomandibular postherpetic neuralgia
disorder
Trigeminal neuralgia
Extremities Arms Carpal tunnel Brachial plexus
syndrome neuropathy
Raynaud’s disease War injuries
CRPS type I CRPS type II
Scleroderma
Legs Chronic venous Meralgia
insufficiency paraesthetica
Peroneal muscular Gout
atrophy
Piriformis syndrome Intermittent
claudication
Raynaud’s disease CRPS type II
CRPS type I
Viscera Bowel Chronic constipation Duodenal ulcer
Irritable bowel
syndrome
Proctalgia fugax
Esophagus Esophagitis
Pancreas Pancreatic disease
Gall bladder Postcholecystectomy
pain

2691
 Autoimmune Lupus erythematosus Reiter’s syndrome
Multiple sclerosis
Rheumatoid arthritis
CRPS, complex regional pain syndrome.

In a meta-analysis of studies examining sex differences in pain response

in healthy subjects less than 60 years old, the authors found women report
higher pain severity at lower thresholds and have less tolerance to noxious
stimulation than males.283 In a large multicenter trial, Rolke and
colleagues254 used quantitative sensory testing (QST) to determine sensory
detection thresholds and pain thresholds for thermal and mechanical
noxious stimuli. Females had lower pain thresholds, with the greatest
disparities for sex differences found for heat pain threshold, followed by
cold pain and pain to blunt pressure.
Many other physiologic, sociocultural, and psychological variables have
been identified as contributing to the differences between the two sexes
about pain. One factor includes the endpoint being examined, such as pain
threshold versus pain tolerance.283–285 Pool and colleagues286 showed that
pain tolerance is highly malleable and strongly influenced by the subject’s
“gender” norms. Males who are highly identified with the “male” role
tolerate higher levels of noxious stimuli, but those males who do not have
this belief tolerate noxious stimuli at the same level as females. The age of
the subject also modifies the pain threshold. Advancing age is positively
associated with pain threshold.253,254 Pickering and colleagues285 found
that the difference in score between males and females decreased with
advancing age. The significant sex difference seen in thermal and
mechanical threshold and in tolerance in younger volunteers became
nonsignificant in volunteers greater than 40 years old.
As discussed earlier, the sex difference in humans is neither a universal
nor a large effect. Furthermore, no difference between sexes is found in at
least one-third of the published studies, and effect sizes are often in the
small to moderate range.283 Other investigators have sought objective
measures of pain as a result of the numerous factors that have been shown
to influence and in some cases abolish the pain threshold and tolerance
differences between the sexes. Paulson and colleagues284 used positron
emission tomography (PET) to investigate regional brain activation after a

2692
painful somatic thermal stimulus in healthy normal volunteer male and
female subjects. They reported that females had significantly greater
activation of the contralateral prefrontal cortex, the contralateral insula,
and the thalamus compared to males suggesting sexual dimorphism in
response to pain. Unfortunately, this study reflected a difference in brain
activation that was more likely the result of different pain intensities rather
than a true sex difference. In a later study also using PET technology, the
pain intensity was matched between the sexes and the results were the
opposite of the earlier study—males had greater activation than
females.287 Finally, a study using matched pain intensity and functional
magnetic resonance imaging (fMRI) showed no sex-based difference in
brain activation.288 Other PET studies have described sex differences in
responses to visceral pain from rectal balloon distension, although
principally with chronic visceral pain patients.289,290 However, the
differences reported were predominantly in the direction of greater
activation in men. These studies were replicated using fMRI with similar
results of a male predominance of neuronal activation in pain-related areas
of the brain.289
Pain thresholds in humans vary by internal factors such as sex, gender,
female menstrual phase, and psychological variables including
catastrophizing, anxiety, and depression. External factors also affect the
outcome including testing environment, sex, and gender of the examiner
and the modality of the noxious stimuli. In the largest study assessing the
role of sex on pain thresholds using multiple modalities, it was found that
females had lower pain thresholds in thermal and mechanical pain
testing.254 Unfortunately, this subjective difference has not been
consistently supported by other confirmatory techniques including PET or
fMRI brain imaging. Awareness of the possible differences between males
and females in response to pain is the only clinical application of the
present data with no guidance for situations.
Unlike the abundance of literature addressing the question of drug-
induced sex differences in experimental pain in rodents, the human
literature is not as voluminous. Many in the literature address the response
to µ-opioid receptor agonists and the remainder addresses κ-opioid
receptor agonists. There has not been testing of other clinically available

2693
medications on humans in models of experimental pain. In multiple
studies, either no difference291–293 was noted between sexes or females
had a significantly greater response to the medication.294–296 Although
initial studies attributed the difference to pharmacokinetic differences,297
the metabolism of morphine to morphine-6-glucuronide (M6G), more
recent work by Romberg and colleagues292 demonstrate that no sex
differences exist in M6G concentrations. To further exclude
pharmacokinetic explanations for the sex differences, the same
investigative group subsequently published findings using the potent
synthetic µ-opioid receptor agonist alfentanil. The subject’s response to
alfentanil did not differ based on his or her sex.298
The human response to κ-opioid receptor agonists is somewhat variable.
In a postsurgical model of pain, females had a greater analgesic response
to κ agonist-antagonist medications including pentazocine, nalbuphine,
and butorphanol.299–301 However, in experimental models of pain, either
no difference between males and females was noted302 or males had an
increased sensitivity to the medications.303 Mogil and colleagues303
suggest that the increased responsiveness to κ-opioid receptors agonists
may be related to the absence of the MC1r gene. In an elegant study, this
group studied women with fair skin and red hair who often have a
functional reduction in MC1r. The women with a genetically proven loss
of function polymorphisms experienced an accentuated analgesic response
to pentazocine. Their analgesic response was indistinguishable from the
male subjects in the study.303 This finding has led to the proposal that the
MC1r gene product acts as an antiopioid and therefore when removed
unmasks the true κ-opioid effect. This enhanced effect would be
inconsistent with the finding that females have an increased response to κ-
opioid receptor agonists in clinical models of pain (e.g., postoperative)
because fair-skinned red-headed females represent only a minority of
women in general. Unfortunately, it does not explain the lack of difference
or the greater analgesic response of females to µ opioids in clinical and
experimental models or κ opioids in experimental models of pain.
Unfortunately, the data regarding opioid analgesics garnered from
human trials is not sufficient to guide clinical practice. The studies, so far,
do not justify the conclusion that males or females have a greater

2694
responsiveness to µ or κ opioid receptor agonists, and therefore, they
should continue to receive similar acute pain management until more
definitive studies are conducted.

Inpatient Pain Services

Although dedicated individuals can improve postoperative pain control for
a few patients, more comprehensive interdisciplinary pain services
developed specifically to treat this problem can address the needs for all
patients within an institution. The organizational aspects of such
comprehensive services are considerable. With skills in regional anesthetic
techniques and knowledge of the neurobiology of nociception and the
pharmacology of analgesics and local anesthetics, anesthesiologists have
been leaders in postoperative pain relief and development of inpatient pain
services.
Although there are several models for the development of inpatient pain
services,304,305 the key organizational aspects are similar. Development
and maintenance of inpatient pain services require a commitment and
financial support at the national and local level. In the United States,
because there are financial burdens associated with the establishment of an
acute pain service, high-volume or larger hospitals are more likely have
acute pain services and have access to more high-tech analgesic techniques
such as epidural analgesia.306,307 Whether inpatient pain services improve
outcomes is unclear. Two systematic reviews have examined the impact of
acute pain services on patients outcomes,308 and although systematic
reviews suggest that the introduction of acute pain services is associated
with a decrease in pain scores, the effect of acute pain services on the
incidence of analgesic-related side effects such as nausea and vomiting,
satisfaction, and overall costs or cost reductions are uncertain.308 Despite
the direct costs (e.g., personnel, equipment, medication) associated with
managing a pain service, there is no available properly conducted
pharmacoeconomic study to examine the cost-effectiveness of a pain
service. Use of postoperative epidural analgesia in the context of pain
services may decrease the cost of patient care through shorter intensive
care unit stays and a decreased rate of complications.12

2695
Long-term Impact of Acute Pain
Chronic postsurgical pain (CPSP) is a largely unrecognized problem which
may occur in 10% to 50% of postoperative patients (depending on type of
surgery) with 2% to 10% of these patients experiencing severe CPSP.309
Poorly controlled acute postoperative pain or acute pain in general may be
an important predictive factor in the development of chronic pain.50,310
Increasing experimental and clinical evidence suggests that the transition
from acute to chronic pain occurs very quickly and that long-term
behavioral and neurobiologic changes occur much earlier than previously
anticipated.311 CPSP is relatively common after procedures such as limb
amputation (30% to 83%), thoracotomy (22% to 67%), sternotomy (27%),
breast surgery (11% to 57%), and gallbladder surgery (up to 56%).50
Although studies suggest that the severity of acute postoperative pain may
be an important predictor in the development of CPSP, a causal
relationship between severity of acute postoperative pain and subsequent
CPSP has not been definitively established and other factors may be more
important in predicting the development of CPSP.
Control of acute pain may improve long-term recovery or patient-
oriented outcomes including quality of life or return of function. Patients
whose pain is controlled in the early postoperative period (especially with
use of continuous epidural or peripheral catheter techniques) may be able
to actively participate in postoperative rehabilitation, which may improve
short- and long-term recovery after surgery.312 In a recent study, a
multimodal approach to acute analgesia using either epidural or spinal
analgesia reduced the patient’s area of hyperalgesia and allodynia in the
acute phase and diminished the long-term pain as well.313 Another study
examined the showed that acute postoperative pain was an important risk
factor for the development of chronic pain.314 Optimizing treatment of
acute postoperative pain can improve health-related quality of life
(HRQL).315 Postsurgical chronic pain that develops as a result of poor
acute pain control can interfere with patients’ activities of daily living and
reduce a person to a less functional status.
In addition to CPSP, long-term opioid use following surgery has
emerged as a significant public health concern. One source of confusion

2696
relates to the definition of persistent opioid use after surgery as studies
have commonly used time points from 90 days up to 1 year
postoperatively. Although large retrospective studies have suggested a low
1-year incidence of opioid use (0.4% to 1.4%), only a certain subset of
surgeries was examined.316,317 Different surgical types such as lumbar
fusion or femur fixation have been characterized by rates of 27.9% to 85%
or 36% for opioid therapy 1 year following surgery, respectively.318,319
Patient factors such as preoperative opioid use, depression, preoperative
hypnotic use, and catastrophization have also been linked to persistent
postsurgical opioid use.316,320–322 Other patient risk factors (e.g., age,
anxiety, pain at surgical site) have predicted persistent postsurgical opioid
use is some populations but not others.320,321 Future work must focus on
surgery and population specific risk indices to account for the unique
nociceptive and biopsychosocial variables that occur across surgical
subtypes.

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2004;8(5):435–450.
281. Isacson D, Bingefors K. Epidemiology of analgesic use: a gender perspective. Eur J
Anaesthesiol Suppl 2002;26:5–15.
282. Myers CD, Riley JL III, Robinson ME. Psychosocial contributions to sex-correlated
differences in pain. Clin J Pain 2003;19(4):225–232.
283. Riley JL III, Robinson ME, Wise EA, et al. Sex differences in the perception of noxious
experimental stimuli: a meta-analysis. Pain 1998;74(2–3):181–187.
284. Paulson PE, Minoshima S, Morrow TJ, et al. Gender differences in pain perception and
patterns of cerebral activation during noxious heat stimulation in humans. Pain 1998;76(1–
2):223–229.
285. Pickering G, Jourdan D, Eschalier A, et al. Impact of age, gender and cognitive functioning on
pain perception. Gerontology 2002;48(2):112–118.
286. Pool GJ, Schwegler AF, Theodore BR, et al. Role of gender norms and group identification on
hypothetical and experimental pain tolerance. Pain 2007;129(1–2):122–129.
287. Derbyshire SW, Nichols TE, Firestone L, et al. Gender differences in patterns of cerebral
activation during equal experience of painful laser stimulation. J Pain 2002;3(5):401–411.
288. Moulton EA, Keaser ML, Gullapalli RP, et al. Sex differences in the cerebral BOLD signal
response to painful heat stimuli. Am J Physiol Regul Integr Comp Physiol 2006;291(2):R257–
R267.
289. Berman SM, Naliboff BD, Suyenobu B, et al. Sex differences in regional brain response to
aversive pelvic visceral stimuli. Am J Physiol Regul Integr Comp Physiol 2006;291(2):R268–
R276.
290. Naliboff BD, Berman S, Chang L, et al. Sex-related differences in IBS patients: central

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 processing of visceral stimuli. Gastroenterology 2003;124(7):1738–1747.
291. Fillingim RB, Ness TJ, Glover TL, et al. Morphine responses and experimental pain: sex
differences in side effects and cardiovascular responses but not analgesia. J Pain
2005;6(2):116–124.
292. Romberg R, Olofsen E, Sarton E, et al. Pharmacokinetic-pharmacodynamic modeling of
morphine-6-glucuronide-induced analgesia in healthy volunteers: absence of sex differences.
Anesthesiology 2004;100(1):120–133.
293. Wasan AD, Davar G, Jamison R. The association between negative affect and opioid
analgesia in patients with discogenic low back pain. Pain 2005;117(3):450–461.
294. Pud D, Yarnitsky D, Sprecher E, et al. Can personality traits and gender predict the response
to morphine? An experimental cold pain study. Eur J Pain 2006;10(2):103–112.
295. Sarton E, Olofsen E, Romberg R, et al. Sex differences in morphine analgesia: an
experimental study in healthy volunteers. Anesthesiology 2000;93(5):1245–1254.
296. Zacny JP. Characterizing the subjective, psychomotor, and physiological effects of a
hydrocodone combination product (Hycodan) in non-drug-abusing volunteers.
Psychopharmacology (Berl) 2003;165(2):146–156.
297. Murthy BR, Pollack GM, Brouwer KL. Contribution of morphine-6-glucuronide to
antinociception following intravenous administration of morphine to healthy volunteers. J Clin
Pharmacol 2002;42(5):569–576.
298. Olofsen E, Romberg R, Bijl H, et al. Alfentanil and placebo analgesia: no sex differences
detected in models of experimental pain. Anesthesiology 2005;103(1):130–139.
299. Gear RW, Gordon NC, Heller PH, et al. Gender difference in analgesic response to the kappa-
opioid pentazocine. Neurosci Lett 1996;205(3):207–209.
300. Gear RW, Miaskowski C, Gordon NC, et al. Kappa-opioids produce significantly greater
analgesia in women than in men. Nat Med 1996;2(11):1248–1250.
301. Gordon NC, Gear RW, Heller PH, et al. Enhancement of morphine analgesia by the GABAB
agonist baclofen. Neuroscience 1995;69(2):345–349.
302. Fillingim RB, Gear RW. Sex differences in opioid analgesia: clinical and experimental
findings. Eur J Pain 2004;8(5):413–425.
303. Mogil JS, Wilson SG, Chesler EJ, et al. The melanocortin-1 receptor gene mediates female-
specific mechanisms of analgesia in mice and humans. Proc Natl Acad Sci U S A
2003;100(8):4867–4872.
304. Rawal N. 10 years of acute pain services—achievements and challenges. Reg Anesth Pain
Med 1999;24(1):68–73.
305. Bardiau FM, Braeckman MM, Seidel L, et al. Effectiveness of an acute pain service inception
in a general hospital. J Clin Anesth 1999;11(7):583–589.
306. Merry A, Judge MA, Ready B. Acute pain services in New Zealand hospitals; a survey. N Z
Med J 1997;110(1046):233–235.
307. Carr DB, Miaskowski C, Dedrick SC, et al. Management of perioperative pain in hospitalized
patients: a national survey. J Clin Anesth 1998;10(1):77–85.
308. Lee A, Chan S, Chen PP, et al. Economic evaluations of acute pain service programs: a
systematic review. Clin J Pain 2007;23(8):726–733.
309. Kehlet H, Jensen TS, Woolf CJ. Persistent postsurgical pain: risk factors and prevention.
Lancet 2006;367(9522):1618–1625.
310. Macrae WA. Chronic pain after surgery. Br J Anaesth 2001;87(1):88–98.
311. Carr DB, Goudas LC. Acute pain. Lancet 1999;353(9169):2051–2058.
312. Capdevila X, Barthelet Y, Biboulet P, et al. Effects of perioperative analgesic technique on the
surgical outcome and duration of rehabilitation after major knee surgery. Anesthesiology
1999;91(1):8–15.

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313. Lavand’homme P, De Kock M. The use of intraoperative epidural or spinal analgesia
modulates postoperative hyperalgesia and reduces residual pain after major abdominal
surgery. Acta Anaesthesiol Belg 2006;57(4):373–379.
314. Poleshuck EL, Katz J, Andrus CH, et al. Risk factors for chronic pain following breast cancer
surgery: a prospective study. J Pain 2006;7(9):626–634.
315. Carli F, Mayo N, Klubien K, et al. Epidural analgesia enhances functional exercise capacity
and health-related quality of life after colonic surgery: results of a randomized trial.
Anesthesiology 2002;97(3):540–549.
316. Sun EC, Darnall BD, Baker LC, et al. Incidence of and risk factors for chronic opioid use
among opioid-naive patients in the postoperative period. JAMA Intern Med
2016;176(9):1286–1293.
317. Soneji N, Clarke HA, Ko DT, et al. Risks of developing persistent opioid use after major
surgery. JAMA Surg 2016;151(11):1083–1084.
318. Anderson JT, Haas AR, Percy R, et al. Chronic opioid therapy after lumbar fusion surgery for
degenerative disc disease in a workers’ compensation setting. Spine (Phila Pa 1976)
2015;40(22):1775–1784.
319. Al Dabbagh Z, Jansson KA, Stiller CO, et al. Long-term pattern of opioid prescriptions after
femoral shaft fractures. Acta Anaesthesiol Scand 2016;60(5):634–641.
320. Carroll I, Barelka P, Wang CK, et al. A pilot cohort study of the determinants of longitudinal
opioid use after surgery. Anesth Analg 2012;115(3):694–702.
321. Goesling J, Moser SE, Zaidi B, et al. Trends and predictors of opioid use after total knee and
total hip arthroplasty. Pain 2016;157(6):1259–1265.
322. Clarke H, Soneji N, Ko DT, et al. Rates and risk factors for prolonged opioid use after major
surgery: population based cohort study. BMJ 2014;348:g1251.

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CHAPTER 52
Regional Anesthesia Techniques
for Acute Pain Management
MARIE N. HANNA, JEAN-PIERRE P. OUANES,
and VICENTE GARCIA TOMAS

Acute pain management has become a focus of the health care system and
an important ethical responsibility of the medical profession. Although
opioids have been the primary analgesic agents used for treating moderate
and severe pain after surgery for past few decades, aggressive multimodal
analgesic interventions utilizing primary a combination of nonopioid
analgesic agents and techniques have become widely used during the
perioperative period. Maximum benefit occurs when pain interventions are
extended into the postoperative phase.1
Multimodal analgesia involves the administration of different agents
that exert their effects via different analgesic mechanisms and act
synergistically at different sites in the nervous system, thereby providing
superior analgesia with fewer side effects. Multimodal analgesia can
include regional analgesia with local anesthetics, acetaminophen,
nonsteroidal anti-inflammatory drugs (NSAIDs), and opioids.2
Perioperative neuraxial and peripheral analgesia provide superior
analgesia than do that from systemic opioids. Continuous analgesic
techniques have the advantage of decreasing adverse perioperative
pathophysiology and improving patient outcomes, including major
morbidity.3,4 This chapter focuses on regional anesthesia techniques,
including central neuraxial, truncal, and peripheral perineural analgesia,
for acute postoperative pain management. Indications, techniques,
mechanisms of action, side effects, and complications are described.

Continuous Epidural Analgesia

2714
THORACIC EPIDURAL ANALGESIA
Thoracic epidural analgesia (TEA) is commonly used for the treatment of
pain after upper abdominal/thoracic procedures and rib fractures. TEA is
often used intraoperatively as an adjunct to general anesthesia and in the
postoperative period for many upper abdominal and thoracic procedures
(Table 52.1). Its use in video-assisted thoracic surgery and laparoscopic
procedures is less common and may be recommended only for high-risk
patients. The use of TEA offers superior analgesia compared with that
from systemic opioids.5 Postoperative use of continuous epidural analgesia
is associated with improved patient morbidity as it is associated with
decreases in pulmonary,6–9 cardiovascular,6,7,9,10 and gastrointestinal11,12
complications in high-risk patients and after high-risk procedures. It also
may improve outcomes in patients with multiple rib fractures.13

2715
 TABLE 52.1 Procedures Commonly Appropriate for Thoracic
Epidural Analgesia
Upper Abdominal Lower Abdominal Lower Abdominal
Thoracic Procedures Procedures Procedures (GI) Procedures
Thoracotomy Gastrectomy Bowel resection Nephrectomy
Lobectomy Esophagectomy Colectomy Cystectomy
Thymectomy Pancreatectomy Abdominal aortic Abdominal
aneurysm repair prostatectomy
Thoracic aortic Cholecystectomy Exploratory Abdominal
aneurysm repair laparotomy hysterectomy
Pectus repair Liver resection Pelvic exenteration
VATS
GI, gastrointestinal; VATS, video-assisted thoracic surgery.

Many factors affect the overall outcomes of continuous epidural

analgesia. Among them are the congruency of epidural catheter location
and surgical incision, the type of analgesic regimen used, and whether the
epidural is used as part of a multimodal approach.14,15 When compared
with the systemic administration of opioids, local anesthetic-based
epidural regimens provide superior analgesia and may decrease opioid-
related side effects; epidural infusion of opioids alone may be used to
avoid hypotension when sympathetic blockade is a concern.
The role of high TEA in cardiac surgery with cardiopulmonary bypass
and in off-pump coronary artery bypass surgery remains controversial. It
might improve distribution of coronary blood flow,16 reduce the incidence
of supraventricular tachycardia,17 and decrease surgical stress response.18
Some studies found no difference in the rates of mortality and myocardial
infarction when compared with those of traditional opioids,6 but others
showed significant reduction in postoperative pulmonary and cardiac
arrhythmias while improving pain scores, especially with off-pump
procedures.19
A recent randomized control study of 600 patients undergoing elective
cardiac surgery both on and off pump20 reported no difference in 30-day
mortality and morbidity, no difference in intensive care unit (ICU) stay or
length of hospital stay, and no difference in quality of life at 30-day
follow-up. Until there are more conclusive outcome data, the role of TEA

2716
remains controversial.

BLOCK TECHNIQUE: EPIDURAL

Epidural blockade may be performed with the patient in the sitting or
lateral position through a midline or paramedian approach. With the
midline approach, the epidural needle is oriented in the same plane as the
spinous processes, with slight cephalad orientation toward the interlaminar
space. After subcutaneous injection of local anesthetic at the needle
insertion site, the epidural needle is directed through the skin wheal from
the local anesthetic and slowly advanced through the supraspinous and
interspinous ligaments to enter the ligamentum flavum. The practitioner
inserts a syringe containing air or saline which may include a small air
bubble. Upon entering the epidural space, the practitioner will feel a
sudden, significant loss of resistance to plunger displacement. A 20-gauge
radiopaque catheter with 1-cm graduation is passed through the epidural
needle. The catheter is generally advanced 3 to 5 cm beyond the needle tip
into the epidural space. The needle is then withdrawn over the catheter and
the catheter secured to the patient’s back. After a test dose of 3 mL of a
local anesthetic with 1:200,000 epinephrine is injected, the patient is
observed for signs and symptoms of intrathecal (IT) or intravascular
injection. The local anesthetic should be administered in 3- to 5-mL
increments, ideally with intermittent aspiration to assess for accidental IT
or intravascular placement, until the appropriate total dose is given.
Alternatively, a paramedian-lateral or paramedian-lateral oblique
approach to the epidural space may be used. For this approach, the
epidural needle insertion site is approximately one fingerbreadth lateral to
the insertion site of the midline approach. The epidural needle is directed
with slight cephalomedial orientation to allow the needle to bypass the
supraspinous and interspinous ligaments as it is advanced to enter the
triangular-shaped ligamentum flavum. Once the needle enters the
ligamentum flavum, the loss-of-resistance technique is used to enter the
epidural space at the midline. Although the paramedian approach may be
used for both lumbar and thoracic epidurals, it is extremely advantageous
in the midthoracic vertebrae (T4–T10) where the steep angle of the
spinous processes limits midline access to the interlaminar foramen.

2717
 Postoperative epidural analgesia may be delivered as a fixed continuous
infusion or as patient-controlled epidural analgesia (PCEA). Based on the
principles of patient-controlled analgesia (PCA), PCEA allows
individualization of postoperative analgesic requirements, reduces drug
use, improves patient satisfaction, and provides superior analgesia.21,22
The drug chosen for epidural analgesia is usually a local anesthetic with a
long duration of action. It should exhibit preferential clinical sensory
blockade and cause only minimal impairment of motor function.23 A
lipophilic opioid (e.g., fentanyl or sufentanil) or hydrophilic opioid (e.g.,
morphine or hydromorphone) may be added for postoperative analgesia to
allow relatively rapid titration of analgesia and densening of the block.24
Even though clonidine and epinephrine are potentially useful adjuvants,
neither is widely used clinically in adults. Clonidine may enhance
postoperative analgesia by activating the descending noradrenergic
pathway; however, its clinical usefulness is typically limited by the
presence of hypotension, bradycardia, and sedation.25,26 Epinephrine has
been shown to improve epidural analgesia and increase sensory block in
the postoperative setting.27

Subarachnoid/Intrathecal Analgesia
Spinal analgesia may offer postoperative analgesia through additives like
IT opioids for multiple procedures, including obstetric and gynecologic
procedures; genitourinary procedures; orthopedic procedures of the lower
extremity; and abdominal, vascular, spine, thoracic, and cardiac surgery.
IT additives, including fentanyl, sufentanil, morphine, hydromorphone,
and clonidine are discussed in the following text.

TECHNIQUE
Subarachnoid block may be performed with the patient in the sitting,
lateral, or prone position through a midline or paramedian approach. After
the patient is positioned, the appropriate interspace is identified, prepped,
and draped in sterile fashion. Local anesthetic is infiltrated at the needle
insertion site. The introducer needle is placed midline and advanced in the
midline plane with slight cephalad angulation through the supraspinous

2718
ligament and into the interspinous ligament. The depth to the subarachnoid
space must be anticipated to avoid inadvertent dural puncture with the
introducer needle in thin patients. The spinal needle is then advanced
through the introducer while the introducer is stabilized with the
nondominant hand. As the needle passes through the ligamentum flavum,
an increase in resistance is appreciated, followed by a loss of resistance,
with a characteristic “pop” indicating penetration of the dura and entry into
the subarachnoid space. The spinal needle stylet is removed, and free
cerebrospinal fluid (CSF) flow is confirmed through the needle. If free
CSF flow is not visualized, the hub of the needle may be rotated 90
degrees, followed by slight advancement of the needle if necessary. If CSF
free flow is unable to be confirmed, the needle is slowly withdrawn in
slight increments, with 90-degree rotation at each increment to allow for
free CSF flow. Upon obtaining free flow of CSF, the dorsal aspect of the
nondominant hand is firmly placed against the patient’s back with the
index finger and thumb stabilizing the spinal needle hub for injection. The
syringe with local anesthetic and additive is attached to the spinal needle
hub and injected with the dominant hand. If redirection of the spinal
needle is necessary secondary to bone contact, paresthesia, or failure to
obtain CSF, the anatomy should be reevaluated and the introducer
repositioned as necessary at the same or a new level. If a paresthesia is
encountered at any time, needle advancement or injection should be
stopped and resolution of paresthesia confirmed before and during
subsequent advancement and or injection.
The paramedian-lateral and paramedian-lateral oblique approaches offer
alternatives to the midline approach in patients with narrow interspinous
spaces for both subarachnoid and epidural blocks. For the paramedian-
lateral approach, the spinal introducer insertion site is approximately one
fingerbreadth lateral to the insertion site of the midline approach. The
introducer is oriented with slight medial and cephalad direction to allow
the spinal needle to bypass the supraspinous and interspinous ligaments,
pass through the triangular-shaped ligamentum flavum, and enter the
subarachnoid space at the midline.
In the paramedian-lateral oblique approach, the caudad spinous process
of the desired interspace is identified. The needle is inserted approximately

2719
one fingerbreadth lateral to this point and directed with cephalomedial
orientation to bypass the supraspinous and interspinous ligaments, pass
through the triangular-shaped ligamentum flavum, and enter the
subarachnoid space at the midline. Alternatively, the needle is initially
oriented perpendicular to the skin in all planes and advanced with the
intent to contact lamina. Upon contact with lamina, the needle is walked
off the superior edge of the lamina and advanced through the ligamentum
flavum to enter the subarachnoid space.

CLINICAL SUBARACHNOID ANALGESIA

Opioids
Highly lipophilic, short-acting opioids, such as fentanyl, can be added to
local anesthetics to improve short-term analgesia for inpatient or outpatient
procedures.28–30 The addition of 10 µg fentanyl to bupivacaine 0.5%
(hyperbaric) significantly improves the quality and duration of analgesia,
with no further advantage occurring if the dose is increased up to 40 µg.31
Hydrophilic opioids, however, provide extended postoperative analgesia in
the inpatient setting. Data from two meta-analyses that investigated the use
of IT morphine in surgical patients suggest that use of IT morphine (0.05
to 0.2 mg) for surgical procedures will decrease pain scores and systemic
opioid requirement after surgery.32,33 Dose–response trials have shown
that low doses of hydrophilic opioids maximize postoperative analgesia
with a lower incidence of side effects. For example, Cole et al.34 reported
that 0.3 mg of IT morphine significantly reduces pain and PCA
requirements compared to those of placebo after knee arthroplasty, with no
significant difference in hypoxemia and apnea between groups. For opioid-
tolerant patients, higher doses are probably acceptable, whereas doses of
less than 0.3 mg may be ideal for opioid-naive individuals.35 IT opioids
have been used for cardiac surgery with improved analgesia; however,
concerns with bleeding complications in patients who are receiving
heparin and demonstrations of prolonged extubation times may have
limited their use. Alhashemi et al.36 showed that 250 µg is the optimal
dose of IT morphine to provide significant postoperative analgesia without
delaying tracheal extubation after coronary artery bypass graft surgery. IT
opioid combinations provide better analgesia than systemic opioids in

2720
patients undergoing vascular and thoracic procedures. Compared to those
who received intravenous (IV) PCA morphine, patients who received a
mixture of either 20 µg of sufentanil with 0.2 mg of morphine, or 50 µg of
sufentanil with 0.5 mg of morphine, have improved pain control with
minimal side effects other than an increased frequency of urinary
retention.9,37 Although epidural analgesia with local anesthetics and
opioids is likely superior to IT opioids in decreasing pulmonary
complications after thoracotomy,38 IT opioids may be a good alternative to
epidural analgesia when an epidural catheter cannot be used.

Clonidine
Studies have shown that IT clonidine at doses from 15 to 150 µg improves
postoperative analgesia while minimizing side effects. Adding concurrent
administration of 25 to 75 µg clonidine with 250 µg morphine to a
bupivacaine spinal anesthetic decreased 24-hour IV morphine
consumption and improved 24-hour visual analog scale (VAS) scores as
compared to adding 250 µg IT morphine alone to bupivacaine spinal
anesthetic.39–41

Combined Spinal and Epidural

The combined spinal epidural (CSE) technique offers the advantage of
both spinal and epidural techniques. CSE provides rapid-onset surgical
anesthesia,42,43 the ability to titrate to the desired sensory level and
duration, and the ability to deliver postoperative analgesia through the
epidural catheter.
The CSE technique is widely used in obstetric anesthesia and analgesia.
In labor analgesia, CSE provides quick onset of pain relief while
maintaining ambulation ability. Studies have shown great benefit of using
small opioid doses (e.g., 10 to 15 µg of IT fentanyl44) while adding a small
dose of isobaric bupivacaine,45 ropivacaine, or levobupivacaine.46,47 CSE
may be associated with reduced duration of the first stage of labor in
primiparous mothers48 but does not shorten total labor time compared to
conventional epidural analgesia.49
Another advantage of using this technique is that small doses of the

2721
spinal anesthetic can be used and the risk of a high spinal block and
prolonged hypotension50,51 can be avoided in patients who are already
hypovolemic. Potential challenges associated with CSE are the inability to
properly test the epidural catheter, increased incidence of catheter
migration to the IT space, and enhanced spread of the spinal local
anesthetic.52

TECHNIQUE OF COMBINED SPINAL EPIDURAL

Needle through Needle Technique
Neuraxial techniques in general can be performed with the patient in either
a lateral or sitting position. The CSE technique is typically performed with
patients sitting. It should be noted that during needle insertion, the distance
from skin to epidural space is greater when patients are in the lateral
position than when they are in the sitting position. After the epidural
needle is inserted, a loss of resistance to plunger displacement indicates
entrance into the epidural space. At that point, the plunger is carefully
removed and a spinal needle is passed through the epidural needle until the
characteristic “pop” is felt, indicating penetration of the dura and entry into
the subarachnoid space. After free CSF flow is confirmed, the dorsal
aspect of the nondominant hand is firmly placed against the patient’s back,
with the index finger and thumb stabilizing the hub for injection. Local
anesthetic with additive is injected, and the spinal needle is withdrawn. A
20-gauge radiopaque catheter with 1-cm graduation is passed through the
epidural needle. The catheter is advanced 4 to 5 cm beyond the needle tip
into the epidural space. The needle is then withdrawn over the catheter,
and the catheter secured to the patient’s back. Prior to dosing, a test dose
should be administered through the catheter.

Separate Needles Techniques

Two-needle, two interspace techniques: CSE could be carried out with
two separate needles, one spinal and one epidural, with either the same
interspace53,54 or two different interspaces.55–57 With the same-interspace
technique, the epidural catheter will be placed first to allow proper testing
before spinal anesthesia. This testing is mainly to decrease risks of IT or
intravascular catheter migration. This technique carries the risk of

2722
shearing58,59 the epidural catheter with the introduction of the spinal
needle. In the different-interspaces technique, the practitioner places the
spinal needle but does not inject local anesthetic. He or she then places the
epidural catheter and tests it at a different interspace before administering
the spinal dose. This technique allows testing of the epidural catheter while
avoiding shirring of the catheter.
Regardless of which step is taken first, these techniques carry a
disadvantage of taking longer to perform and requiring two separate
injections. When the needle through needle (NTN) and separate needles
techniques (SNT) have been compared,60,61 some have reported better
success and lower failure rate with SNT but greater patient acceptance,
less discomfort, and quicker procedure time with the NTN.

COMPLICATIONS AND CHALLENGES WITH

COMBINED SPINAL EPIDURAL
Spinal migration of the epidural catheter and IT administration of epidural
drugs are more likely to occur with the NTN technique.62–64 Regardless of
the technique used, all epidural medications should be administered in
small incremental doses while the patient’s hemodynamics are closely
monitored.
Failure of the spinal block is a possibility and depends on the provider’s
experience. Failures occur mainly as a result of the spinal needle being too
short,65 failure to puncture the dura with a small-caliber spinal needle,66
and diverging from the midline.67 Additionally, delay while placing the
epidural catheter68 might affect the density and level of the spinal block.
Another complication from CSE is possible nerve damage from needle
or catheter trauma that occurs when the practitioner places an epidural in a
patient who has received spinal anesthesia. Although this is a rare
complication, the absence of sensation after spinal anesthesia may prevent
identification of paresthesia that would alert anesthesiologists to needle
misplacement.

Contraindications of Neuraxial Techniques

Although complications of neuraxial analgesia are extremely rare, they can

2723
be very serious. Among those complications are neuraxial hematoma,
abscess, and permanent nerve injuries. Evaluation of the risks and benefits
of neuraxial analgesia is always helpful and should be based on the
patient’s comorbidities and risk factors.

SEPSIS, FEVER, AND VIRAL INFECTIONS

Infectious complications of neuraxial techniques are extremely rare, and
data are insufficient to determine whether epidural analgesia should or
should not be initiated in septic patients.69 The possibility of introducing
blood-borne pathogens into the neuraxial space is a very valid concern for
many practitioners. Regional anesthesia in the presence of low-grade fever
should be based on an individual risk–benefit analysis. Antibiotics should
be used before initiating the block, and the practitioner should use strict
aseptic techniques during postprocedure monitoring to detect any signs of
central nervous system (CNS) infection.
The CNS is affected early in the course of HIV infection,70 and there is
no evidence that epidural placements or an epidural blood patch for
treatment of postdural puncture headache (PDPH) causes any additional
spread of the virus to the CNS. It is advisable to obtain thorough
documentation of any neurologic deficit before attempting a neuraxial
technique in these patients. Studies have shown no reported incidence of
CNS infection with neuraxial blocks in patients with recurrent herpes
simplex infection.71,72 However, a neuraxial block or catheter is
contraindicated in the presence of active herpes zoster at the site of
injection. Complications such as aseptic meningitis and encephalitis might
develop from spread of the virus to the CNS.73

COAGULOPATHY, THROMBOCYTOPENIA, AND

BLEEDING DISORDERS
Neuraxial techniques are contraindicated if the patient refuses it and in
those with severe coagulopathy and disseminated intravascular coagulation
(DIC). DIC can result from severe trauma, sepsis, amniotic fluid
embolism, massive transfusion, and placental abruption, among many
other diseases. Initiating an epidural in the presence of coagulopathy is an
absolute contraindication, but keeping an epidural in the presence of

2724
coagulopathy is controversial. The epidural should be removed only after
normal coagulation is restored. Epidural catheter removal could be as
traumatic as placement, and the same precautions should be applied.74
Anticoagulants should be held in a timely fashion before initiation or
removal of an epidural catheter. Placement of an epidural catheter is
considered a relative contraindication in the presence of some bleeding
disorders like hemophilia and von Willebrand disease, but it is considered
safe after factor levels and partial thromboplastin time have reached
normal values.
Thrombocytopenia is another relative contraindication to neuraxial
anesthesia. Currently, no guidelines exist for a platelet count below which
epidural placement is contraindicated. Some clinicians feel comfortable
with a platelet count of 80,000, whereas others will go as low as 70,000.75
The etiology of thrombocytopenia, the patient’s bleeding status, and the
trend in platelet count must be taken into consideration before placement
of an epidural catheter. One can obtain a thromboelastography (TEG) to
assist in determining whether to place an epidural or not. Ultimately, the
decision is based on the risks and benefits for the individual patient.

CENTRAL NERVOUS SYSTEM DISORDERS

In the past, neuraxial blockade was contraindicated in patients with
preexisting CNS disease, including multiple sclerosis (MS). However, a
recent retrospective study76 of 35 patients with MS showed no evidence of
MS relapse after neuraxial block. It is reasonable to use low concentrations
and low volumes of local anesthetics in these patients and thoroughly
document any preexisting neurologic deficits before initiating a neuraxial
block. A thorough informed consent should be given to the patient
explaining the possibility of MS symptom aggravation.77
The risk of neurologic complication during a neuraxial technique is
higher in anesthetized patients because they cannot respond to pain or
paresthesia during needle placement.78 The risk of neurologic
complications is minimal during placement of a lumbar epidural in
anesthetized patients,79 and it is uncertain whether the risk might be higher
with thoracic epidural. Previous back surgery and back pain are not
considered contraindications for neuraxial techniques. In a large

2725
retrospective study of patients with a history of spinal stenosis, peripheral
neuropathy, or lumbar radiculopathy, these conditions did not affect the
efficacy or complications of neuraxial techniques.80 The practitioner
should discuss an informed thorough consent with the patient and explain
the increased risk of technical difficulties, dural puncture, and
unsuccessful block.

Analgesic Adjuvants for Central and Peripheral

Analgesia
INTRODUCTION
Nociceptive pathways in the central and peripheral nervous systems are
very complex and not easily blocked by one drug type or one technique.
The use of agonists at inhibitory receptors and antagonists at excitatory
receptors in the pain pathways allows a “multimodal” approach with
optimization of pain control and reduction of adverse effects.
Neuraxial drugs such as opioids selectively decrease nociceptive
afferent input from Aδ and C fibers without affecting dorsal root axons or
somatosensory-evoked potentials.81 Opioid receptors in the ventral medial
medullary reticular formation may be involved in activation of
noradrenergic pathways. Additionally, a descending inhibitory pathway
projecting through the dorsolateral funiculus may reinforce other analgesic
mechanisms.82,83 The advantages of neuraxial opioids lay in the absence of
sympathetic blockade and postural hypotension, providing for potentially
easier ambulation of patients.
The last few decades have witnessed important advances in the
knowledge of nociceptive transmission from the peripheral nervous system
to the CNS. A number of drugs have been tested, and some have proven
clinically useful when added to local anesthetics for central and peripheral
nerve block (PNB). These drugs, known as analgesic adjuvants, include
opioids, dexamethasone, and α2 agonists. They may have benefit if applied
in the peripheral nervous system.84 Some adjuvants added to local
anesthetics might speed their onset, prolong their effect, or reduce total
required dose. Adjuncts are also used to enhance analgesia while
minimizing side effects.

2726
NEURAXIAL OPIOIDS
Opioids are classified by their lipophilic property. Lipophilic opioids (e.g.,
sufentanil and fentanyl) tend to provide a fast onset and short duration of
analgesia as a result of rapid clearance from the CSF. Hydrophilic opioids
(e.g., hydromorphone and morphine) remain within the CSF after
neuraxial administration and produce a delayed but long duration of
analgesia. They also tend to cause a higher incidence of side effects
because of CSF spread. Hydrophilic opioids provide analgesia primarily
via a spinal mechanism, whereas lipophilic opioids provide analgesia via
either a spinal or systemic mechanism.85,86 Single-shot neuraxial
administration of a lipophilic opioid is appropriate for short-duration
analgesia,87 and single-shot neuraxial administration of a hydrophilic
opioid is appropriate for longer duration analgesia.88
Neuraxial opioids are associated with side effects that could affect
patients’ quality of recovery. Side effects include nausea and vomiting in
up to 50% of patients89,90 and pruritus in up to 60%,91 as opposed to 15%
to 18% for PCEA with local anesthetic or systemic opioids.92,93 Other
adverse effects include urinary retention in up to 80% of patients and early
or delayed respiratory depression in 0.2% to 1.9%.90 These side effects are
not limited to any specific opioid, and it is not clear whether their
incidence is dose dependent. PCEA with combined local anesthetic and
neuraxial opioids results in a low incidence of respiratory depression that
varies from 0.07% to 0.4%,94–96 thus making PCEA relatively safe to use
in an unmonitored hospital setting. It is essential that the dose of neuraxial
opioid be reduced when used in elderly patients.97

PERINEURAL OPIOIDS
Some systematic reviews98,99 found little evidence for the benefit of
adding opioids to local anesthetics in peripheral nerve blockade.
Preliminary results suggest that buprenorphine and tramadol98,100–102 are
the two opioid agonists that have demonstrated analgesic efficacy when
administered perineurally. Buprenorphine is a partial µ-receptor agonist
with a very high receptor affinity compared with that of fentanyl or
morphine. In addition, it has intermediate lipid solubility, which allows it
to cross the neural membrane.103,104 Buprenorphine was found to

2727
markedly increase the duration of analgesia when added to mepivacaine
and tetracaine for axillary blocks,105 with no significant increase in
adverse effects. Similar results were found when a 100-mg dose of
tramadol was used as an adjuvant to mepivacaine in axillary brachial
plexus block.106,107 One study reported an increased duration of motor and
sensory blockade in the axillary tramadol group that significantly (P < .01)
outlasted both IV and placebo groups.108

PERINEURAL CLONIDINE AND DEXMEDETOMIDINE

Clonidine, an α2 agonist with some α1-stimulatory effects, is traditionally
used as an antihypertensive agent but for many years has been noted to
have sedative and analgesic effects. α2 Receptors exist in the dorsal horn
of the spinal cord, and their stimulation produces analgesic effects by
inhibiting the presynaptic release of excitatory transmitters, including
substance P and glutamate.109–111 IT clonidine mediates analgesia by
increasing acetylcholine levels. Clonidine injected close to peripheral
nerves with or without local anesthetic drugs appears to mediate analgesia
in a number of ways. Clonidine has local anesthetic properties112 and has a
pharmacokinetic effect on local anesthetic redistribution mediated by a
vasoconstrictor effect at the α1-receptor.113
Many studies have examined the effect of clonidine on local anesthetics
in PNB. There is good evidence from these studies that clonidine in doses
up to 1.5 µg/kg prolongs sensory block and analgesia when administered
with local anesthetics for PNB.114 Some studies have compared clonidine
added to PNB to systemic clonidine. Clonidine added to the axillary
brachial plexus block delayed the onset of pain twofold compared with
subcutaneous clonidine injections, without producing adverse effects.115
A meta-analysis by Pöpping and colleagues116 estimated that clonidine
prolonged postoperative analgesia, sensory block, and motor block by 122,
74, and 141 minutes, respectively. Clonidine also increased the probability
of hypotension (odds ratio [OR], 3.61), fainting (OR, 5.07), sedation (OR,
2.28), and bradycardia (OR, 3.09).
Ifield et al.117,118 have demonstrated in two studies that the addition of
clonidine to continuous PNBs is not beneficial. It failed to reduce pain
scores or oral analgesic use after upper extremity surgery.

2728
 Dexmedetomidine is selective for the α2 receptor and at present is
mainly studied as a sedative agent in ICUs. Dexmedetomidine may be
expected to produce not only more profound analgesia but also greater
adverse effects because of the selectivity of action.119

PERINEURAL DEXAMETHASONE
Dexamethasone is a potent synthetic corticosteroid with approximately 7
times the anti-inflammatory potency of prednisolone.120 The half-life is
approximately 36 to 54 hours in the perioperative setting. The
effectiveness of dexamethasone as a postoperative antiemetic (4 to 10 mg
IV) has been confirmed by many randomized controlled trials.121 In a
recent meta-analysis that included 2,751 patients,122 the analgesic effects
of a single IV dose of dexamethasone was found to be very modest up to
24 hours postinjection.
Corticosteroids administered via perineural application are thought to
exert their effect by several mechanisms, including attenuating the release
of inflammatory mediators, reducing ectopic neuronal discharge, and
inhibiting potassium channel–mediated discharge of nociceptive C
fibers.123–125 It is widely believed that dexamethasone improves the
quality and duration of peripheral nerve blockade when administered in
conjunction with local anesthetics. The U.S. Food and Drug
Administration (FDA), however, has not approved dexamethasone for
perineural administration.
Multiple studies have assessed the effects of using dexamethasone (4 to
10 mg) with local anesthetic for PNBs.126–131 Dexamethasone was shown
to prolong analgesia or sensory/motor block from approximately 50% to
75% beyond that of nerve blocks with local anesthetic alone. Nevertheless,
some concerns have been raised over complications related to
dexamethasone, such as effects on blood glucose and neurotoxicity.
However, in several studies, a single dose of dexamethasone, whether
administered perineurally or systemically, did not increase blood glucose
to a clinically significant degree,132–134 and IT administration did not
produce neurotoxicity.135
Adjuvants have been added to local anesthetic for single perineural
analgesia in an attempt to improve analgesia quality, spare local anesthetic

2729
consumption, and minimize motor block. To date, clinical benefits such as
improving pain have been found for adding adjuncts to continuous
PNBs.117,118,136,137 No additive medications are currently approved for
continuous perineural administration, and some additives that have been
reported in clinical trials have undesirable side effects.138,139

Transversus Abdominis Plane Block, Ilioinguinal

Iliohypogastric Block, Rectus Sheath Block
Innervation of the anterolateral abdominal wall arises from the anterior
rami of spinal nerves T7–L1. These include the intercostal nerves (T7–
T11), the subcostal nerve (T12), and the iliohypogastric and ilioinguinal
nerves (L1). The anterior divisions of T7–T11 continue from the
intercostal space to enter the abdominal wall between the internal oblique
and transversus abdominis muscles until they reach the rectus abdominis,
which they perforate and supply, ending as anterior cutaneous branches
supplying the skin of the front of the abdomen. Midway in their course,
they pierce the external oblique muscle giving off the lateral cutaneous
branch, which divides into anterior and posterior branches that supply the
external oblique muscle and latissimus dorsi respectively.

TRANSVERSUS ABDOMINIS PLANE BLOCK

It may play a role in postsurgical pain control. Transversus abdominis
plane (TAP) blocks may improve analgesia in patients undergoing
laparotomy for colorectal surgery, laparoscopic cholecystectomy, and open
and laparoscopic appendectomy.140–142 Blocks can be achieved by using
anatomic landmarks or by ultrasound-guided techniques.143,144
The aim of a TAP block is to deposit local anesthetic in the plane
between the internal oblique and transversus abdominis muscles, targeting
the spinal nerves in this plane. The innervation to abdominal skin, muscles,
and parietal peritoneum will be interrupted. If surgery traverses the
peritoneal cavity, dull visceral pain (from spasm or inflammation
following surgical insult) will still be experienced.

Landmark Technique

2730
The landmark technique for performing a TAP block advocates a single
entry point, the triangle of Petit, to access a number of abdominal wall
nerves.145 The lumbar triangle of Petit is situated between the lower costal
margin and the iliac crest. It is bound anteriorly by the external oblique
muscle and posteriorly by the latissimus dorsi. This TAP technique relies
on feeling double pops as the needle traverses the external oblique and
internal oblique muscles. A blunt needle will make the loss of resistance
more appreciable.

Ultrasound-Guided Transversus Abdominis Plane

Ultrasound guidance for the TAP block can help the practitioner localize
and deposit the local anesthetic and thereby improve accuracy.146 The
ultrasound probe is placed in a transverse plane to the lateral abdominal
wall in the midaxillary line, between the lower costal margin and the iliac
crest (Figs. 52.1 and 52.2). The local anesthetic is deposited in the correct
neurovascular plane between the transverse abdominis and internal oblique
muscles. If prolonged analgesia is required beyond the duration of a single
shot of local anesthetic, a catheter can be introduced into the TAP through
a Tuohy needle. After opening up the plane with 2 mL of saline, the
practitioner introduces the catheter approximately 3 cm beyond the needle
tip. The position is verified by injecting a local anesthetic bolus (20 mL).
An infusion of a dilute local anesthetic is started at a rate of 7 to 10 mL per
hour.
There has been controversy in the literature regarding the spread and
level of block achieved with a single TAP injection. Early studies showed
a T7–L1 spread after a single posterior injection, making the block suitable
for midline abdominal incisions.147 Other studies, however, failed to
demonstrate a spread cephalad to T10, making it more suited for lower
abdominal surgery.148 It is reasonable to expect a good analgesic effect in
the region between T10 and L1 after a single posterior injection.
Augmentation with a subcostal injection will help attain a higher block up
to T7. The subcostal TAP is a modification of the original technique in
which the ultrasound probe is placed just beneath the costal margin and
parallel to it (see Fig. 52.1). The needle is then introduced from the lateral
side of the rectus muscle in plane of the ultrasound beam, and 10 mL of

2731
local anesthetic is injected into the TAP to extend the analgesia provided
by the posterior TAP block above the umbilicus.

FIGURE 52.1 Surface landmarks for abdominal wall block. TAP, transversus abdominis plane.
(Reproduced with permission from Ouanes et al.
http://anesthesiology.hopkinsmedicine.org/international-obstetric-and-regional-anesthesia/.
Accessed July 18, 2018.)

Reported complications include intraperitoneal injection or hemorrhage,

transient femoral nerve palsy, and local anesthetic toxicity.149–151 One case
report has been published of intrahepatic injection with blind technique.152
Local anesthetic toxicity could also result from the large volumes required
to perform this block, especially if it is done bilaterally. As with any
regional technique, careful aspiration will help avoid intravascular
injections.

ILIOHYPOGASTRIC AND ILIOINGUINAL BLOCK

The iliohypogastric nerve (L1) divides between the internal oblique and
transversus abdominis near the iliac crest into lateral and anterior
cutaneous branches, the former supplying part of the skin of the gluteal
region and the latter supplying the hypogastric region. The ilioinguinal
nerve (L1) communicates with the iliohypogastric nerve between the

2732
internal oblique and transversus abdominis near the anterior part of the
iliac crest. It supplies the upper and medial part of the thigh and part of the
skin covering the genitalia.
This block is indicated for any lower abdominal surgery, including
appendectomy, hernia repair, cesarean section,153 abdominal
hysterectomy,154 and prostatectomy.155 Efficacy in laparoscopic surgery
has also been demonstrated.156 Bilateral blocks can be administered for
midline incisions or laparoscopic surgery. The needle is introduced in
plane of the ultrasound probe directly under the probe and advanced until
it reaches the plane between the internal oblique and transversus
abdominis muscles (see Figs. 52.1 and 52.3).

FIGURE 52.2 Ultrasound image transversus abdominis plane block. Left: Labeled sonoanatomy.
Right: In-plane needle position with injection in the plane between the internal oblique and
transversus abdominis. (Reproduced with permission from Ouanes et al.
http://anesthesiology.hopkinsmedicine.org/international-obstetric-and-regional-anesthesia/.
Accessed July 18, 2018.)

FIGURE 52.3 Ultrasound image of ilioinguinal iliohypogastric nerve block. DCIA, deep
circumflex iliac artery; IH, iliohypogastric nerve; Il, ilioinguinal nerve. (Reproduced with
permission from Ouanes et al. http://anesthesiology.hopkinsmedicine.org/international-obstetric-
and-regional-anesthesia/. Accessed July 18, 2018.)

RECTUS SHEATH BLOCK

2733
Local anesthetic deposition bilaterally within the posterior rectus sheath
provides dense and predictable analgesia over the middle anterior wall
from the xiphoid process to the symphysis pubis, as shown in Figures 52.1
and 52.4. It is used for surgery with midline (or paramedian) abdominal
incision. Rectus sheath block does not provide analgesia for the lateral
abdomen, but it will provide somatic pain relief for abdominal wall
structures superficial to the peritoneum. Patients with rectus sheath
catheters typically exhibit low pain scores and low opiate
requirements.157,158

FIGURE 52.4 Left: Needle approach for rectus sheath block. Right: Labeled ultrasound image.
IO, internal oblique; TA, transversus abdominis. (Reproduced with permission from Ouanes et al.
http://anesthesiology.hopkinsmedicine.org/international-obstetric-and-regional-anesthesia/.
Accessed July 18, 2018.)

Bilateral rectus sheath block might be helpful after emergency

laparotomy. This patient group may have sepsis, coagulopathy, and
hemodynamic instability. Administering an epidural postoperatively is
usually not possible owing to positioning difficulty and safety concerns
regarding placement of epidurals in unconscious patients.

Peripheral Nerve Blocks and Catheters

PNBs are an integral part of a postoperative multimodal analgesic
regimen.159 Use of regional anesthesia techniques have been associated
with postanesthesia care unit (PACU) phase 1 bypass, fewer unplanned
hospital admissions, and lower hospital costs.160 These techniques
improve analgesia and reduce the amount of IV analgesics required, thus
decreasing opioid-related side effects.161–163 Some of the benefits of
single-injection nerve blocks are limited by the duration of action of the
local anesthetic used.

2734
 Peripheral nerve catheters (PNCs) offer the possibility of extending the
effects of the nerve block. Continuous peripheral nerve blockade (CPNB)
provides postoperative analgesia equivalent to that of epidural techniques
and may be associated with higher patient satisfaction, improved side-
effect profile, and fewer complications than epidurals.162,164 Strong
evidence suggests that continuous perineural blockade provides superior
analgesia compared to opioids for all catheter locations while reducing
opioid consumption and opioid-related side effects.4 The use of CPNB
decreases the time to readiness for discharge of inpatients and allows for
more aggressive rehabilitation in the postoperative period.165 In the case of
continuous interscalene nerve block for arthroscopic rotator cuff repair, its
analgesic effects have been shown to extend into postoperative day 7.166
The use of CPNB may allow surgical procedures that traditionally
required hospital admission to be performed in an outpatient setting
without a significant increase in complications.167 CPNB may be provided
after discharge with a portable infusion pump, affording patients the
possibility to convalesce in the comfort of their home while reducing
inpatient costs.168 Shorter inpatient stays may also have other benefits,
such as lower morbidity related to nosocomial infections or medical
error.169 Complications associated with home CPNB are uncommon, the
most common being block failure resulting from catheter dislodgment.
Other potential complications include infection, pulmonary-related side
effects as local anesthetic infusions may affect the phrenic nerve, systemic
local anesthetic toxicity, and patient falls.170 Patient selection plays a key
role in the success of ambulatory CPNB, and although the optimal method
and frequency of patient monitoring remains to be established, daily phone
calls seem to be a widely accepted method. A retrospective review of
1,059 ambulatory supraclavicular and popliteal catheters placed over a 2-
year period and infused over a mean duration of 5 days failed to reveal an
increased incidence of complications.171
Among the different techniques for performing PNBs, ultrasound-
guided regional anesthesia (UGRA) is becoming the method of choice.
Compared with nerve stimulation, UGRA has been shown to provide a
faster onset of blockade, better success rate, fewer needle passes with
associated faster block performance, less patient discomfort, and greater

2735
patient satisfaction.172–174 Additionally, there is level Ib evidence for a
grade A recommendation that UGRA improves success of sensory block
and decreases local anesthetic requirements.175 Interscalene catheters
placed under UGRA after shoulder surgery were shown to be more
effective in the first 24 hours than neurostimulation.176 Based on large
prospective series, the complication rate does not seem to differ between
UGRA and neurostimulation.177,178

Interscalene Block
INDICATIONS
The interscalene block (ISB) is usually performed for surgical procedures
involving the shoulder and upper arm. The brachial plexus is targeted at
the trunk level; however, it commonly results in sparing blockade of the
inferior trunk (C8–T1), making it less suitable for elbow, forearm, and
hand procedures. ISB causes concomitant block of the phrenic nerve
because of its close proximity, particularly at the cricoid cartilage level. At
this level, the plexus and phrenic nerve are 2 to 4 mm apart. This distance
increases progressively in a caudad direction.179 Horner syndrome and
recurrent laryngeal nerve block resulting in hoarseness can occur. Relative
contraindications to ISB include respiratory failure, contralateral phrenic
nerve lesion, and contralateral recurrent laryngeal nerve lesion. The plexus
can be accessed at the interscalene groove through a lateral approach or a
cervical paravertebral approach.180,181

LANDMARKS
The brachial plexus is formed mainly by the anterior rami of the spinal
nerves C5–T1. These nerves coalesce into three trunks (superior, middle,
inferior), which emerge through the interscalene groove between the
anterior and middle scalene muscles.

TECHNIQUES
Nerve Stimulation
At the level of the cricoid cartilage, the interscalene groove can be
palpated behind the posterior border of the sternocleidomastoid muscle

2736
(SCM). The stimulating needle is introduced in a cephalocaudal and
slightly medial direction. Adequate needle placement is identified by the
presence of motor response to stimulation between 0.2 and 0.5 mA in the
deltoid, triceps and biceps, forearm, or hand muscles. Contraction of the
diaphragm or neck musculature indicates anterior placement of the needle
tip, whereas contraction of the trapezius muscle indicates posterior
placement.

Ultrasound Guidance
The practitioner places the high-frequency ultrasound probe transversally
at the C6 (cricoid) level and slides it laterally while observing the internal
jugular, carotid artery, and SCM superficially. As the posterior border of
the SCM is visualized, the anterior and middle interscalene muscles appear
deep to the SCM, with the trunks of the brachial plexus emerging between
them as round hypoechoic structures. Alternatively, the probe can be
placed in the supraclavicular fossa, where the divisions of the brachial
plexus are visualized posterior and lateral to the subclavian artery and
above the first rib. The practitioner then slides the probe in a cephalad
direction, observing the divisions converge into trunks at the interscalene
level. The needle can be advanced in plane lateromedially, allowing for
visualization of the entire needle shaft and tip (Figs. 52.5 and 52.6).
Alternatively, the needle can be introduced out of plane to the ultrasound
beam, resulting in a dot in the ultrasound image when the tip of the needle
crosses the beam.

FIGURE 52.5 Left: Ultrasound image of interscalene anatomy. Right: Ultrasound image with
anatomy labeled. Yellow, C5–C7 nerve roots. AS, anterior scalene; MS, middle scalene; SCM,
sternocleidomastoid muscle. (Reproduced with permission from Ouanes et al.
http://anesthesiology.hopkinsmedicine.org/international-obstetric-and-regional-anesthesia/.
Accessed July 18, 2018.)

2737
FIGURE 52.6 Left: In-plane approach of interscalene block. Right: Ultrasound image of in-plane
approach of interscalene nerve block. Green, local anesthetic; yellow, C5–C7 nerve roots. AS,
anterior scalene; MS, middle scalene; SCM, sternocleidomastoid muscle. (Reproduced with
permission from Ouanes et al. http://anesthesiology.hopkinsmedicine.org/international-obstetric-
and-regional-anesthesia/. Accessed July 18, 2018.)

CLINICAL EFFECTS
Single-injection ISB for shoulder arthroscopies may be associated with
fewer side effects and fewer and shorter hospital admissions than that seen
with general anesthesia. In the ambulatory setting, ISB results in decreased
postanesthesia unit stay and fewer unplanned hospital admissions for pain,
sedation, and nausea.182,183 ISB is effective at reducing the demand for IV
PCA-delivered opioids and associated adverse effects after shoulder
surgery.163 Abdallah et al.184 concluded in a recent meta-analysis that
single-injection ISB provides effective analgesia for up to 8 hours
postoperatively, whereas the opioid-sparing profile and lower adverse
effects are limited to the first 12 and 24 postoperative hours respectively.
In contrast to these findings, good evidence indicates that continuous ISB
provides better analgesia, greater patient satisfaction, and fewer side
effects than IV opioid PCA.185–187
In a comparison of single-injection to continuous ISB for arthroscopic
rotator cuff repair, Malik et al.188 concluded that continuous ISB for 3
days provides better analgesia than single-injection ISB and is associated
with less opioid consumption and better sleep patterns. Such benefits may
extend through the first postoperative week.189 A retrospective review of
continuous ISB performed for shoulder surgery revealed similar effects on
analgesia and reduction of opioid requirements in the PACU, although
these benefits were not associated with enhancing fast-track capability.190
In contrast, a recent prospective randomized clinical trial comparing

2738
single-injection ISB to general anesthesia alone for shoulder arthroscopy
showed significantly faster postoperative recovery time with ISB.191
Continuous ISB with an indwelling catheter facilitates early physical
therapy and enhances postoperative patient rehabilitation.192 Better
functional outcomes stemming from superior analgesia and early
mobilization have also been described in patients receiving ISB for
proximal humerus fracture repair.193
ISB should be considered with caution in patients with underlying
severe pulmonary morbidity. Continuous ISB does not significantly
prolong the duration of unilateral phrenic paresis compared to that with
single injection ISB.194 A clinical comparison of patients randomized to
anterior and posterior approaches to ISB did not show a difference in
incidence of phrenic nerve block.195 Ghodki et al.196 found a higher
incidence of hemidiaphragmatic paresis, as assessed by ultrasonographic
evaluation and pulmonary function tests, when ISB was performed with
peripheral nerve stimulation than when it was performed with ultrasound
guidance. Extrafascial injection (4 mm lateral to the brachial plexus
sheath) has also been reported to reduce the incidence of
hemidiaphragmatic paresis compared to that with conventional intrafascial
injection (between C5 and C6 within the interscalene groove) while
resulting in similar analgesia.197 Maga et al.198 reported that faster onset
was the only advantage of injection inside the brachial plexus sheath over
injection outside the sheath. There was no statistically significant
difference in sensory blockade after 10 minutes, but injection inside the
sheath resulted in a higher incidence of transient paresthesia.

Supraclavicular Block
INDICATIONS
The supraclavicular nerve block (SCB) targets the brachial plexus at the
trunks/divisions level. It has been used for surgical procedures involving
the shoulder, arm, forearm, and hand. It can be performed as a single
injection or with a continuous infusion through a catheter. The
supraclavicular approach has a high incidence of success in blocking the
ulnar and musculocutaneous nerves, which are commonly missed with

2739
interscalene and axillary blocks, respectively.199 Therefore, the SCB has a
broader spectrum of applications for both surgical anesthesia and
postoperative analgesia.

LANDMARKS
At the supraclavicular level, the brachial plexus is composed of the
anterior and posterior divisions of the three trunks. It is surrounded by its
own fascia and located superior and lateral in relation to the subclavian
artery, between the clavicle and the first rib.

ULTRASOUND TECHNIQUE
With the patient’s head turned to the contralateral side of the block, the
ultrasound probe is placed on the supraclavicular fossa, yielding a cross-
sectional image of the brachial plexus and subclavian artery. The plexus is
confirmed to lie superior and lateral to the artery. The optimal view is
obtained when the first rib appears as a hyperechoic structure with its
corresponding acoustic shadow just inferior to the subclavian artery and
the brachial plexus. In this view, excessive advancement of the block
needle should encounter the first rib, thereby reducing the risk of
pneumothorax. The needle is introduced in plane from the lateral end of
the ultrasound probe (Figs. 52.7 and 52.8).

FIGURE 52.7 Left: Supraclavicular block. In-plane needle approach. Right: Ultrasound image
with anatomy labeled. (Reproduced with permission from Ouanes et al.
http://anesthesiology.hopkinsmedicine.org/international-obstetric-and-regional-anesthesia/.
Accessed July 18, 2018.)

2740
FIGURE 52.8 Supraclavicular approach to the brachial plexus block. Left: Initial needle approach
and injection point between first rib and brachial plexus. Right: Additional injection point between
superior and middle trunks to spread above the plexus. LA, local anesthetic; SA, subclavian artery.
(Reproduced with permission from Ouanes et al.
http://anesthesiology.hopkinsmedicine.org/international-obstetric-and-regional-anesthesia/.
Accessed July 18, 2018.)

CLINICAL EFFECTS
A duration of sensory block of up to 17 hours has been described after
SCB.200 A recent randomized controlled trial of patients undergoing open
rotator cuff repair found that continuous SCB provided analgesia in the 24-
hour postoperative period equivalent to that of continuous ISB while
reducing the incidence of hemidiaphragmatic paresis.201 Similar results
were reported when these two block modalities were compared for
arthroscopic shoulder surgery.202 SCB has been reported to cause
hemidiaphragmatic paresis in approximately one-third of cases.203
Therefore, it should be chosen carefully for patients with significant
respiratory comorbidities.
Studies have shown no significant advantages of using a double-
injection technique over a single-injection technique for the SCB under
ultrasound guidance.204,205 However, Arab et al.206 found that although a
triple-injection technique was associated with a longer performance time
than a single-injection, it provided a more successful nerve blockade in the
first 20 minutes. There was no difference in the success of surgical
anesthesia between the two groups at 30 minutes. Subfascial injection of
the local anesthetic (deep to the brachial plexus sheath) under ultrasound
guidance resulted in a faster onset of surgical blockade and longer duration
of postoperative analgesia than did an extrafascial injection (superficial to
the sheath).207
Over the past decade, the application of ultrasound to SCB has reduced
the probability of complications, including pneumothorax, Horner
syndrome, phrenic nerve palsy (50% to 70% incidence), and local

2741
anesthetic systemic toxicity.208,209 Ultrasound also allows a faster onset
time of the sensory blockade, prolongs duration, and reduces the local
anesthetic dose.199,209 Because of the proximity of the pleura to the
supraclavicular fossa, pneumothorax can be a significant complication of
the SCB. The incidence of pneumothorax was described to be as high as
6.1% when SCB was performed without ultrasound guidance. A
prospective observational study of 6,366 ultrasound-guided SCBs found a
pneumothorax incidence of 0.06%, suggesting that ultrasound decreases
the incidence of this complication.210 A 5-year retrospective study
confirmed the extremely low pneumothorax complication rate, including
when SCB was performed by residents-in-training under direct faculty
supervision. These findings suggest that ultrasound guidance has a
significance in reducing pneumothorax complications.211
The incidence of phrenic nerve palsy after SCB is 50% to 70%. The use
of ultrasonography, by virtue of reducing the volume of local anesthetic
required for an effective block, has not been associated with
hemidiaphragmatic paresis with volumes of 20 mL.212 A recent
prospective review of outcomes in upper limb surgery reinforced the
efficacy and safety of ultrasound-guided SCB, with reported patient
satisfaction in 96.7% of cases.213

Infraclavicular Block
INDICATIONS
The infraclavicular nerve block (ICB) targets the brachial plexus at the
level of the cords and provides adequate analgesia or anesthesia of the
elbow, forearm, and hand. The block can be performed as a single
injection or continuously via a catheter. The infraclavicular approach is
particularly well suited for continuous blockade. The pectoralis muscles
aid in anchoring the catheter in place, which, in conjunction with the
limited range of motion of the infraclavicular area, helps to minimize
unintended catheter migration.

LANDMARKS
At the infraclavicular level, the brachial plexus is composed of three cords

2742
(medial, lateral, and posterior). These cords are named in accordance to
their position relative to the axillary artery at the level of the pectoralis
minor muscle (Pmm). However, there is significant individual variation in
the position of the cords around the artery (Fig. 52.9). The level at which
the block is performed is approximately 2 cm medial and 2 cm caudad to
the coracoid process.

FIGURE 52.9 Infraclavicular block. Variations in cord position relative to the axillary artery. L,
lateral cord; M, medial cord; P, posterior cord. (Reprinted with permission of the American Society
of Regional Anesthesia and Pain Medicine.)

TECHNIQUE
The patient is positioned with the head turned to the contralateral side of
the arm to be blocked, which is abducted and externally rotated at
approximately 90 degrees. This maneuver causes the plexus to become
more superficial and displaces the clavicle cephalad. The needle can then
be introduced further away from the ultrasound probe at a smaller angle,
thereby allowing better needle visualization (Fig. 52.10). The transducer is
placed perpendicular to the clavicle in the deltopectoral groove. At this
level, the pulsatile axillary artery and compressible axillary vein are
visualized in cross-section deep to the Pmm (Fig. 52.11). The needle is

2743
introduced from the superior end of the transducer and advanced in plane
to the ultrasound beam. The initial injection point is deep to the axillary
artery, between the artery and the posterior cord (see Fig. 52.10). Injection
at this point usually results in medial spread around the artery toward the
medial cord. As the needle is withdrawn, local anesthetic is injected to
bathe the lateral cord. It may be necessary to redirect the needle over the
artery to a point between the artery and vein to ensure proper blockade of
the medial cord.

FIGURE 52.10 Infraclavicular approach to the brachial plexus block. Left: Infraclavicular in-
plane needle insertion approach. Right: Corresponding ultrasound image. Ax a., axillary artery.
Green, local anesthetic. (Reproduced with permission from Ouanes et al.
http://anesthesiology.hopkinsmedicine.org/international-obstetric-and-regional-anesthesia/.
Accessed July 18, 2018.)

FIGURE 52.11 Infraclavicular approach to the brachial plexus block. Left: Ultrasound image for
the infraclavicular sonoanatomy. Right: Ultrasound image with anatomy labeled. Ax a., axillary
artery; Ax v., axillary vein; m., muscle. (Reproduced with permission from Ouanes et al.
http://anesthesiology.hopkinsmedicine.org/international-obstetric-and-regional-anesthesia/.
Accessed July 18, 2018.)

CLINICAL EFFECTS
The ICB has been shown to offer faster recovery, cause fewer adverse

2744
events, and provide better analgesia than general anesthesia with local
wound infiltration.214 A systematic review that compared ICB to other
brachial plexus blocks confirmed that ICB posed a lower likelihood of
tourniquet-related pain and provided more reliable blockade of the
musculocutaneous nerve than did axillary block.215 Ilfeld et al.216 reported
improved analgesia, decreased opioid use, decreased incidence of related
side effects, fewer sleep disturbances, and greater patient satisfaction when
continuous ICB was used for outpatients after upper extremity orthopedic
surgery. An observational cohort study demonstrated a high success rate of
single-injection ultrasound-guided ICB regardless of the operator’s
expertise.217 In a randomized comparison study, continuous ICB provided
superior analgesia to that of supraclavicular continuous block on the first
postoperative day. Patients in the ICB group also required fewer oral
analgesics for breakthrough pain in the first 18 to 24 postoperative
hours.218

Axillary Block
INDICATIONS
The brachial plexus block at the axillary level targets terminal branches of
the brachial plexus (ulnar, median, radial, and musculocutaneous nerves).
The axillary sheath at this level is often discontinuous. At this level, the
risk of pneumothorax or phrenic nerve palsy is negligible. Its low
incidence of complications has made it a popular choice for elbow,
forearm, wrist, and hand procedures.219 A catheter can be placed at this
level for continuous blockade. However, owing to the mobility of the
axillary area and more superficial location of the plexus at this level, the
catheter can be easily dislodged. This site may also be more susceptible to
infection when an indwelling catheter is used.

LANDMARKS
At the axillary level, the neurovascular sheath contains the axillary artery
surrounded by the radial, median, and ulnar nerves. Outside of this sheath
are the intercostobrachial, axillary, and musculocutaneous nerves.

2745
TECHNIQUES
Nerve Stimulation
The patient is positioned supine with the head turned to the contralateral
side and the arm to be blocked abducted and externally rotated. The
axillary artery is palpated in the axilla and stabilized with two fingers. The
stimulating needle is introduced superior to it at a 30- to 45-degree angle
to the skin. Finger flexion and/or thumb opposition indicate adequate
needle placement. The needle should be adjusted so that muscle
contraction is lost less than 0.5 mA prior to injection of local anesthetic.
At the axillary level, the musculocutaneous nerve has typically branched
off the neurovascular bundle and travels within the coracobrachialis
muscle. If musculocutaneous nerve block is required, a second injection is
necessary. The coracobrachialis muscle is palpated underneath the biceps
at the midhumeral level. The stimulating needle is introduced and its
position adjusted until biceps contraction is elicited. Care must be taken
not to introduce the needle into the biceps muscle itself, which could result
in direct stimulation and contraction of the muscle but a failed block.

Transarterial Technique
If accidental puncture of the axillary artery occurs during the
neurostimulation technique, evidenced by aspiration of blood, the needle
should be advanced until blood is no longer aspirated. At this location,
behind the artery, two-thirds of the local anesthetic is injected. The needle
is then retracted slowly and the tip placed back inside the artery. When no
blood is aspirated, the needle tip is located anterior to the axillary artery,
and the remaining third of the local anesthetic is injected. Compression of
the artery for a few minutes is advised to reduce the incidence of a
hematoma.

Ultrasound Guidance
The patient is positioned as described earlier for the neurostimulation
technique. The ultrasound probe is placed at the axillary level
perpendicular to the forearm. The probe position is adjusted until a cross-
sectional image of the axillary artery is obtained (Fig. 52.12). The axilla is
a highly vascularized space, and releasing pressure from the probe

2746
typically exposes several axillary veins in the vicinity of the artery. The
radial, median, and ulnar nerves are identified around the axillary artery as
hyperechoic structures. There is significant individual variation in the
position of the nerves relative to the artery. However, the radial nerve most
often lies posterior to the artery, with the ulnar nerve being medial and the
median nerve anterior to the axillary artery. Sequential scanning
proximally and distally will reveal the trajectory of the musculocutaneous
nerve and help identify it as a hypoechoic structure with a hyperechoic
rim. Proximally, it lies closer to the axillary neurovascular bundle. When
scanning distally, the practitioner can trace the nerve travelling toward the
coracobrachialis muscle, lying between it and the biceps muscle.

FIGURE 52.12 Axillary approach to the brachial plexus block. Left: Ultrasound image for the
axillary anatomy. Right: Ultrasound image with anatomy labeled. a, axillary artery; v, axillary
veins; m., muscle; MC n., musculocutaneous nerve; n., nerve. (Reproduced with permission from
Ouanes et al. http://anesthesiology.hopkinsmedicine.org/international-obstetric-and-regional-
anesthesia/. Accessed July 18, 2018.)

The needle can be advanced from the lateral end of the probe in plane,
and the needle position adjusted to allow local anesthetic spread around
each nerve (Fig. 52.13).

FIGURE 52.13 Axillary approach to the brachial plexus block. Left: In-plane needle insertion
approach. Right: Corresponding ultrasound image. a, axillary artery; m., muscle; MC n.,
musculocutaneous nerve; n., nerve; v, axillary veins. (Reproduced with permission from Ouanes et
al. http://anesthesiology.hopkinsmedicine.org/international-obstetric-and-regional-anesthesia/.
Accessed July 18, 2018.)

2747
CLINICAL EFFECTS
Axillary brachial plexus block has been shown to provide several
advantages over general anesthesia for outpatient hand surgery, including
the ability to fast-track patients to phase 2, resulting in shorter PACU
stays, better pain control, reduced opioid consumption prior to discharge,
and lower incidence of nausea/vomiting.220 The use of ultrasound
guidance with axillary brachial plexus block has been associated with
increased success rate, shorter time to onset of anesthesia, and reduced
time to perform the block.221 When studying novice practitioners,
however, Barrington et al.222 were unable to demonstrate any differences
between ultrasound guidance and nerve stimulator techniques. A
prospective review of axillary brachial plexus block-associated
complications that included over 27,000 procedures confirmed the
extremely safe profile of this block, with an overall incidence of
postoperative neurologic symptoms of 0.37 per 10,000.219

Suprascapular and Axillary Nerve Block

INDICATIONS
Innervation to the shoulder joint from the brachial plexus is primarily
carried out by the suprascapular and axillary nerves. In fact, the
suprascapular nerve accounts for 70% of the sensory innervation of the
shoulder.223 Thus, the suprascapular nerve block (SSNB) has been widely
used for analgesia in procedures involving the shoulder, particularly when
an interscalene nerve block may be contraindicated (e.g., with severe
pulmonary disease).

LANDMARKS
The suprascapular nerve emerges as a branch of the superior trunk and
courses through the supraspinous groove toward the shoulder. The axillary
nerve is a branch of the posterior cord.

ULTRASOUND TECHNIQUE
Positioning the ultrasound probe along the long axis of the supraspinous
fossa (Fig. 52.14) enables visualization of the greater suprascapular notch.

2748
The suprascapular nerve and artery may also be visualized although not
consistently. The needle is introduced in plane in a medial-to-lateral
direction, and local anesthetic is deposited on the lateral aspect of the
fossa, underneath the supraspinatus muscle (Fig. 52.15).

Axillary Nerve Block

The ultrasound probe is placed over the posterior surface of the humerus
along its short axis, allowing visualization of the axillary artery and nerve
in their short axis. Local anesthetic is deposited adjacent to the axillary
artery on the posterior surface of the humerus (Fig. 52.16).

FIGURE 52.14 Suprascapular nerve block. Left: Ultrasound image for the suprascapular
anatomy. Right: Ultrasound image with anatomy labeled. m., muscle; n., nerve. (Reproduced with
permission from Ouanes et al. http://anesthesiology.hopkinsmedicine.org/international-obstetric-
and-regional-anesthesia/. Accessed July 18, 2018.)

FIGURE 52.15 Needle approach and sonoanatomy for suprascapular nerve block. Left: In-plane
needle insertion approach. Right: Corresponding ultrasound image. m., muscle; n., nerve.
(Reproduced with permission from Ouanes et al.
http://anesthesiology.hopkinsmedicine.org/international-obstetric-and-regional-anesthesia/.
Accessed July 18, 2018.)

2749
FIGURE 52.16 Axillary nerve block. Left: Ultrasound image for the axillary nerve anatomy.
Right: Ultrasound image with anatomy labeled. (Reproduced with permission from Ouanes et al.
http://anesthesiology.hopkinsmedicine.org/international-obstetric-and-regional-anesthesia/.
Accessed July 18, 2018.)

CLINICAL EFFECTS
SSNB is effective for providing analgesia in the postoperative period after
shoulder surgery.223,224 The combination of SSNB and axillary nerve
block (ANB) provides superior analgesia and higher patient satisfaction
after arthroscopic rotator cuff repair than SSNB alone.225 SSNB and ANB
combined with IV PCA has also proven to be a better analgesic choice
than SSNB plus IV PCA, or IV PCA alone.226 Dhir et al.227 reported
differences between the analgesic profile of SSNB combined with ANB
and the profile of ISB. In their prospective randomized study, SSNB in
combination with ANB provided better pain relief for patients at rest, with
fewer side effects, whereas ISB was associated with better analgesia in the
first 6 postoperative days. This difference in analgesic profile is consistent
with a prior study by Pitombo et al.228 who also described a significantly
lower degree of motor blockade with the combination of SSNB and ANB.
Combining ISB with SSNB provides superior analgesia to ISB alone
within 48 hours after arthroscopic rotator cuff repair.229

Brachial Plexus Terminal Branch Blocks at the

Elbow and Below
INDICATIONS
Blockade of the terminal branches of the brachial plexus at the elbow can

2750
offer certain advantages over more proximal blocks. It allows the
possibility of selectively blocking a specific sensory distribution of the
hand while preserving motor function of the proximal upper limb.230
Distal blocks may cause more patient discomfort if multiple nerves are
blocked, as they usually require a separate injection for each nerve. The
nerve paths at this level are further restricted by surrounding muscular
structures, potentially making these locations more susceptible to nerve
injury associated with compression ischemia.

TECHNIQUES
Nerve Stimulation
The median nerve can be blocked by introducing the stimulating needle 2
cm above the elbow and 2 cm medial to the point at which the brachial
artery is palpated. Needle position is adjusted to obtain the corresponding
motor response (forearm pronation, flexion of second and third digits,
thumb opposition), and then, 5 mL of local anesthetic is injected.
The ulnar nerve runs in the canal between the olecranon and the medial
epicondyle. This canal is narrow and superficial, making the nerve at this
point susceptible to lesion from direct needle trauma or increased pressure
from the injectate.
Consequently, the block is performed 1 to 2 cm proximal to this canal.
The elicited motor response includes flexion of the fourth and fifth digits
and wrist flexion toward the ulnar side.
To block the radial nerve at the elbow, the practitioner palpates the
biceps tendon 1 to 2 cm proximal to the elbow and introduces the
stimulating needle lateral to it. Radial nerve stimulation should elicit
extension of the hand and forearm as well as forearm supination.

Ultrasound Guidance
The individual nerves can be blocked at various locations. At the elbow,
proximal forearm and midforearm are described (Fig. 52.17).

2751
FIGURE 52.17 Terminal branch blocks: at the elbow (A), proximal forearm (B), and midforearm
(C). (Reproduced with permission from Ouanes et al.
http://anesthesiology.hopkinsmedicine.org/international-obstetric-and-regional-anesthesia/.
Accessed July 18, 2018.)

Median Nerve Block

The median nerve can be block at various locations. The patient is
positioned supine with the arm abducted and forearm supinated. The nerve
can be visualized in the A position medial to the brachial artery (see Figs.
52.17 and 52.18) as well as in the B and C positions of Figure 52.17 (see
also Figs. 52.19 and 52.20).

2752
FIGURE 52.18 Median nerve at the elbow. Left: Location of the ultrasound cross-section.
Middle: Ultrasound anatomy image at the elbow. Right: Corresponding image with anatomy
labeled. a., artery; m., muscle; n., nerve. (Reproduced with permission from Ouanes et al.
http://anesthesiology.hopkinsmedicine.org/international-obstetric-and-regional-anesthesia/.
Accessed July 18, 2018.)

Ulnar Nerve Block

With the patient supine and the arm straight and supinated, the ultrasound
probe is placed over the ulnar artery at the wrist and traced proximally.
The ulnar nerve can be seen medial to the artery. Eventually, the
ultrasound probe is moved further away to rest in between the flexor carpi
ulnaris and flexor digitorus profundus (see Figs. 52.17, 52.19, and
52.21).230

FIGURE 52.19 Median and ulnar nerves at the proximal forearm. Left: Location of the
ultrasound cross-section. Middle: Ultrasound anatomy image at the proximal forearm. Right:
Corresponding image with anatomy labeled. a, artery; FCR m., flexor carpi radialis muscle; FDP
m., flexor digitorum profundus muscle; FDS m., flexor digitorum superficialis muscle; n., nerve; PL
m., palmaris longus muscle. (Reproduced with permission from Ouanes et al.
http://anesthesiology.hopkinsmedicine.org/international-obstetric-and-regional-anesthesia/.
Accessed July 18, 2018.)

FIGURE 52.20 Median and radial nerves at the midforearm. Left: Location of the ultrasound

2753
cross-section. Middle: Ultrasound anatomy image at the midforearm. Right: Corresponding image
with anatomy labeled. a, radial artery; BR m., brachioradialis muscle; ECRL m., extensor carpi
radialis longus muscle; FCR m., flexor carpi radialis muscle; FDS m., flexor digitorum superficialis
muscle; v, medial antebrachial vein. (Reproduced with permission from Ouanes et al.
http://anesthesiology.hopkinsmedicine.org/international-obstetric-and-regional-anesthesia/.
Accessed July 18, 2018.)

FIGURE 52.21 Ulnar nerve at the proximal forearm. Left: Location of the ultrasound cross-
section. Middle: Ultrasound anatomy image at the proximal forearm. Right: Corresponding image
with anatomy labeled. FDP m., flexor digitorum profundus muscle; FDS m., flexor digitorum
superficialis muscle. (Reproduced with permission from Ouanes et al.
http://anesthesiology.hopkinsmedicine.org/international-obstetric-and-regional-anesthesia/.
Accessed July 18, 2018.)

Radial Nerve Block

The patient is positioned supine with the arm abducted and forearm
supinated. The radial nerve is visualized lying adjacent to the radius bone.
It is flanked by the pronator teres muscle medially and by the
brachioradialis muscle, the extensor carpi ulnaris longus muscle, and
supinator muscle laterally (see Figs. 52.20 and 52.22).

FIGURE 52.22 Radial nerve at the proximal forearm. Left: Location of the ultrasound cross-
section. Middle: Ultrasound anatomy image at the proximal forearm. Right: Corresponding image
with anatomy labeled. a, radial artery; BR m., brachioradialis muscle; ECRL m., extensor carpi
radialis longus muscle; PT m., pronator teres muscle; Sup m., supinator muscle; v, medial
antebrachial vein. (Reproduced with permission from Ouanes et al.
http://anesthesiology.hopkinsmedicine.org/international-obstetric-and-regional-anesthesia/.
Accessed July 18, 2018.)

CLINICAL EFFECTS

2754
For most outpatient hand and wrist bone surgeries, an effective anesthetic
and analgesic plan includes selective distal blocks with long-acting local
anesthetics without vasoconstrictors like epinephrine and a concomitant
axillary block with short-acting local anesthetic.231 This combination
allows for muscle function preservation in the proximal upper limb. The
presence of motor block in the affected limb in the immediate
postoperative period has been associated with lower patient satisfaction.232
A prospective study that compared proximal brachial plexus blocks to
terminal branch blocks performed at the level of the forearm for hand
surgery found no differences in adequacy as a primary anesthetic,
postoperative pain scores, or opioid consumption.233 However, terminal
branch blocks at the level of the elbow will not prevent tourniquet pain in
an unsedated patient because upper arm cutaneous innervation is supplied
by the medial cutaneous nerve, musculocutaneous nerve, posterior
cutaneous nerve, and intercostobrachial nerve.

Paravertebral Nerve Block

INDICATIONS AND LANDMARKS
Paravertebral nerve blocks (PVBs) provide anesthesia and analgesia to the
thorax and abdomen. They have been successfully described for breast
surgery, thoracotomy, thoracoscopy, nephrectomy, hip surgery, cardiac
surgery, and lung transplant surgery.234–238 The goal of the PVB is to
deposit local anesthetic in the paravertebral space adjacent to the vertebral
bodies, where spinal nerves emerge from the spinal canal and bifurcate
into the ventral and dorsal rami. This space is delineated medially by the
vertebral bodies and discs and the intervertebral foramina; anterolateral by
the parietal pleura at the thoracic levels or iliopsoas muscle; and
posterolateral by the ribs, transverse processes, and intercostal spaces. The
epidural space is a continuous space in the craniocaudal dimension.
Therefore, local anesthetic injected at one level will spread to adjacent
levels. Contralateral spread occurs in approximately 10% of cases. PVBs
can be performed with single-injection or continuous techniques.

TECHNIQUES

2755
Landmark Technique
The patient is positioned sitting up with the neck and back flexed. The
spinous processes are identified and marked. Additional marks are made
2.5 cm laterally from the spinous process on the side intended to block,
which will correspond with the transverse process (Fig. 52.23). The needle
is introduced at the lateral mark, perpendicular to the skin, until contact is
made with the transverse process. Contact occurs at a depth of 2 to 4 cm,
depending on the body habitus of the patient. If the transverse process is
not encountered at 4 cm, the needle is redirected cephalad or caudad.
Continuing to advance without prior contact with the transverse process
carries the risk of pleural puncture. Regardless of body habitus, the
paravertebral space is typically located 1 cm beyond the transverse process
at the thoracic levels, or 0.5 cm at the lumbar levels because the transverse
processes are thinner in this area. After contacting the transverse process,
the needle is redirected caudad, walked off the transverse process, and
advanced 1 cm (0.5 in the lumbar area) into the paravertebral space. It may
be possible to feel a loss of resistance as the needle is advanced through
the superior costotransverse ligament at the thoracic levels. However, this
sensation can be very subtle and difficult to appreciate.

FIGURE 52.23 Thoracic paravertebral block landmarks.

Ultrasound Technique
Transverse Approach
The ultrasound probe is placed transversally over the midline at the level
intended to block (Figs. 52.24 and 52.25). The acoustic shadow of the
spinous process is identified, along with the transverse process and

2756
costotransverse joint. The probe is then moved cephalad or caudad over
the intercostal space, which allows for visualization of the pleura. The
needle is introduced in plane and the local anesthetic deposited at the
corner formed by the transverse process and pleura.235,239

FIGURE 52.24 Thoracic paravertebral block transverse approach. Left: Ultrasound image for the
transverse thoracic paravertebral anatomy. Right: Ultrasound image with anatomy labeled. TP,
transversus process. (Reproduced with permission from Ouanes et al.
http://anesthesiology.hopkinsmedicine.org/international-obstetric-and-regional-anesthesia/.
Accessed July 18, 2018.)

FIGURE 52.25 Needle approach and sonoanatomy for the transverse thoracic paravertebral block.
Left: In-plane needle insertion approach. Right: Corresponding labeled ultrasound image. CTL,
costotransverse ligament; TP, transversus process. (Reproduced with permission from Ouanes et al.
http://anesthesiology.hopkinsmedicine.org/international-obstetric-and-regional-anesthesia/.
Accessed July 18, 2018.)

Parasagittal Approach
The ultrasound probe is placed longitudinally 5 to 10 cm lateral to midline.
At this level, the ribs are visualized in their short axis as curved structures
with an acoustic shadow and the parietal pleura underneath. The probe is
then slid medially and scanned over the level of the transverse processes,
which appear as more square osseous structures. A slight tilt of the probe
laterally will improve visualization of the pleura. The needle can be
advanced in plane or out of plane into the paravertebral space (Figs. 52.26
and 52.27).240 Injection of local anesthetic causes depression of the

2757
parietal pleura and spread to the adjacent levels.

FIGURE 52.26 Thoracic paravertebral block parasagittal approach. Left: Ultrasound image for
the parasagittal thoracic paravertebral anatomy. Right: Ultrasound image with anatomy labeled. TP,
transversus process. (Reproduced with permission from Ouanes et al.
http://anesthesiology.hopkinsmedicine.org/international-obstetric-and-regional-anesthesia/.
Accessed July 18, 2018.)

FIGURE 52.27 Needle approach and sonoanatomy for the parasagittal thoracic paravertebral
block. Left: In-plane needle insertion approach. Right: Corresponding labeled ultrasound image.
CTL, costotransverse ligament; TP, transversus process. (Reproduced with permission from Ouanes
et al. http://anesthesiology.hopkinsmedicine.org/international-obstetric-and-regional-anesthesia/.
Accessed July 18, 2018.)

CONTRAINDICATIONS
In addition to the general contraindications for PNBs, empyema and tumor
invading the paravertebral space are specific for PVB. The same
considerations for coagulopathy and neuraxial anesthesia apply to PVB.

CLINICAL EFFECTS
PVBs are effective in providing analgesia after breast cancer surgery and
have been shown to decrease pain scores and mean opioid consumption up
to 72% both intraoperatively and postoperatively,235 decrease opioid-

2758
related side effects, shorten hospitalization, and possibly decrease chronic
postsurgical pain at 6 months.239 Some of these benefits might be greatest
in patients undergoing bilateral mastectomies with simultaneous breast
reconstruction.241 However, many of these benefits have been replicated in
studies involving post-mastectomy breast reconstructions.242,243 Multilevel
PVB is associated with better postoperative pain control with movement as
well as decreased analgesic consumption.239,244 During infusion,
continuous PVB has the additional benefit of improving analgesia and
decreasing functional deficit, compared with single-injection
techniques.245 A recent study reported that PVB provided effective
postoperative analgesia after thoracotomy, albeit inferior to that of
epidurals.246 However, two recent meta-analyses found no difference in
pain analgesic efficacy and reported that PVB was associated with less
hypotension, nausea and vomiting, and urinary retention than epidurals
were.237,238

Nerve Blocks of the Lumbar Plexus

INDICATIONS AND LANDMARKS
The lumbar plexus (LP) is formed within the psoas muscle from the
anterior rami of T12–L4. The branches of LP are the iliohypogastric (T12–
L1), ilioinguinal (L1), genitofemoral (L1–L2), lateral femoral cutaneous
(L2–L3), femoral (L2–L4), and obturator nerves (L2–L4)247 (Fig. 52.28).
Of these, the femoral, lateral femoral cutaneous, and obturator nerves are
most important for lower extremity surgery.

2759
FIGURE 52.28 Lumbar plexus anatomy. (Reprinted with permission from Anderson MK.
Foundations of Athletic Training. 5th ed. Baltimore, MD: Lippincott Williams & Wilkins; 2012.
Figure 12-4.)

The LP block, also known as the psoas compartment block, was first
described in 1976 by Chayen et al.248 It is a deep block of the LP, and the
local anesthetic is deposited within the body of the psoas muscle. At the
L4 level, it is thought to be the most consistent approach to block the
entire LP with a single injection; however, it consistently provides
anesthesia or analgesia in the distributions of the femoral, lateral femoral
cutaneous, and the obturator nerves.249

TECHNIQUES
Landmark Technique
There are two common methods of landmark-based nerve stimulation-
assisted LP block.
For both techniques, the patient is placed in the lateral decubitus
position with the operative side up (Fig. 52.29). Both mark palpated
anatomy. In the first approach, the practitioner palpates the iliac crests and
follows an imaginary line to the spinous processes of the lumbar spine to
approximately the L4 spinous process. An insulated needle is inserted 4
cm lateral to the spinous process perpendicular to the skin and advanced

2760
until a quadriceps twitch is elicited or until bone is contacted. When the
needle contacts bone, it is redirected off the bone either cephalad or
caudad and advanced approximately 2 cm until quadriceps stimulation is
obtained with current between 0.5 and 1 mA. If quadriceps stimulation is
not elicited and no bony contact is made, the practitioner should reassess
the landmarks.

FIGURE 52.29 Landmark approaches to lumbar plexus (psoas compartment) block. PSIS,
posterior superior iliac spine. (Reproduced with permission from Jeng CL, Rosenblatt MA. Lower
extremity nerve blocks: Techniques. In: UpToDate, Post TW [Ed], UpToDate, Waltham, MA.
[Accessed on September 13, 2018.] Copyright © 2018 UpToDate, Inc. For more information visit
www.uptodate.com.)

The second commonly described landmark technique follows the same

nerve stimulation principles with slightly modified landmarks (see Fig.
52.29). A line is drawn between the two iliac crests and another is drawn
connecting the lumbar spinous processes. A third line is drawn through the
posterior inferior iliac spine. Finally, a line is drawn perpendicular to the
other lines at the level of L4 and divided into thirds. The needle is inserted
1 cm cephalad to this line at the point of the lateral third marking.

2761
 Several descriptions of various techniques for the psoas compartment
blocks have been described in the literature.250–252 All rely on bony
contact with the transverse process as a guide to depth of needle
placement. Chayen et al.248 estimated the distance from the skin to the LP
to be 8 cm in men (range, 6 to 10 cm) and 7 cm in women (range, 5 to 9
cm) based on CT images obtained in their patients. They found the depth
of the LP from the transverse process to be consistently less than 2 cm.
This relationship of transverse process to the LP was found to be
independent of body mass index or gender. Thus, contact with the
transverse process provides a consistent landmark to guide the user and
help avoid very deep penetration.248

Ultrasound Guidance
Several descriptions of various techniques have been published for the use
of ultrasound to guide peripheral blocks and sonoanatomy of the LP.253,254
Using ultrasound guidance for the LP block is still challenging owing to
the depth of the nerve and presence of the “acoustic shadow” formed by
the transverse processes.255,256 In clinical practice, ultrasound can be used
for preprocedural scanning or for real-time guidance in combination with
nerve stimulation.
With the patient in a lateral decubitus position, a curved array, low-
frequency ultrasound is placed parasagittal at the lumbosacral junction.
With the sacrum identified, the practitioner counts the transverse process
of each vertebra cephalad until L2, L3, and L4 are identified. The
longitudinal sonogram exhibits an acoustic shadow of the transverse
processes produced, or what Karmakar et al.253 call the trident sign
because of its similarity to the trident (Fig. 52.30). They describe
visualizing the roots of the LP within the psoas muscle in 60% of their
patients. The needle is inserted from the caudal end of the probe and
advanced through the space between the transverse processes of L3 and L4
into the posterior part of the psoas muscle. The needle takes a very steep
angle in the plane view.254 After negative aspiration, local anesthetic is
injected, and its spread is observed within the muscle.

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FIGURE 52.30 Longitudinal sonogram. Note the hyperechoic transverse processes with their
acoustic shadow that produces the trident sign. The psoas muscle is seen in the acoustic window
between the transverse processes and is recognized by its typical striated appearance. Part of the
lumbar plexus is also seen as a hyperechoic shadow in the posterior part of the psoas muscle
between the transverse processes of L3 (TPL3) and L4 (TPL4) vertebrae. The inset shows the
orientation of the ultrasound transducer and the direction in which the needle is introduced (long
axis) during an ultrasound-guided lumbar plexus block. TPL2, transverse process of L2 vertebra.
(Reprinted from Karmakar MK, Ho AMH, Li X, et al. Ultrasound-guided lumbar plexus block
through the acoustic window of the lumbar ultrasound trident. Br J Anaesth 2008;100[4]:533–537.
Copyright © 2008 British Journal of Anaesthesia. With permission.)

COMPLICATIONS
Unlike most other PNBs described, the American Society of Regional
Anesthesia and Pain Medicine (ASRA) recommends that anticoagulation
guidelines for neuraxial blocks be followed when performing an LP block
because of its deep nature.257
This block has the highest incidence of complications among PNBs,
although the estimated rate of complication is low overall.249 The most
common complication is neuraxial spread leading to bilateral block.
Epidural spread is more common than total spinal.247,249,258,259 Epidural
spread after LP block has been reported with an incidence range from
27%260 to 50%.178 Cases of cardiac arrest after LP block have been
reported in patients who were found to have high dermatomal block

2763
levels.261 Other complications include injury to surrounding structures,
including renal hematoma, pneumocele, total spinal anesthesia, and
unintended intra-abdominal and intervertebral penetration.247,249,258,259
Vascular injury can lead to retroperitoneal hematoma, which can go
unnoticed for some time and lead to serious complications.253,262,263
Dolan263 pointed out in a letter to the editor that ultrasound LP allows for
visualization of the distribution of local anesthetic in real time and may
translate to fewer complications.264
To ensure the proper position of the needle during psoas compartment
block and avoid excessive needle insertion, it is recommended that the
transverse process be intentionally sought during the landmark approach.

CLINICAL EFFECTS
The LP block is usually used as a supplement to general anesthesia for
pain control after lower extremity surgery. It may also be used as an
alternative to neuraxial analgesia as a primary anesthetic to minimize the
chance of sympathectomy and bilateral lower extremity block. However, if
anesthesia of the lower leg or posterior thigh is required for the procedure,
the sacral nerve roots must be blocked separately.249
LP block has been described as useful for hip and knee surgery.265–268
The posterior approach provides analgesia to the lateral portions of the hip
and knee joints.269 In a prospective, randomized, blinded clinical trial that
compared stimulating catheters and nonstimulating catheters for LP block,
Cappelleri et al.269 found that the minimum effective anesthetic volume
was 12 mL with the stimulating catheter and 25 mL with the
nonstimulating catheter. They reported 100% successful block in the
stimulating catheter group and 69% success rate in the nonstimulating
group.

Femoral Block
INDICATIONS
The femoral nerve is the main LP branch nerve (L2–L4) and responsible
for sensation of the anterior medial skin of the thigh and medial leg from
the tibia to the medial aspect of the foot, with articular branches

2764
innervating the hip and knee.247 The femoral nerve block (FNB) provides
adequate analgesia or anesthesia of the thigh, knee, and medial leg. It can
be performed as a single injection or continuously via a catheter. The
block usually requires supplementation as it does not completely cover the
entire lower extremity. It usually requires supplementation with sacral
plexus nerves if it is used as an anesthetic for the lower extremity.

LANDMARKS
The femoral nerve is one of the major branches of the LP. Consistently
lateral to the femoral artery, it is encased by splitting of the fascia iliaca,
superficial to the iliopsoas muscle. At the femoral triangle, from medial to
lateral, one should locate the femoral vein (compressible), femoral artery
(noncompressible/pulsating), and femoral nerve.

TECHNIQUES
Nerve Stimulator-Guided Femoral Block
The common femoral artery and inguinal ligaments are palpated in the
groin. The insulated needle is inserted just below the inguinal ligament and
1.5 cm lateral to the artery in an anterior-posterior direction. Stimulation of
the femoral nerve produces a motor response of the quadriceps muscle.
Optimal needle position is achieved when twitches are present between 0.3
and 0.5 mA. After negative aspiration, 20 to 30 mL of local anesthetic is
injected in 5-mL increments, with aspiration between injections. A
sartorius twitch, a band-like twitch along the medial side of the thigh, leads
to unreliable analgesia because the sartorius branches run outside the
femoral nerve sheath. The needle will need to be directed more posterior
(Fig. 52.31).

2765
FIGURE 52.31 Anatomic landmarks for the (1) lateral femoral cutaneous, (2) femoral, and (3)
obturator nerve blocks. (Reprinted with permission from Yao FSF. Yao & Artusio’s
Anesthesiology. 8th ed. Baltimore, MD: Lippincott Williams & Wilkins; 2016. Figure 47.3.)

Ultrasound Technique
With the patient supine, the practitioner places the ultrasound transducer in
the inguinal crease to identify the sonoanatomy (Fig. 52.32). The
hyperechoic femoral nerve can be visualized lateral to the hypoechoic
pulsatile common femoral artery and nonpulsatile femoral vein (Fig.
52.33). An in-plane or out-of-plane approach can be used. The needle is
inserted and the tip placed adjacent to the nerve. The needle can be placed
either above or below the femoral nerve. One should note that the nerve is
enveloped in the fascia iliaca; if it is not penetrated, the block will be
inadequate. Local anesthetic is injected adjacent to the nerve under
ultrasound visualization (see Fig. 52.33).

FIGURE 52.32 Femoral nerve block. Left: Ultrasound image for the femoral nerve sonoanatomy.
Right: Ultrasound image with anatomy labeled. a., artery; m., muscle; n., nerve; v., vein.
(Reproduced with permission from Ouanes et al.

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http://anesthesiology.hopkinsmedicine.org/international-obstetric-and-regional-anesthesia/.
Accessed July 18, 2018.)

FIGURE 52.33 Patient position and transducer for in-plane femoral nerve block. Left: Femoral
nerve block in-plane needle insertion approach. Right: Corresponding ultrasound image. Green,
local anesthetic. a., artery; m., muscle; n., nerve; v., vein. (Reproduced with permission from
Ouanes et al. http://anesthesiology.hopkinsmedicine.org/international-obstetric-and-regional-
anesthesia/. Accessed July 18, 2018.)

COMPLICATIONS
Similar to other PNBs, complications include vascular puncture with
subsequent local anesthetic toxicity, hematoma, and neurologic trauma.
Axillary and femoral PNCs pose a greater risk of infection than do other
PNCs. The bacterial colonization rates have been reported to be between
13% and 57%. However, the progression to infection is between 0.05%
and 3%.270–272 Duration of catheter implant for more than 48 hours has
been associated with increased risk of infection. Therefore, the block site
should be examined daily for signs of inflammation.
Because of the high incidence of quadriceps weakness after FNB,
adductor canal blocks (ACB) have become more popular as a
postoperative analgesia choice for ambulating patients.

CLINICAL EFFECTS
When compared to IV opioids, FNBs have been shown to improve
outcome after major knee and vascular surgery of the lower
extremity.273–275 Femoral nerve catheters used to be very popular for pain
control after total knee arthroscopy (TKA). The perineural catheter offers
an advantage over single injections as the postsurgical pain usually outlasts
the duration of the longest acting single-injection PNB,276,277 and a single-
injection nerve block with a bolus of local anesthetic results in profound
sensory and motor block.278 A dense sensory and motor block provides

2767
excellent pain control, but it is undesirable because it inhibits quadriceps
function mobilization.278–280 A meta-analysis from 2013 highlights the
evidence regarding FNB efficacy for postoperative pain control in patients
with TKA.281 The authors report that FNB as either a single injection or a
continuous infusion provides better pain control than PCA alone.281
Continuous infusion of dilute ropivacaine (0.2% at 5 to 8 mL per hour)
has been the recommended local anesthetic for continuous femoral nerve
catheters. This dosing has been shown to provide adequate analgesia while
minimizing motor block.282 A Cochrane review showed that FNB was
superior to PCA for other outcomes in addition to pain control. Chan et
al.283 reported higher patient satisfaction, less nausea and vomiting, and
improved postoperative range of motion. They also reported that
continuous FNB provided equivalent analgesia for TKA with fewer side
effects than epidural techniques.
Using a PNC after TKA is not without risk. A meta-analysis by Johnson
et al.284 suggested that patients who received a PNC were at greater risk
for perioperative falls than were patients who received either single-
injection PNB or no block. The concern for falls is legitimate as femoral
nerve blockade does result in quadriceps weakness.285 Memtsoudis et
al.286 sites the incidence of fall for patients after TKA as 1.6%. They did
not attribute use of PNB to an increased risk for fall. Hence, caution
should be used when mobilizing postsurgical patients with blocked lower
extremities because of residual quadriceps weakness.

Adductor Canal Block

INDICATIONS
Enhanced recovery pathways and expedited early mobilization pathways
after TKA have led clinicians to search for PNB sites that have minimal
effect on ambulation while providing postoperative analgesia.287 Concern
has been raised over the quadriceps weakness and delayed rehabilitation
caused by the FNB. These concerns have led to growing support for the
ACB (Fig. 52.34).

2768
FIGURE 52.34 Adductor canal block. Top left: Analgesic coverage in dark blue. Left: Anatomic
cross-section of the adductor canal. Bottom: Anatomic approach to the ultrasound-guided block.
Top right: Cross-section of adductor canal with corresponding ultrasound image. (Reprinted with
permission of the American Society of Regional Anesthesia and Pain Medicine.)

The ACB technique was introduced in 2009 as a feasibility study.288 In

2011, Lund et al.289 compared quadriceps strength after ACB and FNB in
a randomized controlled trial. ACB offered the potential advantage of
preserving quadriceps strength288,289 while providing pain relief
comparable to that of FNB.290 Additionally, in a placebo-controlled,
double-blind, randomized controlled trial, Nader et al.291 found that the
ACB effectively reduced pain and opioid requirements in the postoperative
period for TKA patients.
Three meta-analyses and systematic reviews have compared ACB and
FNB.292–294 In a meta-analysis and systematic review of randomized
controlled trials, Jiang et al.292 evaluated the efficacy and safety of the
ACB for early postoperative pain management in patients undergoing
TKA. The pooled results showed that the ACB resulted in less
postoperative analgesic consumption than the saline group and less pain at
rest and during activity. FNB and ACB had similar effects on
postoperative analgesic consumption and pain, but the quadriceps strength

2769
and ability to ambulate were better in the ACB group. The two groups had
similar rate of complications.
Compared with placebo groups, patients receiving ACB have
demonstrated decreased perioperative opioid requirements, decreased pain
during active range of motion, and early ambulation.295,296 A
noninferiority study by Abdallah et al.297 found that when compared with
FNB, the ACB preserved quadriceps strength and provided noninferior
postoperative analgesia for outpatients undergoing ACL reconstruction.
However, despite evidence supporting preserved quadriceps strength, there
have been case reports of quadriceps weakness after single-injection and
continuous ACB.298,299 Proximal spread of local anesthetic in the femoral
triangle or anatomic variations in the motor branches to the quadriceps
muscles have been suggested as possible mechanisms for quadriceps
muscle weakness after ACB.298–300
ACBs have been described in the past to target only sensory function of
the saphenous nerve.301,302 However, in light of recent meta-analyses
demonstrating noninferiority to FNBs and improved quadriceps strength
over the FNBs, several studies have examined the contents of the adductor
canal and spread outside the canal.303–305 The sensory innervation of the
knee is provided by branches of the femoral nerve and sciatic nerve, and
some variable input from the obturator nerve. Cadaveric studies have
demonstrated key nerves involved in analgesia after TKA.306–309 The
adductor canal begins at the apex of the femoral triangle and ends at the
adductor hiatus.247 The anatomic borders of the tunnel are anteriorly the
aponeuroses of the surrounding muscles. The anterolateral border is the
vastus medialis, the anteromedial border is the sartorius and the posterior
border formed by the adductor magnus.247 Burckett-St Laurant et al.305
identified and traced the terminal branches of the saphenous nerve and the
nerve to the vastus medialis and deep nerve plexus of the adductor canal.
They found that both the vastus medialis and saphenous nerve provide
innervation to the anteromedial joint capsule and subcutaneous tissues
over the medial aspect of the knee.
Two studies of healthy volunteers support the claim that ACB is
superior to FNB for patients undergoing TKA.278,279 Three studies of TKA
patients also demonstrated preserved quadriceps strength with ACB over

2770
FNB in both single-shot and catheter-based techniques.280,310,311 Two
cohort studies showed earlier postoperative ambulation in the continuous
ACB group than in the continuous FNB group.312,313 Mudumbai et al.312
showed that when used in an established TKA clinical pathway, patients
who received adductor canal catheters instead of femoral nerve catheters
as part of a multimodal regimen were able to ambulate further on the day
after surgery without any difference in pain control.313 These findings
support a functional advantage for using ACB that does not sacrifice pain
control as long as a multimodal analgesic regimen is used.

CLINICAL EFFECTS
Several authors noted motor block with the ACB.298,299,303 Deloach and
Boezaart314 noted that the ACB spreads proximal into the femoral triangle
and thus covers more nerves than just the saphenous. Gautier et al.304
conducted a study in fresh human cadavers and demonstrated spread of the
injectate outside the adductor canal and toward the popliteal fossa with
some spread in the sciatic distribution. A cadaveric study by Andersen et
al.315 also noted that 15 mL of injectate into the adductor canal spread
throughout the canal and beyond both proximally to the femoral triangle
and distally, potentially covering some sciatic distribution.
Because the current options for local anesthetic are not very selective to
motor or sensory nerve, the anesthesiologist is limited to choosing the
optimal site and concentration. van der Wal et al.316 compared the
landmark transsartorial approach to the saphenous with saphenous field
blocks and found that the transsartorial approach provided 94% success
versus 40% success at providing complete anesthesia of the medial
malleolus.

TECHNIQUE
Ultrasound Guidance
With the patient supine and leg and hip externally rotated, the practitioner
places the ultrasound transducer on the midthigh, identifies the femur, and
medially scans to identify the vastus medialis muscle until the sartorius
muscle starts to appear superficial to the superficial femoral artery and
vein. At this point, the probe is toggled to increase the echogenicity of the

2771
hyperechoic nerve lateral to the artery. The ultrasound is scanned
proximally until the sartorius muscle is symmetrical above the artery (Fig.
52.35). An in-plane or out-of-plane approach can be taken to inject the
local anesthetic below the sartorius muscle and adjacent to the nerve (Fig.
52.36).

FIGURE 52.35 Adductor canal block. Left: Ultrasound image for the adductor canal
sonoanatomy. Right: Ultrasound image with anatomy labeled. a, superficial femoral artery; m.,
muscle; n., nerve; v, superficial femoral vein. (Reproduced with permission from Ouanes et al.
http://anesthesiology.hopkinsmedicine.org/international-obstetric-and-regional-anesthesia/.
Accessed July 18, 2018.)

FIGURE 52.36 Left: Patient position and transducer for adductor canal block. Right: Needle
position lateral to the nerve in the adductor canal with local anesthetic surrounding it. Green, local
anesthetic. a, femoral artery; m., muscle; n., nerve; v, femoral vein. (Reproduced with permission
from Ouanes et al. http://anesthesiology.hopkinsmedicine.org/international-obstetric-and-regional-
anesthesia/. Accessed July 18, 2018.)

Landmark Approach
The approach of van der Wal et al.316 is to advance a 20-gauge blunt

2772
Tuohy needle through the sartorius muscle by using a loss-of-resistance
technique.

COMPLICATIONS
Similar to that seen in other PNBs, complications can include vascular
puncture with subsequent local anesthetic toxicity, hematoma, and
neurologic trauma. Neal et al.317 reported a case series of local anesthetic-
induced myotoxicity after continuous ACB that significantly impacted the
patients’ early rehabilitation and attributed to long-term impairment. Their
institutional prevalence for this complication was 0.98/1,000. Clinical
concentrations of all local anesthetics have been reported to be myotoxic
in animal models, but these toxic effects are noted to be subclinical in
humans.298,299,318–321
It was not clear317 why clinically apparent local anesthetic-induced
myotoxicity had occurred in patients who received continuous ACB but
not in those with known intramuscular injection such as psoas. Continuous
ACB is unique in that it occurs in a location similar to that of thigh
tourniquet. The authors noted that tourniquet inflation is associated with
progressive acidosis within the muscle, whereas myotoxicity is associated
with alkalosis. They felt that direct tourniquet injury was unlikely;
however, they introduced the idea of a “double hit” contribution of the
tourniquet plus continuous ACB.
The degree to which ACB affects quadriceps function or the patient’s
ability to safely ambulate postoperatively is controversial. A number of
studies have reported that these blocks result in little or no quadriceps
weakness when compared with FNB. However, published studies have
reported quadriceps weakness after ACB, and a logical explanation would
be spread of local anesthetic outside the adductor canal.304,314 Therefore,
patients should be monitored for motor strength to potentially reduce the
risk of falls.

Fascia Iliaca Block

INDICATIONS
The fascia iliaca block (FIB) was originally described as the fascia iliaca

2773
compartment block in children.322 Fascia iliaca compartment blocks are
designed to be a three-in-one block. They are considered to be an anterior
LP block that targets the femoral nerve, lateral femoral cutaneous nerve
(LFCN), and obturator nerve.323 The goal is to deposit local anesthetic in
high volume under the fascia iliacus and allow it to spread over the three
earlier mentioned nerves. As it is a fascial compartment block, the FIB is
thought to cause less risk of bleeding and nerve injury than the traditional
approach to the LP block. The technique has evolved from a landmark
fascial click procedure with poor rate of success to an ultrasound-guided
procedure with higher rates of success.
The FIB may be used in combination with other techniques to provide
anesthesia and postoperative analgesia to the lower extremity. It has been
used in procedures such as skin graft harvesting,324 incisional pain,325
postoperative analgesia after total hip or total knee arthroplasty, and
prehospital analgesia in patients with femur fractures.326,327

TECHNIQUES
Landmark Approach
In the landmark approach, the practitioner should feel a sensation of two
facial pops when the needle traverses the fascia lata and then the fascia
iliaca. Penetration of both layers is essential to the success of the block. It
is recommended that a short-beveled needle or pencil-point needle be used
rather than a cutting needle in order to increase chances of appreciating the
pops or clicks.247
As described by Dalens et al.,328 a line is drawn between the pubic
tubercle and the anterior superior iliac spine (ASIS). This line is divided
into three equal parts and the junction of the middle and lateral thirds
identified. The needle is inserted 1 cm below this point. The blunt needle
is advanced until a double pop sensation is perceived. Then, the needle is
presumed to have penetrated the fascia lata, and subsequently the fascia
iliaca.

Ultrasound Guidance
Classic Technique
The patient is positioned supine and the ultrasound probe placed as for an

2774
FNB. The practitioner slides the ultrasound probe laterally to identify the
hyperechoic lines of the fascia lata and fascia iliaca. He or she may
appreciate the femoral nerve and femoral artery medially on the screen and
the iliopsoas deep to the fascia layers. The block may be performed with
an in-plane or out-of-plane needle approach. In the out-of-plane approach,
the needle is inserted inferior to the ultrasound probe with a slight
cephalad direction. Tissue displacement of the fascial planes may be
appreciated. Direct visualization of local anesthetic spread below the fascia
iliaca confirms correct needle placement. With the in-plane approach, the
needle is advanced from the lateral edge of the ultrasound probe and
visualized until it reaches below the fascia iliaca and confirmed with
injection of local anesthetic.

Suprainguinal Technique
With the patient supine, the ultrasound probe is placed in the parasagittal
plane on the ASIS and tilted medially. The probe is then moved medially
along the inguinal ligament and kept at the same angle until the
“hourglass” or “bow-tie” pattern is recognized, usually at the junction of
the lateral one-third and medial two-thirds of the inguinal ligament (Fig.
52.37). The inferior part of the hourglass is formed by the sartorius muscle
and the superior part by the internal oblique. The deep circumflex iliac
artery is seen just beneath the posterior part of superior hourglass (internal
oblique) (see Fig. 52.1). The muscle under the hourglass is the iliacus
muscle, and the fascia iliaca can be easily recognized overlying the iliacus
muscle. Using an in-plane technique, the needle is introduced in an
inferior-to-superior direction. It passes through the sartorius (inferior part
of hourglass) and pierces the fascia iliaca. The correct placement of the
needle is confirmed by the appearance of local anesthetic that pushes the
iliacus down. The spread of local anesthetic is seen as a black lens sitting
between the iliacus muscle and fascia. The black lens quickly disappears
as the local anesthetic spreads between the fascia iliaca and the iliacus.
The needle can be advanced into the hydro-dissected space for more
proximal spread of local anesthetic toward the pelvic cavity.329

2775
FIGURE 52.37 Suprainguinal ultrasound image of the fascia iliac block with the hourglass
pattern. (Reprinted with permission from Singh H, Jones D. Hourglass-pattern recognition
simplifies fascia iliaca compartment block. Reg Anesth Pain Med 2013;38[5]:467–468.)

All of these blocks have been described as volume blocks and require
large volumes to sufficiently spread into the fascial plane.

CLINICAL EFFECTS
When comparing the landmark approach to ultrasound-guided FIB, Dolan
et al.330 found that patients who were randomized to the ultrasound group
had a greater loss of thigh sensation and greater motor blockade. They
found that successful sensory loss in the anterior, medial, and lateral
aspects of the thigh increased from 47% by landmark to 82% with
ultrasound. The fascial pop or click landmark technique has had reported
success rates of only 35% and 47%.323,330 The success rate with ultrasound
guidance has been reported as 82% and 87%.330,331
The evidence regarding efficacy of FIB for total hip arthroplasty is
divided, as two randomized controlled trials have demonstrated no
analgesic effect,332,333 whereas two others have demonstrated efficacy at
decreasing pain scores and opioid consumption.334,335 All authors
described different techniques. Shariat et al.332 and Kearns et al.333 each
described using transverse infrainguinal techniques because they had been
described as successful in previous studies.330,334,336 Stevens et al.334 and
Bang et al.335 used suprainguinal approaches to the FIB. Stevens et al.334
used a double pop technique and Bang et al.335 used a suprainguinal
parasagittal ultrasound technique. Following the article by Shariat et al.,332

2776
several letters to the editor pointed out that the distal injection site may
explain the lack of effect from the FIB in total hip arthroplasty. Hebbard et
al.337 described a novel suprainguinal parasagittal ultrasound approach that
was successful in more than 150 patients. They supported their claim with
a dye study in fresh cadavers, which showed consistent spread of dye in
the lateral femoral cutaneous and femoral nerve distributions. Some
studies have demonstrated a beneficial effect of the FIB in reducing the
incidence of postoperative cognitive dysfunction and perioperative
delirium in elderly patients.336,338 Others have reported beneficial effect
for treating hip fracture pain in the elderly.339,340

COMPLICATIONS
Transient femoral neuropathy has been reported after FIB.341 Also a
knotted fascia iliaca catheter has been reported.342

Lateral Femoral Cutaneous Nerve Block

INDICATIONS AND LANDMARKS
The LFCN is formed by the L2–L3 root. The nerve emerges from the
lateral border of the psoas major muscle deep to the fascia iliaca. It
perforates the inguinal ligament approximately 1 cm from the ASIS where
it enters the thigh. The LFCN is a sensory-only nerve, and its innervation
supplies an inconsistent area of skin over the lateral and anterior thigh.247
Small studies have reported variable success rates with landmark and
nerve-stimulation techniques. Hopkins et al.343 reported a success rate of
87.5% with the landmark nerve stimulation technique. Shannon et al.344
reported a success rate of 100% using nerve stimulation to achieve
paresthesia for confirmation of LFCN block. The same group also reported
a 40% success rate when using the landmark fanning technique.
Anatomic studies have demonstrated that the distance from the LFCN at
the inguinal ligament to the ASIS can range from 3 to 7.3 cm.345–347
Ultrasound guidance is particularly suited for injection of a structure such
as the LFCN because of its anatomic variability.345–347 A study in
cadavers and healthy human volunteers showed that the LFCN could be
visualized consistently with ultrasound.348

2777
 Hurdle et al.349 presented a technical description and case series in
which they described successful and reliable blockade of the LFCN with
ultrasound guidance. Others have described using the ultrasound technique
as well.349–352 Ultrasound-guided injections of the LFCN provide
consistent blockade of the nerve with minimal volumes between 2 and 8
mL.351

TECHNIQUES
Landmark Technique
The patient position is supine. The LFCN block is performed with a
modified field block technique in which a blunt needle is inserted
perpendicular to the skin at a point 2 cm caudad and 2 cm medial to the
ASIS (see Figs. 52.30 and 52.31). The needle is advanced until a pop is
felt as it penetrates the fascia lata. Nerve stimulation can be added, and the
patient should be asked if he or she feels a paresthesia or tapping in the
lateral aspect of the thigh. If nerve stimulation is used, 5 to 10 mL of local
anesthetic is injected whether or not the patient shows a response. If the
patient shows no nerve stimulation response, the needle is withdrawn to
the subcutaneous skin and redirected medially until a pop is felt and then
an additional 5 mL of local anesthetic is administered. The needle is
withdrawn to the subcutaneous skin and redirected laterally until a pop is
felt and another 5 mL of local anesthetic administered.

Ultrasound Guidance
The ASIS is palpated and visualized with the ultrasound probe as a
hyperechoic structure with posterior acoustic shadowing. The lateral end
of the linear probe is placed on the ASIS, and the medial end extends
medially in an anatomic transverse plane. With the probe in this position,
the medial part of the probe is angled slightly in a caudal direction so the
transducer is parallel with the inguinal ligament. The transducer is gently
moved in a medial-caudal direction while the operator searches for the
echo signature of the LFCN. With this approach, the LFCN will appear in
cross-section as an oval hyperechoic structure containing several circular
hypoechoic fascicles.349 Alternately, the FNB image is obtained (see Fig.
52.32) and the probe is slid laterally identifying the sartorius muscle. Just

2778
lateral to the sartorius muscle, the LFCN can be visualized (see Fig.
52.37). This structure can be traced distally and often seen splitting into
two separate structures and then retraced proximally to where it can be
blocked easily (Fig. 52.38). The nerve is often found in the interfascial
plane lateral to the sartorius muscle.

FIGURE 52.38 Ultrasound image of the lateral femoral cutaneous nerve.

CLINICAL EFFECTS
Thybo et al.353 studied the effect of ultrasound-guided LFCN in a group of
patients that underwent a posterior approach to total hip arthroplasty. They
reported no additional analgesic effects of the LFCN block when
combined with their standard analgesic regimen of paracetamol, ibuprofen,
and oxycodone. They noted that overall, the pain scores were low in all
groups. A year later, Thybo et al.354 published the effects of blocking the
LFCN after total hip arthroplasty and found that movement-related pain
during first hip flexion on postoperative day 1 or 2 was significantly
reduced if the baseline pain was moderate or severe. They noted no effect
on pain at rest.
LFCN blockade has been described for treating cases of meralgia
paresthesia when patients do not respond to oral medications or
conservative measures.355,356

COMPLICATIONS
No complications have been reported with this block.

Obturator Nerve

2779
INDICATIONS AND LANDMARKS
The obturator nerve arises from the nerve roots of L2–L4. It exits the
pelvis inferior to the superior pubic ramus. The nerve travels with the
obturator artery and vein through the obturator canal and into the thigh
where it branches into anterior and posterior divisions. The anterior
division provides innervation to the adductor brevis, adductor longus,
pectineus, and gracilis muscles. It also gives off an articular branch to the
anteromedial hip capsule and cutaneous branches to the skin over the
medial aspect of the thigh. The posterior branch is primarily a motor nerve
for the adductors of the thigh; however, it also may provide articular
branches to the medial aspect of the knee joint.
The obturator nerve block was first described by Labat357 in his
textbook in 1922. In 1973, Winnie and colleagues358 described it as part of
the 3-in-1 technique along with the LFCN and FNB. In 1993, Wassef
described the interadductor approach to blocking the nerve.359 This block
provides anesthesia of the medial distal thigh and can be used in
combination with femoral, lateral femoral cutaneous, and sciatic blocks for
procedures on the distal thigh and lower leg, and prevention of tourniquet
pain during lower leg surgery. The obturator nerve is occasionally blocked
to prevent stimulation of the adductor muscles during transurethral
resection procedures. The obturator nerve runs close to the lateral bladder
wall, where direct surgical stimulation can result in adductor spasm, which
causes bladder perforation and other anatomic injuries.360 Several papers
report efficacy of obturator nerve block during transurethral resection
surgery.361–364

TECHNIQUES
Landmark Technique
With the patient positioned supine, the femoral artery is palpated and the
tendon of the adductor muscle identified at the pubic tubercle. In the
inguinal crease, a line is drawn from the femoral artery to the medial
border of the adductor longus muscle (identified by abduction of the thigh)
(Fig. 52.39). An insulated block needle is inserted at the midpoint of this
line aimed cephalad and advanced until stimulation of the adductor muscle
is elicited (see Figs. 52.31 to 52.33). The needle is advanced further and

2780
slightly lateral until hip adduction motor response. At that point, 10 mL of
local anesthetic is injected. Then, the needle is withdrawn until the original
motor response is obtained, and another 10 mL of local anesthetic is
injected.

FIGURE 52.39 Lateral femoral cutaneous nerve block. Left: Labeled sonoanatomy. Right:
Corresponding ultrasound image during injection. LFCN, lateral femoral cutaneous nerve; m.,
muscle. Green, local anesthetic. (Reproduced with permission from Ouanes et al.
http://anesthesiology.hopkinsmedicine.org/international-obstetric-and-regional-anesthesia/.
Accessed July 18, 2018.)

Ultrasound Guidance
With the patient supine and leg externally rotated, a linear ultrasound
probe is placed in the transverse orientation in the inguinal crease, and the
femoral nerve, artery, and vein are identified. The probe is moved medially
to enable visualization of the pectineus, adductor longus, adductor brevis,
and adductor magnus muscles. The anterior branch of the obturator nerve
is a hyperechoic structure found between the adductor longus and brevis
muscles. The posterior branch is a hyperechoic structure found between
the adductor brevis and magnus muscles (Fig. 52.40). The needle approach
may be either in plane or out of plane. The needle is directed in the fascial
planes between the adductor longus and adductor brevis muscles for the
anterior branch of the obturator and between the adductor brevis and
adductor magnus muscles for the posterior branch.

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FIGURE 52.40 Ultrasound image for the obturator sonoanatomy. Anterior branch (ObN Ant Br)
of the obturator nerve is located in the facial plane between the adductor longus (Add Long m.) and
the adductor brevis (Add Br m.). The posterior branch (ObN Post Br) is located in the facial plane
between the Add Br m. and the adductor magnus (Add Mag m.). (Reproduced with permission from
Ouanes et al. http://anesthesiology.hopkinsmedicine.org/international-obstetric-and-regional-
anesthesia/. Accessed July 18, 2018.)

Helayel et al.365 described a comparison of the interductal approach in

12 cases to the traditional approach in 12 other patients of ultrasound-
guided obturator nerve blocks with a success rate of 91%. Kakinohana366
described the interductal approach to the obturator nerve block in a case
series of 12 patients.

COMPLICATIONS
Intravascular injection; local anesthetic toxicity; and bladder, rectum,
vagina, and spermatic cord injury have all been reported with Labat’s
classic approach to the block.359

Sacral Plexus-Sciatic Nerve Block

INDICATIONS
The sciatic nerve block is performed to achieve anesthesia and analgesia of
the distal lower extremity, including the anterior and posterior lateral leg,
ankle, and foot. The saphenous nerve (branch of the femoral/LP) is the
only sensory nerve that innervates the medial aspect of the leg. It is
required to achieve complete analgesia or anesthesia to provide sensory
block to the medial aspect of the leg below the knee in addition to

2782
blockade of the sciatic nerve.

LANDMARKS
The sacral plexus is formed within the pelvis by L4–L5 and S1–S4. It
provides motor and sensory innervation to portions of the entire lower
extremity, including the hip, knee, and ankle. The most important nerves
of the sacral plexus for surgery of the lower extremity are the sciatic nerve
and its terminal branches. The sciatic nerve is a mixture of two large
nerves initially bound together by connective tissue. The sciatic nerve exits
the pelvis via the greater sciatic notch and beneath the piriformis muscle.
In the upper part of the popliteal fossa, the sciatic nerve lies posterolateral
to the popliteal vesicles. The sciatic nerve usually divides into the tibial
and common peroneal nerves at the upper aspect of the popliteal fossa.247
Vloka et al.367 reported a mean distance of 6 ± 3 cm above the popliteal
crease. The tibial nerve provides motor innervation to the ankle flexors and
sensory to the plantar aspect of the foot. The peroneal nerve is smaller than
and lateral to the tibial nerve. It provides motor supply to the ankle
extensor muscles and sensory innervation to the webspace of the first two
toes. The sural nerve is purely sensory and travels with the tibial and
common peroneal nerves. It supplies the posterolateral aspect of the leg
and ankle and the dorsal surface of the foot.

TECHNIQUES
Several approaches can be made to this nerve. It can be targeted
proximally or distally. The classic proximal approach was first described
by Gaston Labat in 1922.368 This approach has undergone several
described modifications since the original description.369–372

Landmark Technique
Classic Labat Approach
The patient is positioned in a modified lateral Sims position with the
operative side up. A line is drawn connecting the posterior superior iliac
spine with the greater trochanter of the femur. A second line is drawn from
the greater trochanter of the femur to the sacral hiatus. A third line is
drawn from midline of line 1 to bisect line 2. At this point where the two

2783
lines cross, an insulated block needle is advanced until motor response or
paresthesia is elicited. If bone is contacted, the needle is redirected
laterally (Figs. 52.41 and 52.42).

FIGURE 52.41 Patient position for the classic Labat approach to the sciatic nerve.

FIGURE 52.42 Illustration of the anatomic landmarks of the classic Labat approach to the sciatic
nerve. (Reprinted with permission from Yao FSF. Yao & Artusio’s Anesthesiology. 8th ed.
Baltimore, MD: Lippincott Williams & Wilkins; 2016: Figure 47-7.)

Subgluteal Approach
The patient is positioned in a modified lateral Sims position with the
operative side up. A line is drawn connecting the ischial tuberosity with
the greater trochanter of the femur. A second line is drawn from the center
of the first line 4 to 6 cm caudad. Anywhere along line 2 is where the
block can be attempted. An insulated block needle is advanced until motor
response or paresthesia is elicited (Fig. 52.43). If no motor response or
paresthesia is elicited, the needle is redirected medially or laterally.

2784
FIGURE 52.43 Illustration of the anatomic landmarks of the subgluteal approach to the sciatic
nerve. (From Horlocker TT, Kopp SL, Wedel DJ. Peripheral nerve blocks. In: Miller RD, Cohen
NH, Eriksson LI, et al, eds. Miller’s Anesthesia. 8th ed. Philadelphia: Saunders; 2015:1721–1751.)

Anterior Sciatic Nerve Block

With the patient supine and the surgical leg in a neutral position, the
practitioner draws a line from the greater trochanter of the femur to the
medial thigh parallel to the crease of the groin. At the midpoint of that line,
an insulated block needle is inserted perpendicular to the skin until the
femur is contacted. The needle is walked off in a cephalad medial direction
until it walks off the lesser trochanter of the femur. Motor stimulation of
the foot is elicited (Fig. 52.44).

2785
FIGURE 52.44 Landmark anterior sciatic approach.

Popliteal Fossa
With the patient in the prone position, the practitioner identifies the
borders of the popliteal fossa by slightly bending the knee. The lateral
border of this anatomical triangle is the biceps femoris, and the medial
border is the semimembranosus muscle. The practitioner measures 5 to 9
cm proximal from the base of the anatomical triangle and inserts a
stimulating block needle just off the medial aspect of the lateral border of
the triangle until a motor response is observed with nerve stimulation or
paresthesia is elicited (Fig. 52.45).

2786
FIGURE 52.45 Landmark approach to the sciatic nerve in the popliteal fossa. a., artery; m.,
muscle; n., nerve; v., vein. (Reprinted from Horlocker TT, Kopp SL, Wedel DJ. Peripheral nerve
blocks. In: Miller RD, Cohen NH, Eriksson LI, et al., eds. Miller’s Anesthesia. 8th ed. Philadelphia,
PA: Saunders; 2015. Fig 57-23. Copyright © 2015 Elsevier. With permission.)

Ultrasound Technique
Classic Technique
The patient is placed in the modified lateral Sims position. Choice of an
ultrasound probe depends on the patient’s body habitus. Typically, a low-
frequency curvilinear probe is used. The probe is placed on the posterior
thigh to identify the hyperechoic femur (with dropout shadow below). The
practitioner traces the femur proximally until the greater trochanter is
encountered and then slides the probe medially on the gluteus maximus
muscle. Deep to the gluteus maximus is the sciatic nerve, and deep to the
nerve is the quadratus femoris muscle. The nerve at this level is oval or
triangular. It is often visualized at the level of the bones between the
ischium and the femur. An in-plane or out-of-plane technique can be
employed (Figs. 52.46 and 52.47).

2787
FIGURE 52.46 Subgluteal approach to the sciatic nerve block. Left: Ultrasound image for the
subgluteal sonoanatomy. Right: Ultrasound image with anatomy labeled. m., muscle; n., nerve.
(Reproduced with permission from Ouanes et al.
http://anesthesiology.hopkinsmedicine.org/international-obstetric-and-regional-anesthesia/.
Accessed July 18, 2018.)

FIGURE 52.47 Left: Patient position and transducer for in-plane ultrasound sciatic approach.
Right: Corresponding ultrasound image. m., muscle; n., nerve. Green, local anesthetic.
(Reproduced with permission from Ouanes et al.
http://anesthesiology.hopkinsmedicine.org/international-obstetric-and-regional-anesthesia/.
Accessed July 18, 2018.)

Alternative Technique (Anterior Approach)

The patient is positioned supine with the block leg externally rotated and
knee slightly bent. The low-frequency curvilinear probe is placed in the
transverse plane over the medial thigh approximately 10 cm below the
femoral crease. The sciatic nerve appears as a hyperechoic nerve medial
and deep to the femur. It is located between the adductor magnus muscle
and the hamstrings. The nerve may be approached in an in-plane or out-of-
plane technique.

Lateral Ultrasound Technique with Popliteal Approach

The patient position is usually lateral but may be prone or supine. With the
patient in the lateral position, a high-frequency linear ultrasound probe is

2788
placed transversely in the popliteal crease, and the popliteal artery and
popliteal vein are identified. Lateral and superficial to the vessels are the
two component branches of the sciatic nerve. The tibial is usually larger
and medial, and the common peroneal is usually smaller and lateral. The
probe usually needs to be tilted toward the foot to increase the
echogenicity of the nerves. The nerves are traced cephalad until they join
to become the sciatic nerve. The needle may be inserted proximal or distal
to the branch point of the nerves. Either an in-plane or out-of-plane needle
technique can be used. The needle needs to be adjacent to the nerves in
order to coat them with local anesthetic (Figs. 52.48 and 52.49).

FIGURE 52.48 Left: Ultrasound image for the popliteal sonoanatomy. Right: Ultrasound image
with anatomy labeled. a., artery; n., nerve; v., vein. (Reproduced with permission from Ouanes et al.
http://anesthesiology.hopkinsmedicine.org/international-obstetric-and-regional-anesthesia/.
Accessed July 18, 2018.)

FIGURE 52.49 Patient and transducer position for ultrasound-guided lateral approach to popliteal
nerve block. Left: Patient position in-plane needle approach. Right: Corresponding ultrasound
image. (Reproduced with permission from Ouanes et al.
http://anesthesiology.hopkinsmedicine.org/international-obstetric-and-regional-anesthesia/.
Accessed July 18, 2018.)

2789
CLINICAL EFFECTS
Ultrasound guidance has been shown to enhance the quality of popliteal
sciatic nerve block compared to that with a single-injection, nerve
stimulator-guided block that uses either a tibial or peroneal motor
response.369 According to one study, ultrasound guidance resulted in
higher success rates, faster onset, and faster progression of sensorimotor
block, without increasing complications.373 Another study reported that at
the transgluteal level, ultrasounds allow a practitioner to easily identify the
greater trochanter, the ischial tuberosity, and the sciatic nerve located
between them.374
A paraneural sheath that surrounds the sciatic nerve needs to be
penetrated for optimal local anesthetic spread. Two studies analyzed
injections in this space.375,376 Andersen et al.375 showed that dye injected
under the paraneurium of cadavers spread along the nerve both proximally
and distally. They also noted that when the sheath was not penetrated, the
dye did not spread as well. The second study compared patients who had
injections of local anesthetic outside the paraneurium to those whose
injections were inside the paraneurium. Using three-dimensional
ultrasound reconstruction and clinical correlation with sensory exam, the
authors concluded that block efficacy was superior when injections were
made under the paraneurium.376 A subparaneural injection hastens the
onset time and also increases the duration of the sensory blockade
compared to that with circumferential extraneural injection.377 Another
study supported the findings of the first study and further defined the target
for local anesthetic injection as the subparaneural space.259
Tran et al.378 performed a randomized comparison between ultrasound-
guided subepineural popliteal sciatic nerve block proximal to the
bifurcation and ultrasound-guided injection of the individual branches of
the peroneal and tibial nerves distal to the bifurcation. They found that
compared with separate injections around each nerve (without being
subepineural), a single injection at the neural bifurcation has a faster onset
time, provides higher success rates, and can be performed more quickly.378
Several studies have looked at minimal dosing, optimal local
anesthetics, and optimal injection sites. The effective local anesthetic
volume for the sciatic nerve block ranged from 0.10 to 0.15 mL/mm2 of

2790
cross-sectional nerve area.379,380 Other groups have identified the ED50
and ED95 for 0.5% ropivacaine in ultrasound-guided popliteal sciatic
nerve block as 6 and 16 mL, respectively.381 They had success rates of
sensory blockade of 69% for the tibial nerve and 88% for the peroneal
nerve.381 Bang et al.382 undertook a prospective study to identify the
minimum effective dose of 0.75% ropivacaine in subparaneural
ultrasound-guided popliteal nerve blocks. They found the ED90 to be 9
mL. Taboada et al.383 published a prospective randomized comparison
between the popliteal and subgluteal approach. They reported the ED95
for adequate block of the sciatic nerve to be 17 mL in the subgluteal group
and 30 mL in the popliteal group. The authors concluded that a larger
volume of local anesthetic is necessary to block the sciatic nerve at a more
distal site (popliteal) than at a more proximal level (subgluteal).

COMPLICATIONS
The incidence of nerve injury associated with sciatic PNCs has ranged
from 0% to 1.0%282,384–387 and includes persistent paresthesia after a
popliteal sciatic catheter in a patient population followed for an 18-month
period.282,386 Bondar et al.388 reported a pudendal nerve injury after sciatic
nerve block with the posterior approach.

Ankle Block
INDICATIONS
The ankle block was first described in 1922 by Gaston Labat in his
Textbook of Regional Anesthesia.389 It is carried out to achieve anesthesia
and analgesia of the foot. It does not provide anesthesia or analgesia to the
ankle. The ankle block targets the terminal branches of the sciatic nerve
and saphenous nerve. Five nerves need to be anesthetized. Two are located
beneath the deep fascia, and three are in the subcutaneous tissue. The
posterior tibial nerve and deep peroneal nerve are found in the deep layer,
and the superficial peroneal, saphenous, and the sural nerves are
superficial.

TECHNIQUES

2791
Landmark Technique
To anesthetize the deep fascial nerves (deep peroneal, posterior tibial),
place the patient in the supine position. Start with the deep blocks because
subcutaneous infiltration can often deform the surface anatomy (Fig.
52.50).

FIGURE 52.50 Illustration of the anatomic landmarks of the ankle block. (From
http://cursoenarm.net/UPTODATE/contents/mobipreview.htm?1/41/1688. Accessed July 16, 2018.)

Deep Peroneal Nerve

Palpation of the extensor hallucis longus (EHL) is often achieved by
asking the patient to dorsiflex his toes. Just lateral to the EHL, the block
needle is inserted until it contacts bone. Gentle pressure is released from
the needle and 2 to 3 mL of local anesthetic without epinephrine is
injected. Because this is a blind procedure, a fanning technique is used to
increase the chances of successfully blocking the nerve. Fanning is

2792
redirecting the needle and repeating the block in a medial and lateral
position with the same puncture site.

Posterior Tibial Nerve

The block needle is inserted posterior to the medial malleolus. Similar to
the deep peroneal nerve block, the needle is advanced until bone is
contacted. Then, pressure from the needle is released, and 2 to 3 mL of
local anesthetic without epinephrine is injected. This procedure is repeated
with the needle redirected in a medial and lateral position through the same
puncture site.

Superficial Nerves (Sciatic Terminal Branches—Sural and Superficial

Peroneal, Femoral Terminal Branch—Saphenous)
The three superficial cutaneous nerves are blocked by injecting local
anesthetic without epinephrine into the subcutaneous tissue at the level of
the medial malleolus along a line that joins both malleoli over the anterior
aspect of the ankle. Usually, an injection volume of 10 to 20 mL is
sufficient.390

Classic Ultrasound Technique

To identify the four nerves of sciatic origin, a linear high-frequency probe
is used (Fig. 52.51). The tibial nerve is usually located between the medial
malleolus and the Achilles tendon posterior to the posterior tibial artery
and veins. On the anterolateral aspect of the ankle next to the anterior tibial
artery, the deep peroneal nerve can be identified. The superficial peroneal
nerve is scanned before it becomes subcutaneous 10 to 15 cm proximal to
the lateral malleolus. The sural nerve is located between the lateral
malleolus and the Achilles tendon, close to the saphenous vein.391
Injection of 3 to 8 mL of local anesthetic per nerve has been described.391
The goal is to surround the nerve in anesthetic.

2793
FIGURE 52.51 Probe position and ultrasound images of the nerves at the level of lower leg and
ankle. AT, Achilles tendon; DPN, deep peroneal nerve; MM, medial malleolus; PM, peroneal
muscles; SPN, superficial peroneal nerve; SuN, sural nerve; TN, tibial nerve. (From López AM,
Sala-Blanch X, Magaldi M, et al. Ultrasound-guided ankle block for forefoot surgery: the
contribution of the saphenous nerve. Reg Anesth Pain Med 2012;37[5]:554–557.)

CLINICAL EFFECTS
Compared with the conventional approach, the application of ultrasound
increases the success rate and reduces the onset time of the ankle
block.392–394 Rudkin et al.390 conducted a prospective study on 1,000
landmark ankle blocks. They found a success rate of 94.7% and attributed
the short time frame between block and incision as a risk factor for block
failure. Meyerson et al.395 published their landmark ankle block
experience on 1,295 patients and reported a success rate of 95%.
Redborg et al.392 randomized 18 volunteers to ultrasound-guided or
landmark sural nerve block at the ankle. They found that ultrasound use
led to a more complete and longer lasting sural nerve block than did the
traditional landmark technique. Although multiple techniques have been
described, little evidence-based medicine is available to evaluate different
techniques for blocking the tibial nerve at the ankle. Therefore, the same
researchers also compared the effectiveness of ultrasound-guided and
landmark-guided blocks of the tibial nerve at the ankle. The tibial nerve is
arguably the most important nerve to anesthetize during an ankle block
because it provides the majority of sensation to the foot. They noted a 72%
success rate (defined as complete block at 30 minutes) with the ultrasound-
guided technique but only a 22% success rate in the landmark group.394

2794
Lopez et al.391 found that the ultrasound-guided ankle block was highly
effective for bunion surgery and that every nerve in the ankle was
successfully blocked within 10 minutes of injection.

COMPLICATIONS
Noorpuri et al.396 raised concern for the possibly of masking acute
compartment syndrome after forefoot revision arthroplasty in a patient
with ankle block. Myerson et al.395 published a complication rate of 0.3%
and described it as local anesthetic toxicity.

Quadratus Lumborum Block

INDICATIONS
The quadratus lumborum block (QLB) is a more posterior extension of the
TAP block. It was first described by Blanco in 2007 at a scientific meeting
as a technique for postoperative abdominal analgesia. He later wrote that
the analgesic efficacy obtained from the TAP was superior when it spread
beyond the TAP plane and into the thoracic paravertebral space.397 Several
variations of optimal injection points have been described. Blanco
originally described deposition of local anesthetic at the anterolateral
border of the QL, a technique he named the QL1 block. He noted that the
spread pattern of local anesthetic obtained by the QL1 was similar to that
of the landmark TAP with thoracic paravertebral spread.397,398 In a
randomized controlled trial for postoperative pain control, Sauter et al.399
published a modified version of the block that used a transmuscular QL
injection and clearly identifiable landmarks, which they coined the
“shamrock” method. The shamrock sign is made up of the following four
components: the erector spinae, the QL, the psoas major muscle, and the
transverse process of the L4 vertebra (Fig. 52.52). Borglum’s group400
demonstrated that the original QLB is characterized by a 30-minute block
onset time and that a single 30-mL injection of ropivacaine 0.375% will
anesthetize both the lateral and anterior cutaneous branches from T7 to
L1–L4. The transmuscular approach involves injection of local anesthetic
in the plane between the QL and psoas major muscles. This technique has
mostly been described as a single-shot procedure. Chakraborty et al.401

2795
reported success when they left the catheter between the QL and
transversalis fascia. Blanco also offered the possibility of depositing the
local anesthetic posterior to the QL muscle between the QL and
transversalis fascia and coined this the QL2 block397 (Fig. 52.53).

FIGURE 52.52 Shamrock lumbar plexus block. A: The psoas muscle, erector spinae muscle,
quadratus lumborum (QL) muscle, and the L4 transverse process represent the pattern of a
shamrock. B: The star and arrow indicates the L3 spinal nerve root. C: The point of needle insertion
is situated on a line representing the intersection of the ultrasound beam with the skin. D: The
cannula (marked with arrowheads) is advanced in a posterior-anterior direction. (From Sauter AR,
Ullensvang K, Niemi G, et al. The Shamrock lumbar plexus block: a dose-finding study. Eur J
Anaesthesiol 2015;32:764–770.)

2796
FIGURE 52.53 Top: Illustration of Blanco’s optimal point of injection in both QLB I and II.
Bottom: Corresponding ultrasound images, with blue color representing QLB I injection (left) and
the QLB II (right). eo, external oblique; io, internal oblique; QLB, quadratus lumborum block; ta,
transversus abdominus.

The QLB is indicated for abdominal surgeries because it provides

analgesia to visceral and somatic nerves. Some say that it produces better
analgesia than a TAP block because it not only provides analgesia to the
anterior abdominal wall but also blocks visceral pain.
A landmark approach has not been described.

ULTRASOUND TECHNIQUE
Quadratus Lumborum 1
With the patient in a lateral or prone position, a curvilinear probe in the
transverse orientation is placed superior to the iliac crest. The transducer is
then moved dorsally until the QL muscle is identified with its attachment
to the lateral edge of the transverse process of the L4 vertebra. The
shamrock landmarks are identified as the psoas major muscles anteriorly,
the erector spinae muscle posteriorly, and the QL muscle adjacent to the
transverse process399 (Fig. 52.52A).

2797
FIGURE 52.54 Modified single-injection technique for PECS I and PECS II. A: Scanning
ultrasonogram showing the third rib (R), pleura (P), serratus anterior (SA), pectoralis minor muscle
(Pmm), and pectoralis major muscle (PMm). B: Needle (N) enters in plane, strikes the rib, and
withdraws a little to lie above SA. C: Needle is withdrawn to give the PECS I injection (1) between
PMm and Pmm, after injecting the PECS II injection (2) between SA and Pmm. The local
anesthetic (LA) is seen spreading between the muscles as a hypoechoic layer. (From Chakraborty
A, Khemka R, Datta T, et al. COMBIPECS, the single-injection technique of pectoral nerve blocks
1 and 2: a case series. J Clin Anesth 2016;35:365–368.)

CLINICAL EFFECTS
The literature available for the QLB includes several case reports
describing the successful use of the QLB402 and continuous QLB
catheters.401–403 A review of the evidence by Abrahams et al.404 in 2016
gave the evidence a grade of B based on one level Ib study, one level IIb
study, and five level III studies that all supported the use of ultrasound for
QLBs.

COMPLICATIONS
No complications have been reported as of the writing of this chapter.
However, because possible damage to intraperitoneal structures have been
reported in the TAP literature and this block was developed as an
extension of the TAP, it is not unreasonable to be concerned by the

2798
potential for similar complications to that seen with TAP blocks.152,405,406

PECS/Serratus Anterior Plane Block

INDICATIONS
Thoracic wall blocks, which include PECS I, PECS II, and the serratus
anterior plane (SAP) block, are novel, ultrasound-guided fascial plane
blocks that are thought to provide anesthesia or analgesia to the chest wall
without the neuraxial risk associated with epidural and paravertebral
blocks. The PECS I was originally described by Blanco407 in 2011. The
report described depositing local anesthetic adjacent to the
thoracoacromial artery in the fascial plane between the pectoralis major
(PMm) and Pmm to target the lateral pectoral nerve and medial pectoral
nerve. The original block was subsequently modified by Perez et al.408 and
further refined to include more analgesic coverage by Blanco et al.,409
which the group called PECS II. The PECS II is performed more laterally
with the local anesthetic deposited in the fascial plane between the Pmm
and the serratus anterior muscle at the level of the third and fourth ribs (see
Figs. 52.55 and 52.56). The broader coverage of the PECS II includes the
long thoracic nerve and thoracic intercostal nerves. Sensory testing showed
analgesia of T2–T4 dermatomes. Blanco et al.409 described good results
with single injections and catheters in over 100 patients. Chakraborty et
al.410 even further modified the block to a single insertion site (Fig. 52.54).
Two years after the PECS I was introduced, Blanco’s group411 went on to
describe a variation of the PECS II block known as the SAP block, with
improved analgesia. Blanco et al.411 described the SAP block in four
healthy volunteers and reported that it provided sensory dermatomal
analgesia of T2–T7. The local anesthetic could be injected either
superficially or deep to the serratus anterior muscle with the superficial
one providing double the analgesia (see Figs. 52.55 and 52.56).
The indications for PECS blocks include superficial anterior chest wall
procedures such as pacemaker insertions412; postoperative analgesia for
breast surgeries such as lumpectomies, mastectomies, and breast tissue
expanders; and even arteriovenous fistulas revision to cover the
intercostobrachial nerve.413–415

2799
 A landmark approach has not been described.

ULTRASOUND TECHNIQUE
PECS I and PECS II
The patient is placed supine, and a linear array ultrasound probe is held in
the parasagittal plane. The clavicle is identified cranially, and the pertinent
sonoanatomy is identified from superficial to deep: the PMm and the Pmm
deep to it. Between the PMm and Pmm, the thoracoacromial artery is
identified. Deep to the pectoral muscles are the axillary artery, vein, and
cords of the brachial plexus. With a medial tilt of the ultrasound probe, the
serratus anterior muscle, intercostal muscles, ribs, and pleura are
identified. The second rib is usually encountered first if the probe is
traveling from a cephalad to a caudad path, with the clavicle identified first
on screen. The probe is rotated toward the axilla. The needle is introduced
from a cephalomedial orientation to caudolateral position. The practitioner
should pass the needle through PMm, avoiding the thoracoacromial artery,
and deposit 10 to 20 mL of local anesthetic between the Pmm and serratus
muscle at the level of the third rib. The targeted nerves here are the lateral
rami of the intercostal nerves and the long thoracic nerve. The practitioner
then withdraws the needle and injects 10 mL of local anesthetic into the
interfacial plane between the PMm and Pmm lateral to the thoracoacromial
artery (Figs. 52.55 and 52.56).

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FIGURE 52.55 Graphic representing probe position and corresponding ultrasound image obtained
during a PECS I block (left), PECS II block (middle), and serratus plane block (right). (From
Blanco R, Parras T, McDonnell JG, et al. Serratus plane block: a novel ultrasound-guided thoracic
wall nerve block. Anaesthesia 2013;68[11]:1107–1113.)

FIGURE 52.56 Graphic representing the distribution of local anesthetic (light blue) during a
PECS I block (left), PECS II block (middle), and serratus plane block (right). Aa, axillary artery;
Am, orientation anteromedial; Av, axillary vein; Caud, caudal; icn, intercostal nerve; Lc, lateral
cord; Ldm, latissimus dorsi; Mc, medial cord of the brachial plexus; Pc, posterior cord; Pl,
posterolateral; PM, pectoralis major; Pm, pectoralis minor; Prox, proximal; r3, rib 3; r4, rib 4; r5,
rib 5; Sm, serratus muscle; TMm, teres major. (From Blanco R, Parras T, McDonnell JG, et al.
Serratus plane block: a novel ultrasound-guided thoracic wall nerve block. Anaesthesia
2013;68[11]:1107–1113.)

Serratus Anterior Plane Block

With the patient lateral, the ultrasound probe is moved caudally and
laterally from the PECS II position toward the midaxillary line. At the
level of the fifth rib, 20 mL of local anesthetic is deposited either
superficial or deep to the serratus anterior muscle. Directing the needle
trajectory toward the fifth rib decreases the chance of pneumothorax by
providing a bony stop for the needle if it is inadvertently advanced too

2801
deep. The described difference of analgesic duration was double if local
anesthetic was injected superficial to the serratus anterior muscle (see Figs.
52.55 and 52.56).

CLINICAL EFFECTS
The advantage of the PECS blocks over paravertebral or thoracic epidural
is that they are theoretically less risky and simple to perform for those
facile with the ultrasound and are not contraindicated when a patient is on
anticoagulation.
Because it is a relatively new block that that has undergone refinement
and evolution, not many clinical studies have evaluated the efficacy of this
technique. Wahba and Kamal416 compared ultrasound-guided PECS I and
PECS II blocks with landmark-guided thoracic paravertebral block at the
T4 level in patients undergoing a modified radical mastectomy. They
found that the PECS group required less opioid intraoperatively and
reported better postoperative pain control. The study compared an
ultrasound technique to landmark-guided, single-level paravertebral block
with half the local anesthetic volume as the PECS group. Additional
studies are warranted to compare multiple-level paravertebral blocks.
The literature available for the SAP block is limited to case reports
describing successful single-shot and catheter techniques for breast
surgeries and thoracotomies.410,417–420 A review of the evidence by
Abrahams et al.404 in 2016 gave the evidence a grade of A based on one
level Ib study, one level IIb study, and two level II studies that all
supported the use of ultrasound for PECS blocks.

COMPLICATIONS
No complications have been reported as of the writing of this chapter.
However, pneumothorax and vascular injury to the thoracoacromial vessel
are possible with this technique.

Complications of Peripheral Nerve Blocks

Complications associated with PNBs are rare. In addition to the
complications specific to certain blocks that were discussed earlier, some

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complications are relevant to all PNBs. They can be divided into two
groups: neurologic complications resulting in sensory deficits, paresthesia,
motor deficits, and pain; and nonneurologic complications, including those
related to local anesthetic systemic toxicity, infection, and bleeding.

NEUROLOGIC COMPLICATIONS
The reported incidence of neurologic complications associated with
regional anesthesia can vary because of multiple factors such as inadequate
sample size, the different definitions of complications and their duration,
the accuracy of patient follow-up to identify potential complications, and
the limited ability of postoperative testing to discern among different
causes for postoperative neurologic injury.421 Horlocker et al.422 reported
that 89% of postoperative neurologic injuries after ANB were the result of
the surgical procedure, whereas 11% were related to the anesthetic
technique. Although early postoperative neurologic symptoms are
relatively frequent during the first month, their incidence reduces
progressively with time. According to the largest studies performed since
2002, the incidence is 1.49/10,000 for deficits lasting up to 6 months
(Table 52.2).

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 TABLE 52.2 Incidence of Neurological Complication after
Peripheral Nerve Blocks
PNB Neurologic Incidence
Author Year Type Technique N Outcome (%)
Auroy et 2002 All NS, L 20,223 Neurologic 0.014
al.178 complication
Barrington et 2009 All US, NS, L 8,189 Neurologic 0.02
al.177 complication

Sites et al.423 2012 All US 12,668 Postoperative 0.09

neurologic
symptom
Allegri et 2016 All US, NS, L 29,545 Postoperative 0.01
al.424 neurologic
symptom
L, landmark; NS, nerve stimulation; PNB, peripheral nerve block; US, ultrasound.

The mechanisms associated with peripheral nerve injury (PNI) may be

mechanical, ischemic, or neurotoxic. Mechanical trauma related to the
block needle may distort the nerve anatomy and cause histologic
derangement, particularly when the needle tip disrupts the perineurium,
resulting in an intrafascicular injection.425,426 Intraneural injections can
increase intraneural pressure, potentially causing neural ischemia.
Additionally, intrafascicular injections elevate the neurotoxic effect of
local anesthetics by direct exposure to the axons, while simultaneously
prolonging the duration of this exposure.425 Current ultrasound technology
does not allow for differentiation between intrafascicular and
interfascicular (also referred to as subepineurial) injections. The
introduction of ultrasound for regional anesthesia in the last few decades
has not been associated with a decrease in PNI.208,427 Although some
small studies have reported intrafascicular injections not resulting in
PNI,428,429 the American Society of Regional Anesthesia and Pain
Medicine advises against intentional intraneural injections.422 In addition
to anesthetic factors, surgical-related risk factors may also result in
mechanical and/or ischemic PNI from traction, stretch, transection, or
compression injuries related to tourniquet, casts, dressings, hematoma
formation, or compartment syndrome.421
Additionally, certain risk factors may also predispose patients to

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anesthesia-related PNI. Such factors involve preexisting neuropathies,
whether clinical or subclinical, related diabetes, prior exposure to
chemotherapy, entrapment neuropathies, or other metabolic diseases. A
recent retrospective review of 380,680 anesthetic cases found diabetes,
tobacco use, and hypertension to be independent risk factors for
postoperative PNI.430

POSTSURGICAL INFLAMMATORY NEUROPATHY

Awareness has increased in recent years of the role of autoimmune or
inflammatory pathways leading to neurologic deficits in postoperative
patients. This condition has been termed postsurgical inflammatory
neuropathy and is believed to result from an immune-mediated response to
a physiologic stress such as surgery, vaccination, or infection.431 The
distinctive features that set it apart from other postsurgical neuropathies
are as follows: delayed appearance (within 30 days, although immediate
symptoms have also been described) with a return of neurologic function
to postoperative baseline before the onset of symptoms, deficits in a
distribution unrelated to anesthetic or surgical procedures, and symptoms
originating with pain that subsequently subside and give rise to weakness.
Radiographic imaging is negative, and the diagnosis is confirmed with a
peripheral nerve biopsy, which demonstrates microvasculitis and axonal
loss.432 Current treatment of choice is immune suppression with high-dose
corticosteroids or immunoglobulin.421 It is important to consider the
possibility of postsurgical inflammatory neuropathy when confronted with
patients exhibiting typical symptoms because most will improve if
diagnosed and treated early. This approach is in contrast to the common
management of conservative observation for other postoperative
neuropathies.431

NONNEUROLOGIC COMPLICATIONS
Most case reports of hematomas associated with PNBs involve patients on
anticoagulants despite observance of the ASRA guidelines. At highest risk
are PNBs near vascular structures in expandable or noncompressible sites.
Many of the cases of hematoma after PNB in patients with anticoagulation
involve lumbar paravertebral blocks.258,262,433 Consequently, these blocks

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traditionally have been managed according to ASRA’s guidelines for
neuraxial anesthesia, whereas evidence to support recommendations with
most other PNBs in patients taking anticoagulation or antiplatelet therapy
is lacking. In the guidelines for pain procedures in patients on
anticoagulant or antiplatelet therapy, ASRA included PVBs and epidurals
in the same intermediate-risk procedure category.434 Symptoms associated
with PNB hematoma include pain, drop in hemoglobin concentration,
hypotension, and sensory or motor deficits. Diagnosis involves ultrasound
or CT, and treatment may be conservative or require surgical evacuation.
Infectious complications related to PNBs are rare.178,435 Capdevila et
al.384 reported the incidence of bacterial colonization of PNB catheters to
be 28%, with 3% of patients exhibiting local signs of inflammation. There
were no cases of bacteremia. Independent risk factors for local infection
were postoperative monitoring in intensive care, catheter duration greater
than 48 hours, male sex, and absence of antibiotic prophylaxis.
Local anesthetic systemic toxicity also has a very low incidence that
ranges from 0.08 to 0.98/1,000 PNBs according to different studies.423
Patients may show signs of CNS toxicity (agitation, confusion, seizure,
somnolence, and apnea) and/or cardiovascular toxicity (hypertension,
tachycardia, arrhythmias, hypotension, bradycardia, asystole). Cardiac
toxicity occurs from binding of local anesthetic to sodium channels.
Especially susceptible are patients in the extremes of age and those with
heart failure or ischemic heart disease. The treatment is supportive,
managing the patient’s airway to prevent hypoxia and acidosis (both of
which increase local anesthetic toxicity), treatment of seizures with a
benzodiazepine or propofol, and lipid emulsion therapy. If cardiac arrest
ensues, advanced cardiac life support (ACLS) algorithm should be
initiated, with slight modifications: Epinephrine should be used with
smaller initial doses because it is arrhythmogenic, and vasopressin is not
recommended.436,437

SUMMARY OF TREATMENT OF LOCAL ANESTHETIC

SYSTEMIC TOXICITY
• Get help.
• Initial focus

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 Airway management: Ventilate with 100% oxygen.
Seizure suppression: Benzodiazepines are preferred; avoid propofol
in patients with signs of cardiovascular instability.
Alert the nearest facility having cardiopulmonary bypass capability.
• Management of cardiac arrhythmias
Basic and ACLS with medication adjustments
Avoid vasopressin, calcium channel blockers, β-blockers, or local
anesthetic.
Reduce individual epinephrine doses to <1 µg/kg.
• Lipid emulsion (20%) therapy
Bolus 1.5 mL/kg (lean body mass) intravenously over 1 minute
Continuous infusion 0.25 mL/kg/min
Repeat bolus once or twice for persistent cardiovascular collapse.
Double the infusion rate to 0.5 mL/kg per minute if blood pressure
remains low.
Continue infusion for at least 10 minutes after attaining circulatory
stability
Recommended upper limit: approximately 10 mL/kg lipid emulsion
over the first 30 minutes
For local anesthetics dosing recommendations, see Tables 52.3, 52.4,
and 52.5.

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 TABLE 52.3 Upper Extremity Peripheral Nerve Block Dosing
Local Anesthetic (20–30 mL) Anesthesia (h) Analgesia (h)
3% 2-Chloroprocaine (+ epinephrine) 1.5 2.0
1.5% Mepivacaine 2–3 2–4
1.5% Mepivacaine (+ epinephrine) 2.5–4 3–6
2% Lidocaine (+ epinephrine) 3–6 5–8
0.5% Ropivacaine (+ epinephrine) 6–8 8–12
0.75% Ropivacaine (+ epinephrine) 8–10 12–18
0.5% Bupivacaine (+ epinephrine) 8–10 16–18
Continuous infusion ropivacaine 0.2% or dilute concentration of bupivacaine or levobupivacaine;
6–8 mL/h with a 2–4 mL hourly bolus.

TABLE 52.4 Lower Extremity Peripheral Nerve Block Dosing

Local Anesthetic (20–30 mL) Anesthesia (h) Analgesia (h)
3% 2-Chloroprocaine (+ epinephrine) 1.5 2.0
1.5% Mepivacaine 2–3 2–4
1.5% Mepivacaine (+ epinephrine) 2.5–4 3–6
2% Lidocaine (+ epinephrine) 3–6 5–8
0.5% Ropivacaine (+ epinephrine) 6–8 8–12
0.75% Ropivacaine (+ epinephrine) 8–10 12–18
0.5% Bupivacaine (+ epinephrine) 8–10 16–18
Continuous infusion ropivacaine 0.2% or dilute concentration of bupivacaine or levobupivacaine;
8–10 mL/h or 5 mL/h with 5 mL hourly bolus or 8 mL/h with 4 mL every 30 min bolus.

TABLE 52.5 Lower Thoracic/Lumbar Paravertebral Block Dosing

Local Anesthetic (3–5 mL at Each Space for
Multiple-Injection Technique or 15–20 mL for
Single-Injection Technique) Anesthesia (h) Analgesia (h)
1.5% Mepivacaine (+ epinephrine) 2–3 3–4
2% Lidocaine (+ epinephrine) 2–3 3–4
0.5% Ropivacaine 3–5 8–12
0.75% Ropivacaine 4–6 12–18
0.5% Bupivacaine (+ epinephrine) 4–6 12–18
0.5% L-Bupivacaine (+ epinephrine) 4–6 12–18
Continuous infusion ropivacaine 0.2% or dilute concentration of bupivacaine or levobupivacaine;
10 mL/h or 5–6 mL/h with 4–5 every 30 min boluses.

Summary
Regional anesthesia techniques are one of the analgesic strategies available

2808
when implementing a multimodal approach to postoperative analgesia.
Such techniques include neuraxial as well as PNBs and involve depositing
local anesthetics perineurally. The blocks may be performed as continuous
techniques for prolonged duration of action, and adjuvants can be added to
the local anesthetic in order to improve analgesia, prolong the effect of the
block, or reduce adverse effects. The choice of block is largely dependent
on the location of the target area, and the majority of the blocks can
successfully be performed via landmark techniques, nerve stimulation,
ultrasound guidance, or a combination thereof.

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358. Winnie AP, Ramamurthy S, Durrani Z. The inguinal paravascular technic of lumbar plexus
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359. Wassef MR. Interadductor approach to obturator nerve blockade for spastic conditions of
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360. Kitamura T, Mori Y, Ohno N, et al. Case of bladder perforation due to the obturator nerve
reflex during transurethral resection (TUR) of bladder tumor using the TUR in saline (Turis)
system under spinal anesthesia [in Japanese]. Masui 2010;59:386–389.
361. Fujiwara Y, Sato Y, Kitayama M, et al. Obturator nerve block using ultrasound guidance.
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362. Augspurger RR, Donohue RE. Prevention of obturator nerve stimulation during transurethral
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363. Deliveliotis C, Alexopoulou K, Picramenos D, et al. The contribution of the obturator nerve
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364. Tatlisen A, Sofikerim M. Obturator nerve block and transurethral surgery for bladder cancer.
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365. Helayel PE, da Conceição DB, Pavei P, et al. Ultrasound-guided obturator nerve block: a
preliminary report of a case series. Reg Anesth Pain Med 2007;32:221–226.
366. Kakinohana M, Taira Y, Saitoh T, et al. Interadductor approach to obturator nerve block for
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367. Vloka JD, Hadzic A, April E, et al. The division of the sciatic nerve in the popliteal fossa:
anatomical implications for popliteal nerve blockade. Anesth Analg 2001;92:215–217.
368. Jacob AK. Sciatic nerve blockade. In: Hebl JR, Lennon RL, eds. Mayo Clinic Atlas of
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369. Raj PP, Parks RI, Watson TD, et al. A new single-position supine approach to sciatic-femoral

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 nerve block. Anesth Analg 1975;54:489–493.
370. Mansour NY, Bennetts FE. An observational study of combined continuous lumbar plexus
and single-shot sciatic nerve blocks for post-knee surgery analgesia. Reg Anesth
1996;21:287–291.
371. Di BP, Bertini L, Casati A, et al. A new posterior approach to the sciatic nerve block: a
prospective, randomized comparison with the classic posterior approach. Anesth Analg
2001;93:1040–1044.
372. Karmakar MK, Kwok WH, Ho AM, et al. Ultrasound-guided sciatic nerve block: description
of a new approach at the subgluteal space. Br J Anaesth 2007;98:390–395.
373. Perlas A, Brull R, Chan VW, et al. Ultrasound guidance improves the success of sciatic nerve
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374. Chan VW, Nova H, Abbas S, et al. Ultrasound examination and localization of the sciatic
nerve: a volunteer study. Anesthesiology 2006;104:309–314.
375. Andersen HL, Andersen SL, Tranum-Jensen J. Injection inside the paraneural sheath of the
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376. Missair A, Weisman RS, Suarez MR, et al. A 3-dimensional ultrasound study of local
anesthetic spread during lateral popliteal nerve block: what is the ideal end point for needle tip
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377. Choquet O, Noble GB, Abbal B, et al. Subparaneural versus circumferential extraneural
injection at the bifurcation level in ultrasound-guided popliteal sciatic nerve blocks: a
prospective, randomized, double-blind study. Reg Anesth Pain Med 2014;39:306–311.
378. Tran DQ, Dugani S, Pham K, et al. A randomized comparison between subepineural and
conventional ultrasound-guided popliteal sciatic nerve block. Reg Anesth Pain Med
2011;36:548–552.
379. Latzke D, Marhofer P, Zeitlinger M, et al. Minimal local anaesthetic volumes for sciatic nerve
block: evaluation of ED 99 in volunteers. Br J Anaesth 2010;104:239–244.
380. Keplinger M, Marhofer P, Marhofer D, et al. Effective local anaesthetic volumes for sciatic
nerve blockade: a clinical evaluation of the ED99. Anaesthesia 2015;70:585–590.
381. Jeong JS, Shim JC, Jeong MA, et al. Minimum effective anaesthetic volume of 0.5%
ropivacaine for ultrasound-guided popliteal sciatic nerve block in patients undergoing foot and
ankle surgery: determination of ED50 and ED95. Anaesth Intensive Care 2015;43:92–97.
382. Bang SU, Kim DJ, Bae JH, et al. Minimum effective local anesthetic volume for surgical
anesthesia by subparaneural, ultrasound-guided popliteal sciatic nerve block: a prospective
dose-finding study. Medicine (Baltimore) 2016;95:e4652.
383. Taboada M, Rodriguez J, Valino C, et al. What is the minimum effective volume of local
anesthetic required for sciatic nerve blockade? A prospective, randomized comparison
between a popliteal and a subgluteal approach. Anesth Analg 2006;102:593–597.
384. Capdevila X, Pirat P, Bringuier S, et al. Continuous peripheral nerve blocks in hospital wards
after orthopedic surgery: a multicenter prospective analysis of the quality of postoperative
analgesia and complications in 1,416 patients. Anesthesiology 2005;103:1035–1045.
385. Neuburger M, Breitbarth J, Reisig F, et al. Complications and adverse events in continuous
peripheral regional anesthesia. Results of investigations on 3,491 catheters [in German].
Anaesthesist 2006;55:33–40.
386. Compere V, Rey N, Baert O, et al. Major complications after 400 continuous popliteal sciatic
nerve blocks for post-operative analgesia. Acta Anaesthesiol Scand 2009;53:339–345.
387. Wiegel M, Gottschaldt U, Hennebach R, et al. Complications and adverse effects associated
with continuous peripheral nerve blocks in orthopedic patients. Anesth Analg 2007;104:1578–
582.

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388. Bondar A, Egan M, Jochum D, et al. Case report: pudendal nerve injury after a sciatic nerve
block by the posterior approach. Anesth Analg 2010;111:573–575.
389. Labat G. Regional Anesthesia: Its Technic and Clinical Application. Philadelphia: W. B.
Saunders; 1922.
390. Rudkin GE, Rudkin AK, Dracopoulos GC. Ankle block success rate: a prospective analysis of
1,000 patients. Can J Anaesth 2005;52:209–210.
391. Lopez AM, Sala-Blanch X, Magaldi M, et al. Ultrasound-guided ankle block for forefoot
surgery: the contribution of the saphenous nerve. Reg Anesth Pain Med 2012;37:554–557.
392. Redborg KE, Antonakakis JG, Beach ML, et al. Ultrasound improves the success rate of a
tibial nerve block at the ankle. Reg Anesth Pain Med 2009;34:256–260.
393. Chin KJ, Wong NW, Macfarlane AJ, et al. Ultrasound-guided versus anatomic landmark-
guided ankle blocks: a 6-year retrospective review. Reg Anesth Pain Med 2011;36:611–618.
394. Redborg KE, Sites BD, Chinn CD, et al. Ultrasound improves the success rate of a sural nerve
block at the ankle. Reg Anesth Pain Med 2009;34:24–28.
395. Myerson MS, Ruland CM, Allon SM. Regional anesthesia for foot and ankle surgery. Foot
Ankle 1992;13:282–288.
396. Noorpuri BS, Shahane SA, Getty CJ. Acute compartment syndrome following revisional
arthroplasty of the forefoot: the dangers of ankle-block. Foot Ankle Int 2000;21:680–682.
397. Blanco R, McDonnell JG. Optimal point of injection: the quadratus lumborum type I and II
blocks. 2014. Available at: http://www.respond2articles.com/ANA/forums/post/1550.aspx.
Accessed July 16, 2018.
398. Blanco R, Ansari T, Girgis E. Quadratus lumborum block for postoperative pain after
caesarean section: a randomised controlled trial. Eur J Anaesthesiol 2015;32:812–818.
399. Sauter AR, Ullensvang K, Niemi G, et al. The Shamrock lumbar plexus block: a dose-finding
study. Eur J Anaesthesiol 2015;32:764–770.
400. Borglum J, Christensen AF, Hoegberg LCG, et al. Bilateral-dual transversus abdominis plane
(BD-TAP) block or thoracic paravertebral block (TPVB)? Distribution patterns, dermatomal
anaesthesia and LA pharmacokinetics [abstract]. Reg Anesth Pain Med 2012;37:E137–E139.
401. Chakraborty A, Goswami J, Patro V. Ultrasound-guided continuous quadratus lumborum
block for postoperative analgesia in a pediatric patient. A A Case Rep 2015;4:34–36.
402. Kadam VR. Ultrasound guided quadratus lumborum block or posterior transversus abdominis
plane block catheter infusion as a postoperative analgesic technique for abdominal surgery. J
Anaesthesiol Clin Pharmacol 2015;31:130–131.
403. Visoiu M, Yang C. Ultrasound-guided bilateral paravertebral continuous nerve blocks for a
mildly coagulopathic patient undergoing exploratory laparotomy for bowel resection. Paediatr
Anaesth 2011;21:459–462.
404. Abrahams M, Derby R, Horn JL. Update on ultrasound for truncal blocks: a review of the
evidence. Reg Anesth Pain Med 2016;41:275–288.
405. Lancaster P, Chadwick M. Liver trauma secondary to ultrasound-guided transversus
abdominis plane block. Br J Anaesth 2010;104:509–510.
406. Jankovic Z, Ahmad N, Ravishankar N, et al. Transversus abdominis plane block: how safe is
it? Anesth Analg 2008;107:1758–1759.
407. Blanco R. The “pecs block”: a novel technique for providing analgesia after breast surgery.
Anaesthesia 2011;66:847–848.
408. Perez MF, Miguel JG, de la Torre PA. A new approach to pectoralis block. Anaesthesia
2013;68:430.
409. Blanco R, Fajardo M, Parras MT. Ultrasound description of Pecs II (modified Pecs I): a novel
approach to breast surgery. Rev Esp Anestesiol Reanim 2012;59:470–475.
410. Chakraborty A, Khemka R, Datta T, et al. COMBIPECS, the single-injection technique of

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 pectoral nerve blocks 1 and 2: a case series. J Clin Anesth 2016;35:365–368.
411. Blanco R, Parras T, McDonnell JG, et al. Serratus plane block: a novel ultrasound-guided
thoracic wall nerve block. Anaesthesia 2013;68:1107–1113.
412. Fujiwara A, Komasawa N, Minami T. Pectoral nerves (PECS) and intercostal nerve block for
cardiac resynchronization therapy device implantation. Springerplus 2014;3:409.
413. Perez MF, Duany O, de la Torre PA. Redefining PECS blocks for postmastectomy analgesia.
Reg Anesth Pain Med 2015;40:729–730.
414. Bashandy GMN, Abbas DN. Pectoral nerves I and II blocks in multimodal analgesia for breast
cancer surgery: a randomized clinical trial. Reg Anesth Pain Med 2015;40:68–74.
415. Chakraborty A, Khemka R, Datta T. Ultrasound-guided truncal blocks: a new frontier in
regional anaesthesia. Indian J Anaesth 2016;60:703–711.
416. Wahba SS, Kamal SM. Thoracic paravertebral block versus pectoral nerve block for analgesia
after breast surgery. Egyptian Journal of Anaesthesia 2014;30:129–135.
417. Madabushi R, Tewari S, Gautam SK, et al. Serratus anterior plane block: a new analgesic
technique for post-thoracotomy pain. Pain Physician 2015;18:E421–E424.
418. Purcell N, Wu D. Novel use of the PECS II block for upper limb fistula surgery. Anaesthesia
2014;69:1294.
419. Khemka R, Chakraborty A, Ahmed R, et al. Ultrasound-guided serratus anterior plane block
in breast reconstruction surgery. A A Case Rep 2016;6:280–282.
420. Bhoi D, Pushparajan HK, Talawar P, et al. Serratus anterior plane block for breast surgery in a
morbidly obese patient. J Clin Anesth 2016;33:500–501.
421. Neal JM, Barrington MJ, Brull R, et al. The second ASRA practice advisory on neurologic
complications associated with regional anesthesia and pain medicine: executive summary
2015. Reg Anesth Pain Med 2015;40:401–430.
422. Horlocker TT, Kufner RP, Bishop AT, et al. The risk of persistent paresthesia is not increased
with repeated axillary block. Anesth Analg 1999;88:382–387.
423. Sites BD, Taenzer AH, Herrick MD, et al. Incidence of local anesthetic systemic toxicity and
postoperative neurologic symptoms associated with 12,668 ultrasound-guided nerve blocks:
an analysis from a prospective clinical registry. Reg Anesth Pain Med 2012;37:478–482.
424. Allegri M, Bugada D, Grossi P, et al. Italian Registry of Complications associated with
Regional Anesthesia (RICALOR). An incidence analysis from a prospective clinical survey.
Minerva Anestesiol 2016;82:392–402.
425. Farber SJ, Saheb-Al-Zamani M, Zieske L, et al. Peripheral nerve injury after local anesthetic
injection. Anesth Analg 2013;117:731–739.
426. Hadzic A, Dilberovic F, Shah S, et al. Combination of intraneural injection and high injection
pressure leads to fascicular injury and neurologic deficits in dogs. Reg Anesth Pain Med
2004;29:417–423.
427. Orebaugh SL, Williams BA, Vallejo M, et al. Adverse outcomes associated with stimulator-
based peripheral nerve blocks with versus without ultrasound visualization. Reg Anesth Pain
Med 2009;34:251–255.
428. Bigeleisen PE. Nerve puncture and apparent intraneural injection during ultrasound-guided
axillary block does not invariably result in neurologic injury. Anesthesiology 2006;105:779–
783.
429. Bigeleisen PE, Moayeri N, Groen GJ. Extraneural versus intraneural stimulation thresholds
during ultrasound-guided supraclavicular block. Anesthesiology 2009;110:1235–1243.
430. Welch MB, Brummett CM, Welch TD, et al. Perioperative peripheral nerve injuries: a
retrospective study of 380,680 cases during a 10-year period at a single institution.
Anesthesiology 2009;111:490–497.
431. Kopp SL, Jacob AK, Hebl JR. Regional anesthesia in patients with preexisting neurologic

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 disease. Reg Anesth Pain Med 2015;40:467–478.
432. Watson JC, Huntoon MA. Neurologic evaluation and management of perioperative nerve
injury. Reg Anesth Pain Med 2015;40:491–501.
433. Horlocker TT, Wedel DJ, Rowlingson JC, et al. Regional anesthesia in the patient receiving
antithrombotic or thrombolytic therapy: American Society of Regional Anesthesia and Pain
Medicine Evidence-Based Guidelines (Third Edition). Reg Anesth Pain Med 2010;35:64–101.
434. Narouze S, Benzon HT, Provenzano DA, et al. Interventional spine and pain procedures in
patients on antiplatelet and anticoagulant medications: guidelines from the American Society
of Regional Anesthesia and Pain Medicine, the European Society of Regional Anaesthesia and
Pain Therapy, the American Academy of Pain Medicine, the International Neuromodulation
Society, the North American Neuromodulation Society, and the World Institute of Pain. Reg
Anesth Pain Med 2015;40:182–212.
435. Bergman BD, Hebl JR, Kent J, et al. Neurologic complications of 405 consecutive continuous
axillary catheters. Anesth Analg 2003;96:247–252.
436. Weinberg GL, Di GG, Ripper R, et al. Resuscitation with lipid versus epinephrine in a rat
model of bupivacaine overdose. Anesthesiology 2008;108:907–913.
437. Di GG, Schwartz D, Ripper R, et al. Lipid emulsion is superior to vasopressin in a rodent
model of resuscitation from toxin-induced cardiac arrest. Crit Care Med 2009;37:993–999.

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CHAPTER 53
Burn Pain
SHELLEY A. WIECHMAN and SAM R. SHARAR

If burn injuries in themselves are not the most painful type of trauma a
person can sustain, then they likely reach this status once the nature of
their treatment is considered. Contemporary treatment of burn injuries
involves a multitude of invasive and rehabilitative procedures that
continue—often on a daily basis—for days, weeks, or months. Each
intervention is critical to achieving optimal wound healing and long-term
physical/occupational function yet has the potential for inflicting more
pain, on a repeated basis, than that of the initial trauma. Burn injuries are
pervasive in both industrial nations and developing countries around the
world and affect individuals across a wide demographic span. In the
United States, it is estimated that burn injuries account for 40,000
hospitalizations annually (about half of these hospitalizations are children
or adolescents) and 3,275 deaths.1 This is down from 5,500 deaths just 15
years ago. As death rates for burn injuries decline, due primarily to burn
prevention strategies and improved surgical care, more patients with large
burns are surviving and pose unique physical and psychological
rehabilitation challenges such as scarring, contractures, amputations,
psychological adjustment, and pain.2
Despite this increased challenge to provide effective pain relief, there
has long been substantial evidence that pain from burn injuries is
undertreated, particularly in children and the elderly.3,4 Furthermore, the
magnitude of pain reported after burn injury and during burn care
correlates strongly with long-term adverse psychological outcome in this
patient population.5,6 Thus, there are humane, medical, and economic
reasons to better control burn pain in a practical and cost-effective fashion.
Pain management is closely tied to a patient’s satisfaction with care, and
uncontrolled pain is associated with poorer long-term outcomes in both

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adults and children.7–11 Evidence-based pain management protocols have
been shown to reduce pain.12 Both the United States and New Zealand
have developed clinical guidelines for the management of burn pain that
were based on rigorous standards for evaluation and treatment,13,14 and the
American Burn Association has identified priority topics for research and
additional clinical guidance.15

The Nature of Burn Pain

Treating the human suffering from burn pain is challenging from the
perspectives of both the patient and clinician. It is well known that a burn
injury results in one of the most intense types of sensory nociception
imaginable, attributable to the unique tissue injury that results from a
thermal insult to the dermal sensory organs and acute inflammatory
response that, at least in the early postburn period, is related to the depth of
tissue injury (Figs. 53.1 and 53.2).

FIGURE 53.1 Anatomic layers of skin. Graphic representation of skin layers including the outer
epidermis, the thin papillary dermis, the collagen-dense reticular dermis, and the deep subcutaneous
fat. The dermal sensory neurons of mechanoheat receptors and dermal capillaries are shown,
relative to a first-degree burn injury (confined to the outer epidermal skin layer). (Reprinted from
Sharar SR, Patterson DR, Wiechman-Askay S. Burn pain. In: Waldman SD, ed. Pain Management.
1st ed. Philadelphia: Saunders-Elsevier; 2007:240–256. Copyright © 2007 Elsevier. With
permission.)

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FIGURE 53.2 Definitions and examples of partial- and full-thickness burn injuries. Superficial
and deep skin burns are defined, including clinical characteristics (etiology, physical exam findings,
tissue injury, and usual treatment), photographic examples, and graphic representations of tissue
injury (including zones of hyperemia, stasis, and coagulation). (Reprinted from Sharar SR,
Patterson DR, Wiechman-Askay S. Burn pain. In: Waldman SD, ed. Pain Management. 1st ed.
Philadelphia: Saunders-Elsevier; 2007:240–256. Copyright © 2007 Elsevier. With permission.)

First-degree burns (e.g., sunburn) are characterized by tissue injury that

is limited to the epidermal skin layer and an inflammatory response in the
superficial dermal layers and results in hyperemia (manifest as erythema),
an intact epidermis (no skin blistering), and sensitization of dermal sensory
organelles producing hyperalgesia and mild to moderate pain. Second-
degree or partial-thickness burns involve tissue injury that extends to
variable depths into the dermis; superficial second-degree burns involve
only the upper, papillary dermis and are more likely to heal spontaneously,
whereas deep second-degree burns involve the deeper, collagen-dense
reticular dermis and are more likely to require surgical treatment. Because
second-degree burns consistently injure and/or inflame sensory receptors
in the dermis, these burns are associated with marked hyperalgesia and
produce moderate to severe pain. Third-degree burns are characterized by
complete destruction of the dermis, including its sensory and vascular

2834
structures, such that although pain may still be a presenting symptom,
hypalgesia to cutaneous stimulation, a leathery skin texture, and lack of
capillary refill are common. Complaints of acute pain with third-degree
burns are typically minimal but can be variable and are universally present
with respect to the transition zone between burned and unburned skin. All
burn injuries involving the dermis (i.e., second- and third-degree) result in
sensitized and reorganized states of both peripheral mechanoheat receptors
and dorsal horn neurons. Models of these cellular alterations provide a
conceptual framework for understanding how such peripheral neuronal
injuries that are present after a burn can cause acute and subacute pain,
hyperalgesia, and chronic pain and are described in detail elsewhere.16,17
In addition to the significant pain caused by the burn injury itself, the
major clinical analgesic challenge results from procedural and
postoperative pain associated with contemporary burn care, which
incorporates a series of aggressive procedures that stimulate nociceptive
peripheral afferent fibers on a daily basis for days, weeks, or months after
the initial injury. In the typical treatment paradigm, a burn injury will first
be assessed as to its depth and then treated accordingly. Shallow burns will
be left to heal on their own, and full-thickness thermal injuries will
typically be excised and covered with a skin graft. Burns of indeterminate
depth in many burn centers will undergo a series of wound débridements
and dressing changes, typically on a daily basis, until burn depth can be
more accurately determined. Burn care–related pain can be anticipated and
treated, to a large degree, based on the clinical setting in which the pain
occurs. Wound débridement, limb/joint mobility exercises, therapeutic
skin stretching, and other medical procedures result in procedural pain,
which is of high intensity but limited duration. Patients who are between
procedures and have minimal physical activity continue to experience
resting pain that is relatively less intense but almost constant in duration.
When pain control interventions fail to control resting pain, patients will
experience breakthrough pain. Finally, because surgical interventions are a
frequent treatment for severe burn injuries, postoperative pain is an
additional type of pain to be considered. Each of these four types of burn
pain has specific treatment strategies, as described later in this chapter.
In addition to these four distinct yet overlapping clinical settings, burn

2835
pain varies somewhat temporally with the phase of treatment, most often
divided into the resuscitative, healing, and remodeling phases.17 In the
resuscitative phase immediately after the injury, the patient is stabilized
hemodynamically and initial wound treatments are performed. This phase
is usually of short duration (e.g., hours), but depending on the size of
injury can last up to 72 hours, as in the case of large surface area burns.
Initial wound care in this phase is often intensely painful and, in the rush
of treating life-threatening events, analgesia may be unintentionally de-
emphasized. Pain in the healing phase is characterized by repeated
episodes of burn wound care and dressing changes, wound examinations,
needle sticks for intravenous (IV) access or blood sampling, and surgical
procedures including débridement and grafting. The healing phase can last
from days to several weeks depending on the severity of the burn and
progress of the systemic response to the injury. It has been reported that
hyperalgesia is more severe during this phase, independent of the size and
degree of the burn. In the remodeling phase, the systemic and local
inflammatory responses decrease, wound healing is nearing completion,
and rehabilitative activities gain emphasis. Depending on the
characteristics of the wound scar, this phase is characterized by not only
reductions in resting pain but also ongoing episodic procedural pain
associated with physical and occupational therapy sessions. It is important
to note that the duration and sequence of these phases can vary depending
on the clinical progress of wound treatment. For example, a patient who
has progressed to the remodeling phase can return to the healing phase
after a surgical procedure recreates an open wound (e.g., burn site or skin
graft donor site).
Although the clinical and temporal settings of burn care can provide
some prediction as to the pain a patient might experience, the magnitude
and quality of a given individual’s pain experience have proven extremely
difficult to anticipate. The sensory and affective qualities of burn pain have
received scant attention in the literature, and few studies have addressed
pain patterns over the course of hospitalization. For example, Choinière
and colleagues18 observed the evolution of burn pain experienced over the
course of hospitalization and found that it varied substantially both within
and across patients over time. They also reported that burn pain was not

2836
accurately predicted by sociodemographic factors or burn size (the latter
finding is contrary to the inaccurate assumptions of many clinicians
inexperienced in treating burns). Similarly, patient pain reports do not
correlate with the quantity of opioid analgesics received, a finding first
published in 1981 and still reported over two decades later.3,19 This
unpredictable and often opioid-resistant nature of burn pain has been
hypothetically linked to underlying sensory nerve damage20,21 and
contributes to the difficulty of effectively treating burn pain.
Although capturing the pain experience of an individual patient will
likely continue to prove elusive for the reasons listed, it remains important
to continue to treat burn pain aggressively. Not only can burn recovery
(like that from any trauma) be hindered by the presence of acute pain,22–24
burn pain has also been reported to influence posthospitalization emotional
recovery more than the size of the burn, the duration of hospitalization, or
even the patient’s preinjury mental health. Ptacek and colleagues5 reported
that inpatient pain scores in adults correlated more strongly with distress
and quality of life scores at 1 month after discharge than did any other
independent variable studied, a finding that persisted at 1- and 2-year
follow-up periods.6 Similarly, Saxe et al.25 reported that the amount of
morphine received by burn-injured children may impact their subsequent
development of posttraumatic stress disorder (PTSD). Future studies will
likely further substantiate the practical utility of adequately treating burn
pain.

Psychological Factors
It is well known that pain processing may be largely subjective and that
the degree to which pain is interpreted as a threat will influence how much
patients will suffer. A burn injury is a form of trauma that has dire
emotional consequences for many survivors, and the threat value of the
injury will likely have an impact on the amount of pain they perceive.
Moreover, the nature of a patient’s preinjury psychological makeup also
has a great deal to do with how much pain he or she will perceive. In
considering psychological factors, it is then important to consider the
preinjury status of patients as well as their emotional adjustment during

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and after hospitalization.
Burn injuries often occur when people are at risk because of low social
resources or because of personality and/or psychiatric factors. The
estimates of preinjury psychological problems in some studies of burn
patients are so high that injuries of this type should be considered to be, in
part, a symptom of social ills.26 Estimated rates of psychiatric diagnoses in
patients admitted for burn care have ranged from 25% to 75%, with the
most prevalent diagnoses including depression, personality disorders, and
substance abuse.26 Psychopathology and psychological problems are
common in patients with burn scars that impact body function and
image.27 In addition, the nature in which the burn injury occurred is often
cause for concern: suicide attempts, child and elder abuse (or neglect),
domestic violence, illicit drug manufacturing (methamphetamine
production, hash oil production), and juvenile fire setting are all common
sources of the injury. Psychological disturbances that predate the burn
injury have the potential to increase complications, lengthen hospital stays,
and lead to more serious long-term adjustment problems.28,29 A number of
these preinjury complications have direct relevance to pain control.
Patients with drug and alcohol histories may show lower pain tolerance,
more delirium, and higher drug-seeking behaviors. Particularly, those with
a prior opioid addiction will be more sensitive to pain and greater have a
greater tolerance to opioids. Diagnostic and Statistical Manual of Mental
Disorders, 5th edition (DSM-5) Axis II character disorders can present a
particular challenge to clinicians. Patients with such personality
predispositions may show not only drug-seeking but also dramatic acting
out behaviors, manipulation, staff splitting, and low frustration tolerance.
Patients with borderline personality disorders, in particular, engage in
parasuicide behavior and self-mutilation. All of these factors might
complicate pain control, in addition to making the patient’s overall
management a challenge.
Both the burn care environment and psychological reactions to burn
injuries contribute to pain and complications in its management. Patients
with large unhealed burn areas or other significant medical complications
are usually placed in intensive care units (ICUs). In the critical care
setting, delirium and other psychotic reactions are common.30,31 There has

2838
been recent emphasis on managing delirium more aggressively in the ICU
as it leads to complications such as more infections, respiratory problems,
and longer lengths of hospitalization. Unfortunately, there is a dilemma in
achieving optimal management as opioids and anxiolytics are needed for
pain control but are the primary contributors to delirium. Furthermore,
uncontrolled pain can also increase delirium. Finding appropriate doses
requires constant vigilance and adjustment. Poor communication from
altered mental status or endotracheal intubation may further impede pain
assessment. Anxiety is commonly reported by burn-injured patients, both
at greater levels than reported to be tolerable and for prolonged periods
throughout hospitalization.32 As a result, anxiety assessment tools specific
for burn-injured patients have been reported and validated and may predict
burn pain and postdischarge functional capacity better than other anxiety
assessment tools.33 As hospitalization persists and patients show greater
mental capacity, depression becomes increasingly common and is well
known to interact with pain.34 Depressive symptoms have a prevalence as
high as 54% during postburn hospitalization35 and are a significant
predictor of physical health at 2 months postdischarge.36 PTSD is another
complication that can negatively impact pain control as PTSD can cause
agitation and hypervigilance.27,37
The manner in which the burn environment and patients’ personality
factors can amplify pain is particularly notable in children, for whom the
burn unit environment can be extremely strange and frightening. There is
little opportunity for the burn staff to prepare children psychologically for
the repeated medical procedures they must endure, and conditioned
anxiety to the stimuli associated with burn care can be expected. Children
will also often demonstrate regression and behavioral acting out in
response to hospitalization, making pain control during procedures a
particular challenge. It should be noted that although many burn centers
have pediatric-specific pain protocols, their emphasis is appropriately on
safety; hence, they are often not aggressive enough to adequately address
pain or prevent procedural anxiety in every child. As previously
mentioned, aggressive treatment of pain may serve to reduce the
subsequent development of PTSD in children.25 A comprehensive review
of issues specific to pediatric burn pain can be found elsewhere.38,39

2839
 There is growing evidence that although pain was once thought to be a
problem only during the early phases (e.g., resuscitative and healing
phases) of burn care, a significant number of patients experience ongoing
pain long after hospital discharge. For example, a long-term, neuropathic
pain syndrome has been recently described in burned patients, presenting
approximately 4 months after the initial injury40 and persisting for an
average of 13 months. Similarly, in a survey of 358 respondents of a burn
survivor support group,41 52% reported ongoing pain, 66% said that it
interfered with their rehabilitation, and 55% said the pain interfered with
their daily lives. Respondents in this study also reported that thoughts of
the accident and depression made their pain worse. Although much
research has been done to address acute pain control after a burn injury,
little is known about ongoing opioid needs once patients are discharged.
Wibbenmeyer et al.42 tracked opioid use from discharge to the outpatient
setting and found that 85% of patients were on opioids at discharge with a
morphine equivalent (ME) of 114. Although 90% had weaned off by 14
days postdischarge, these high doses are within the range (50 to 100 ME)
associated with harmful drug effects reported in nonburn populations.43
Furthermore, patients may show persistent depression, anxiety, or PTSD
that can interfere with pain control, with both depression and anxiety
predicting worse outcomes in pain, fatigue, and physical functioning
assessments up to 2 years postdischarge.44 Sleep problems are prevalent,
yet frequently overlooked in postdischarge phase, and may reflect
inadequate pain treatment.45 When psychological or pain problems persist
long after hospital discharge, the possibility of social or financial
disincentives should be entertained. Although some patients will certainly
have internally generated psychological problems, for others, the issues
will persist because of such factors as litigation or the desire to avoid
returning to an undesirable job.

Generalized Treatment Paradigm for Burn Pain

Because burn pain is highly variable and cannot be reliably predicted by
either clinical assessment of the patient or his or her burn wound, we
recommend a structured approach to burn analgesia that incorporates both

2840
pharmacologic and nonpharmacologic therapies, targets specific pain
issues unique to the burn patient, and can be tailored to anticipated
variations in patient need and institutional capability. One clear goal of
such a paradigm is to avoid the undertreatment of burn pain.
In the generalized burn pain management paradigm, selection of an
analgesic regimen is individualized and based on two broad categories: (1)
the clinical need for analgesia (i.e., treatment of background vs. procedural
vs. postoperative pain) and (2) limitations imposed by the patient (e.g.,
presence of IV access, endotracheal tube, or opioid tolerance) or by
clinical facilities (available monitoring capabilities and personnel). The
presence or absence of IV access directly influences analgesic drug choice,
particularly in children in whom IV access may be problematic. Patients
who are endotracheally intubated and ventilated are “protected” from the
risk of opioid-induced respiratory depression; thus, opioids may be more
generously administered in these individuals, as is often indicated for
complex burn débridement procedures in patients with more extensive or
severe burn injuries. Individual differences in opioid efficacy should be
considered in all patients, including opioid tolerance in patients requiring
prolonged opioid analgesic therapy or in those with preexisting substance
abuse histories. Due to the development of drug tolerance with prolonged
medical use or recreational abuse of opioids (both commonly seen in burn
patients), opioid analgesic doses needed for burn analgesia may
significantly exceed those recommended in standard dosing guidelines.
One clinically relevant consequence of drug tolerance is the potential for
opioid withdrawal to occur during inpatient burn treatment. Thus, the
period of inpatient burn care is not an appropriate time to institute
deliberate opioid withdrawal or detoxification measures in the substance-
abusing patient because such treatment ignores the very real analgesic
needs of these patients. Similarly, when reductions in analgesic therapy are
considered as burn wounds heal, reductions should occur by careful taper,
in order to prevent acute opioid withdrawal syndrome.
Institutional capability to provide adequate monitoring as required for
“moderate sedation” (as defined by the American Society of
Anesthesiologists; Table 53.1)46 may also dictate which agents are used
for procedural analgesia, as some of the more potent opioids (e.g.,

2841
fentanyl) and anesthetic agents (e.g., ketamine, propofol) may
unpredictably result in potentially dangerous levels of sedation (“deep
sedation” or “general anesthesia”). The use of potent opioids and
anxiolytics should only occur in settings with adequate monitoring,
personnel, and resuscitation equipment appropriate for the degree of
sedation anticipated. For many burn wound débridement procedures and
most rehabilitative therapy sessions in the hospital ward or outpatient
clinic setting, opioid analgesia with “minimal sedation” is sufficient and
no special monitoring is required. Larger or more potent doses of opioids,
or the concurrent use of anxiolytic sedatives (e.g., benzodiazepines), may
not only produce more pronounced sedation (“moderate sedation”) but
could also progress to “deep sedation” where patient–staff communication
and/or patient consciousness are lost. Current guidelines of The Joint
Commission,47 as well as adult46 and pediatric48 physician specialty
professional organizations, dictate both general and specific levels of
monitoring (e.g., continuous pulse oximetry, presence of an independent
observer specifically responsible for monitoring ventilation and vital signs)
for patients requiring each of these levels of procedural analgesia and
sedation.

TABLE 53.1 American Society of Anesthesiologists Continuum of

Depth of Sedation
Moderate
Minimal Sedation/Analgesia
Sedation (Conscious Deep General
(Anxiolysis) Sedation) Sedation/Analgesia Anesthesia
Responsiveness Normal Purposeful* Purposeful* Unrousable
response to response to response even with
verbal verbal or tactile following painful
stimulation stimulation repeated or stimulus
painful
stimulation
Airway Unaffected No intervention Intervention may be Intervention
required required often
required
Spontaneous Unaffected Adequate May be inadequate Frequently
ventilation inadequate
Cardiovascular Unaffected Usually maintained Usually maintained May be
function impaired

2842
*
Reflex painful withdrawal from a painful stimulus is NOT considered a purposeful response.
Approved by the American Society of Anesthesiologists House of Delegates on October 13, 1999,
and amended on October 27, 2004.
Reprinted with permission from American Society of Anesthesiologists Task Force on Sedation and
Analgesia by Non-Anesthesiologists. Practice guidelines for sedation and analgesia by non-
anesthesiologists. Anesthesiology 2002;96(4):1004–1017.

Because nociception at the burn site is the predominant mechanism of

pain and suffering in these patients during the resuscitative and healing
phases, pharmacologic treatment with potent opioids, anxiolytics, and
other agents (e.g., ketamine) is the first line of therapy. However,
nonpharmacologic methods of treating burn pain are also extremely useful.
Some pain control techniques should be second nature to the staff and
integrated into standard care (e.g., minimizing the number and
intrusiveness of dressing changes, limb elevation, brief educational
approaches). Other, more novel nonpharmacologic analgesic techniques
are more practically implemented after a stable pharmacologic regimen is
established or may require special expertise (e.g., hypnosis). To reinforce a
consistent approach to analgesic management, particularly in centers
where house staff physicians or nursing staff may rotate or change
frequently, the establishment of succinct yet detailed institutional
guidelines may help physicians and nurses with choosing and
administering analgesics that target specific analgesic needs,12,49,50 as
shown in Table 53.2. To maximize simplicity and utility, it is
recommended that such guidelines be safe and effective over a broad range
of ages, be explicit in their dosing recommendations, have a limited
formulary to maximize staff familiarity, and allow the bedside nurse to
continuously evaluate efficacy and safety.50 In addition, the regular use of
a weight-based pediatric medication worksheet (placed at the bedside and
in the patient record), containing all analgesic and resuscitation drugs
likely to be administered, provides a supplemental safeguard against
accidental overdose, particularly in the young pediatric age group.51

TABLE 53.2 Harborview Medical Center/University of Washington

Burn Center Burn Analgesia and Sedation Guidelines for Adults
ICU No PO ICU Taking Ward Large Ward Small Open
Intake PO Open Areas Areas/Predischarge

2843
 Background Continuous Scheduled Scheduled Scheduled
pain morphine methadone methadone NSAIDs/acetaminophen
sulfate (IV) or MS or MS or scheduled oxycodone
drip Contin Contin or none
Procedural pain Morphine Oxycodone, Oxycodone, Oxycodone
sulfate (IV) fentanyl IV, fentanyl IV,
or fentanyl or fentanyl Nitrox (IH)
(IV) ACTIQ or fentanyl
ACTIQ
Breakthrough Morphine Oxycodone Oxycodone NSAIDs/acetaminophen
pain (PRN sulfate (IV) or oxycodone
dosing) or fentanyl
(IV)
Background Scheduled Scheduled None or None
anxiolysis lorazepam lorazepam scheduled
(IV) or lorazepam
continuous
lorazepam
(IV)
Procedural Lorazepam or Lorazepam None or None
anxiolysis midazolam lorazepam
Discharge or NA For transfer to Oxycodone Oxycodone or NSAIDs for
transfer pain ward: wean for procedural pain
medications drips, procedural
establish pain;
PO pain methadone
meds early, taper or MS
anticipate Contin
dose taper if
tapering as applicable
needs
decrease
NOTE: Medications are to be given orally unless otherwise specified. Exception: fentanyl ACTIQ
is given transmucosal. Analgesic and anxiolytic choices are simplified to a minimum number of
agents to encourage staff familiarity and are targeted to specific pain and anxiety needs. Therapy
can be individualized to include agents not in this guideline when clinically indicated. This chart
is laminated and prominently displayed in all patient care areas.
ICU, intensive care unit; IH, inhalation; NA, not applicable; Nitrox, 50% nitrous oxide/50% oxygen
inhaled; NSAIDs, nonsteroidal anti-inflammatory drugs; PRN, as needed.

In recent years, a number of comprehensive reviews of burn pain

management that emphasize such a systematic and multidisciplinary
approach to burn pain management have been published,17,52–55 including
practice guidelines from the American Burn Association.14 The reader is
referred to these sources for additional perspective and detail.

2844
Pharmacologic Approaches
In describing pharmacologic approaches for burn analgesia, three
consistent observations can be made. First, for patients with injuries
extensive enough to require hospitalization, pain from the burn itself is
severe. Thus, potent opioids form the cornerstones of pharmacologic pain
control in these patients, leaving few indications for the sole use of
nonsteroidal anti-inflammatory drugs (NSAIDs) or acetaminophen, with
notable exceptions of minor burns and outpatient treatment. Second,
because burn pain has well-defined components described previously—
notably background, procedural, breakthrough, and postoperative pain—
pharmacologic choices for analgesia should target each pain pattern
individually. Final, because burn pain will vary somewhat unpredictably
throughout hospitalization due to surgical intervention and activity levels,
analgesic regimens should be continuously evaluated and reassessed to
avoid problems of under- or overmedication.6 Pain assessment is
facilitated by the regular use of standardized, self-report scales for adults
and older children and observational scoring systems for the very young,
as described in Chapter 20. A reliance on nurse assessment of patients’
burn pain can be problematic, however, as it is well documented that
nurses’ and patients’ assessment of burn pain and analgesia are not always
comparable18,56,57 with nursing staff typically underestimating the need for
analgesic therapy.

OPIOIDS
Opioid agonists are the most commonly used analgesics in the treatment of
burn pain, in part because (1) they are effective, (2) the benefits and risks
of their use are familiar to the majority of care providers, and (3) they
provide some dose-dependent degree of sedation that can be advantageous
to both burn patients and staff, particularly during burn wound care
procedures. The wide spectrum of opioids available for clinical use (see
Chapter 79) provides dosing flexibility (i.e., variable routes of
administration, variable duration of action) that is ideal for the targeted
treatment of burn pain. The pharmacokinetics of opioids in burn patients
are not consistently different from nonburn patients,58,59 although

2845
decreased volume of distribution and clearance and increased elimination
half-life have been reported for morphine.60 Similarly, pharmacodynamic
potency of opioids has inconsistently been reported as increased61 and
decreased60 in burn patients.
The route of opioid administration is an important consideration in burn
patients, with the principal choice between IV, oral, or transmucosal
administration dictated by the severity of burn (critically ill patients
require IV access and may have abnormal gut function) and high risk of
burn patients for developing IV catheter–related sepsis (hence, physician
reluctance to maintain long-term IV access).62 Intramuscular opioid
administration is avoided because of the need for repeated, painful
injections and because of variable vascular absorption due to unpredictable
compartmental fluid shifts and muscle perfusion in burn patients,
particularly in the resuscitative phase. Patient-controlled analgesia (PCA)
with IV opioids offers the burn patient a safe and efficient method of
achieving more flexible analgesia for both background and procedural
analgesia. PCA also offers the patient some degree of control over his or
her medical care, this being a major issue for burn patients whose waking
hours are often completely scheduled with care activities ranging from
wound care to physical and rehabilitation therapy. Some studies comparing
PCA opioid use to other routes of administration in the burn population
have shown potential benefits of PCA.63–65 The PCA administration of
potent, short-acting opioids (e.g., fentanyl,66 alfentanil,67 remifentanil) for
procedural analgesia may also have a useful role in burn analgesic
management, but this has not been extensively investigated.
Because IV access is infrequently present in hospitalized burn patients
outside of the critical care setting (for reasons noted previously), oral and
transmucosal opioid delivery are frequently employed. For background
pain, long-acting oral opioids (e.g., methadone) or sustained-release
opioids are often utilized. However, the latter agents are not available in
appropriate dose ranges for pediatric patients, so a reliance on shorter
acting oral opioids is often necessary. For background pain control in this
population, the use of regularly scheduled oral opioids is recommended
over as needed (PRN) dosing so that more stable plasma opioid
concentrations and analgesic effects may be obtained.68 Similarly, the use

2846
of short-acting oral opioids is common for anticipated procedural pain,
emphasizing early administration of the drug so that adequate plasma
levels and associated analgesia are present prior to beginning the
procedure. Alternatively, oral transmucosal administration of opioids is
reported in burn patients to be particularly advantageous in those patients
without IV access and in children, in both the inpatient69 and outpatient70
clinic settings.

NONOPIOIDS
The list of nonopioid analgesics in widespread use for the treatment of
burn pain is relatively extensive, although clinical evidence to support
such use is variably found in the published literature. Oral NSAIDs and
acetaminophen, as outlined previously, are only mild analgesics and
exhibit a ceiling effect in their dose–response relationship, rendering them
unsuitable as sole agents for the treatment of typical, severe burn pain.
However, they are of benefit in treating minor burns, particularly in the
outpatient setting and in combination with more potent analgesics for their
“opioid-sparing” effects. Topical application of NSAIDs on burn wounds
can theoretically inhibit nociception at the injury site with minimal
systemic uptake71 yet does not result in significant analgesia.72 The opioid
agonist-antagonist drugs (e.g., nalbuphine, butorphanol) not only produce
“mixed” actions at the opiate receptor level, theoretically providing
analgesia (agonist property) with lesser side effects (antagonist properties)
but also exhibit ceiling effects. Although studies have shown this class of
drugs to be effective in treating burn pain,73 experience with them is both
limited and suggestive of efficacy in patients with only relatively mild
burn pain.
Antidepressants, anticonvulsants, antipsychotics, α2 agonists, and
systemic administration of local anesthetics have been proposed as
potential analgesic agents for burn pain74 based on their known
mechanisms of action in other pain states yet have not been studied
extensively in the setting of burns. As neuropathic pain can occur in
patients with healed burns,21,40,41 these agents may have specific
application in this setting, as suggested by a preliminary reports with a
variety of nonopioid agents including gabapentin,75,76 dexmedetomidine,77

2847
clonidine,78 IV lidocaine,79 and haloperidol.80

ANXIOLYTICS
Current, aggressive therapies for cutaneous burn wounds, together with the
persistent and repetitive qualities of background and procedural pain, make
burn care an experience that is likely to engender anxiety in both adult and
pediatric patients. It is also recognized that anxiety can exacerbate acute
pain.22 This has led to the common practice of using anxiolytic drugs in
combination with opioid analgesics, a practice that has persisted since the
1980s.81 A recent survey of North American burn centers reported that up
to 39% of hospitalized pediatric burn victims regularly receive anxiolytics
as part of their pain and sedation management regimen.82 Intuitively, this
practice is particularly useful in premedicating patients for daily wound
care procedures, due to the anticipatory anxiety experienced by these
patients prior to and during débridement. Although previously shown that
benzodiazepine therapy improves postoperative pain scores in nonburn
settings,83 it is also reported that low-dose benzodiazepine administration
significantly reduces burn wound care pain reports.84 It appears that the
patients most likely to benefit from this therapy are not those with high
trait (premorbid) anxiety but rather those with high state (at the time of the
procedure) anxiety or those with high baseline pain scores.

ANESTHETICS
Inhaled nitrous oxide is an analgesic agent safe for administration by
nonanesthesiology personnel to achieve moderate sedation. It provides
safe and effective analgesia without loss of consciousness for moderately
painful procedures in other health care settings (e.g., dentistry) and is also
a commonly used, although less well-studied, agent for the treatment of
burn pain.85,86 It is typically used as a 50% mixture in 50% oxygen and is
self-administered by an awake, cooperative, spontaneously breathing
patient via a mouthpiece or mask. A secondary benefit of nitrous oxide
use, like that of PCA opioid administration, is the element of control given
to the patient for his or her care. Nitrous oxide is less useful with critically
ill or uncooperative patients. It has also been implicated in a very small but
measurable incidence of toxicity issues (e.g., spontaneous abortion, bone

2848
marrow suppression) to patients or staff exposed for prolonged
periods,87,88 although not in the setting of burn pain treatment.
Although it is obvious that general anesthesia is required for the surgical
excision and grafting of deep burn wounds, it is not uncommon to
encounter specific wound care procedures that are on a scale below that of
surgical burn care yet are nevertheless difficult to perform on a conscious
patient, particularly a child. These procedures are ideally suited for deep
sedation or general anesthesia and include (1) the removal of hundreds of
skin staples from recently grafted wounds, (2) meticulous wound care of
recently grafted and often tenuous skin on the face or neck, and (3) wound
care procedures in variably cooperative children. Historically, IV,
intramuscular, or oral ketamine have been used for these procedures,89,90
and there is limited evidence that ketamine administration acutely after
experimental skin burns may prevent hyperalgesia and “wind-up.”91 More
recently, some high-volume burn centers have developed specific training
and skill retention programs in ketamine administration by
nonanesthesiologists and report that satisfactory sedation for bedside
procedures can be achieved in children with a low incidence of side
effects.92 However, ketamine is a dose-dependent anesthetic that can
produce deep sedation and general anesthesia in an unpredictable manner;
thus, appropriate patient monitoring is requisite, and nonanesthesiologists
administering the drug must have specialized training and airway
management skills as well as anesthesiologist backup. In addition, its use
is limited by the potential risk of associated emergence delirium reactions
(5% to 30% incidence), particularly in the elderly.
The extension of full anesthetic care capabilities with anesthesiology
staffing outside of the operating room and into the burn unit has been
successfully implemented in some specialized burn centers.93,94 This has
been facilitated by the recent introduction into clinical anesthetic practice
of a variety of drugs with a rapid onset and short duration of action, a more
rapid awakening/recovery, and fewer associated side effects—ideal
qualities for agents to be used for procedural burn wound care. These
agents include IV propofol and remifentanil and inhaled sevoflurane and
desflurane. Propofol is particularly advantageous and can be titrated to
effect both in terms of level of consciousness and duration of action using

2849
continuous IV infusion techniques.95 The provision of brief, dense
analgesia/anesthesia in a comprehensively monitored setting by
individuals specifically trained to provide the service appears safe and
efficient, both in terms of allowing wound care to proceed rapidly under
ideal conditions for patient and nursing staff and in terms of cost-effective
use of the operating room only for true surgical burn care procedures.
Local anesthetics are of obvious use in regional blockade for wound
care procedures but have also been used for burn pain analgesia as a
topical gel or IV infusion. Topical local anesthetic use on the burn wound
is controversial. Prilocaine-lidocaine cream (EMLA) has no effect on burn
pain in volunteers96; however, topical 5% lidocaine applied at 1 mg/cm2
offers analgesic benefit without associated side effects.97 Topical lidocaine
use is significantly tempered by reports of local anesthetic-induced
seizures due to enhanced systemic absorption at the open wound site.98
The analgesic benefit of an IV lidocaine bolus (1 mg/kg) and 3-day
continuous infusion (40 mg/kg/min) has also been reported acute burn
injuries,99 although whether its mechanism is due to anti-inflammatory or
analgesic actions is unclear. Subcutaneous tumescent infiltration of local
anesthetics for cutaneous surgery may provide adequate surgical
anesthesia, with less blood loss from the graft donor sites.100–102 In one
feasibility study (n = 8 patients), postoperative pain was decreased by
continuous infusion of subcutaneous bupivacaine into the donor sites.103
Neuraxial administration of local anesthetics (and/or opioids) via epidural
catheter would seem to be of benefit in patients with lower extremity
burns, resulting in both analgesia (particularly during procedural burn
care) and sympathectomy (of theoretical benefit to wound healing).
However, such use has only been reported anecdotally.104 A major
drawback of this technique is the use of an indwelling catheter in patients
densely colonized with infectious organisms at the wound site, thus
increasing the risk for epidural abscess formation.105 Nonneuraxial
regional blocks have recently been reported to be of benefit for the pain
associated with surgical skin donor site preparation on the anterolateral
thigh, both a single injections106 and as continuous infusions.107

PHARMACOLOGIC OPTIONS FOR BACKGROUND

2850
PAIN MANAGEMENT
Because background pain is relatively constant, it is best treated with mild
to moderately potent analgesics administered so that plasma drug
concentrations remain relatively constant throughout the day. Examples
include the continuous IV infusion of fentanyl or morphine (± PCA), the
oral administration of long-acting opioids with prolonged elimination (e.g.,
methadone) or prolonged enteral absorption (e.g., sustained-release
morphine, sustained-release oxycodone), or oral administration on a
regular schedule of short-acting oral analgesics (e.g., oxycodone,
hydromorphone, codeine, acetaminophen). Background pain generally
decreases with time as the burn wounds (and associated donor sites) heal
so that analgesics can be slowly tapered in the absence of significant
analgesic tolerance.

PHARMACOLOGIC OPTIONS FOR PROCEDURAL

PAIN MANAGEMENT
In contrast to background pain, procedural pain is significantly more
intense but shorter in duration; therefore, analgesic regimens for
procedural pain are best composed of moderately to highly potent opioids
that have a short duration of action, with a sedation target level of
moderate sedation. IV access is helpful in this setting, with ketamine and
short-acting opioids (e.g., fentanyl, alfentanil) offering a potential
advantage over more longer acting agents (e.g., morphine,
hydromorphone). In the absence of IV access, orally administered opioids
(e.g., morphine, hydromorphone, oxycodone, codeine) are commonly
used, although their relatively long durations of action (2 to 6 hours) may
potentially limit postprocedure recovery for other rehabilitative or
nutritional activities. Oral ketamine, oral transmucosal fentanyl, and
nitrous oxide are agents of particular use when IV access is not present,
due to their rapid onsets and short durations of action. Finally, when a
particularly painful dressing change or one that requires extreme
cooperation in a noncompliant patient (e.g., face débridement in a young
child) is anticipated, the provision of brief deep sedation or general
anesthesia with appropriate patient monitoring, administered by
anesthesiologists or appropriately trained nonanesthesiologists may be

2851
helpful. A variety of approaches to managing procedural pain associated
with burn wound care have been recently summarized.108

PHARMACOLOGIC OPTIONS FOR POSTOPERATIVE

PAIN MANAGEMENT
Postoperative pain deserves special mention because of the increased
analgesic needs that should be anticipated following burn excision and
grafting. This is particularly true when donor sites have been harvested, as
these are often the principal source of increased postoperative pain
complaints, rather than the grafted burn. Typically, this increased analgesic
need is limited to 1 to 4 days following surgery before returning to
preoperative levels.

Nonpharmacologic Approaches
COGNITIVE INTERVENTIONS AND COPING STYLES
In terms of pain control, cognitions can be thought of as behaviors that can
be modified and that may influence the amount of pain that patients
experience. Although such approaches are common in chronic pain
control, there are few studies of cognitive-behavioral interventions in
patients with burn injuries.109,110 In understanding such interventions, it is
important to emphasize that burn injuries are unexpected and have far-
reaching consequences for patients. Furthermore, as noted previously, the
aggressive procedural medical care typically associated with burn injuries
adds further stress and uncertainty through the daily demands of surgery,
rehabilitation, dependency on caregivers, and pain. Such uncertainty often
leads to feelings of helplessness in both adult and pediatric burn patients. It
is almost impossible to predict the style with which an individual patient
reacts and responds to such stress; however, if one is able to determine
some characteristics of the patient’s cognitive style, this insight can be
useful in choosing the most appropriate psychologically based
interventions.
Burn patients bring different cognitive styles in the manner in which
they respond to stressful medical procedures. One critical distinction lies
in how much information patients desire regarding their injury and care.

2852
Whereas some patients will seek out as much information as possible,
others would just as soon leave their care to health care
professionals.111–113 In applying cognitive interventions to burn patients, it
will be useful for the clinician to be aware of how they cope with stressful
medical procedures. Paramount to such thinking is whether the patient will
approach procedures with a tendency toward cognitive avoidance, in
which case they will distract or dissociate themselves from painful stimuli.
This is in contrast to patients who tend to respond to acute pain by
focusing on the procedures. Such patients may take a hypervigilant stance
toward pain and may find distractions difficult. Patients often fall into
position along a continuum of coping styles, from an approach coping
style to an avoidance coping style. If one can determine where they fall
along this continuum, it is easier to determine what type of psychological
intervention will be most useful (Fig. 53.3).53,111

FIGURE 53.3 Control coping continuum and associated nonpharmacologic techniques. The
spectrum of coping styles from approach to avoidance is depicted, including specific clinical
interventions for patients whose coping styles fall on different positions along the continuum (see
text for details).

If patients fall on the avoidance end of the continuum, too much

information and focus on the details of care procedures will likely make
them more anxious. In contrast, distraction will likely be useful for
patients who possess this coping style. In the burn unit, simple distraction
is more likely to be of benefit with brief procedures such as blood draws or
line placements, and studies have reported that music can be effective for
such simple distraction with burn pain.114,115 Children at certain
development levels may benefit from not seeing their wounds or by being
more engaged by the clinicians. Such distraction will be less effective with
older children or adults during the more extensive wound care procedures.
In such instances, engaging patients in deep relaxation with distracting
imagery will likely be more useful, although imagery often requires

2853
substantially more training time for both patients and staff. A particularly
elaborate form of distraction involves the use of computer-generated
immersive virtual reality (see the following text). For both children and
adults, deep breathing has been found to be a simple and effective means
of reducing pain during procedures.116 In contrast, when patients cope
with painful procedures by carefully focusing on them and even
participating in their own care (i.e., approach coping style), they are
usually less viable candidates for distraction techniques. Such patients may
benefit from reappraisal techniques. Rather than focusing away from pain,
reappraisal techniques might encourage patients to attend to their
nociception. They can then be encouraged to differentiate sensory from
affective components of pain as well as evaluate the meaning of the
sensation. As is the case with chronic pain, patients may benefit from
being taught to differentiate “hurt from harm” with respect to their pain
sensations.117 It is also useful to teach such patients that increased pain
sensation is usually a positive sign with respect to burn wound healing.
Specifically, full-thickness burns often destroy nerve endings and the
capacity for nociception, but as these burn wounds heal, skin buds emerge
which are highly enervated and sensitive to pain and temperature.
Teaching patients the latter two principles will likely be useful to them
independent of their cognitive styles in response to acute pain.
Furthermore, with enough focus on pain sensations, some patients are able
to gain the sense that they are able to modify them and thus be in more
control of their perceptions.

PREPARATORY INFORMATION
Providing patients with information about impending procedures can
provide a powerful means of mitigating pain and anxiety. Such
interventions have been found to enhance pain control with acute pain
from a variety of different procedures.118 Patients may be provided with
preparatory information (what steps will be taken during a procedure) or
sensory information (what they will likely feel). The use of preparatory
information has not been studied with burn patients, but there is evidence
that it can be useful with a variety of medical procedures such as cardiac
catheterization, endoscopies, cast removal, and surgery.119–121

2854
Unfortunately, burn injuries often do not easily lend themselves to such
interventions. Certainly, it is not possible to anticipate that a burn injury
will occur and medical procedures are often performed quickly and in an
invasive matter. There is little time to prepare patients, and this can be
particularly difficult for children. In addition, with some medical
procedures in nonburn settings, understanding what will occur may reduce
anxiety and pain associated with those procedures. Unfortunately, the
frequent challenge with burn care is that the procedures are very painful,
invasive, and truly threatening, unlike many other types of medical
procedures that simply have the appearance of being threatening.
Preparation is particularly relevant to two phenomena associated with
burn care. First of all, nociceptive input may often increase as a burn
wound heals. As mentioned earlier, full-thickness burn injuries may not be
that painful, whereas healing injuries with new skin buds may be
particularly sensitive. Care providers should take care to communicate to
such patients that increased pain is actually a sign that the wound is
healing, information that may help allay patient anxiety. The second
beneficial instance of preparatory information involves informing patients’
family members of important medical issues. For example, burn patients
often show periods of delirium when in the ICU, a clinical phenomenon
that can be frightening to both patients and their family members. Letting
them know in advance that such confusion is a common and usually
benign occurrence can mitigate subsequent anxiety.

BEHAVIORAL INTERVENTIONS
Behavioral interventions might seem more applicable to chronic pain
conditions yet have surprising relevance to burn pain treatment. The
application of such principles to burn can be divided into classical
(stimulus) and operant (respondent) strategies. Stimulus conditioning
applications have to do with the patient’s state prior to wound care.
Certainly, decreasing the patient’s level of arousal through relaxation
training, or any other means available, can minimize the ensuing cycle
between anxiety and nociception. With children, the stimulus context of
painful procedures can be particularly relevant. Children and many adults
will often show heightened anxiety and fear just by being exposed to the

2855
stimuli associated with painful procedures (e.g., nursing scrubs, procedures
rooms). If the threatening nature of the wound care environment can be
reduced, pain control can be enhanced by virtue of stimulus–response
principles. As a nonburn example, some children’s hospitals have
instituted the creative approach of having a magnetic resonance imaging
(MRI) scan tunnel appear as a cave in a jungle environment (rather than
the morgue-like drawer such equipment more typically seems to
resemble). What follows from this logic is that the burn-injured child’s
room should be considered a safe environment in which painful procedures
do not occur.
Operant (reinforcement) principles are also highly applicable to burn
pain management. One application has to do with medication scheduling.
The tendency in many acute care settings is to simply medicate patients on
a PRN schedule, an approach that is nonsensical for several reasons in
burn care. Certainly, the notion of waiting until the patient hurts does not
make sense from a pharmacologic perspective.2,68,122 However, operant
principles would also suggest that PRN medication schedules reinforce
patients’ pain complaints, both in terms of the euphoria-producing
properties of opioid analgesics and the attention received from caregivers.
Providing opioid analgesics on a regular schedule that reflects their
pharmacokinetic properties will minimize the potential for operant factors
to exacerbate the pain problem. For emotionally dependent or anxious
patients, as-needed pain scheduling can actually create a paradigm for
creating more pain behaviors and pain perception.117
A regular analgesic drug administration schedule is particularly
important with patients who have substance abuse histories. Such patients
may demonstrate frequent pain complaints and/or drug-seeking behaviors
on the burn unit. The tendency of such patients to approach multiple
caregivers for analgesics has the potential to create “staff splitting” and
resentment (i.e., counter-transference) toward the patients. Accordingly,
the burn unit staff may hold punitive attitudes about the patient’s substance
abuse history and/or the excessive nature of his or her pain complaints.
Regularly scheduled medications will often minimize such conflict, as well
as provide more transparent management of the patient’s pain. In addition,
channeling communications and negotiations about changing doses or

2856
types of medication through a single caregiver can be very useful in
decreasing conflict between the patient and staff members.
In rare instances, the patient’s pain behavior might be so exaggerated in
the face of apparently adequate analgesia that burn staff must consider an
operant-based model of pain management. Effective burn team members
are trained to be highly attentive to the pain complaints of their patients.
However, occasional patients may show excessive complaints based on
such factors as strong dependency needs or somatic tendencies. As in any
case, it is important that such patients receive adequate doses of
analgesics. However, operant approaches, in which discussions of pain are
minimized and patients are distracted from their complaints,117 may
become the prominent intervention. In other words, there would be
discussions with the patient that medications changes will be limited to
circumscribed periods and, in between such times, the patient will be
encouraged to focus away from the issue of pain.
Burn rehabilitation involves continuously increasing activity levels, and
patients may become simply overwhelmed with the pain associated with
such movements. The quota system123 represents a useful application of
operant principles to burn care in such instances. The repeated, invasive
nature of burn care has the potential to create a state of learned
helplessness in patients.124 The quota system uses rest as a reinforcement
for activity and keeps activity levels well within the patient’s level of
physical endurance. Ehde and colleagues123 have reported that with
overwhelmed, seemingly unmotivated patients, it is useful to encourage
the burn team to reduce their overall demands, take baseline behaviors,
and gradually increase demands on what the patient’s baseline behavior
suggests is within their range of tolerance. Such interventions can create
steady increases in activity in patients who have been overwhelmed by
care, and also a sense of mastery, as they are able to see steady
improvement in their activities.
Avoiding the rewarding of escape behavior during procedures is a final
application of operant principles. With children, it is particularly essential
to do all the interventions possible to enhance pain control during
procedures such as adequate analgesics and anxiolytics, sufficient
emotional preparation, optimizing the wound care environment, and

2857
including parents when appropriate. Children also do better if allowed to
have control of their wound care procedures, perhaps by doing their own
dressing removal.124 However, there are times when it is important to set
firm limits during wound care by following through with procedures;
otherwise, pain behaviors can exacerbate. Establishing this balance can
certainly be a challenge for caregivers because it is not appropriate to force
treatment when children are inadequately medicated. The point here is that
once all that can be done that is possible in terms of analgesia, the timing
of when a child can refuse or rest during wound care becomes an
important issue in operant management.

HYPNOSIS
In terms of randomized controlled studies, hypnosis is one of the areas
where the most evidence exists for psychologically based interventions in
burn care.125 A recent review by Patterson and Jensen126 indicates that
burn pain constitutes some of the best evidence in the literature that
hypnosis can be effective. Furthermore, a number of additional reports
have focused on the use of hypnosis to treat complications from burns
other than pain, although with few exceptions; these reports have been
anecdotal.127,128
There are a number of reasons why burn patients appear to be such good
candidates for hypnotic-based pain control interventions.129 First, because
burn patients are in high levels of pain, they are motivated to engage in
hypnosis, a technique that they might ordinarily resist. In support of this,
patients with high levels of initial pain seem to show a better analgesic
response to hypnosis.130,131 Second, patients with unanticipated traumatic
injuries, such as burns, may be more cooperative because of the
dependency that might often be a normal reaction to trauma care (i.e., a
willingness to allow others to take care of one). Third, the dissociation that
may accompany a burn injury may also be a factor that moderates
hypnotizability. Certainly, dissociative tendencies have been related to
hypnosis,132 as well as the acute stress disorder is a typical early reaction
to burn injuries. Finally, and on a more simplistic level, hypnosis is most
effective when it can be applied to a predictable, discrete event—a
description that characterizes most burn wound care procedures, as painful

2858
as they are.
There have been two recent publications describing the delivery of
hypnosis through immersive virtual reality technology (see the following
text) in order to treat burn pain.133,134 The advantage of this approach is
that the clinician can rely on technology to achieve hypnotic induction and
suggestion; thus, extensive training for hypnosis is not required. Although
these reports are anecdotal, their preliminary results with this technology
demonstrate analgesic effects that are equivalent to those obtained when a
“live” clinician is used.

VIRTUAL REALITY
Immersive virtual reality is a particularly attention-grabbing distraction
technique and is designed to give users the illusion of going inside a
computer-generated virtual environment (Fig. 53.4). Virtual reality appears
to provide significant cognitive distraction to users because it is interactive
and places significant cognitive demand on patients through the provision
of multisensory input (visual, aural, and sometimes tactile). In addition, it
utilizes a head-mounted display that blocks visual and aural input to the
user from the immediate and often frightening, real-world burn care
environment. Thus, virtual reality may exert its analgesic effect by
diverting conscious attention away from concurrent nociceptive
stimulation, resulting in an attenuated subjective pain experience.
Functional brain imaging studies have shown the virtual reality results in
pain reduction that is similar to that of systemic opioid administration,
both in terms of magnitude of analgesia and brain activity changes, and is
also additive to opioid analgesia when administered concurrently.135 The
use of adjunctive, immersive virtual reality was first reported to provide
clinically meaningful pain relief in the setting of burn wound
débridement,136 with findings subsequently replicated in larger
populations of burn patients.137,138 Virtual reality analgesia is also
advantageous for the less severe pain associated with certain types of
postburn rehabilitation activities139–141 (Fig. 53.5) and has been combined
with hypnotic suggestion (as noted previously) to provide
nonpharmacologic analgesia for burn wound care.133,134

2859
FIGURE 53.4 Virtual reality environment “SnowWorld” as seen by the patient/user. Snow/ice
motif and blue/white/lavender colors suggest a cool temperature setting in direct contrast to the hot
setting in which most burn injuries occur. Virtual igloos, penguins, and snowmen on canyon walls
facilitate user interaction with the virtual world through user-targeted shooting of virtual snowballs
at these virtual objects.

FIGURE 53.5 Clinical use of virtual reality distraction during burn wound care. A burn patient
undergoes postburn skin stretching and passive joint range of motion while experiencing immersive
virtual reality analgesia. Both auditory and visual stimulation are provided through a lightweight
head-mounted display that can track the user’s position in the virtual environment by assessment of
head position, and user interaction with objects in the virtual environment is controlled by manual
trackball.

Conclusion
Effective treatment of burn injuries requires an appreciation of the unique
patterns of nociception caused by this trauma and their interaction with

2860
psychological factors. Aggressive use of opioid analgesics tailored to the
nature of the pain (e.g., procedural, background, postoperative) serves as
the cornerstone of a multifaceted approach to burn pain. Procedural pain
often involves consideration of a variety of supplemental pharmacologic
approaches, ranging from mild sedation to general anesthesia.
Nonpharmacologic approaches should be woven into the structure of burn
care as adjuncts to pharmacologic analgesia (i.e., multimodal analgesia).
The undertreatment of burn pain remains an unfortunate reality,
particularly because adequate analgesia may facilitate recovery and
posthospital adjustment as well as represent a more humane course of
treatment.

ACKNOWLEDGMENT
The authors’ work was supported in part by funding from the National
Institutes of Health (RO1 GM042725 and RO1 DA 026438).

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the management of postoperative split-thickness skin graft donor site pain. J Burn Care Res
2013;34:e257–e262.
104. Punja K, Graham M, Cartotto R. Continuous infusion of epidural morphine in frostbite. J Burn
Care Rehabil 1988;19:142–145.
105. Still JM, Abramson R, Law EJ. Development of an epidural abscess following staphylococcal
septicemia in an acutely burned patient: case report. J Trauma 1995;38:958–959.
106. Cuignet O, Mbuyamba J, Pirson J. The long-term analgesic efficacy of a single-shot fascia
iliaca compartment block in burn patients undergoing skin grafting procedures. J Burn Care
Rehabil 2005;26:409–415.
107. Cuignet O, Pirson J, Boughrouph J, et al. The efficacy of continuous fascia iliaca
compartment block for pain management in burn patients undergoing skin grafting
procedures. Anesth Analg 2004;98:1077–1081.
108. Myers R, Lozenski J, Wyatt M, et al. Sedation and analgesia for dressing change: a survey of
American Burn Association burn centers. J Burn Care Res 2017;38:e48–e54.
109. Everett JJ, Patterson DR, Chen ACN. Cognitive and behavioral treatments for burn pain. Pain
Clin 1990;3:133–145.
110. Fauerbach JA, Lawrence JW, Haythornthwaite JA, et al. Coping with the stress of a painful
medical procedure. Behav Res Ther 2002;40:1003–1015.
111. Martin-Herz SP, Thurber CA, Patterson DR. Psychological principles of burn wound pain in
children. II: treatment applications. J Burn Care Rehabil 2000;21(5):458–472.
112. Thompson SC. Will it hurt less if I can control it? a complex answer to a simple question.
Psychol Bull 1981;90:89–101.
113. Strickland BR. Internal-external expectancies and health-related behaviors. Journal of
consulting and clinical psychology. 1978;46:1192–1211.
114. Prensner JD, Yowler CJ, Smith LF, et al. Music therapy for assistance with pain and anxiety
management in burn treatment. J Burn Care Rehabil 2001;22:82–88.
115. Tan XMM, Yowler CJ, Super DM, et al. The effect of music therapy protocols for decreasing
pain, anxiety and muscle tension levels during burn dressing changes. J Burn Care Res
2010;31(4):590–597.
116. Park E, Oh H, Kim T. The effects of relaxation breathing on procedural pain and anxiety
during burn care. Burns 2013;39(6):1101–1106.
117. Fordyce WE. Behavioral methods for chronic pain and illness. St. Louis, MO: Mosby Year
Book; 1976.
118. Tan S. Cognitive and cognitive-behavioural methods for pain control: a selective review. Pain
1982;12:201–228.
119. Kendall PC, Williams L, Pechacek TF, et al. Cognitive-behavioural and patient education
interventions in cardiac catheterization procedures: the Palo Alto Medical Psychology Project.
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120. Johnson JE, Morrisey JF, Leventhal H. Psychological preparation for an endoscopic
examination. Gastrointest Endosc 1973;19:180–182.
121. Johnson JE, Kirchhoff KT, Endress MP. Altering children’s distress behaviour during
orthopedic cast removal. Nursing Res 1975;24:404–410.
122. Paice JA, Noskin GA, Vanagunas A, et al. Efficacy and safety of scheduled dosing of opioid
analgesics: a quality improvement study. J Pain 2005;6:639–643.
123. Ehde DM, Patterson DR, Fordyce WE. The quota system in burn rehabilitation. J Burn Care
Rehabil 1998;19:436–439.
124. Kavanagh CK, Lasoff E, Eide Y, et al. Learned helplessness and the pediatric burn patient:
dressing change behavior and serum cortisol and beta-endorphin. Adv Pediatr 1991;38:335–

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125. Frenay MC, Faymonville ME, Devlieger S, et al. Psychological approaches during dressing
changes of burned patients: a prospective randomised study comparing hypnosis against stress
reducing strategy. Burns 2001;27:793–799.
126. Patterson DR, Jensen MP. Hypnosis and clinical pain. Psychol Bull 2003;129:495–521.
127. Chester SJ, Stockton K, De Young A, et al. Effectiveness of medical hypnosis for pain
reduction and faster wound healing in pediatric acute burn injury: study protocol for a
randomized controlled trial. Trials 2016;17:223.
128. Berger MM, Davadant M, Marin C, et al. Impact of a pain protocol including hypnosis in
major burns. Burns 2010;36:639–646.
129. Patterson DR, Adcock RJ, Bombardier CH. Factors predicting hypnotic analgesia in clinical
burn pain. Int J Clin Exp Hypn 1997;45:377–395.
130. Patterson DR, Everett JJ, Burns GL, et al. Hypnosis for the treatment of burn pain. J Consult
Clin Psychol 1992;60:713–717.
131. Patterson DR, Ptacek JT. Baseline pain as a moderator of hypnotic analgesia for burn injury
treatment. J Consult Clin Psychol 1997;65:60–67.
132. Spiegel H, Spiegel D. Trance and Treatment. Washington, DC: American Psychiatric Press;
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133. Patterson DR, Tininenko JR, Schmidt AE, et al. Virtual reality hypnosis: a case report. Int J
Clin Exp Hypn 2004;52:27–38.
134. Patterson DR, Wiechman SA, Jensen M, et al. Hypnosis delivered through immersive virtual
reality for burn pain: a clinical case series. Int J Clin Exp Hypn 2006;54:130–142.
135. Hoffman HG, Richards TL, Van Oostrom T, et al. The analgesic effects of opioids and
immersive virtual reality distraction: evidence from subjective and functional brain imaging
assessments. Anesth Analgesia 2007;105:1776–1783.
136. Hoffman HG, Doctor JN, Patterson DR, et al. Use of virtual reality for adjunctive treatment of
adolescent burn pain during wound care: a case report. Pain 2000;85:305–309.
137. Das DA, Grimmer KA, Sparnon AL, et al. The efficacy of playing a virtual reality game in
modulating pain for children with acute burn injuries: a randomized controlled trial
[ISRCTN87413556]. BMC Pediatr 2005;5:1.
138. van Twillert B, Bremer M, Faber AW. Computer-generated virtual reality to control pain and
anxiety in pediatric and adult burn patients during wound dressing changes. J Burn Care Res
2007;28:694–702.
139. Sharar SR, Carrougher GJ, Nakamura D, et al. Factors influencing the efficacy of virtual
reality distraction analgesia during postburn physical therapy: preliminary results from 3
ongoing studies. Arch Phys Med Rehabil 2007;88:S43–S49.
140. Faber AW, Patterson DR, Bremer M. Repeated use of immersive virtual reality therapy to
control pain during wound dressing changes in pediatric and adult burn patients. J Burn Care
Res 2013;34(5):563–568.
141. Jeffs D, Dorman D, Brown S, et al. Effect of virtual reality on adolescent pain during burn
wound care. J Burn Care Res 2014;p35:395–408.

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 PAIN IN SPECIAL POPULATIONS

CHAPTER 54
Persistent Pain in Children
BOBBIE L. RILEY, TONYA M. PALERMO, GARY A. WALCO,
CHARLES BERDE, and NEIL L. SCHECHTER

Persistent pain problems in children, as in adults, may stem from a wide

variety of causes. They may be associated with ongoing illnesses such as
cancer or sickle cell disease (SCD), may be the residua of pathologic
processes that have resolved but have sensitized the peripheral or central
nervous system such as postinfectious myalgias, or may represent a
nonprogressive disorder whose main manifestation is pain such as
headaches, widespread musculoskeletal pain, or functional abdominal
pain. Regardless of the etiology of the pain, its assessment, its impact, and,
often, the modalities used to treat are remarkably similar and often distinct
from approaches used to address acute pain. For example, although the
broader context of pain, including an array of genetic, developmental,
environmental, and individual factors, is rarely a major focus of
assessment in acute pain, these factors are essential to consider when pain
is recurrent or persistent. Likewise, treatment goals may shift from pain
eradication in acute pain to pain reduction, rehabilitation, and improved
coping in chronic pain.
In this chapter, we describe the epidemiology of chronic pain, define its
impact on children and families, and offer general approaches to its
evaluation and treatment. Discussion of cancer pain is contained elsewhere
in this book, as are more detailed descriptions of specific pain problems.

Epidemiology of Chronic Pain in Children

The epidemiology of the various chronic pain problems in children is often
hard to ascertain primarily due to variability in the methodologies in the

2868
available research. Although this fact is an issue for adults as well, the
relative limitations of the pediatric literature in the area of chronic pain,
the added dimension of development when applying diagnostic criteria,
child variants of adult disorders, the potential association between various
pain syndromes, and the limitations in the young child’s ability to report
symptoms give us pause as we sift through data on the prevalence of
persistent pain syndromes in children.
Recent efforts have been made to refine the taxonomy of chronic pain
conditions,1 and the need to maintain a life span developmental approach
was highlighted.2 This implies that rather than parse out pediatric
conditions as separate entities, it is imperative to view the emergence of
chronic pain as a developmental phenomenon from birth, through
adulthood, and into the elderly years. Included is a focus on continuities
and discontinuities in pain problems, highlighting longitudinal data to
understand the specific genetic, epigenetic, and environmental roots of
pain problems. Simply stated, children are not little adults, but adults are
big children! With this as background, a sample of the epidemiology of
selected persistent pain problems in children follows.

MUSCULOSKELETAL PAIN
One of the most common sites for pain in children and adolescents is the
musculoskeletal system, including joint pain, bone pain, and muscle pain.
Discomfort may arise from disease processes (e.g., inflammation
associated with arthritis), may be related to central pain processing
difficulties (e.g., juvenile fibromyalgia syndrome), or may be related to
trauma or injury, typically focusing on a specific area of the body (e.g.,
back pain or neck pain). A recent study sought to better identify the
etiology of musculoskeletal pain, which is a major first step in better
grasping its epidemiology.3 Demographic, clinical, and laboratory data
were gathered on over 400 pediatric patients presenting with
musculoskeletal pain, swelling, or limitation of movement. The etiology of
these difficulties was identified in over 97% of cases, with by far the most
common being noninflammatory and mechanical conditions (42.2%),
followed by rheumatic diseases (31%), infection-related disorders (21.6%),
and malignancy (2.4%). Age differences were noted, such that the

2869
prevalence of rheumatic disease was higher in those over 12 years,
whereas younger age was associated with higher prevalence of infectious
issues.

Arthritis
Estimates of the prevalence of juvenile arthritis have shifted a good deal
over the years due to a number of factors, including diagnostic difficulties,
changes in the classification schemas used, differences in research
methodology, cohort effects, and factors occurring with the passage of
time. Estimates of prevalence range from 10 to 220 cases per 100,000.
Recent estimates suggest that 294,000 children between 0 and 17 years of
age are being affected by “arthritis or other rheumatic conditions.”4
Regarding pain in this population, Schanberg et al.5 found that children
with polyarticular juvenile arthritis had pain an average of 73% of the
days. Although for most children this pain was in the mild to moderate
range, 31% reported pain in the severe range. Baseline and up to 5-year
follow-up data from the Childhood Arthritis Prospective Study helped
identify pain trajectories over time in children with arthritis.6 Patients
between the ages of 1 and 16 years with new-onset juvenile idiopathic
arthritis were followed, and three basic trajectories were identified:
consistently low pain (53%), improved pain (30%), and consistently high
pain (17%). A study in Canada showed similar results, with five pain
severity trajectories: mild-decreasing pain (56%), moderate-decreasing
pain (29%), chronically moderate pain (7%), minimal pain (4%), and mild-
increasing pain (4%).7

Nonrheumatologic Musculoskeletal Pain

A number of studies have tried to identify the prevalence of
musculoskeletal pain in children and adolescents not associated with
arthritis or other rheumatologic conditions. De Inocencio8 reported on a
review of 6,500 office visits of children 3 to 14 years of age and found that
6.1% were for musculoskeletal complaints, the majority of which were for
arthralgias and soft tissue pain. Common etiologies included trauma as
well as mechanical or overuse pathology.
More generally, many children and adolescents report significant

2870
episodes of chronic nonspecific pain at least once in their lifetime,
including limb pain (4.2% to 33.6%), knee pain (up to 18.5%), and back
pain (7.6% to 34%).9 Mikkelsson et al.10 followed third and fifth graders
over 1 year and found that pain occurring at least once per week persisted
in 52.4%, with neck pain having the highest persistence.
Recognizing the risk of contiguity between chronic pain problems in
children and adolescents with challenges later in life, a group of Danish
researchers conducted a prospective 3-year school-based cohort study of
children 8 to 14 years of age at baseline to gather information about
musculoskeletal pain.11 Through weekly mobile phone contacts, parents
reported on the presence or absence of musculoskeletal pain in their
children; a subset of children also underwent a more thorough clinical
assessment. It was found that approximately half of the children had lower
extremity pain every study year. This was hardly trivial—children
experienced an average of 2.5 episodes, lasting for a total of 8 weeks each
study year. Upper extremity pain was also present, but less substantial, as
it occurred in approximately one quarter of the sample, lasting on average
3 weeks during a study year (about 1.5 episodes). Upper extremity pain
tended to be more related to trauma than lower extremity pain. The most
common sites of pain included knees and the ankle and foot area. Of note,
this same research group went on to conduct a systematic review of other
population based studies, with similar results.12

Fibromyalgia Syndrome
The prevalence of fibromyalgia syndrome in children and adolescents is
difficult to determine. Mikkelsson et al.13 used a structured pain
questionnaire in a large sample of Finnish third- and fifth-grade children
and found that 22 of them (1.25% overall) met criteria for fibromyalgia
syndrome. In a retrospective review of patients referred to a pediatric
rheumatology clinic between 1989 and 1995, 7% were diagnosed with
fibromyalgia syndrome.14 Data from the UK General Practice Research
Database for the years 1990 to 2001 showed that the annual incidence of
fibromyalgia increased from less than 1 per 100,000 to 35 per 100,000.15
Female gender predominance is a well-replicated finding.16 Although
various studies have shown correlates to the presence of the syndrome,

2871
such as chronic fatigue,17 joint hypermobility,18 temperament,19 familial
aggregation,20 and psychiatric symptoms,13 causal relationships have not
been shown.

Complex Regional Pain Syndrome

There are few studies reporting on the prevalence of complex regional pain
syndrome (CRPS) in children and adolescents. A 2017 review found only
10 studies (only 1 population-based) with relevant data, which showed a
mean age at onset of 12.5 years, with 85% of patients being female. The
majority of patients (71%) had a history of trauma. Contrary to adults,
lower limbs were affected in 75% of patients, with secondary site
involvement in 15% of cases.21

Back Pain
Back pain represents a somewhat distinct form of musculoskeletal pain. A
recent comprehensive review indicated that low back pain is rarely seen in
children younger than school age and prevalence rates rise until age 18
years, at which time rates parallel those of adults.22 Contrary to prior
beliefs, sinister diagnoses are rare, as pain tends to be nonspecific and is
self-limiting.
Beyond the incidence of chronic musculoskeletal pain, a critical issue is
also the transition from the acute phase to more persistent pain problems.
A recent study followed 88 10- to 17-year-olds who had presented to the
emergency department or orthopedic clinic with new musculoskeletal pain
complaints, approximately 35% of whom continued to have persistent pain
4 months later. Regression analyses showed that depressive symptoms and
poorer pain modulation were key risk factors related to this transition.23
An earlier systematic review identified 65 potential risk factors for the
onset of and 43 potential prognostic factors for the persistence of
musculoskeletal pain. Results showed that low socioeconomic status
(strong evidence) as well negative emotional symptoms and regularly
smoking in childhood or adolescence (moderate evidence) may be
associated with persistence of pain. Interestingly, high body mass index,
taller height, and joint hypermobility were not found to be risk factors for
the onset of pain.24

2872
Temporomandibular Disorders
Temporomandibular disorder (TMD) pain is often underrecognized in
children and adolescents. A systematic review and meta-analysis
conducted to assess the prevalence of clinical signs of temporomandibular
joint (TMJ) disorders in children and adolescents captured 17,051
participants.25 The overall prevalence of clinical signs of intra-articular
joint disorders was 16%, the prevalence of TMJ sounds was 14%, clicking
(10.0%), and jaw locking (2.3%). Significant correlates include bruxism
and tooth-grinding as well as bite and tooth positioning.26

HEADACHE
Determining the incidence of headache in the pediatric population is
difficult due to changing diagnostic criteria and attempts to apply adult
diagnostic criteria to children. In a review by Hershey et al.,27 it was
concluded that up to 75% of children have had significant headaches by
the age of 15 years, with up to 28% of adolescents describing symptoms
consistent with migraine headaches. Previous meta-analytic reviews
suggested a gradual increase in headache incidence over childhood with
37% to 51% of children reporting a significant headache by 7 years and up
to 82% by 15 years.28 A more recent meta-analysis of 64 cross-sectional
studies (including a total of 227,249 subjects) yielded an estimated overall
mean prevalence of headache was 54.4%, with an overall mean prevalence
of migraine at 9.1%.29
The distinction between migraine and tension-type headache is often
complex, particularly in pediatric headache. For example, when applying
International Classification of Headache Disorders-II criteria to a large
sample of German children age 7 to 14 years, Kröner-Herwig and
colleagues30 found that 7.5% of the headaches could be classified as
migraine, 18.5% as tension-type, and the majority were unclassifiable.
Virtanen et al.31 found that among children who were classified as having
migraines at age 6 years, half were unchanged at age 13 years, whereas for
32%, there was a shift toward tension-type headaches. Other authors found
a similar lack of stability in headache type over time with headache types
shifting or disappearing entirely. For example, a 10-year longitudinal study
of principally preadolescent children diagnosed with migraine, only 46%

2873
continued to have migraine and the frequency of attacks had diminished.32
Therefore, the precise relationship between various types of headaches
in children remains unclear. In addition, various authors report close
relationships between headache pain and other difficulties, including neck
pain,33 back pain,34 abdominal pain,35 sleep disturbances,36 fatigue,37
epilepsy,38,39 epistaxis,40 psychiatric difficulties, and risk of suicide.41–43
Nonetheless, headaches in children appear to be quite common;
however, precisely what differentiates migraine headache from tension-
type headaches is difficult to discern at times. Headaches increase in
frequency and severity with age with a clear shift around the time of
puberty and are more common and problematic in females, and health-
related quality of life (HRQOL) may be significantly impacted.44

CHRONIC ABDOMINAL PAIN

Chronic abdominal pain accounts for 2% to 4% of pediatric visits. Hyams
et al.45 found that 75% of middle school and high school students reported
abdominal pain, whereas 21% reported it was severe enough to affect
activities, and 8% visited a physician for it. Like other pain problems,
various definitions and correlates of persistent abdominal pain (recurrent
abdominal pain, chronic abdominal pain, functional abdominal pain,
functional gastrointestinal disorder [FGID] nonorganic abdominal pain,
and psychogenic abdominal pain) have led to varying perspectives in its
prevalence.
A recent study of parental reports of 4- to 18-year-olds in a
representative community sample of the United States indicated that
23.1% had at least one FGID, with functional constipation and abdominal
migraine being the most common (Rome III criteria). The Rome III criteria
for abdominal pain–related FGIDs in children and adolescents include
functional dyspepsia, irritable bowel syndrome (IBS), abdominal migraine,
childhood functional abdominal pain, and childhood functional abdominal
pain syndrome.46 A revision of these criteria, Rome IV, will include
additional categories that include motility disturbance, visceral
hypersensitivity, altered mucosal and immune functioning, altered gut
microbiota, and altered central nervous system processing, all of which
reflect recent advances in the field and will likely lead to more insight into

2874
incidence and etiologies.47
It appears that the roots of nonspecific abdominal pain may be identified
quite early in development based on chart reviews of a cohort of children
followed from birth to 5 years. Chitkara et al.48 found an incidence of
abdominal pain of unknown origin of 4.5/1,000 person years leading to
repeated visits to the pediatrician. Finally, as was the case with prior pain
problems, there is growing evidence the difficulties with chronic
abdominal pain early in life are associated with the risk of future
abdominal pain, other pain problems (e.g., headache), and broader somatic
concerns later in childhood and beyond.49,50

DISEASE- OR TREATMENT-RELATED PAIN

Sickle Cell Disease
For many years, the focus of pain management in children and adolescents
with SCD were episodes of vasoocclusion. Dampier and colleagues51
gathered pain diary data in children and adolescents with SCD. They found
that vasoocclusive pain is experienced on 2% of days in preschool-age
children and on 5% to 10% of days in school-age children and young
adolescents. School-age children tended to have less intense pain than
adolescents, and girls tended to report a higher number of painful sites
than boys. Subsequent data52 showed that 40% to 50% of school-age
children experience one pain episode a month, whereas about 10%
experience more than two episodes a month. Although the majority of
these episodes lasted 1 day or less, about 5% of episodes in older children
last longer than 2 weeks.
More recently, however, it is clear that children with SCD are affected
by a number of recurrent chronic pain concerns beyond those related to
vasoocclusion. Although Niebanck et al.53 found that overall the
prevalence of tension-type and migraine headaches in children with SCD
approximates that of healthy peers, they found that headache was more
common in younger children with SCD and that there were relationships
noted between frequency of headache and frequency of vasoocclusion.
This suggests that factors related to SCD may increase the risk of headache
pain. In addition, sequelae of splenic sequestration may lead to ongoing
visceral pain in the left upper quadrant and irreversible joint damage, such

2875
as related to aseptic necrosis, may cause ongoing discomfort.

Cystic Fibrosis
Koh et al.54 evaluated 46 children with cystic fibrosis (CF) and found that
nearly half of the sample described pain occurring at least weekly with
primary locations of the abdominal and pelvic region, chest, head, and
neck. Although most children reported mild pain intensity and relatively
short duration, a small subgroup reported moderately intense pain in the
chest that was of longer duration. Pain in this group was thought to be
musculoskeletal in nature, related to pulled or torn intercostal muscles,
costochondritis, pleuritis, pneumothorax, or rib fracture. A Web-based
study of adolescents and young adults with CF found that about half
experienced moderate daily pain of 2 hours duration or less, with disability
highest in areas of recreation, occupation, and social activities.55

Phantom Limb
Phantom pain occurs when a limb has been amputated and the individual
continues to feel pain in a part of the body that is no longer there. In an
early attempt to ascertain the prevalence of such conditions in children,
Krane and Heller56 conducted a retrospective survey of 5- to 19-year-olds
who had undergone limb amputation in the preceding 10 years.
Amputations were secondary to congenital deformity, trauma/infection, or
cancer. Phantom sensations were experienced in all patients, and the
overwhelming majority stated they experienced phantom pain as well.
Melzack et al.57 reported that phantom limbs are experienced by 20% of
those with congenital limb deficiencies and 50% of those who underwent
amputation before age 6 years. Phantom pain was reported in 20% and
42% of these groups, respectively. Using diary data, Wilkins et al.58 found
recurrent episodes of phantom pain due to congenital limb deficiencies,
surgery, and trauma, with an average intensity of 6.43 out of 10.

ADDITIONAL CONSIDERATIONS
The earlier review should make it clear that there is an array of chronic and
recurrent pain problems that affect children and adolescents. It is unwise,
therefore, to focus on “chronic” or “recurrent” pain as a unified entity but

2876
rather as diverse syndromes, perhaps with certain common factors. As is
discussed in the following text, a broad biopsychosocial perspective is
deemed optimal, which embraces genetic, developmental, and
environmental influences.
In the remainder of this chapter, we discuss the impact of persistent pain
on children and offer a general approach to evaluating and managing it. A
more detailed review on a number of more common entities is offered as
well. Additional information on many of these problems is available in
other sections of this book, such as Chapters 25, 49, 57, and 61.

Impact of Persistent Pain on Children and Families

Recurrent and chronic pain can have a major impact on the daily lives of
children, adolescents, and their families. Whereas some children
experiencing pain symptoms have minimal day-to-day impairment, other
children exhibit psychological distress and have significant activity
limitations due to pain. The children who seek treatment for their chronic
pain symptoms likely represent the group who is experiencing the most
impairment.59 For many children, chronic pain has been associated with
poorer HRQOL, psychosocial difficulties, academic problems, and
disruptions in peer and family relationships.60,61
Disability or activity limitations that results from chronic pain is a
separate concept from pain itself, and it is equally important to consider in
assessment and management of pediatric pain patients.62 Disability refers
to those areas in an individual’s life that are limited due to pain.63 The
domains of functioning that seem to be particularly impacted by chronic
pediatric pain are participation in physical and social activities, school and
academics, sleep, and family functioning. Specifically, chronic pain has
been associated with more frequent school absences and academic
difficulties.64,65 Missed schooling can have direct effects on academic
performance and school success as well as important effects on
socialization and maintenance of peer relationships. Difficulties with peer
relationships have been found in children with chronic pain, with one
study of children with juvenile fibromyalgia reporting that children were
more isolated, less well liked, and less socially accepted than their healthy

2877
peers.66,67
Activities limited due to pain vary depending on the level of pain
children experience. Higher levels of pain intensity, greater pain extent,
and longer pain duration have been associated with greater activity
limitations and impairment.68–71 Specific domains of activity restriction
have also been associated with pain level. In one study of children with
SCD, although children decreased participation in all activities (school,
play, sports, social) when pain was high, they were able to maintain school
attendance and social activities when pain levels were low.69 Future
research is needed to better understand the relationship between pain and
activity restriction among different populations.
Sleep disturbances are highly comorbid with chronic pain, affecting
over half of youth.72,73 The most commonly experienced sleep disturbance
is insomnia (i.e., difficulties falling asleep or staying asleep), which is
reported by over 50% of youth with chronic pain.73 It is associated with
diminished physical function, poor quality of life, and increased depressive
symptoms.74 Untreated, insomnia symptoms persist over a 1-year period
for youth with chronic pain.67
Psychological factors, including anxiety, depression, and coping, have
been identified as important in the development and maintenance of
chronic pain and disability in children (e.g., Simons and Kaczynski,75
Nodari et al.76). Children with chronic pain report increased general
anxiety, pain-specific anxiety, posttraumatic stress symptoms, and
depressive symptoms than youth without pain conditions, which is
associated with greater pain-related disability.60,77,78 In large-scale
epidemiologic studies, individuals with a history of chronic pain in
adolescence subsequently report higher rates of lifetime anxiety and
depressive disorders, as compared with individuals without a history of
adolescent chronic pain.79 Moreover, children’s coping style (particularly
maladaptive coping) and catastrophizing behaviors are associated with
increased psychological distress and physical limitations.80
HRQOL refers to an individual’s perception of the impact a disease or
condition has on his or her physical health status, psychological
functioning, and emotional well-being. Chronic pain may impair school
attendance, mobility, self-care, interpersonal interactions, life activities,

2878
and community activities as well emotional functioning.62 Several
examinations of HRQOL in children and adolescents with pain conditions
(e.g., headache, SCD, mixed pain conditions) have found that they report
significantly poorer HRQOL in comparison to healthy children.76,81
Moreover, unexplained chronic pain in adolescents has been associated
with poor quality of life for the adolescent and his or her family.59
Predictors of poor HRQOL within pain populations include the presence of
sleep problems,82 fatigue,83 pain-related hospitalizations,81 low
socioeconomic conditions,84 and increasing child age.
Pediatric chronic pain is embedded in a broader family context that
influences the child’s adjustment to chronic pain, so caregivers are a
unique and integral part of pediatric chronic pain treatment.85 Studies
show that caring for a child with chronic pain has a negative impact on
parent caregivers, expressed in higher anxiety, depression, and increased
parental role stress.80 Although it is unknown whether these symptoms
precede the pain condition, or develop in response to parenting a child
with chronic pain, high levels of parental distress have been linked to
increased pain and disability in children.85,86 Furthermore, parents may
respond with increased attention, sympathy, or discouragement of activity
if they perceive their child’s pain as a potential sign of harm or damage.
Such protective or solicitous responses can provide positive reinforcement
and increase illness behavior, which may exacerbate or maintain children’s
pain and disability.87,88 This bidirectional influence is illustrated in the
integrative model of family and parent factors for children with chronic
pain, developed by Palermo and Chambers,89 that outlines parent and
family influences on child experience of pain. Consequently, caregivers
have become important targets in psychological interventions for children
with chronic pain.
Parents may experience significant financial burden due to the
evaluation and management of their child’s recurrent and chronic pain.
Pediatric chronic pain is costly to society, with estimates of $19.5 billion
per year spent on pain treatment in the United States.90 Costs to parents
and caregivers include lost employment time, transportation expenses,
childcare, and incidental costs. The stress of chronic pain on families is
also associated with increased levels of family conflict and poorer family

2879
functioning.91 Previous studies have shown more family problems in
children with chronic pain compared to healthy children92 and that poorer
family environments are associated with increased disability.86,93

Clinical Evaluation of the Child with Chronic Pain

BACKGROUND
In the position statement published by the American Pain Society, chronic
pain in children was defined as the result of a dynamic integration of
biologic processes, psychological factors, and sociocultural factors
considered within a developmental trajectory.94 Therefore, evaluating a
child with chronic pain can be time-consuming and complicated as a
multitude of factors contribute to its development and maintenance.
Children who present with persistent pain often receive extensive
evaluations by both primary care providers and specialists in different
disciplines due to the complexity of the pain presentation and the
associated symptoms. If the pain appears to result from a previously or
newly identified organic disease (e.g., ulcerative colitis, SCD, cancer), the
treatment focus is on addressing the underlying illness while
simultaneously treating the associated pain symptoms. In other situations,
the source of the pain may be known and often time-limited but may not
be amenable to direct treatment, and therefore, the focus is typically solely
on addressing the pain (e.g., persistent postoperative, posttraumatic, or
postviral pain). For both of these groups of children, there is no need for an
extensive search for an explanation for their pain and the clinician can
focus on its treatment.
The more challenging situations and the emphasis of the majority of this
chapter occur when no obvious pathophysiologic source of the pain has
been identified. The child is suffering, the parents are frustrated, extensive
evaluation is often undertaken, and no treatable disease process emerges to
explain the pain. In these situations, the clinician must attempt to identify
those children who may have an as yet undiagnosed underlying
progressive disease process and separate them from those who have
chronic pain syndromes, which although uncomfortable, do not represent
life-threatening illness. This is not an easy task, given the inherent

2880
vagueness and subjectivity of the symptoms, the inadequacies of children
as historians, the strong desire of most children and their families for an
“organic treatable diagnosis,” and the vast differential diagnosis. In these
situations when source of pain does not have a clear or treatable organic
etiology despite adequate evaluation, the treatment focus changes and is
ultimately on educating the family and patient on the pathophysiology of
chronic pain including the process of central sensitization and on the value
of a biopsychosocial rehabilitative approach.
Initially, however, a delicate balance must be struck between adequate
evaluation and overinvestigation. The physician must be comfortable that
he or she has enough information to rule out potentially serious or life-
threatening causes of pain on the one hand while avoiding an endless
search for the underlying etiology of the discomfort on the other.
Continued laboratory investigation often convinces the child and family
that there must be a biologic explanation for the problem and suggests to
them that the “answer” may be found in the next laboratory test. Clinicians
may report that they are ordering additional tests “for the sake of
completeness” and both clinicians and families often find it difficult to
draw a diagnostic line in the sand where all are content with extent of the
investigation. Furthermore, pediatricians do not always agree on the
diagnostic approach. Konijnenberg and colleagues95 highlighted this
problem in a series of papers in which 17 different pediatricians reviewed
the medical records of 134 children with unexplained chronic pain.
Consensus of the group was defined as an agreement among 80% of the
pediatricians on the panel. Yet, there was disagreement on diagnostic
approach in over a third of the patients and on the primary cause of the
pain in over one-half.95 Unfortunately, this diagnostic uncertainty often
leads to further excessive and expensive laboratory and imaging studies. It
is particularly unfortunate if, after completing an extensive battery of tests,
which are negative, the doctor implies that the problem must be solely
psychological and refers the child to a mental health professional.
Therefore, one of the most critical aspects of the evaluation of the child
with unexplained chronic pain is the development of a trusting relationship
with the child and family96 and their acceptance that the medical
investigation has been sufficient to allow the primary focus of the

2881
encounter to be on the management of the pain regardless of its etiology.
Etiologically, chronic pain is thought to stem from an interplay between
biologic vulnerability, psychological variables, and environmental
variables which allow for abnormalities of sensory processing, enhanced
responsiveness, and excitability in the central nervous system known as
central sensitization and amplification. Central sensitization is discussed in
numerous other chapters throughout this book in detail, but it is the term
used to describe the dysfunction or pathology of the nervous system that
results in an amplified responsiveness of the central nervous system to
painful and nonpainful stimuli. This increased responsiveness of the
nervous system is thought to be a key element in the development and
maintenance of chronic pain.97–100
These factors must be considered in the evaluation and treatment of all
children with chronic pain. As outlined in the American Pain Society
consensus statement,94 a comprehensive clinical assessment of a child with
chronic pain should include a complete medical and pain history including
onset, intensity, quality, location, duration, variability, predictability,
exacerbating, and alleviating factors with ongoing management and
reassessment emphasizing functional improvements. The physical exam
should include a complete neurologic exam, with observation of the
child’s general appearance, posture, and gait. Although laboratory and
radiologic studies may be useful if a specific disease is suspected, the
diagnosis of a chronic pain condition is predominately made by history
and physical exam and best assessed by a pediatric interdisciplinary pain
management team typically including pain medicine clinicians, mental
health providers, and physical and occupational therapists.94

HISTORY
Traditional elements of the pain history for adults are applicable to
evaluating chronic pain in children. Although younger children are
developmentally less capable of presenting a coherent narrative, they are
capable of reporting on specific aspects of their pain. Using
developmentally appropriate tools, children are able to define pain
intensity as well as radiation, exacerbating and relieving factors of the
pain, and quality of the pain. Chronic pain in children has a significant

2882
impact on daily function which can be seen in school attendance and work
quality, social relationships, and mood.78 The history of impact on daily
function should be integral in ongoing reassessment of pain management
as improvement in function may occur well before a decrease in pain
intensity. Roth-Isigkeit and colleagues61 studied 750 German school
children and found that 30% to 40% reported restrictions in daily living
secondary to pain. Chalkiadis’s101 study of chronic pain in Australian
youth revealed that 71% of children had difficulty sleeping and over 90%
were unable to be involved in sports.
Because evidence supports that early exposure to painful stimuli and
other adverse events potentially predisposes the child to changes in
nociception, it is important to be aware of the child’s medical history.
Fitzgerald and colleagues’102–105 study of rat pups has demonstrated long-
lasting hypersensitivity to pain from early tissue injury. Grunau and
coworkers,106–109 in a series of papers, compared toddlers who were born
prematurely to babies of normal gestation and birth weight and found
differences in pain sensitivity and somatization. Measurable differences
between the groups were found even when the children had reached 8 to
10 years. Anand and Scalzo110 has even suggested that there are increased
rates of attention-deficit/hyperactivity disorder (ADHD), substance abuse,
and anxiety in children who have been exposed to repeated neonatal pain
and stress.
Another essential element to query is the history of pain problems in the
family. Although some authors, such as Borge and Nordhagen,111 question
whether chronic pain symptoms run in families, on the whole, the majority
of studies have suggested that parent and family history of pain are
predictors of child pain. This pattern has been identified in children with
rheumatologic disease,112 recurrent abdominal pain, migraine, and
fibromyalgia.113 The mediators of this phenomenon are unclear. They may
be physiologic (such as altered pain thresholds) or psychological (e.g.,
social modeling of catastrophizing behavior) or most likely a combination
of both. Regardless of the mediators for this phenomenon, it is essential
that family history of pain be examined. The child’s pain cannot be
adequately addressed if the parent’s pain is not recognized.
Psychological and social factors should be explored in children with

2883
chronic pain and their families regardless of the pain’s etiology. Such an
exploration does not imply causation, but there is clearly a transactional
relationship between chronic pain and anxiety and depression.114,115 As is
evident throughout this chapter, anxiety, depression, and other mental
health concerns frequently co-occur with chronic pain and need to be
assessed. Questions regarding anxiety, depression, and excessive
irritability should be posed to both the child and his or her family. The use
of existing standardized questionnaires has been described earlier in this
chapter and should be encouraged. In addition to mental health concerns in
the child, Eccleston and colleagues116 report that parents who have
chronically ill children are often anxious and depressed (60% and 40%),
and these symptoms may be a response to parenting a sick child or may
predate the child’s illness.113 Chronic pain is likely to bring severe
disruption to the social and family structure,62,117 which should be
examined as part of gathering the history of the pain and its impact.
The child’s school experience should also be explored in an effort to
identify further impact on daily function.118 Increased school absenteeism
is commonly reported in most chronic pain syndromes,119 widespread
musculoskeletal pain,10 and abdominal pain.120 This may be a result of
underlying stress from learning disabilities, attentional problems, or social
difficulties such as bullying. Frequent absences may also become a source
of extreme stress for the child when faced with the need to reintegrate
making a frank discussion about the child’s grades, competencies, social
skills, friendships, and existing school accommodations a necessary part of
the history gathering. The Pediatric Pain Screening Tool (PPST) is a 9-
item screening tool available to identify factors associated with adverse
outcomes among youth who present with pain complaints, providing risk
stratification and potential guidance for effective pain treatment
recommendation in the clinic setting.96
Finally, red flags or alarm signs specific to the common functional pain
syndromes that help delineate a need for additional investigation is
discussed in specific sections pertaining to each syndrome (headache,
abdominal pain, and musculoskeletal pain).

MEASUREMENT OF PAIN AND FUNCTIONING

2884
A thorough biopsychosocial assessment of the child with chronic pain is
critical for individualizing pain treatment strategies. The clinician aims to
gather detailed information about the child’s current pain and pain history
and assess areas of child daily functioning that are disrupted by pain while
considering the child’s developmental stage. Many evidence-based self-
report questionnaires have been developed and validated across the
pediatric age range, which complement a semi-structured interview.
Assessment is considered an iterative process, with follow-up assessment
conducted throughout treatment to track progress toward treatment goals.
Measurement of aspects of recurrent and chronic pain requires tools that
measure the frequency, intensity, duration, time course, and activity
interference due to pain. Validated measures have been developed to
capture most of these domains (e.g., Eccleston et al.,121 Stinson et al.122).
Developmental considerations will guide selection of the most valid and
reliable tool. In children ages 4 through 12 years, Faces Pain Scales have
demonstrated good validity and reliability.123 In youth 8 years of age and
older, Visual Analogue Scales, using anchors such as “no pain” and “worst
pain ever,” are considered most valid and reliable. The verbal Numerical
Rating Scale (NRS) is often used clinically, on which participants rate
their pain on an 11-point scale representing increasing pain intensity (e.g.,
0 to 10). Data indicate that the NRS is a valid and reliable measure for
ages 8 years and older.124
In addition to assessment of pain intensity, there are other characteristics
of pain (e.g., duration, frequency, pain quality, spatial distribution) that are
important to evaluate in children with chronic pain. Daily monitoring of
pain and using a diary or log provides information about pain patterns as
well as variations in children’s behaviors (e.g., activities participated in)
and emotions (e.g., positive or negative affect).125 A body map identifies
the spatial distribution of pain, including the number of pain locations, and
indicates how widespread the pain is. It is also helpful to obtain
information from parents and children about the history and course of the
pain problem, including past and present treatments for pain, perceived
efficacy of treatments, and beliefs about the cause of pain and expectancies
for pain relief. Electronic pain diaries (e.g., smartphones and Web sites)
have become increasingly used in children and adolescents to document

2885
chronic pain symptoms. For example, Stinson and colleagues125 developed
a multidimensional electronic diary to collect data on pain intensity,
duration, location, and impact in adolescents with arthritis.
A critical area to assess is function. Measures such as the Functional
Disability Inventory63 and the Child Activity Limitations Interview126
provide information about interference of pain in normal daily activities.
These measures are brief and can be administered easily to document
children’s functional disability at baseline and treatment progress. Many
children with chronic pain conditions experience significant school
impairment including a high number of absences from school and
difficulties making academic progress.127,128 Role functioning can be
assessed on broadband measures, such as HRQOL and pain impact
measures. To supplement interview and survey assessment, objective
measures of school attendance and performance (e.g., report cards,
attendance records) are useful to obtain.
There are several multidomain measures that can be used for efficient
assessment of multiple domains of functioning. The Patient-Reported
Outcomes Measurement Information System (PROMIS) is a National
Institutes of Health initiative. The PROMIS Pediatric Cooperative Group
developed self-report item banks to assess general health domains,
including depressive symptoms, anxiety, mobility, pain interference,
fatigue, peer relationships, and pain intensity in children.129 When used as
a comprehensive battery, 25-, 37- and 49-item versions are available to
assess multiple domains. These measures are appropriate for children ages
8 to 17 years130 and can be supplemented by a parent proxy report. The
Bath Adolescent Pain Questionnaire131 assesses seven domains of
functioning affected by pain (social functioning, physical functioning,
depression, general anxiety, pain-specific anxiety, family functioning, and
development), and a parent report is also available.132 The Pediatric
Quality of Life Inventory133 is a well-validated HRQOL measure for
children (age 5 to 18 years) to self-report functioning in four broad
domains (physical, emotional, social, school) and has a parent proxy
instrument for younger children.
Psychosocial assessment is an important component in the assessment
of a child with chronic pain in order to evaluate psychological, social, and

2886
family functioning which may contribute to pain or pain-related disability.
Psychosocial assessment may consist of clinical interviews, administration
of standardized psychological measures, and observation of child and
family members. A detailed clinical interview should cover
developmental, behavioral, and psychiatric concerns in the patient’s and
family’s history. Potential stressors and areas of maladaptive coping
should be inquired about as well as a comprehensive school history and
history of peer and social relationships. Ideally, a separate psychosocial
assessment is conducted with child and parent alone in order to obtain their
individual perspectives. Many outpatient pediatric pain clinics use intake
questionnaire packets that cover demographics, developmental history, and
other aspects of psychological functioning in order to consistently obtain
this information in the evaluation of new patients. Review of intake
packets may then provide details that serve as a springboard for more
focused clinical interviews or additional psychological assessments during
the intake visit.
Depending on the particular presenting concerns, standardized
psychological measures may be administered to screen for mental health
diagnoses, in particular, anxiety and depressive symptoms, to assess
coping behaviors and family functioning. A variety of standardized
instruments can be used in the clinical setting with the advantage of
obtaining a quick assessment of children’s psychological functioning given
the limited time available for in-depth psychological evaluation in the
medical setting. Many valid and reliable measures are available to assess
anxiety and depression in youth such as the Revised Child Anxiety and
Depression Scale,134,135 and PROMIS Emotional Distress anxiety and
depressive symptoms.136 Posttraumatic stress disorder (PTSD) symptoms
can be measured using standardized tools like the 24-item Child PTSD
Symptoms Scale.137 When psychological measures are used to screen for
psychological distress, it is important to consider the limitations of self-
report and, in particular, that children may want to present themselves in a
favorable light (social desirability response bias), which has been
described in children and adolescents with chronic pain.138
Beyond general internalizing symptoms, it is also useful to assess pain-
specific dimensions of anxiety (e.g., catastrophizing, pain-related fear).

2887
There are developmentally adapted versions of the Pain Catastrophizing
Scale available to assess child catastrophic thoughts about pain139 as well
as parent catastrophic thinking about their child’s pain.140 Other measures
are available to assess pain-related anxiety, such as the Child Pain Anxiety
Symptoms Scale141 and the Fear of Pain Questionnaire,142 which also has
a parent report.143
Parental and family functioning has also been a major area of focus in
pediatric chronic pain assessment.89 There are measures available to assess
parent behaviors (e.g., frequently attending to pain symptoms or allowing
avoidance of regular activities) that may contribute to pain-related
disability (e.g., Adult Responses to Children’s Pain Questionnaire).144 In
addition, overall family functioning can be assessed with several measures
including the Family Assessment Device.145 In some cases, it may be
important to screen parents for their own psychological distress, given the
risk for high levels of caregiver stress in this population (e.g., Brief
Symptom Inventory). For a comprehensive review of measures available
to assess parental impact of chronic pain, see Eccleston et al.121
There are also measures of child coping that have been validated on
pediatric chronic pain samples including the Pain Response Inventory146
and the Pain Coping Questionnaire.147 Measures of specific areas of
coping, including catastrophizing, are available such as the Pain
Catastrophizing Scale, Child Version (PCS-C).139
Well-established measures of sleep in pediatric chronic pain include the
Children’s Sleep Habits Questionnaire (CSHQ),148 the Adolescent Sleep–
Wake Scale (ASWS),149 and the Adolescent Sleep Habits Scale
(ASHS).149 The CSHQ is a parent-report measure used to assess multiple
aspects of sleep in school-age children (ages 4 to 10 years), including
bedtime behavioral issues and symptoms of sleep disordered breathing.148
The ASWS and ASHS are complementary measures of sleep quality and
sleep habits, respectively. Although reliable and relevant to pediatric pain,
all three questionnaires are lengthy and potentially burdensome to
complete. A short form (10-item) of the ASWS was recently developed
that may be useful to integrate into quick-paced tertiary care settings.90 For
a comprehensive review of available sleep measurement tools in pediatric
pain, see de la Vega and Miró.150

2888
PHYSICAL EVALUATION
Information gathered from the physical examination in conjunction with
the history can help differentiate a primary/functional pain disorder from
pain secondary to an underlying disease. General appearance (sickly or
well appearing) may be helpful, although individuals who are in pain for a
prolonged period of time may look pale and wan. Growth parameters
should be examined as chronic illness may well impede growth. Because
of the association between chronic pain and postural orthostatic
tachycardia syndrome, heart rate should be obtained both supine and
standing.
The child should be asked to localize his or her pain. The differential
diagnosis and intervention strategies are very different for generalized
discomfort versus highly localized pain. Specific discussion of the
examination of the back, abdomen, and joints is beyond the scope of this
review, but regardless of the origin of the pain, the clinician should obtain
general impressions of the child’s mood, cooperativeness, irritability, and
eye contact along with a comprehensive neurologic exam and more
focused musculoskeletal exam, noting the child’s gait and posture.
Although hypermobility does not predict future musculoskeletal pain in
the preteen and adolescent population, literature currently supports the
association of chronic musculoskeletal pain with hypermobility.151 The
Beighton score is a valid measurement of generalized joint hypermobility
in children. A score of 6/9 indicates hypermobility.152 When positive,
discussion regarding hypermobility can be helpful both in its suggestion of
biologic vulnerability to pain as well as providing guidance in the
development of additional goals for physical therapy such as joint
protection, postural control, and improved proprioception as a part of the
multidisciplinary plan.152–154 Regardless of the origin, a Beighton score
should be calculated on all children with chronic pain.155

CLINICAL FORMULATION
The task for the clinician is to examine the data that emerged from the
history and physical and determine whether or not there are sufficient red
flags to warrant further investigation for progressive disease. If there are,
the child and family should be informed that the investigation is ongoing.

2889
If there are not, the clinician should report to the child and family that the
child most likely has a chronic pain syndrome. In either situation, the pain
should be treated appropriately, although the approach, both
philosophically and practically, will vary between the two. If the pain is
thought to be a manifestation of a time-limited disease process, although
the approach will be multifactorial, there will often be an emphasis on
more aggressive pharmacologic intervention while the disease process runs
its course. If the pain is associated with a chronic condition or represents a
chronic pain syndrome, the emphasis is more typically on a rehabilitative
approach.

FEEDBACK WITH THE FAMILY

During initial evaluation, history and physical may warrant further
investigation for progressive disease, in which case, further evaluation
should be discussed with the child and family. However, if the need for
additional investigation is not indicated, the clinician should review with
the child and family that the more likely cause is a primary/functional pain
disorder.96 This initial feedback is, in effect, the first treatment
intervention and will set the tone for the subsequent relationship with the
child and family.114,115
Regardless of the etiology of the pain, feedback should include a
number of elements. Ensuring the family at this time that the pain is “real”
is critical as many families of children with chronic pain report that they
have felt dismissed and feel that their child has not been believed. It is
imperative that the clinician informs the family that he or she is familiar
with the pain symptom complex. Even if the exact problem is not clearly
defined, chronic pain problems share numerous overlapping features
which need to be addressed such as sleep disturbances, school
reintegration, and return to physical and social activities. Another key
element is that of optimism. It is clear that expectations can influence the
outcomes of chronic pain treatment.156
Providing an understandable explanation of the pain is a critical element
of the initial feedback. The current conceptualization of chronic pain is
that it results from the interplay between biologic vulnerability and
psychological and environmental variables which ultimately lead to

2890
abnormalities of sensory processing, enhanced responsiveness, and
excitability in the central nervous system known as central sensitization.
Central sensitization is discussed in numerous other chapters throughout
this book in detail, but it is the term used to describe the dysfunction of the
nervous system that results in an amplified responsiveness to painful and
nonpainful stimuli. This increased responsiveness of the nervous system is
thought to be a key element in the development and maintenance of
chronic pain.97–100 Because chronic pain typically represents nerve
“hypersensitivity” and not progressive disease and damage, the traditional
dichotomization of pain into organic or psychological causation is
inaccurate and often harmful.98–100 It is also essential therefore that the
child and family be aware that pain persistence does not serve a warning
protective function as it does in acute pain and that although pain may
“hurt,” it is not causing “harm.” This all must be explained to the child and
family in an understandable way as Moseley and others have documented
the importance of “neuroeducation” in promoting recovery and compliance
with recommendations.157,158 The use of metaphors (“pain is a false
alarm”; “the pain is a software glitch, not a hardware problem”) may be
quite helpful in conveying this message.159,160
As previously stated, due to the complex relationship between biologic,
psychological, individual, social, and environmental factors which result in
chronic pain, treatment recommendations should be multidimensional. The
massive stress of school, the loss of normal opportunities to socialize with
friends, and the impact of the immobilization and sleep deprivation often
accompanying chronic pain further contribute to its maintenance and
persistence and therefore should be a part of the treatment plan elucidated
during the feedback.114 Evidence of the positive impact of a
multidisciplinary approach was demonstrated in 5 out of 8 outcome
domains recommended by PedIMMPACT including pain intensity,
disability, school functioning, anxiety, and depressive symptoms114 as well
as by numerous other investigators.161 Lack of acceptance of the
multifactorial nature of pain and its treatment has been identified as one of
the causes of treatment failure.162
The final element that the feedback should convey is that although the
ultimate goal is reduction of pain, initially, it is the return of the child to

2891
functioning. Pain reduction or elimination will often follow.

Treatment
GENERAL PRINCIPLES OF TREATMENT
Interventions offered by multidisciplinary teams for the management of
chronic pain are centered on three main components: pharmacotherapy,
physical therapy, and psychological therapy for a multimodal approach
focusing on improving daily function. Dimensions of daily function
include “the 4 S’s”96: sports, social, sleep, and school, with a primary goal
to improve physical function and facilitate reengagement in age typical
activity.96,114,154 As mentioned previously, educating the child and family
that chronic pain does not offer the warning protective function of acute
nociceptive pain and stating that although the pain is unpleasant, it is not
causing “harm” is essential to alleviate familial anxiety and promote
participation in the main components shown to allow for improved
function.
Initially, frequent scheduled follow-up appointments help the child and
family build confidence through careful monitoring as the child engages in
these therapies. Symptom diaries may provide interim data between
appointments. This approach has been labeled “watchful waiting”163 and
can reassure parents that if new symptoms develop, a potentially
unrecognized disease process will not be missed.
Interventions typically employed to address chronic pain must allow the
child to return to a “normal” life. As a result, medications which
significantly alter the child’s sensorium are inadvisable, along with
prolonged hospital or home stays. Pharmacotherapy to reduce central
sensitization such as antidepressants and anticonvulsants are often the
mainstay of pharmacologic treatment regardless of the etiology of the
chronic pain; however, utilized as a sole therapy for primary pain
disorders, they tend to be ineffective. Although there are limited clinical
trials to support their use, antidepressants and anticonvulsants are used in
children for primary pain disorders. Two of the most common,
amitriptyline and gabapentin, are approved for use in children; however,
few other antidepressants and anticonvulsants have been.164,165 Analgesic

2892
agents for mild acute pain, such as acetaminophen and nonsteroidal anti-
inflammatory drugs (NSAIDs), may be helpful, but there is the risk of
rebound headache or abdominal pain secondary to excessive nonsteroidal
usage.166,167 Guidelines for opioid use for chronic pain have not been
applied to children and adolescents.168 When used for primary pain
disorders, opioids are generally associated with worse clinical
outcomes.169 That said, appropriate use may be indicated in conditions
such as osteogenesis imperfecta, congenital degenerative spine conditions,
other neurodegenerative conditions, and erythromelalgia.168–170
Physical therapy is of particular value in musculoskeletal pain
syndromes such as fibromyalgia but is also valuable in any pain syndrome
in which the child’s activity level has been diminished and he or she has
become deconditioned.171–174 Graded exercise increases the child’s
feelings of well-being and provides reassurance and confidence as the
child regains lost abilities.174 Other physical and occupational therapy
modalities such as desensitization, transcutaneous electrical nerve
stimulation, and stretching or strengthening particular muscle groups are
also helpful.173–177 Physical therapy is also of particular benefit in
individuals who are hypermobile where the focus is on joint protection and
proprioception. Active mind–body techniques, such as biofeedback and
guided imagery, integrate cognitive and emotional processes with
physiologic function and have also demonstrated efficacy in modulating
the pain pathway in chronic pain conditions.178,179
Evidence supports psychological interventions as effective treatment of
chronic pain in children. Multiple reviews and meta-analyses confirm the
strong impact of these approaches which include cognitive-behavioral as
well as psychotherapeutic strategies.180–183 Although many of the
cognitive-behavioral strategies were developed to help cope during acute,
painful procedures, many of these strategies, such as meditation, hypnosis,
and mindfulness, are also effective for chronic pain.178,184 Acceptance and
commitment therapy (ACT) was developed to help individuals function in
the context of ongoing pain.185 Guidance of the child and the family
toward resuming daily function is the overall goal of treatment. Educating
parents on the best way to support their child with ongoing pain symptoms
is an integral step in this process. The natural protectiveness of parents for

2893
their child with pain can hinder progress and become detrimental in
primary pain syndromes. Parents often need help ushering crying,
complaining children off to school when the path of least resistance is to
allow them to remain in bed. Specific criteria for school attendance with
modifications can help the child regain a rhythm of daily school
attendance. In general, school should be mandatory except for those times
when the child has a fever. When efforts to incorporate these dimensions
in an outpatient setting fail to enable a child to normalize daily function,
more intensive daily rehabilitation centers with an interdisciplinary team
approach are shown effective in regaining daily activity and should be
considered.114
In summary, the treatment of chronic pain in children needs to address
the pain itself as well as the life context in which that pain is occurring. As
a result, a multimodal approach incorporating pharmacotherapy, physical
therapy, and cognitive therapy with the goal of regaining normal daily
function are important dimensions of the treatment of chronic pain.

SPECIFIC INTERVENTIONS FOR

CHRONIC/PERSISTENT PAIN
Children who receive care in a multidisciplinary pediatric pain clinic are
typically offered a multicomponent treatment plan, which often involves
psychological therapy, physical therapy, and medication management.
Philosophically, most programs incorporate a rehabilitation approach in
which pain is accepted as a symptom that will be diminished but might not
be entirely eradicated. Therefore, the focus is typically on improving
function and quality of life. The specific structure of each program differs
depending on local factors with some providing inpatient rehabilitation,
whereas others are solely outpatient. Many new programs are developing
in the United States and abroad. Zeltzer and Schlank186 list many pediatric
pain programs in the United States, Canada, and internationally.

Pharmacologic Interventions
Pediatric analgesic pharmacology is summarized in greater detail
elsewhere in this book (see Chapter 50). The current discussion
emphasizes specific uses of analgesics in the setting of chronic persistent

2894
pain, as opposed to acute pain. Pharmacotherapy of chronic pain in
children and adolescents requires patience and balance of risks, benefits,
and side effects. For most patients coming to a chronic pain clinic,
pharmacotherapy should not be used in isolation but only as a component
of a multimodal treatment program. In considering a medication trial,
clinicians’ discussions with patients and parents strike a difficult balance.
The aims of drug therapy and expected benefits should be outlined. Side
effects and risks should be discussed in a manner that is honest but is
tailored to the style of the individual patient and family. There is a growing
literature on how patients hear risk discussions.187
Discussions of side effects do have the potential to generate nocebo
(negative placebo) effects.
For some conditions, treatments can be specific and mechanism-driven.
For example, for children with rheumatoid arthritis, pharmacotherapy is
largely directed at underlying inflammatory processes, and for most
patients, treatment of inflammation serves to treat the pain. Similarly,
pharmacotherapy for migraine and for specific subtypes of chronic
abdominal pain may be directed at underlying mechanisms in some cases.
Acetaminophen and NSAIDs are widely used for pediatric acute pain
management, and NSAIDs are an integral component of management of
chronic inflammatory disorders. Daily use of either of these classes of
medications can produce rebound headaches. There is comparatively little
studies on chronic daily administration of acetaminophen in children.
Chronic administration of NSAIDs in children with rheumatoid arthritis
has been associated with gastropathy and nephropathy but overall with a
lower risk than has been reported in adults.
A majority of trials of cyclooxygenase (COX)-2 inhibitors in children
have involved short-term use. A recent 3-month trial comparing celecoxib
to naproxen showed equal efficacy and no statistically significant
difference in adverse events.188
Opioids have been extensively studied for pediatric acute pain
management and for pain in children with cancer. As with adults, there is
little consensus regarding which children with chronic noncancer pain
have a favorable risk–benefit ratio for long-term opioid analgesia. Overall,
prospective studies on adults in pain clinic populations with non–life-

2895
shortening conditions have not shown good effect of long-term use of
opioids on either pain scores or measures of quality of life or functioning.
Those who defend chronic opioid therapy in adults may argue that these
studies did not address ideal patient subgroups. With children and
adolescents, there are additional concerns. First, opioid tolerance and
opioid-induced hyperalgesia are likely to proceed more rapidly for
children compared to adults.189,190 Second, long-term opioid
administration may have detrimental effects on endocrine function. Third,
with many chronic medical conditions in childhood, longevity is difficult
to predict, and advances in treatment have changed prognosis for many
chronic illnesses of childhood and young adult life. For these reasons, we
do use opioids on a long-term basis for a small subset of children with
chronic pain not due to life-limiting illnesses, but we do so with some
caution and with consideration of alternatives. There is a theoretical
argument in favor of selection of either methadone or buprenorphine for
long-term opioid therapy in younger patients based on a hypothesis that
relates the development of tolerance and hyperalgesia to differential
activation of receptor-mediated activation of second messenger systems
versus receptor-mediated endocytosis.191
For adults with many forms of chronic pain, especially neuropathic pain
disorders, there is evidence for efficacy of several anticonvulsant and
antidepressant medications. We cite some limited pediatric information in
the following text, but at present, most information regarding efficacy
must be extrapolated from clinical trials in adults. In adults, these
medications are side effect–prone and inconsistently effective; they
generally produce partial, rather than complete, pain relief. In adults, there
are very few randomized controlled trials (RCTs) that compare one
antidepressant to another192 or that compare an antidepressant to an
anticonvulsant. There is remarkably sparse evidence for selecting one
medication over another in general for adults with chronic pain except for
specific conditions that are uncommon in pediatrics, such as trigeminal
neuralgia.
One publication is cited here mainly to recommend caution in its
interpretation. The authors use an “indirect meta-analysis” to compare
duloxetine to the anticonvulsants gabapentin and pregabalin for treatment

2896
of neuropathic pain in adults. What is actually done is to use outcomes
from active treatment groups in studies comparing duloxetine to placebo to
the active treatment groups in studies comparing gabapentin or pregabalin
to placebo.193
For antidepressants in trials for neuropathic pain in adults, numbers
needed to treat (NNTs) range from 2 to 4 for trials involving tricyclics
(mostly with “global improvement” as an endpoint) to as high as 5 for
trials involving duloxetine with 50% pain relief as a primary endpoint.
Overall, tricyclics appear to be more effective than selective serotonin
reuptake inhibitors (SSRIs) for neuropathic pain in adults.
For children and adolescents, we commonly choose nortriptyline as a
first-line tricyclic. We encourage starting at a very low dose (e.g., 10 mg
every night for adolescents and older children and 5 mg every night for
younger children). The rate of dose escalation is determined by clinical
circumstances and side effects. For an outpatient who experiences no
adverse symptoms, dosing might be increased every 3 days until there is
good analgesia or he or she reaches a dose around 40 or 50 mg daily.
Dosing is occasionally even more rapid for inpatients with severe
neuropathic cancer pain. Conversely, if the child does experience side
effects, dose escalation proceeds more slowly. If there is no indication of
analgesia or side effects by the time dosing is escalated to 50 mg/daily
(and if we are convinced that the child is taking the medication), we will
often obtain a blood level prior to further dose escalation. Clearance of
tricyclics in children is enormously variable. An electrocardiogram is
widely recommended either prior to initiating treatment or after dose
escalation. We adhere to this recommendation while recognizing that there
is little evidence that electrocardiography can identify patients at risk for
sudden cardiac events.
There are a number of clinical trials and case series on antidepressants
for migraine prophylaxis in pediatrics, including amitriptyline,
nortriptyline, and trazodone, although many have involved open-label
designs or crossover comparisons to other drugs.194,195
There is a widely quoted case series on the SSRI citalopram for
treatment of recurrent abdominal pain in children. Although there is
apparent improvement in a large percentage of patients, this should be

2897
interpreted with great caution because of the open-label and uncontrolled
design of the study.196
There has been extensive controversy regarding potential risks of
antidepressants in triggering suicidal ideation and completed suicide
among adolescents. What is clear to us is that these medications require
close monitoring for changes in a child’s mood and behavior. Prescribing
should begin in low doses, doses should be escalated in a gradual and
stepwise manner, and there should be a system for frequent reassessments,
ideally including regular phone calls in between clinic visits. For guidance
of families, there is a well-written statement on the National Institute of
Mental Health Web site.197
Anticonvulsants are also widely used for treatment of neuropathic pain
in adults. As with antidepressants, side effects are common, treatment
responses tend to be partial rather than full, and NNTs generally range
from as low as 3 to over 5.
Gabapentin emerged as a widely prescribed medication for neuropathic
pain in the 1990s in part because of the widespread belief that it was safer
or easier to prescribe compared to other anticonvulsants. There is a
remarkable dearth of trials comparing anticonvulsants to each other for
neuropathic pain in adults.
As with tricyclics, our recommendation for gabapentin dosing is to start
with small doses and escalate slowly, particularly in ambulatory patients.
Different clinicians begin adolescents in a dose range from 100 mg daily to
300 mg daily. Our preference is to start for a few days with nighttime-only
dosing, to begin morning and then afternoon dosing after about 3 days, and
to escalate every few days as tolerated until there is pain relief, significant
side effects, or dosing reaches a range around 1,800 mg daily over a period
of about 3 weeks. Again, some patients tolerate escalation with no side
effects, and others may tolerate daily doses as low as 300 mg. We
commonly recommend giving half the daily dose at night, with one quarter
in the morning and one quarter in the afternoon. As with tricyclics, dose
escalation of gabapentin may be considerably more rapid for children with
advanced cancer and refractory neuropathic pain.198
In our view, if trials of gabapentin or pregabalin produce minimal
benefit or problematic side effects, there is reason to consider trials of

2898
anticonvulsants with different mechanisms. In particular, for peripheral
neuropathic pain, we often try anticonvulsants with actions on sodium
channels, such as oxcarbazepine.199,200
In our practice, topiramate is used primarily for migraine prophylaxis.
Among the anticonvulsants, topiramate has a relatively high risk for
neurocognitive side effects, especially effects on memory, word finding,
and mental clarity.201
Some of our colleagues have tended to select anticonvulsants rather than
antidepressants as first-line agents because of the aforementioned
controversy regarding suicidal ideation and suicide attempts with
antidepressants in pediatrics. Unfortunately, anticonvulsants may increase
these risks as well. An analysis of placebo-controlled trials of
anticonvulsants for a range of indications found increased frequencies of
suicidal ideation and attempts in the active drug groups compared to
control groups, and this increased risk was apparently not limited to a
particular drug class or a particular patient group.202

Psychological Interventions
A range of psychological therapies has been delivered to youth with
chronic pain conditions, either as single modalities or in combination with
other types of interdisciplinary pain care. The evidence base for
psychological therapies for children with chronic pain is moderate and
growing, with 41 RCTs published across three Cochrane reviews.203–205
Systematic reviews investigating psychological therapies for pain
management including cognitive-behavioral therapy (CBT), behavioral
interventions, hypnotherapy, intensive rehabilitation, and ACT have found
significant declines in children’s pain intensity and disability at
posttreatment, and these were small to moderate size effects. However,
these treatment effects were not maintained at long-term follow-up.
Psychological treatments did not have any effect on depression or anxiety
outcomes at posttreatment or follow-up compared to controls. Although
promising, further work is needed to enhance duration of treatment effects.
CBT is the most frequently delivered psychotherapy to youth with
chronic pain conditions and typically includes a combination of education,
cognitive, and behavioral skills. Cognitive skills involve teaching patients

2899
to identify and alter maladaptive cognitions related to pain. This may
include working with children to recognize negative thoughts and beliefs
about pain and activity engagement. Behavioral skills are intended to
modify what a patient does to manage pain. Thus, these skills focus on
improving patient function by increasing patient activity levels and
involvement in pleasant and valued activities, such as activity pacing and
pleasant activity scheduling. Relaxation is one of the most common
behavioral skills used with children with chronic pain. For example, Van
Der Veek et al.206 taught deep breathing to children with functional
abdominal pain by asking them to breath calmly through the abdomen
(rather than the chest). Cottrell et al.207 instructed progressive and cued
muscle relaxation to youth with migraine over the phone.
Teaching parents appropriate strategies for managing their child’s pain-
related behaviors (e.g., reinforcing adaptive coping, discouraging
maladaptive pain behaviors) is beneficial in treatment, and these strategies
are increasingly being incorporated into psychological therapies.
For example, Levy et al.208 worked with parents to recognize when their
attention was directed to sickness behaviors and to redirect attention
toward wellness behaviors, and this led to a reduction in maladaptive
parent behaviors.
Problem-solving skills training (PSST) is based on the social problem-
solving model209,210 and focuses on teaching parents a positive orientation
and rational skills for solving problems in order to reduce emotional
distress. In a pilot RCT, Palermo et al.211 delivered PSST to parents of
youth with chronic pain using this model to teach five problem-solving
steps (identify a problem, generate alternative solutions, decide and
implement a solution, and then determine whether it worked), finding
promise effects for reducing parent distress. Findings demonstrated that
PSST reduced emotional distress in parents of children with chronic pain
compared to a usual care condition.211
Although effective psychological treatments have been developed,
major barriers exist for children and adolescents to access care due to the
geographical distance from treatment centers with behavioral health
providers, scheduling constraints, and long wait–lists, leaving a significant
unmet clinical need. Availability of information and communication

2900
technology has expanded opportunities for intervening with individuals
remotely. An emerging evidence base now exists for remotely delivered
psychological interventions in both adult and pediatric populations; a
recent systematic review of the pediatric literature identified eight RCTs,
which all delivered CBT, and patients showed improvements in pain and
disability.205 As one recent example, in a large multicenter RCT with 273
adolescents with chronic abdominal, headache, or musculoskeletal pain,
Palermo et al.212 found improvements in daily physical functioning,
depressive symptoms, and parent-perceived impact of pain in families
receiving an 8-week Internet pain self-management program compared to
an Internet pain education control group.
Pilot studies are emerging in the application of ACT to children with
chronic pain.213 ACT is an increasingly popular form of CBT that
emphasizes the importance of accepting pain symptoms and working
toward valued goals, using interventions such as exposure, cognitive
defusion, and mindfulness. Parents are also integrated into treatment using
similar interventions emphasizing exposure to previously avoided private
experiences, acceptance, and defusion exercises. In the only RCT to
evaluate ACT in children with chronic pain, Wicksell et al.214 delivered
exposure treatment within an ACT framework, which emphasized
acceptance of pain and negative thoughts and setting goals with youth
consistent with their values to a small group of youth with chronic pain,
compared to a group receiving standard multidisciplinary and
pharmacologic treatment with amitriptyline. The ACT group reported
reduced symptoms across all outcomes and had significantly lower pain
intensity, pain-related discomfort, and fear of reinjury as well as improved
perceived functional ability at posttreatment and follow-up, relative to the
control group. Given the clinical interest in ACT, it is anticipated that
larger scale studies will be forthcoming using this approach to treat
children and adolescents with chronic pain.
Complementary and alternative medicine (CAM) interventions are
becoming increasingly popular in the treatment of chronic pain and have
been successful in helping children and adults manage pain symptoms.215
CAM refers to therapies (e.g., hypnosis, acupuncture, yoga, and
biofeedback) commonly used in conjunction with conventional medical

2901
treatment. Biofeedback is one type of CAM therapy effective in the
treatment of persistent pediatric pain. Biofeedback involves connecting a
patient to a machine that monitors physiologic responses (e.g., muscle
tension, heart rate). One form of feedback, thermal biofeedback, involves
using electronic instruments (e.g., a temperature probe on the finger) to
measure temperature and a computer monitor to display reinforcing
information back to the patient. Using relaxation approaches, patients can
use the objective biofeedback information to learn to increase peripheral
temperature.
Biofeedback, especially thermal biofeedback, has undergone empirical
evaluation in children with migraine and tension headache, and there is
evidence to recommend biofeedback and/or relaxation to any child who
suffers from headaches.216 Recently, biofeedback has been evaluated in
children with chronic abdominal pain.217,218 Although results from these
studies suggest that biofeedback is effective in reducing pain, RCTs using
larger sample sizes are needed. Like CBT, research shows that
incorporating parenting strategies into biofeedback treatment may increase
the effectiveness of treatment. Children whose parents received behavior
management strategies in combination with the child’s standard
biofeedback treatment demonstrated more clinically significant
improvement in headache pain and showed greater reductions in headache
frequency than those who received biofeedback alone.219,220

School and Social Reintegration

School and social functioning are impaired in many children with chronic
pain. In industrialized societies, school is the work of children. Numerous
studies have documented that children with chronic pain have difficulties
with consistent school attendance and making progress with academic
work, although there may also be specific impairments in peer and social
relationships that are amplified in the school setting. On average, children
with chronic pain miss more school days than do children with other
chronic health conditions, and they often identify school as the most
problematic stressor.62 For example, Stang and Osterhaus119 estimated that
several hundred thousand school days are missed each month as a result of
pediatric headache alone. In a sample of children with SCD-related pain,

2902
Shapiro and colleagues221 reported that on average, children missed 21%
of school days, which is the equivalent of 6 to 8 weeks of the school year.
There is also evidence that children with chronic pain may experience
problems with social competence and peer relationships in the school
setting. In one study, adolescents with juvenile fibromyalgia syndrome
were perceived as being less popular, more isolated, and withdrawn
compared to matched classroom comparison peers.66 Moreover, these
adolescents were less well liked, were selected less often as a best friend,
and had fewer reciprocated friendships. Negative peer interactions were
explored in one study,222 finding that children with chronic abdominal
pain had higher levels of relational victimization in comparison to pain-
free peers.
The school setting may also be perceived as stressful due to problematic
interactions with teachers and perceptions that adults are not supportive of
children with chronic pain. In a study using vignettes, teachers’
attributions about the causes of chronic pain revealed a lack of knowledge
of the biopsychosocial framework and a primary perception that pain was
either physical or psychological.223 Teachers responded more positively to
students when medical evidence supporting the pain problem was
available, and responses were associated with parental attitudes toward the
school. Teachers were more likely to report children were entitled to
accommodations if parents approached the school in a collaborative
manner rather than using a confrontational approach.224
There is variability in how children and families respond to impairments
that may arise in the school setting. Some children and adolescents have
worked out accommodations that allow them to have reduced class time, in
home tutoring, or online courses. Several mechanisms in public education
laws can be used in this regard, including individualized education plans
and Section 504 plans for other health impairments. Some families opt to
remove their child from the school setting and engage in home schooling.
Regardless of the exact setting where school is to occur, addressing the
impairments in school and social functioning are a primary focus of
treatment for the child with persistent pain. Some children and adolescents
have spent extensive time outside of their usual school and social settings,
and therefore, graded plans for reintegration into these settings are needed.

2903
In the context of CBT, parent management guidelines have been
implemented in clinical settings and in treatment studies focused on
operant techniques. In general, parents are encouraged to establish a
reduction of attention paid to pain symptoms in favor of increased
attention paid to functional improvement. Such guidelines often include
recommendations to reduce status checks, that is, allowing the child to
communicate directly about pain symptoms rather than having the parent
repeatedly check in with the child about his or her pain level. Most parents
experience tremendous relief in being released from the role of
documenting the child’s pain level. Often, the focus on pain intensity and a
specific numerical value (e.g., 8 out of 10) provides little in the way of
adaptive coping behaviors and may lead to difficulties making decisions to
reintegrate in school and social settings because of lack of change in pain
levels.
Formal operant systems can be devised with families where children
earn points or rewards for school attendance and participation in other
social activities. The goal is to shift the pattern of contingencies so that the
child experiences reinforcement for their efforts in school or social
activities. An example of a point system would include specifying a target
activity such as attendance at school for 4 hours each day and then
developing rewards for reaching the goal (such as full computer and
television privileges) and consequences for failure to achieve the goal
(such as removal of access from computer and television). Psychologists
and other members of the pain team can work in treatment with children
and parents to develop clear, graded plans for increasing activity.
Typically, an explanation to children and parents is provided that
functional improvement often precedes rather than follows pain relief. It is
important to start where the child is at in terms of their perceived ability to
sit in a chair and focus on school work for an operant system to be
successful. Sometimes, very short time periods of school attendance (e.g.,
1 hour) will need to be built on gradually, and the child will need to have
some control over his or her schedule. For example, it can be helpful to
have the child choose what time of the day (and what classes) he or she
would like to begin with upon the reintegration to school.
Carrying out a graded plan for increasing school and social functioning

2904
requires considerable effort from the parents who must arrange
transportation and other logistics with getting the child to the school
setting at specific times. Clinicians need to communicate sensitively to
parents about their role and make clear the logical sequence of the plan to
ensure its success. Additional interventions may be needed to assist
children with problems related to peer relationships, interactions with
teachers, or specific problems related to the school setting. There are not
yet any published treatment studies evaluating school-related interventions
for children with chronic pain.

Sleep
Sleep difficulties are commonly reported by children and adolescents with
chronic pain in the community61 as well as in clinical samples (e.g.,
juvenile rheumatoid arthritis,225 headache,36 SCD,226,227 abdominal and
musculoskeletal pain, and CRPS228). For example, a recent systematic
review found that children with juvenile idiopathic arthritis experience
greater difficulties with night awakenings, sleep anxiety, and excessive
daytime sleepiness compared to otherwise healthy children.229 Most
commonly, across types of chronic pain conditions, children and
adolescents with chronic pain describe difficulties falling asleep, frequent
night and early morning awakening, and excessive daytime sleepiness.230
Important consequences of sleep problems have also been identified
including decrements in children’s HRQOL, mood, and physical
functioning.72,82 Day-to-day variability in pain, mood, and sleep has been
examined in children with SCD,227 finding that negative mood partially
explained the relationship between more intense pain and poor-quality
sleep on the same and subsequent days. Other studies in youth with mixed
pain conditions have found temporal relationships between pain and sleep,
where nighttime sleep predicted next-day pain.231
Early models described a bidirectional relationship between pain and
sleep,232 where uncontrolled pain can cause sleep disruptions, and in turn,
disturbed sleep can enhance pain sensitivity.233 Recent research has
demonstrated that more studies now support the direction of sleep
impacting pain than vice versa. That is, sleep deficiency has now been
shown to lead to subsequent increased pain. Findings are from studies

2905
using experimental and self-report designs in multiple samples across
childhood and adulthood,234 highlighting its relevance in chronic pain
treatment.
However, there has been very limited attention to either the assessment
or management of sleep problems in children with chronic pain. In clinical
practice, it can be very informative to assess sleep problems in all pediatric
patients with chronic pain and to offer specific sleep interventions to those
patients with significant sleep disturbances. In particular, a detailed history
of sleep patterns should be obtained to identify problems related to
insufficient sleep duration, poor sleep habits, phase delays, or difficulties
falling asleep or staying asleep. Insufficient sleep duration is common
during adolescence with reported sleep in healthy samples of about 7 hours
per night,235 although optimal developmental sleep requirements for
adolescents have been estimated at 9 hours per night.236 In chronic pain
samples, similar restricted sleep of about 7 hours per night has been
reported.237,238 Poor sleep habits including use of caffeine in the evening,
lack of consistent bedtime routines, and the presence of electronics in the
bedroom can also be clear barriers to children receiving adequate sleep
duration. Children with chronic pain may also develop a high level of
vigilance and arousal at bedtime and a high focus on pain when the
distractions of the day are not present. These children may describe
negative thoughts, worries, and somatic tension that interfere with falling
asleep.
Interventions may be needed to help children increase their duration of
sleep, to modify problematic sleep habits, and to teach behavioral
strategies to reduce insomnia symptoms. Sleep interventions can be
included as a component of CBT for chronic pain212,239 or as a stand-alone
treatment. Typically, interventions include modifying sleep hygiene (e.g.,
no phones or screens in bed, regular and relaxing bedtime routine),
keeping a regular bedtime and wake time which allows for adequate
duration of sleep, limiting naps, and reducing negative thoughts about
sleep as well as teaching specific strategies to decrease insomnia
symptoms. For review, see Wu et al.240 Cognitive-behavioral therapy for
insomnia (CBT-I) is recommended by the American Academy of Sleep
Medicine as first-line treatment for adult insomnia.

2906
 Meta-analyses conclude that CBT-I produces reliable and durable
improvement in sleep in adults with co-occurring pain conditions
including arthritis and fibromyalgia.241 There is emerging evidence
suggesting that changes in sleep as a result of behavioral treatment lead to
changes in pain symptoms. For example, in a recent trial of CBT-I in
patients with knee osteoarthritis and insomnia, patients who received CBT-
I had greater improvements in sleep and the baseline-to-posttreatment
change predicted subsequent decreases in pain.242 Moreover, CBT-I is a
flexible treatment with evidence emerging that it can be delivered in group
settings and remotely through the internet with similar positive benefits.
Although the treatment literature for child and adolescent insomnia
interventions is more limited, there has been a recent uncontrolled trial in
an adolescent pain population. In this study, adolescents with a range of
physical and psychiatric comorbidities (e.g., depression, chronic pain,
anxiety, GI problems) received a brief four-session CBT-I intervention.243
CBT-I was associated with treatment improvements in insomnia
symptoms, sleep quality, sleep hygiene, presleep arousal, and sleep
patterns as well as improvements in psychological symptoms and HRQOL.
Sleep interventions appear promising and further research is needed to
understand the impact of sleep interventions on chronic pain and when
these interventions should ideally be delivered to children.

Intensive Rehabilitation Therapy

Intensive rehabilitation for children with chronic pain occurs in either a
day treatment or inpatient setting, during which an interdisciplinary team
of three or more health care professionals works together to increase
patient function. These programs have developed over the past decade in
response to limitations in effectively treating children, especially those
extremely disabled by pain, in the outpatient setting. Psychological
treatment is typically delivered in individual or group-based treatment. A
systematic review evaluating the effectiveness of intensive rehabilitation
programs identified one RCT and nine nonrandomized trials.115 At
posttreatment, the meta-analysis of all included studies showed large
effects for reducing disability and small to moderate effects for programs
at reducing pain and depression. These benefits were maintained for 3

2907
months after treatment and a recent study demonstrated cost-effectiveness,
saving families a projected $27,000 the year following admission.244

Specific Entities
MUSCULOSKELETAL PAIN
Musculoskeletal pain accounts for more than 50% of all the recurrent pains
reported in the pediatric population.245 Differential diagnosis of
musculoskeletal pain is vast. Two questions can help differentiate primary
pain syndromes from progressive disease. Is the pain localized or
widespread? Does the child appear well or unwell? If the pain is localized
and the child is well, the differential diagnosis includes “growing pains,”
CRPS, mechanical pain, pauciarticular juvenile rheumatoid arthritis, and
spondyloarthropathy. If the pain is localized and the child is unwell, the
infectious arthritides should be considered. If the pain is diffuse and the
child is well, hypermobility and diffuse idiopathic pain syndrome (juvenile
fibromyalgia) should be considered. If the pain is diffuse and the child is
unwell, malignancies or autoimmune diseases top the list. Red flags in the
history to guide us in determining the differential include pain in the
morning, swelling, nocturnal pain not relieved by analgesics, poor growth,
or bony tenderness.246
Diffuse or widespread musculoskeletal pain is the term typically used
for generalized musculoskeletal pain which in adults may be termed
fibromyalgia. Diagnostic criteria for “fibromyalgia” in children and
adolescents are not validated. The onset of diffuse idiopathic pain can be
gradual. The pain may have an identified initial insult such as infection,
but often, there is no identified trigger. A number of studies have identified
an increased association between widespread muscular pain and
hypermobility.151 As more evidence is collected, hypermobility-related
disorders also appear to have a strong interrelationship with many primary
pain disorders.153 This may be secondary to central sensitization, induced
by constant subluxation and slippage or may have other etiologies that
cause repeated microtrauma in joints and ligamentous structures with
associated pain leading to disordered sensory processing.151,153,247,248 It is
also important to address syndromes that are associated with

2908
hypermobility such as Ehlers-Danlos or Marfan syndromes which may
have additional problems associated with them.
Treatment for widespread musculoskeletal pain incorporates a
multimodal approach and typically has physical therapy at its
cornerstone.249,250 There is the attempt to restore the normal range of
movement, even if the joint is hypermobile, strengthen the surrounding
musculature to add joint stability, and improve the general level of fitness
in the individual. Premedicating with an analgesic prior to therapy may be
warranted as pain may promote noncompliance with the prescribed
regimen. Improving the child’s level of fitness may help with sleep
promotion and improve his or her general sense of well-being. Bulbena
and others have reported an association between hypermobility and
anxiety disorder in adults and believe that the tissue disorder is a
predisposing factor for trait anxiety.251–253 Even in children without
hypermobility who have chronic musculoskeletal pain, cognitive-
behavioral and, if necessary, pharmacologic interventions which reduce
catastrophizing and panic and promote coping are often appropriate.
Disordered sensory processing has been identified in many individuals
with widespread musculoskeletal pain. Regardless of its origin,
anticonvulsants and/or antidepressants may have a role in dampening
central sensitization and therefore in the management of chronic
musculoskeletal pain. Eccleston and colleagues254 report on the success of
their multidisciplinary program emphasizes family oriented CBT, physical
activity, goal setting, pacing, relaxation, and communication.255,256 As
with other chronic pain problems, a holistic rehabilitation approach to
musculoskeletal pain appears to have better outcomes than a
unidimensional one.

COMPLEX REGIONAL PAIN SYNDROMES

CRPS1, also known as reflex sympathetic dystrophy (RSD), involves limb
pain with neuropathic descriptors (allodynia, paresthesias, dysesthesias)
and variable combinations of neurovascular disturbances (coldness,
mottling, nonarticular swelling, cyanosis or rubor, delayed capillary refill),
sudomotor disturbances, motor abnormalities (spasms, dystonia, “jumping
movements”), and trophic changes, including atrophy, abnormal hair

2909
growth, or joint contractures. Where these findings occur with clinical
signs of injury to a nameable nerve trunk, the terms CRPS2 or causalgia
are used. For purposes of the current discussion, we use the term
RSD/CRPS to refer to these disorders inclusively.
CRPS in children and adolescents has distinct epidemiologic features. It
is much more common in girls than boys, it is uncommon before age 6
years, the apparent onset is most common from around ages 10 to 12
years, and the lower extremities are affected much more commonly than
the upper extremities.257
For a majority of children with CRPS, an effective treatment program
emphasizes patient and parent education about the nonprotective character
of the pain, intensive rehabilitation that involves active exercise,
resumption of weight-bearing, desensitization, and psychological
interventions based primarily on individual and family-based CBT. For
some children, this can be accomplished on an outpatient basis.177 For
others who fail to improve with outpatient treatment, a next step is to do
this type of multidisciplinary rehabilitation program in an inpatient or
intensive day-hospital program.176
In adult pain medicine practice, at least in the United States, there is a
considerable emphasis on early use of nerve blocks and other invasive
approaches, especially sympathetic nerve blocks; spinal cord stimulation;
operative, chemical, or radiofrequency sympathectomies; and, more
recently, intravenous ketamine infusions in the treatment of RSD/CRPS. In
our view, these approaches are not evidence-based in adults, and they are
even less supported by evidence for children and adolescents. In a previous
case series, even though some of the patients did receive regional
anesthetic interventions and even though some reported benefit, there was
no clear association between the duration of symptoms prior to blockade
and the eventual benefit.258
Some pediatric case series report marked improvement in function and
pain scores with no use of nerve blocks.176 Overall, most case series
suggest a good long-term prognosis for the majority of children and
adolescents with CRPS. Hence, in our view, the initial therapeutic
approach should be to emphasize intensive rehabilitation whenever
possible.

2910
 We do make selective use of regional anesthetic approaches for patients
who fail to progress despite a very good rehabilitation program and for
selected patients with very severe limb swelling, dystonia, or very limited
limb movement. In general, our preference is to use combined somatic–
sympathetic blockade using continuous catheter approaches rather than
selective sympathetic blockade or other repeated single-shot blocks. For
lower extremity CRPS confined to a stocking distribution in the lower leg,
our practice is to place continuous popliteal fossa sciatic perineural
catheters under combined ultrasound–nerve stimulation guidance.259
For lower extremity involvement in a wider distribution, we place an
epidural catheter using fluoroscopy and/or nerve stimulation guidance to
ensure proper dermatomal level and sidedness. For upper extremity CRPS,
brachial plexus catheters are placed in either supraclavicular or
infraclavicular sites using combined ultrasound and nerve stimulation
guidance. For all forms of continuous regional anesthesia, catheters are
placed with meticulous attention to sterile technique in the operating room,
and they are tunneled to facilitate skin care and to reduce the chances for
dislodgment. Prophylactic antibiotics are used. Patients are typically
admitted to the hospital for infusions and intensive rehabilitation for
periods of 5 to 8 days. Although outpatient rehabilitation assisted by
peripheral blockade has been described, in our view, there is merit to
inpatient admission to optimize intensive rehabilitation during the course
of the infusions. In addition, our preference is to run higher infusion rates
at nighttime and lower rates during the day to facilitate “cycle-breaking” at
night and active mobilization during the day.
Evidence is lacking for efficacy of many types of analgesic medications
commonly prescribed for adults with CRPS. Pediatric data are limited to
case reports and uncontrolled case series. We do try tricyclic
antidepressants and anticonvulsants for many of these patients. Responses
are inconsistent.

BACK PAIN
Back pain is very common in adults and a major contributor to absence
from the workplace. Persistent back pain is relatively common in
adolescents but uncommon in younger children, and in younger children,

2911
its occurrence mandates earlier consideration of a range of diagnostic
possibilities, including infections (osteomyelitis, pyelonephritis,
intervertebral discitis), tumors, and congenital anomalies of the spine and
central nervous system (tethered spinal cord, diastematomyelia).260,261
In specialist referral practice, back pain in adolescents is commonly
seen in athletes, dancers, gymnasts, and cheerleaders and in children who
are significantly overweight. For many patients with features suggestive of
muscular pain and a normal neurologic exam, initial treatment should
emphasize resumption of daily activities, a moderate exercise program
including core stabilization and postural exercises, and avoidance of high-
impact, high-velocity, or repetitive stresses on the spine. For patients with
significant obesity, dietary counseling may be appropriate. Axial low back
pain that worsens with back extension is commonly seen with
spondylolysis and spondylolisthesis.262,263 There is some support for
bracing in the treatment of these conditions.264
Symptomatic lumbar disk disease is uncommon in children and
relatively less common in adolescents. In our referral practice, lumbar disk
disease is most commonly seen in adolescent athletes. There is an
extensive literature on the advantages and disadvantages of operative
treatment for lumbar radiculopathy in adults; pediatric literature is mostly
limited to relatively small case series and, with few exceptions, to
relatively short-term follow-up. We recently reviewed experience with
fluoroscopically guided epidural steroid injections for lumbar
radiculopathy in children and adolescents. A majority of patients reported
reductions in pain and improvements in straight-leg raising, and the safety
profile was excellent. In 2- to 5-year follow-up, less than 40% of patients
in this case series came to discectomy.265

HEADACHE
Systematic review of pediatric headache burden found that 58% of
children experience a headache at some time in childhood.245,266
Differentiating whether the pediatric headache is primary or secondary is
critical in its evaluation.267 Primary headaches include migraine, tension-
type headache, and cluster headaches. They are classified by their features
as compared to secondary headaches which are classified by the

2912
underlying disorder responsible for them. Secondary headaches are those
attributed to head and neck trauma; intracranial vascular and nonvascular
disorders; substance administration or withdrawal; infection; or pain
associated with disorders of the eyes, cranium, ears, sinuses, or teeth. Red
flags in the history which suggest secondary headache are sudden onset of
a severe headache, neurologic symptoms such as ataxia, lethargy, seizures,
visual impairments, associated symptoms such as depressed mood or aura,
headache associated with systemic illness such as hypertension and
sinusitis, new headache type in a patient with cancer or human
immunodeficiency virus, sudden onset of the “worst headache in your
life,” headaches associated with straining, change in a headache pattern, or
headache in a child under 3 years old. Positive answers to these questions
clearly demand additional investigation as well as imaging studies.268–270
Primary headaches in children are more often a continuum that may
change with age rather than a discrete entity.271–276 Zebenholzer and
colleagues274 found that in a 1.5-year period, 30% of children were
headache-free, 20% had swapped headache type, and 50% continued
having the same type of headache. Such fluidity makes diagnosis and
treatment complex. Criteria for the diagnosis of migraine in children
require five or more headaches that last between 1 and 48 hours (shorter
duration than in adults), are bilateral or unilateral, have a throbbing or
pounding quality, and are aggravated by physical activities. They are
typically accompanied decreased appetite, nausea, vomiting, and
photophobia and phonophobia.277 Tension headaches are typically
categorized by their frequency: episodic (< once monthly), frequent
(greater than once per month but <15 days per month), and chronic daily
headache (>15 days per month). These headaches are typically mild to
moderate pain, “band-like” pressure around the head, bilateral, not
pulsating, not aggravated by physical activity, without nausea, vomiting,
photophobia, or phonophobia. Precipitating factors may include illness,
stress, and muscular tension.
Once the secondary causes of headache have been excluded, the general
approach to primary headache treatment is similar to other primary chronic
pains—a multidisciplinary approach, consisting of cognitive-behavioral
approaches, physical therapy modalities with thoughtful use of

2913
medications in an overall attempt to regain function and improve pain
coping abilities. Maintaining a regular routine and regular exercise is
helpful.278 Limited evidence supports a specific diet or dietary exclusion,
although there may well be individuals for whom food is an important
trigger.272 Overall, SMART (Sleep, Meals, Activity, Relaxation, Trigger
avoidance) lifestyles changes are recommended.279
Behavioral interventions are effective at reducing headache burden
regardless of the headache type. These include biofeedback, progressive
muscle relaxation, distraction, and hypnosis. In a systematic review of the
RCTs of psychological interventions for chronic pain (12 headache and 1
recurrent abdominal pain trial), Eccleston and colleagues182 reported the
odds ratio for a 50% reduction in pain was 9.62, indicating the success of
psychological interventions.
Pharmacologic treatment of pediatric headache is divided into abortive
and preventative treatment. Early intervention is an essential feature of
successful abortive treatment of migraine or tension headache. Early
hydration, ibuprofen, naproxen, and acetaminophen are often effective. For
more severe headache, NSAIDs combined with acetaminophen and/or
caffeine should be tried. Triptans (5-HT-1 receptor inhibitor) such as
sumatriptan nasal spray in the appropriate circumstances can be considered
for severe headache. Oral triptans have also been studied in children.
Rizatriptan can be used in children >6 years old and almotriptan, a
combination of sumatriptan and naproxen in adolescents greater than 12
years old is approved.280,281
Regarding preventive therapy, it is recommended that patients with
disabling headache greater than 4 days a month be considered for daily
preventative therapy. Initiation of these medications should be done with
the guidance that they will take 6 to 12 weeks to become effective. With
this said, few medications have been studied in randomized controlled
studies in pediatric populations. Of them, topiramate, tricyclic
antidepressants such as amitriptyline, nortriptyline, and β-blocker,
propranolol, are used.281 More recent evaluation by the Childhood and
Adolescent Migraine Prevention (CHAMP) study did not detect a
difference between topiramate, amitriptyline, or placebo.282
There is emerging literature on the use of specific vitamins and minerals

2914
for headache prevention. High-dose riboflavin, B2 (400 mg per day), has
been found to reduce migraine frequency and appears safe.282,283
Magnesium has been shown to reduce headache frequency.282,284
Melatonin may be beneficial in the ability to initiate sleep and promote
improved lifestyle.
In summary, there is convincing evidence that cognitive-behavioral
approaches are beneficial in primary pediatric headaches, regardless of
etiology. The evidence on abortive and preventative medications is not
limited, but a number of analgesics, 5-HT receptor agonists,
anticonvulsants, antidepressants, and β-blockers have been shown to be
somewhat effective in children.

FUNCTIONAL GASTROINTESTINAL PAIN

Chronic abdominal pain is defined as long-lasting intermittent or constant
abdominal pain with either functional or organic etiology. Chronic
abdominal pain accounts for 2% to 4% of all pediatric office visits and is
one of the most common complaints in children.285 Red flags for organic
disease include pain that awakens the child from sleep, nocturnal diarrhea,
persistent vomiting, weight loss, persistent right upper or lower quadrant
pain, or dysphagia and should prompt a referral to a gastroenterologist.
Adolescent females presenting with chronic abdominopelvic pain should
be evaluated for gynecologic causes, such as endometriosis particularly
those with GI symptoms and dysmenorrhea or irregular uterine bleeding.
Evaluation and management of endometriosis includes hormonal and
surgical intervention while incorporating a multidisciplinary approach for
chronic symptoms, including neuropathic agents, physical therapy, and
cognitive-behavioral strategies.286–289
If the history and physical examination do not suggest underlying
pathology, more than likely, the patient has one of the pain predominant
FGIDs. FGIDs refer to a group of disorders that are diagnosed according
to the Rome IV criteria when symptoms cannot be explained by
inflammatory, anatomic, metabolic, or neoplastic processes.290 FGIDs are
the most common cause of abdominal pain in children and adolescents
worldwide.285 The associated term functional abdominal pain has been
replaced by central mediated abdominal pain syndrome (CAPS) central

2915
sensitization with disinhibition of pain signals as opposed to increased
peripheral afferent excitability.291 Children with chronic abdominal pain
have lower quality-of-life measures compared with healthy peers and at
risk for school absences, social isolation, depressive disorders, and
increased somatic complaints.292,293 Williams and colleagues294
demonstrated this in preadolescent females with IBS when compared to
healthy peers by showing an impaired endogenous inhibition of somatic
pain. As previously stated, CAPS in childhood and adolescence increased
the risk for a chronic primary pain disorder in adulthood.295,296
In addition to the general strategies for addressing chronic pain,
evidence supports the efficacy of famotidine, pizotifen, CBT, biofeedback,
and peppermint oil enteric-coated capsules.218 For functional dyspepsia,
they suggested treatment with antisecretory agents such as H2 blockers or
proton pump inhibitors is appropriate for pain predominant symptoms,
whereas prokinetics seem appropriate for symptoms dominated by
discomfort such as bloating. For IBS, peppermint oil is suggested, and
when IBS is diarrhea-predominant, the use of antibiotics to treat bacterial
overgrowth is recommended. Antidepressants and serotonergic agents had
limited support in pediatrics despite their efficacy in adults. For abdominal
migraine, avoidance of potential triggers such as caffeine was advised.
Treatment with the preventative agents used for migraine (cyproheptadine,
sumatriptan) are appropriate when paroxysms are frequent. Functional GI
pain syndrome, reduction of psychosocial stressors, and behavioral
treatment are effective for management.267,275,297–300 Dietary interventions
low in fermentable carbohydrates and polyols (FODMAP) and high in
fiber incorporated treatment are effective in subgroups of patients reducing
bloating and improving stool pattern.275,301

Barriers to Care
Most health care systems are stymied by the complicated care necessary to
address the issues raised by children with chronic pain. The family’s
search for a satisfying answer may cause them to solicit multiple opinions
for the pain problem. Additionally, children with chronic pain often report
pain in more than one site and, as a result, multiple specialists are often

2916
involved in their care, each one focusing on one particular pain complaint.
For example, headache and abdominal pain are frequent fellow travelers.
The family may seek the opinion of a neurologist for the headache and a
gastroenterologist for the abdominal pain. They may seek out alternative
providers such as chiropractors, acupuncturists, or naturopaths as well.
Laboratory and imaging studies are frequently performed in multiple
settings. The primary care provider who typically provides care
coordination must collate the records, reconcile often disparate opinions,
be alert to the possibility of interactions among the drugs prescribed by the
myriad of involved physicians, and be on the front line to address each
new symptom and concern without overmedicalizing it. Care coordination
is, therefore, a critical time-consuming and often unreimbursed aspect of
the care for children with chronic pain, and its absence is a barrier to
adequate treatment.
Another problem is the lack of facilities and practitioners capable of
addressing both the biologic and psychological dimensions of chronic
pain. In the outpatient arena, few individuals are comfortable addressing
both realms, and multidisciplinary teams, an alternative, are often not
viable economically. Inpatient facilities are rarely geared to individuals
who may have both psychological and physical problems. A busy inpatient
unit with desperately ill children is not the appropriate setting for a child
with chronic pain, as it tends to overmedicalize the problem. Likewise, the
typical psychiatric ward is often unprepared to deal with the patient who is
moaning in pain and may have an as yet undiagnosed medical illness.
Finally, the inherent vagueness and poignancy of the symptom of
persistent pain often leads families to seek out additional opinions and to
feel that their search is never quite completed. This can create uneasiness
between provider and patient which may interfere with the therapeutic
alliance.

Conclusion
Persistent pain is a relatively common experience for children and may
stem from a variety of causes: ongoing organic disease, persistence of pain
which resulted from organic disease, as well as disorders whose primary

2917
manifestation is pain. Regardless of its origin, however, it has significant
impact on the child and his or her family. In general, the goal of the
clinician is to identify red flags for organic disease and, if not present,
focus on symptom reduction and increasing function. Specific attention
should be given to sleep, mood, school, activity, and family functioning.
Typical interventions include analgesia, physical therapy, cognitive-
behavioral strategies, and other medications targeted to specific symptoms.
Success in the management of chronic pain should be monitored by
improvement in function and not specifically through immediate reduction
in pain intensity.

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242. Smith MT, Finan PH, Buenaver LF, et al. Cognitive-behavioral therapy for insomnia in knee
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243. Palermo TM, Beals-Erickson S, Bromberg M, et al. A single arm pilot trial of brief cognitive
behavioral therapy for insomnia in adolescents with physical and psychiatric comorbidities. J
Clin Sleep Med 2017;13(3):401–410.
244. Evans JR, Benore E, Banez GA. The cost-effectiveness of intensive interdisciplinary pediatric
chronic pain rehabilitation. J Pediatr Psychol 2016;41(8):849–856.
245. King S, Chambers CT, Huguet A, et al. The epidemiology of chronic pain in children and
adolescents revisited: a systematic review. Pain 2011;152:2729–2738.
246. Malleson PN, Beauchamp RD. Rheumatology: 16. Diagnosing musculoskeletal pain in
children. CMAJ 2001;165:183–188.
247. Karaaslan Y, Haznedaroglu S, Oztürk M. Joint hypermobility and primary fibromyalgia: a
clinical enigma. J Rheumatol 2000;27:1774–1776.
248. Fitzcharles MA. Is hypermobility a factor in fibromyalgia. J Rheumatol 2000;27:1587–1589.
249. Keer R, Grahame R. Hypermobility Syndrome: Recognition and Management for
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250. Clinch J, Eccleston C. Chronic musculoskeletal pain in children: assessment and management.
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251. Bulbena A, Duro JC, Porta M, et al. Anxiety disorders in the joint hypermobility syndrome.
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252. Bulbena A, Agulló A, Pailhez G, et al. Is joint hypermobility related to anxiety in a
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253. Martín-Santos R, Bulbena A, Porta M, et al. Association between joint hypermobility
syndrome and panic disorder. Am J Psychiatry 1998;155:1578–1583.
254. Eccleston C, Malleson PN, Clinch J, et al. Chronic pain in adolescents: evaluation of a
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255. Sherry DD, Brake L, Tress JL, et al. The treatment of juvenile fibromyalgia with an intensive
physical and psychosocial program. J Pediatr 2015;167:731–737.
256. Kashikar-Zuck S, Flowers SR, Strotman D, et al. Physical activity monitoring in adolescents
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257. Wilder RT. Management of pediatric patients with complex regional pain syndrome. Clin J
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258. Wilder RT, Berde CB, Wolohan M, et al. Reflex sympathetic dystrophy in children. Clinical
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259. Dadure C, Motais F, Ricard C, et al. Continuous peripheral nerve blocks at home in the
treatment of recurrent complex regional pain syndrome I in children. Anesthesiology
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260. Jones GT, Watson KD, Silman AJ, et al. Predictors of low back pain in British schoolchildren:
a population-based prospective cohort study. Pediatrics 2003;111(4 pt 1):822–828.
261. Pellisé F, Balagué F, Rajmil L, et al. Prevalence of low back pain and its effect on health-
related quality of life in adolescents. Arch Pediatr Adolesc Med 2009;163(1):65–71.
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causes and patterns. Arch Pediatr Adolesc Med 1995;149(1):15–18.
263. Purcell L, Micheli L. Low back pain in young athletes. Sports Health 2009;1(3):212–222.
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266. Abu-Arafeh I, Razak S, Sivaraman B, et al. Prevalence of headache and migraine in children
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267. Headache Classification Subcommittee of the International Headache Society. The
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268. Lipton RB, Bigal ME, Steiner TJ, et al. Classification of primary headaches. Neurology
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270. Carville S, Padhi S, Reason T, et al. Diagnosis and management of headaches in young people
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272. Lewis DW. Headaches in children and adolescents. Am Fam Physician 2002;65:625–632.
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274. Zebenholzer K, Wober C, Kienbacher C, et al. Migrainous disorder and headache of the
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275. Vanuytsel T, Tack JF, Boeckxstaens GE. Treatment of abdominal pain in irritable bowel
syndrome. J Gastroent 2014;49(8):1193–1205.
276. Turner DP, Smitherman TA, Black AK, et al. Are migraine and tension-type headache
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277. Winner P, Wasiewski W, Gladstein J, et al. Multicenter prospective evaluation of proposed
pediatric migraine revision to the HIS criteria. Pediatric Headache Committee of the American
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278. Marcus DA. Reducing headache disability in children and adolescents. Am Fam Physician
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279. Youssef NN, Murphy TG, Langseder AL, et al. Quality of life for children with functional
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280. Saki F. Oral triptans in children and adolescents : an update. Curr Pain Headache Rep
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281. Patniyot IR, Gelfand AA. Acute treatment therapies for pediatric migraine: a qualitative
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283. Schoenen J, Jacquy J, Lenaerts M. Effectiveness of high dose riboflavin in migraine
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284. Peikert A, Wilimzig C, Köhne-Volland R. Prophylaxis of migraine with oral magnesium:
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285. Korterink JJ, Diederen K, Benninga MA, et al. Epidemiology of pediatric functional
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286. Powell J. The approach to chronic pelvic pain in the adolescent. Obstet Gynecol Clinics North
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287. Siristatidis C, Nissotakis C, Chrelias C, et al. Immunological factors and their role in the
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288. Stratton P, Berkley K. Chronic pelvic pain and endometriosis: translational evidence of the
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289. Jarrell J. Endometriosis and abdominal myofascial pain in adults and adolescents. Curr Pain
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290. Palsson OS, Whitehead WE, van Tilburg MA, et al. Rome IV Diagnostic Questionnaires and
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292. Dengler-Crish CM, Horst SN, Walker LS. Somatic complaints in childhood functional
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adulthood. J Pediatr Gastroenterol Nutr 2011;52:162–165.
293. Dengler-Crish CM, Bruehl S, Walker LS. Increased wind-up to heat pain in women with a
childhood history of functional abdominal pain. Pain 2011;152:802–808.
294. Williams AE, Heitkemper M, Self MM, et al. Endogenous inhibition of somatic pain is
impaired in girls with irritable bowel syndrome compared with healthy girls. J Pain
2013;14:921–930.
295. Stabell N, Stubhaug A, Flaegstad T, et al. Widespread hyperalgesia in adolescents with
symptoms of irritable bowel syndrome: results from a large population-based study. J Pain
2014;15:898–906.
296. Walker LS, Dengler-Crish CM, Rippel S, et al. Functional abdominal pain in childhood and
adolescence increases risk for chronic pain in adulthood. Pain 2010;150:568–572.
297. Rasquin A, Di Lorenzo C, Forbes D, et al. Childhood functional gastrointestinal disorders:
child/adolescent. Gastroenterology 2006;130(5):1527–1537.
298. Di Lorenzo C, Colletti RB, Lehmann HP, et al; and American Academy of Pediatrics
Subcommittee on Chronic Abdominal Pain, North American Society for Pediatric
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North American Society for Pediatric Gastroenterology, Hepatology and Nutrition. J Pediatr
Gastroenterol Nutr 2005;40:245–261.
299. Hoekman DR, Zeevenhooven Z, van Etten-Jamaludin FS, et al. The placebo response in
pediatric abdominal pain-related functional gastrointestinal disorders: a systematic review and
meta-analysis. J Pediatr 2017(182):155–163.
300. Teitelbaum JE, Arora R. Long-term efficacy of low-dose tricyclic antidepressants for children
with functional gastrointestinal disorders. J Pediatr Gastroenterol Nutr 2011;53(3):260–264.
301. Horvath A, Dziechciarz P, Szajewska H. Systematic review of randomized controlled trials:
fiber supplements for abdominal pain-related functional gastrointestinal disorders in
childhood. Ann Nutr Metab 2012;61(2):95–101.

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CHAPTER 55
Pain in the Older Person
PAUL M. ARNSTEIN and KEELA HERR

Overview
Medical science continues to expand its capacity to forestall death. As a
result, people are living longer but increasingly spend their final years with
daily, unrelenting pain.1–3 Pain is emerging as a more formidable foe than
death, whose conquest will demand stretching the limits of our technology
and ability to provide compassionate care. Because of its increasing
incidence, high economic costs, and negative impact on quality of life of
patients and their families, uncontrolled pain has become a public health
priority.2,4
Dramatic increases in people over age 65 years globally suggest that
older adults will challenge the capacity of health systems with the
complexity of multiple conditions contributing to pain and its sequelae.
Estimates indicate that by 2050, older adults will comprise a third of the
population in developed countries.5 Although not all older adults have
severe or ongoing pain, a majority do when they seek health care services.
Chronic back and neck pain are the leading cause of disability worldwide,
and the prevalence of chronic pain–producing diseases like arthritis,
diabetes, and cancer continues to increase.6 Older adults have the highest
rates of surgery, hospitalization, injury, and disease, which increases their
risk of pain.7 The problem of pain in older adults has not diminished even
though evidence to guide pain assessment and management has grown
over the past decade.

THE PREVALENCE OF PAIN IN OLDER ADULTS

Although pain is not an inevitable aspect of aging, older persons are at
greater risk for many disorders associated with pain. Delineating the
prevalence of pain with advancing age is a challenge because

2933
epidemiologic studies differ in the age cut points, methods of data
collection and measurement of pain, and the types of pain studied.
However, data across settings and samples suggest that pain is prevalent
and a significant factor impacting quality of life. Approximately 65% of
older persons living in the community have persistent pain* conditions8,9
with more frequent pain (up to 85%) noted in those living in institutions,
particularly nursing homes,10,11 and those in the final months of life (over
80%).12,13 Prevalence of pain in hospitalized older adults is also high with
67% on geriatric units reporting pain present.14
A nationally representative sample of American adults showed back,
knee, and shoulder as the most prevalent pain sites in those 65 to 69 years
old, with little change in this pattern in cohorts of those 90 years old or
older.8 Over 60% of older adults report pain in multiple locations with
women reporting more pain sites and a greater intensity of pain than male
counterparts,15,16 which impacts physical and psychosocial function. Older
women and those with obesity, musculoskeletal conditions, and depressive
symptoms are at higher risk for pain.8
Other common conditions associated with pain in older persons include
atherosclerotic peripheral vascular disease, herpes zoster, trigeminal
neuralgia, diabetic neuropathy, temporal arteritis, polymyalgia rheumatica,
osteoporosis with vertebral compression fractures, lumbar spinal stenosis,
and fibromyalgia.17 Also, injuries, such as hip fractures resulting from
falls, are more common in this population and may result in both acute and
chronic pain.

Pain in the Older Person

IMPACT OF PAIN ON FUNCTIONING AND QUALITY
OF LIFE
Pain in the older adult interferes with the ability to manage and recover
from health challenges given its important and often unrecognized impact
on impaired function and quality of life.18 Acute and persistent pain have
adverse health outcomes in older people.19 Poorly managed acute pain
contributes to delayed ambulation, increased incidence of delirium and
cognitive dysfunction, respiratory complications, longer hospitalization,

2934
and mood disorders.20 Additionally, long-term consequences include
impaired ability to complete activities of daily living (ADL), impaired
mobility development of persistent pain, and cardiovascular disease.19,21,22
More widely studied, persistent pain is known to negatively impact
older adult physical and psychosocial function, including impaired
nutrition and sleep, functional abilities, mood and cognitive function, and
social interactions.23–25 Pain from osteoporosis, osteoarthritis, and chronic
back pain has been shown to significantly affect ADL, placing the older
adult at risk for declining health and potentially institutionalization.26,27
According to Hunt et al.,9 43% of those with dementia are able to
acknowledge and self-report significant functional limitations, including
the ability to perform ADL.
Combined with impaired physical health, the decline in social and
recreational activities produces emotional distress, contributing to
depression,8,28 which is capable of worsening both pain and disability.29
Pain-related factors that worsen health-related quality of life include pain
presence, pain severity, and number of pain sites.6,10,25,30–32 Persistent
pain also is associated with frailty, a syndrome of physiologic decline, and
should be a component assessed when determining frailty phenotype to
improve the prediction of adverse outcomes.33

UNDERTREATMENT OF PAIN IN OLDER PERSONS

Given these potentially serious pain-related consequences, evidence that
pain is commonly undertreated or untreated in older adults is disturbing.
Among those with pain, a significant portion of those over age 65 years do
not receive analgesics or receive inadequate treatment, including 53% of
elders transitioned from acute to skilled nursing care,34 17% to 65% of
institutionalized elders,10,11,35 51% of elders admitted to emergency
departments with pain complaints,20,36 and 20% of elders living with pain
in the community.37 Older patients in emergency departments are more
likely to experience delays in analgesic treatment and have acute pain
undertreated compared to younger patients.38 Pain, depression, and
functional limitations due to pain are particularly undertreated in low-
income and minority older populations.39
The diagnosis and treatment of pain in older persons is more difficult in

2935
those who present with multiple medical problems and a history that
reveals many potential sources of pain. Although there is an undeniable
need to prevent harm from pain-relieving treatments, this focus must be
balanced with a concerted effort to avoid pain-induced harm. Guidelines
for the assessment, treatment, and monitoring of older patients with pain
have been widely distributed advocating for individualized approaches to
pain and balancing concerns for the safety and efficacy of treatments.40–42
It is time to replace unrealistic fears and mistaken beliefs with
guidelines that delineate prudent, safe, effective use of available
treatments. Approaches to managing pain in older adults should
incorporate noninvasive treatments, along with tailored pharmacologic
management, based on a careful risk/benefit analysis of treatment options
and the older person’s unique characteristics and goals.43

CHANGE IN PAIN PROCESSING AND MODULATION

Mounting evidence suggests that strong unrelenting pain changes the
structure and function of nerves that create widespread degenerative
alterations in brain functioning,44,45 which may explain the learning,
memory, and emotional difficulties experienced by older adults with
persistent pain.46 Physiologically, aging alters functions, including a
degeneration of peripheral neuronal structures, which slow transduction
and transmission involved in signaling pain.47 These changes may result in
a slowed pain response, but aging does not decrease sensitivity to pain,
which may actually increase with age.48 Once pain is established, the
lower density of descending inhibitory circuits and an impaired ability to
recover from hyperalgesic states are attributed to aging.49 Although some
of these changes are partially reversible with effective treatment,50,51
changes in endogenous pain modulation increase older adults’ risk for
developing persistent pain following an illness, surgery, or trauma.52
Concerns arise regarding how pain processes, including judgment of its
presence and severity, is experienced in those with dementia. Although
research is mixed, recent studies suggest persons with Alzheimer disease
are less sensitive to the detection of thermal pain but do not differ in
affective response to unpleasant stimuli, contributing to greater pain and
potential damage before identifying and reporting pain.53 Thus,

2936
cognitively impaired older adults are able to feel painful stimuli54 and may
have heightened pain sensitivity.55 Assuming that older adults, particularly
those with cognitive impairment, experience less pain makes them
vulnerable to undertreatment of pain and its consequences.56,57 Although
there are instances of atypical presentations of clinical pain in older adults
(e.g., silent myocardial infarctions and the absence of abdominal pain with
peptic ulcer disease), these exceptions should not be used to suggest that
older adults, particularly those with cognitive impairment, feel less pain.

Assessment of Pain in the Older Person

CLINICAL EVALUATION OF PAIN
A comprehensive approach to assessment is necessary when evaluating
pain in older adults and developing an effective treatment approach,
including identification of the underlying cause of pain, pain
characteristics, and impact on physical and psychosocial function and
quality of life.58 The scope and nature of the pain assessment will depend
on a number of factors such as the physiologic stability of the patient,
whether the situation is an emergency or planned event, and the severity of
the presenting pain complaint. If the older adult presents in moderate to
severe acute pain (e.g., greater than 4 on a 0-to-10 numeric rating scale),
the first priority is to complete an initial, rapid pain assessment and treat
the pain.40,59 Once the older person’s pain is alleviated, a comprehensive
pain assessment should be completed.
As with younger patients, self-report of pain is the criterion standard for
determining pain presence and severity. The numeric rating scale, verbal
descriptor scale, and faces pain scale are the most established tools for the
alert, cognitively intact older adults.60 The Iowa Pain Thermometer
demonstrated comparable results to these scales and is most preferred by
many older adults.61,62 Cultural differences in tool understanding and
preference also inform the need to solicit individual tool preferences.63,64
These scales can be used more effectively in older persons by addressing
sensory deficits (uses eyeglasses, hearing aids, large font/bold print written
tools, etc.). Cognitive impairment can result in underreporting of pain;
however, recent studies document that standard assessment techniques can

2937
be used effectively in older adults with mild to moderate cognitive
impairment.65,66 It is useful to adopt more than one validated tool for use
in clinical settings to accommodate needs and preferences of different
older patients. All team members (including caregivers) need to use the
tool that patient prefers consistently for all pain assessments.
As a multidimensional experience, pain evaluation includes intensity,
affect (how bothersome, distressing and effect on mood), sensory qualities
(such as aching, stabbing, burning), spatial quality (e.g., location),
temporal quality (including pattern and duration), and impact on or
interference with daily activities (including physical and psychosocial
functioning).17 Multiple biopsychosocial factors (e.g., anxiety, depression,
beliefs, insomnia, fear avoidance, biomechanical issues) contribute to the
experience of pain and should be evaluated for their contribution to
impairment or dysfunction.67 Evidence of pain impact includes disrupted
social and family relationships, changes in eating and sleeping patterns,
and altered mood and ability to continue previous activities. Determining
the impact of pain on the older adult’s life requires gathering information
on key quality of life variables from different sources, including the older
adult, significant others, other health care workers, roommates, and
activity therapists. The Brief Pain Inventory (BPI) is useful in many
settings because it records dimensions of pain in addition to intensity (e.g.,
interference with functionality).68 Other tools are available that gather data
on pain and its impact in a clinically useful manner, including one called
the PEG, that examines three BPI items of Pain intensity, Enjoyment in
life, and General activity.68
Expanded assessments including the underlying conditions known to be
painful and comorbid diseases, the desired and undesired effects of prior
and current pain treatments, and current medications (including over-the-
counter drugs) provide important information to guide treatment planning.
A complete physical examination of the pain source, including potential
pain contributors such as leg length discrepancy and myofascial pain,
focuses on the most common sources of pain: the musculoskeletal,
peripheral vascular, and neurologic systems. Laboratory tests to determine
renal and hepatic functioning may be indicated, but diagnostic tests should
be used sparingly given that more than half of older patients with

2938
radiographic evidence of degenerative joint disease are pain-free and
imaging studies are often not necessary or useful.69
For a comprehensive review of pain assessment, the reader is referred to
the clinical practice guidelines on acute and persistent pain available
through the University of Iowa Csomay Center for Gerontological
Excellence (http://www.iowanursngguidelines.com).41,70

NONVERBAL, COGNITIVELY IMPAIRED OLDER

ADULTS
When the patient is unable to reliably self-report the presence or nature of
pain due to severe cognitive impairment or critical illness, clinicians rely
on a combination of assessment strategies to fill this void. An approach for
recognizing pain in nonverbal older adults includes a process of data
gathering that includes (1) attempting self-report, (2) identifying
pathologic conditions or procedures that usually cause pain, (3) identifying
behaviors associated with pain, (4) obtaining input from a family member
or others knowledgeable of the older adult, and (5) attempting an analgesic
trial to verify that suspected behaviors are pain-related.58
Even if the patient is unconscious, intubated, or chemically paralyzed,
the clinician’s understanding of the pain typically associated with the
medical conditions/procedures allows them to make assumptions about the
presence of pain and guide pain prevention and treatment interventions
regardless of cognitive/verbal abilities. A good history and physical
examination provides information on pain-related diagnoses and
conditions that support a judgment of pain present.
Directly observable behaviors, such as grimacing, moaning, guarding,
bracing, and posturing as well as those less common such as agitation,
aggression, restlessness, resisting care, and changes in usual behavior
patterns, are recognized as important indicators of pain in those who
cannot communicate their pain verbally.71,72 Among the behaviors
displayed by people unable to communicate their pain, facial expression is
being recognized as a common and essential element of the behavioral
assessment.71,73 A large number of behavioral pain assessment tools have
been developed for use in this population. Systematic reviews have
evaluated the strengths and limitations of existing behavioral tools

2939
reaching similar conclusions that there is no single tool appropriate for all
patients and settings.74 Updates on existing tools and psychometric
properties, as well as recommendations for use, are available.54,75
Research is ongoing to refine pain behavior indicators and tools to advance
clinically useful methods of pain evaluation in this challenging
population.76
Evidence from any of the aforementioned steps can inform clinician
judgment and decision making about pain presence in the older person
with advanced dementia. Use of an analgesic trial has shown positive
effects in improving disturbing and distressing behaviors,77 confirming
underlying pain etiologies. Pain treatment planning is often oversimplified,
expecting patients to respond similarly to the same noxious stimuli and
therapeutic intervention. This may work with mild, fleeting pain, but when
pain is severe and/or persistent, developing a safe, effective plan needs to
be tailored to the patient’s unique perceptions, capabilities, comorbid
conditions, and responses. The initial goal of any pain treatment plan is to
find and eliminate its source if possible and then balance concerns for pain
reduction, functional improvement, and avoidance of treatment-related
harm. Frequent, ongoing reassessments enhance understanding of the
patient’s unique pain and response to therapy and refinements need to
ensure optimal safety and effectiveness.

Pharmacologic Treatment of Pain in Older Persons

PHARMACOKINETICS AND PHARMACODYNAMICS
ASSOCIATED WITH AGING
With the exception of the rectal route, the rate of medication absorption is
not typically affected by aging. The pattern of drug distribution does
change because of less total body water and more body fat seen in many
older adults. This favors the distribution and accumulation of lipophilic
(fentanyl) agents while decreasing that of hydrophilic (morphine) drugs.
The decline in serum protein concentrations with age can increase the
bioavailability of drugs, like nonsteroidal anti-inflammatory drugs
(NSAIDs), that are highly protein-bound.78 This effect is magnified in
frail, protein-depleted older adults79 and patients taking multiple

2940
medications that displace NSAIDs from protein-binding sites.
The metabolism and excretion of NSAIDs is often compromised due to
the smaller size, lower blood flow, and reduced function of the liver with
age. These hepatic changes combined with fewer drug-metabolizing
enzymes, increase drug elimination time, and slow the metabolism
required to produce active metabolites. Reductions in renal size,
glomerular filtration rate, and renal blood flow raise the risk of side effects
and toxicity from slowed elimination of the drug and active and toxic
metabolites.80 NSAIDs can further contribute to this slowed clearance by
lowering renal blood flow and glomerular filtration rate through its
antiprostaglandin effect.
Pharmacodynamic changes with aging increase sensitivity to both the
desired and undesired effects of opioids.81 Combined with other age-
related changes in the neurologic and pulmonary systems, there is a greater
risk of sedation, sleep apnea, and respiratory depression with opioid
analgesics.82 Combined, these pharmacokinetic and pharmacodynamic
changes warrant using lower doses and longer dosing intervals with
advanced age, especially with known hepatic or renal impairment, and
frailty, with or without cognitive impairment.79

SAFE, EFFECTIVE USE OF NONOPIOIDS IN THE

OLDER PERSON
Acetaminophen
Acetaminophen is considered the safest nonopioid analgesic and is the
first-line analgesic of choice for older patients when pain is mild or
moderate.17,83 Compared to other nonopioids, it has similar or lower
analgesic potency but lacks undesirable gastroduodenopathy and platelet
dysfunction.40,84 Limited effectiveness compared to placebos or other
analgesics call into questions its inclusion as a first-line, first-choice
analgesic for older adults for all types of pain.85 When combined with
warfarin, over-anticoagulation can result.86 Persistent excessive use of
acetaminophen may impair renal function and cause hepatotoxicity,
especially in frail elders and those with chronic alcohol consumption
and/or liver disease. A systematic review of observational studies showed
a consistent dose–response association between acetaminophen and the

2941
same serious gastrointestinal (GI), renal, and cardiovascular adverse drug
events that are often observed with NSAIDs.87 Dosage limits in the range
of 2,400 to 3,250 mg daily have been suggested to minimize the risk of
renal or hepatic toxicity in these populations with the caveat that most
harm results from inadvertent use of multiple acetaminophen-containing
drugs.85,86

Nonsteroidal Anti-inflammatory Drugs

NSAIDs are effective at alleviating pain, especially types that result from
inflammation. When combined with acetaminophen for acute pain,
NSAIDs have a similar potency to weak opioids (e.g., codeine or
tramadol).86,88 NSAIDs have both analgesic and anti-inflammatory
properties; however, there is little evidence they are useful for neuropathic
pain, and they have little effect on back pain.89,90 The use of long-term
NSAIDs needs careful monitoring in older people because of increased
risk of GI ulceration and bleeding and renal and cardiovascular morbidity.
Cautious use of NSAIDs is advised because a quarter of hospitalizations
resulting from adverse drug effects are linked to NSAIDs in older patients.
Thus, use of NSAIDs for more than a several days should be avoided
unless alternatives are ineffective and the patient can take gastroprotective
misoprostol or a proton pump inhibitor (PPI).40,91,92 The PPI option tends
to be better tolerated but exposes older adults to the risk of bone loss,
fractures, Clostridium difficile infections, and subacute cutaneous lupus
erythematosus with long-term use.92,93
Concerned that medication-related problems are a leading cause of
hospitalization and death among older adults, the American Geriatrics
Society updates the Beers Criteria, a list of medications and drug classes
that are inappropriate to prescribe older adults, regardless of frailty. As a
class, the chronic use of any NSAID should be avoided without
gastroprotection. Any use should be avoided in those with a history of
gastroduodenal ulcers, stage IV kidney disease, or congestive heart failure.
Use for more than 8 days, certain products (indomethacin or ketorolac) are
particularly concerning when used in older adults, as is the combination
with other NSAIDs, corticosteroids, antidepressants, anticoagulants, or
antiplatelet agents.94,95 Despite these warnings, NSAIDs are prescribed to

2942
40% of older adults with chronic pain, which may contribute to 3,300
NSAID-linked deaths and 41,000 hospitalizations observed in the United
States per year.85,92,96
The COX-2 selective NSAIDs appear to have less risk of GI ulcerations
and bleeding in the elderly than do nonselective NSAIDs.95 However, the
GI safety advantages of COX-2 selective NSAIDs are significantly
reduced if high doses are used or when used in combination with aspirin or
other NSAIDs. Although celecoxib has been suspected of placing patients
at higher risk of cardiovascular death, a recent 3-year prospective
randomized control trial using 200 mg of celecoxib per day showed a
similar or better cardiovascular, GI, and renal safety profile when
compared with ibuprofen or naproxen.95 When the risks specific to
rofecoxib were examined in a meta-analysis, it was that drug, rather than
COX-2 selectivity, that contributed to elevated risks of cardiovascular
deaths observed with long-term use of these medications.97

Safe Nonsteroidal Anti-inflammatory Drug Product

Selection and Monitoring Use
The decision to use an NSAID in the management of persistent pain for an
older adult requires individualization considering the (pain reduction and
functional improvement) effectiveness balanced against potential harms
considering comorbidities, concomitant medications, and associated risk
factors. If short-term NSAID therapy is considered and GI risk is
considered low, it may be reasonable to select celecoxib, ibuprofen, or
naproxen. Continuing NSAID therapy beyond a few weeks should be done
cautiously with baseline and periodic monitoring of vital signs, renal
functioning, and occult GI bleeding.98 Given an analgesic ceiling, patients
are started at a low dose and asked to record the analgesic effect for 1 to 2
weeks before increasing the dose. If, after titrating to a higher dose, there
is no analgesic advantage, return to the lower dose. To lessen the risk of GI
and renal toxicity, urge the patient to drink a full glass of water with the
NSAID to maintain adequate hydration throughout therapy.
In general, after acetaminophen is deemed inadequate or
contraindicated, NSAIDs with the highest safety margin should be used in
the lowest effective dose for the shortest duration.92 For patients at highest

2943
GI risk (history of ulcers), celecoxib 100 to 200 mg per day plus a PPI is
considered.85 Because traditional NSAIDs (except naproxen) inhibit the
effects of cardioprotective aspirin and increase GI risk, this combination is
avoided.99 Other options for high-risk patients include nonacetylated
salicylates or topical NSAIDs and may have better safety margins than
more traditional options. Salsalate (Disalcid) has advantages of minimal
GI toxicity, no effects on platelets, and a twice-daily dosing regimen.85
Topical NSAIDs are a viable therapeutic option with a more desirable
tolerability profile, less end-organ dysfunction, and GI bleed compared
with their oral counterparts.100 Topical agents are particularly beneficial
when pain is localized, acute, and superficial, as it places a higher
concentration at the target tissue for appropriately selected inflammatory
conditions. Additional advantages include fewer systemic side effects (dry
skin is the primary side effect), a lower pill burden, and avoidance of drug
interactions.85,101

SAFE, EFFECTIVE USE OF OPIOIDS IN THE OLDER

PERSON POTENTIAL RISKS OF OPIOID ANALGESICS
Declines in NSAID use by older adults have paralleled increased
utilization of opioids. An estimated 9% of those older adults living in the
community and 70% of those with persistent pain in nursing homes have
been prescribed opioids. The American Geriatric Society guidelines
identified opioids as the cornerstone for treating moderate and severe pain
unresponsive to other therapy.80,91 The place of opioid therapy is now
being scrutinized given renewed concerns about potential harms,
especially for older adults who are sensitive to their effects and those with
renal or hepatic dysfunction.86,102 Although older adults are generally less
likely to receive opioids than their younger counterparts, they ironically
are more likely to receive opioids when they sustain a fracture.103 Despite
literature continuing to support the undertreatment of older adults with
pain, more opioid therapy does not guarantee better pain control.104
Although far from a panacea for all types of pain, a meta-analysis
showed opioids to be as effective for older adults as younger patients in
yielding pain reduction, functional improvement, better sleep, and quality
of life.105 As many as two-thirds of older adults who start an opioid for

2944
chronic musculoskeletal conditions achieve pain relief, but it remains
unclear how long those benefits are sustained, especially because nearly
half of older adults discontinue therapy because of poorly tolerated
constipation, mental status changes, and nausea.17 It isn’t clear what
percentage of patients would continue therapy if the GI side effects were
effectively treated prophylactically, but every effort should be made to do
so.84,100 It also is unclear about the effect opioids have on mental status
changes in older adults because higher pain, more intravenous fluids, and
baseline antidepressant medication contribute to these changes.106 A study
examining rates of delirium after hip fracture surgery found that severe
pain and the use of low doses of opioids were correlated significantly with
progression to delirium. In contrast, those using higher doses of opioids
did not develop or worsen delirium regardless of their baseline level of
cognitive functioning.107 What is clear is that given known risks associated
with opioid use, the potential negative effects must be weighed against the
consequences of untreated or partially treated pain.

Potential Safety Concerns with Opioids

Opioids increase the risk of falls, particularly during the first 2 weeks of
use.108 This risk is compounded when used in combination with other
medications (e.g., benzodiazepines, antipsychotics, antidepressants) that
affect the central nervous system.80 Patients prescribed with opioids
should be told to abstain from driving or other potentially dangerous
activities until they have been free of visual or cognitive impairment for
several days on a steady dose. As a drug class, opioids can be appropriate
for older adults without a history of falls or fractures with the exception of
propoxyphene, meperidine, and pentazocine which do carry additional
risks for older adults.92 Tramadol, meperidine, and fentanyl can also
increase the risk of serotonin syndrome in older adults when given with
other serotonergic drugs.80
The established risks associated with opioid use must be weighed
against the consequences of poorly controlled pain. Systematic reviews
express concern that effectiveness may wane over time, but the risks for
serious harm remain, especially at higher doses.102,109 Apart from
estimates that tramadol is no stronger than NSAIDs, there is no evidence

2945
to support the superiority of opioid over another.105 Reluctance to
prescribe opioid drugs has probably been overly influenced by political
and social pressures to control illicit drug use.110–112
Among adults 65 years and older, 736 fatalities were reported among
the 33,091 opioid overdose deaths in 2015.113 That represents 2% of
opioid overdose deaths for the year and the lowest rate for any adult age
group. Conversely, adults 45 to 54 years old had the highest death rate
(8/100,000) of any age group. Aside from prescription opioids, overdoses
from heroin and illicit synthetic opioids rose at an overall rate of 21% and
72%, respectively, in 2014 and 2015 accounting for 22,569 deaths
compared to 12,727 deaths attributed to prescription natural and
semisynthetic opioids.113 Many prescription opioid deaths are caused by
abuse or misuse of prescription opioids and being combined with
benzodiazepines, which increases the overdose risk 10-fold.114 In contrast
to young adults who misuse opioids seeking euphoria, older adults may
take additional medication as a result of forgetfulness, being desperate to
achieve pain control, or as part of a suicidal intent.84,102,115 The estimated
prevalence of opioid misuse in older adults is 1% to 3%, which remains
lower and may account for significantly less prevalent opioid overdoses
than their younger counterparts.80 Although substance abuse, diversion,
and addiction disorders do occur in older adults, many are deprived
prescriptions or refuse them because of overstated risks that fail to
discriminate legitimate use from illicit nonmedical opioid use.112

Prudent Product Selection and Use

The decision to initiate opioids is made cautiously including screening
patients for biopsychosocial risk factors, starting with weak, short-acting,
low-dose opioids after discussing risks and the need for vigilant
monitoring with the patient and caregiver.17 Weak, atypical opioids may
also be effective and have reduced likelihood of side effects such as
constipation, a predictable side effect that should be treated
prophylactically in older adults.100 Tapentadol or transdermal
buprenorphine are weak/mixed opioids with less risk for the toxicities
associated with conventional opioids.100,116 For adults over age 75 years
with chronic arthritis or low back pain, tapentadol was shown to be as

2946
effective as oxycodone with fewer side effects over a 2-year trial
period.117,118 Transdermal buprenorphine is simple to administer
(improves adherence) and avoids the first-pass metabolism which results
in fewer drug–drug interactions, with less respiratory, hormonal, and
immune system effects than oral opioids.119 The absorption, distribution,
metabolism, and excretion of buprenorphine, as well as the ceiling to its
respiratory depressant effects, make it a good choice for older adults.119
Given the limits of existing data, however, more familiar and less
expensive opioids are generally preferred.120
Oxycodone and morphine are probably the best first-line opioids agents
for an opioid-naive patient with acute pain. The adage, start low–go slow,
would have the prudent clinician starting as low as 2.5 mg oxycodone, 5
mg oral morphine, or 1 to 2 mg parenteral morphine and then basing
adjustments on the individual response. Tramadol is commonly chosen,
but it has low potency and an association with seizures that requires
cautious patient selection and attention to potential drug–drug
interactions.17,79
For opioid-tolerant patients, methadone is an effective, relatively low-
cost choice for carefully selected and monitored patients with refractory
pain. Its use is limited by pharmacokinetic, cardiac, and drug-interaction
pitfalls that require methadone to be used by highly informed experienced
prescribers.100,121 Levorphanol offers several therapeutic advantages
similar to methadone but without its pharmacokinetic and drug-interaction
pitfalls.100 Drug selection decisions should ultimately depend on severity
of pain, functional status, expected pain duration, and prescriber and
patient preference. Regardless of selection, the lowest tolerated dose that
leads to acceptable relief of pain is used, with frequent, vigilant evaluation
of desired and undesired effects.17,80
Chronic opioid therapy requires additional safeguards be in place.122
This is particularly true for older adults with preexisting respiratory
dysfunction, including chronic obstructive pulmonary disease,
emphysema, kyphoscoliosis, severe obesity, or cor pulmonale. Patients
with persistent pain taking opioids often develop sleep disordered
breathing, with older age and higher doses associated with both central and
obstructive forms of sleep apnea that must be evaluated and treated.82

2947
Opioids can also cause peripheral vasodilatation which may produce
orthostatic hypotension and a corresponding risk of falling. The impact of
endocrine effects, immune system suppression, and opioid-induced
hyperalgesia on older adults is currently being investigated,123–127 as is the
emergence of novel opioids to offset known risks that limit their use.

SAFE, EFFECTIVE USE OF ADJUVANTS IN THE

OLDER PERSON
Adjuvant analgesics include a variety of agents with analgesic activity
whose primary approved indication is for conditions other than pain. Many
of these adjuvants are used “off-label” and have been found clinically
useful for specific pain types.128 These drugs may be used alone, or in
combination with analgesics to treat persistent pain conditions, including
neuropathic pain. A systematic analysis of 52 Cochrane reviews on
anticonvulsants, antidepressants, behavioral, and analgesics found no
treatment for chronic pain met the Centers for Disease Control and
Prevention (CDC) criteria for “adequate long-term trials.” Those reviews
also failed to show any published evidence of a chronic pain treatment that
has stronger evidence of effectiveness than opioids.129 Thus, adjuvant
therapy may need to be used in addition to, rather than instead of, opioid
therapy to achieve optimal benefits.
Among antidepressants with analgesics properties, amitriptyline has the
longest track record of positive trials but should be avoided in older adults
due to its cardiac, anticholinergic, and sedative effects.85 There are fewer
anticholinergic adverse effects with a second-generation tricyclic
antidepressants (nortriptyline or desipramine), suggesting these are better
choices for older adults.84 In hospitalized patients, however, their use is an
independent predictor of postoperative delirium, increased costs, and
prolonged length of stay.106 Serotonin and norepinephrine reuptake
inhibitors (SNRIs) like duloxetine and venlafaxine have fewer of these
undesired effects but a greater risk of drug interactions and elevation of
liver enzymes.130 This class of drugs should be used cautiously as
antidepressant-related deaths rose nearly 40% in the past 15 years, half of
which were suicides.131
Antiepileptic drugs are first-line agents to treat neuropathic pain in older

2948
persons.89 Gabapentin and pregabalin have labeled indications for specific
neuropathic pain disorders and are frequently used for postherpetic
neuralgia, painful diabetic neuropathy, and fibromyalgia. For these
conditions, they provide similar analgesia to antidepressants, with
improvements in mood, sleep, and quality of life.85 Although pregabalin is
regarded as the most effective in the class, a recent study found it no better
than placebo for sciatica over an 8-week treatment course.132 Thus, it
cannot be assumed to be effective for all neuropathic pain types. The side
effects of sedation, mental clouding, and dizziness are dose-limiting
initially, and some patients are unable to tolerate these medications at the
required therapeutic doses. Older antiepileptic drugs like carbamazepine
may also be useful, but drug interactions, renal, liver, and hematologic
toxicity make them less than ideal in older adults.85 This class of
medications carries a similar warning as opioids regarding avoiding their
use in patients with a history of falls and fractures.92
Topical capsaicin is available over the counter at very low
concentrations (0.025% to 0.075%) for the treatment of neuropathic and
musculoskeletal conditions.86 This medication is very safe except for a
redness and burning sensation with thermal hyperalgesia on treated skin.
Residual medication must be removed from the fingers that applied it to
avoid exposing and irritating sensitive mucous membranes. The higher
concentration (8%) synthetic capsaicin adhesive patch is a selective
agonist of transient receptor potential vanilloid 1 channel, approved for
treating peripheral neuropathic pain. A single 30-minute application of the
capsaicin 8% patch significantly improves postherpetic neuralgia pain.86
Additional studies examining a single 60-minute application or several 30-
minute applications 2 months apart have provided good pain relief for
different painful neuropathies.133 Although widely used with reports of
clinical success, topical lidocaine has failed to demonstrate efficacy from
large, good-quality randomized controlled studies treating neuropathic
pain.134
Other adjuvant drugs can be used in the older adult for their coanalgesic
effect or to offset side effects of pain relievers. They are often selected for
their general ability target mechanisms believed to cause or amplify the
patient’s pain, such as α2-adrenergic or γ-aminobutyric acid (GABAB)

2949
agonists, N-methyl-D-aspartate (NMDA) receptor antagonists, or
cannabinoids. Effects vary considerably based on a variety of factors;
therefore, it is prudent to start one agent at a time at a low dose, titrate
carefully, and have frequent monitoring to establish the safety and efficacy
before adding, subtracting, or adjusting other medications.135

Additional Treatments for Pain of Older Person

Pharmacologic management is the foundation of pain treatment in most
settings; however, medications often fall short of providing optimal pain
reduction and functional improvement. Guidelines are now recommending
a trial of nondrug techniques before starting medications.136 When
ineffective alone, nondrug therapies should continue when analgesics are
added for their medication-sparing benefits.136 In conventional medicine,
physical or psychosocial (cognitive/behavioral) modalities are often
provided by a physical therapist, physiatrist, and/or psychologist. A variety
of nonmainstream approaches to relieving pain when combined with
conventional therapy are called complementary and integrative health
(CIH) approaches. Alternative medical systems (e.g., Ayurvedic medicine,
traditional Chinese medicine, homeopathy, and naturopathy) are not
included as CIH approaches when they exclude conventional medical
approaches.
Multidisciplinary pain treatment programs integrate physical, cognitive-
behavioral, and some complementary approaches to optimize the treatment
for patients with complex pain that has not responded to sequential
treatment attempts.137 Many nondrug approaches are underused in older
patients, and professionals are urged to integrate these modalities,
especially cognitive-behavioral therapy (CBT) and exercise into treatment
plans.17

INTERVENTIONAL APPROACHES
Interventional approaches can provide significant benefit to older adults
whose severe, disabling pain is not responsive to less invasive measures.
Proper patient selection and highly trained professionals are needed to
perform specific procedures with precision, followed by ongoing vigilant

2950
monitoring.138 Many specialists use fluoroscopic verification of needle
placement for many nerve blocks procedures to avoid the life-threatening
risk of intravascular injections.139,140 Older adults are particularly at higher
risk in the setting of anticoagulation, uncontrolled diabetes, or
cardiovascular or progressive neurologic disorders.
Guidelines for interventions like facet joint and epidural spinal
injections (ESIs) were developed by a Multisociety Pain Workgroup out of
a concern that the number of these procedures more than doubled between
1994 and 2001 among Medicare patients. Their 17 recommendations
provide strict guidance for patient selection and safety, which have been
widely adopted by payers.141 Recommendations include that cervical and
lumbar interlaminar ESIs be performed with image guidance and
transforaminal ESIs be conducted under real-time fluoroscopy or digital
subtraction angiography. Cervical interlaminar ESIs above C6–C7 are not
advised, and cervical transforaminal ESIs should only be done using
nonparticulate steroids. Safety guidelines include limiting sedation levels
and using precautions to prevent infections.142 Despite these safeguards,
the evidence of effectiveness is still not well established for older adults.84
Implanted spinal cord stimulator technology has rapidly advanced for
back, leg, and phantom pain, holding promise to control pain with few if
any drugs needed.143,144 Innovative less invasive approaches are being
developed that may benefit older adults who are not candidates for existing
surgical procedures or dorsal column stimulation used to treat pain.134,145
Exciting developments in noninvasive interventions, such as pulsed
electromagnetic field (PEMF) therapy, hold promise for common ailments
with advancing age, such as arthritis. This PEMF therapy can be
administered three times a week for several weeks, or patients can self-
apply bands around their affected joint (e.g., knee) every day to reduce
pain, stiffness, and medication use while improving their
functioning.146,147

PHYSICAL MODALITIES
Physical modalities to pain control range from simple applications of
heat/cold, orthotics, or electrical stimulating devices patients can self-
manage to more technical interventions requiring professional expertise

2951
like low-level laser treatments. Active techniques, like therapeutic exercise
and aquatic therapy, work better for able-bodied older adults than passive
approaches like superficial heat, transcutaneous electrical nerve
stimulation (TENS), and acupuncture.148 Physical therapists have
developed graded activity programs to tailor treatments best aligned with
the physical capacity of older adults with pain.149 There are a variety of
therapeutic exercises, salves, nutritional supplements and self-management
techniques commonly used to reduce pain and medication use while
improving well-being.150,151
Promoting active involvement in pain management, like home exercise
programs, pacing activities, or the application of salves, are increasingly
being used to provide relief while reducing medication-related
problems.150,151 Simple advice to remain physically active despite pain, in
the absence of a specific exercise routine, is ineffective.17 More structured
exercise interventions for older adults with chronic pain are evidenced-
based and underutilized and should be a core component of any long-term
treatment plan, even for nursing home residents.151 Moderate pressure
massage and Iyengar yoga (focusing on poses) is increasingly being used
to reduce pain and improve balance and mobility, even for hospitalized
older patients with pain.152,153 Physiotherapist often integrate exercises
that promote balance, flexibility, body mechanics, pacing, endurance, and
strengthening to not only lower pain but also reduce catastrophic thinking
and avoidance behaviors known to make back pain worse.149
Although generally safe, some precautions are advised. Protect the skin
of older adults when topical heat or cold compresses are applied and use
extra lotion or gel when applying TENS pads or giving a massage.154,155
Although commercially available natural products and supplements are
safe when they do not interact with drugs, some herbal remedies have been
tainted with drugs or heavy metals.156,157 Safety precautions are needed
for older adults receiving physical manipulation and body-based therapies
(e.g., chiropractors, osteopaths, physical and massage therapists) because
of the high risk for falls observed among individuals who use these
therapies.158

PSYCHOSOCIAL MODALITIES

2952
A variety of psychosocial modalities strive to change the perception of
pain or alter the unhelpful thoughts, feelings, or behavioral responses that
worsen pain and suffering. Specific techniques include education and
counseling, distraction, coping skills training, relaxation, imagery,
hypnotherapy, and facilitating emotional disclosure that help older adults
with pain.153,159,160 Structured programs like CBT, acceptance and
commitment therapy (ACT), and peer-led self-management programs help
older adults despite barriers to accessing them.17,84 New models of
bringing these programs to older adults are proving feasible and
effective.161–164 Although these and other psychosocial modalities help
many older persons, some lack the physical or mental capacity to
participate, and interventions need to be tailored to their specific (e.g.,
visual or auditory impairment, limited mobility) circumstance.154,165
When psychological attributions for pain, emotional awareness,
emotional approach coping, and alexithymia are directly addressed, large
effects were seen with sustained improvements in pain, functioning, and
mood.160 Pain self-management group programs suggest a smaller but
significant sustained benefits can be achieved through that approach.166
Perhaps a common thread in some of these approaches is moving away
from a traditional style of trying to persuade patients to change behavior
and toward asking thought-provoking questions that prompt desire, ability,
reasons, and need to change, so the patient can take action based on their
individual values and motivators.167
Older adults do benefit from structured CBT or ACT programs and may
be more likely to respond than younger adults.168 It is unclear if “booster
sessions” would help because the effects of pain reduction do persist, but
measures of functional improvement are not sustained.169 Even if physical
functioning is not improved, psychological flexibility, social functioning,
and mental health is improved.170

COMPLEMENTARY AND INTEGRATIVE HEALTH

Pain is the most common health problem driving people to use CIH
approaches. American spend 3 times more in out-of-pocket expenses ($15
billion per year) for complementary therapies than they do for
conventional medicine.171,172 Three-quarters of adults over age 50 years

2953
who use CIH methods reportedly did so to treat a painful condition.173
Arthritis and low back pain are commonly treated with mind–body
therapies, acupuncture, yoga, massage, spinal manipulation,
thermotherapy, and tai chi.172,174 In fact, slightly more older adults use
CIH measures than conventional therapies for low back pain (96% and
95%, respectively),150 which is aligned with recommendations of recent
guidelines.90,136 For older adults, yoga, massage, and natural products are
especially appealing and are demonstrating their cost-effectiveness.159,175
Despite a lack of strong evidence that yoga or qigong decreases low back
pain, the physical postures, breathing techniques, and focused intention do
improve functioning, balance, mood, self-efficacy, and quality of
life.152,176,177 Yoga may also improve memory and cognitive functioning
and reverse some of the atrophic changes in the brain brought on by
chronic pain and aging.178,179
There is evidence spinal manipulation, mind–body therapies, and natural
products CIH modalities are cost-effective for older adults with pain.175,180
Access to CIH, however, may be limited by cost, ease of access, facility
policies, or physician concern. Even when they are used, patients do not
disclose CIH use to health professionals.181,182 Even though CIH is
reluctantly used in frail older adults, many methods have demonstrated
safety, with the added safety of reducing exposure to potentially dangerous
drugs, or the need for physical or chemical restraints.183,184 Some potential
danger exists with some CIH methods, as acupuncture-related infections,
nerve injuries, organ perforation, serious bleeds, and pneumothorax have
been reported in older adults.185,186 To offset these concerns, some are
using the less invasive acupressure to alleviate chronic pain, but a high
dropout rate suggests it is not for everyone.187 Aromatherapy has provided
transient relief of pain, improved mood, and reduced stress levels among
older adults, but additional studies are needed.188,189

MULTIDISCIPLINARY PAIN TREATMENTS

Multidisciplinary pain treatment programs are underutilized for older
adults who respond similarly as younger adults with persistent
pain.84,190,191 Multidisciplinary pain clinics have better outcomes in terms
of pain reduction, functional improvement, and lower health care

2954
utilization than those who receive only single-modality interventions.
About a third of patients with chronic low back pain that has not
responded to other treatments gain significant control of their pain as a
result of a multidisciplinary pain treatment program.192 Even patients who
do not achieve significant pain control in this type of a program are
satisfied with the treatment and feel better able to self-manage their
symptoms,193 which may be why some emergency departments now
provide multidisciplinary education improved pain outcomes.194
Although the cost–benefit ratio has not clearly been delineated for older
adults, there is no compelling evidence to suggest that they should be
denied such treatment. In fact, the potential adverse effects of untreated
pain and/or polypharmacy suggest that multidisciplinary treatment should
be considered for all geriatric patients with significant pain complaints.

Summary
Certainly, there are risks when treating older adults with severe or
persistent pain. In fact, the undertreatment of pain is an important risk that
can contribute to physical harm, mental despair, and social isolation during
what has been dubbed “the golden years.” Although much remains to be
learned, we currently have sufficient knowledge to improve the way pain
is assessed and treated while refining methods to further improve the
safety and efficacy of pain relief efforts. Clear consistent assessment
methods are needed by choosing and using tools validated for older adults.
The patient’s understanding of the tool should be confirmed so that
meaningful information is gathered and recorded. When planning
interventions, a shared decision-making approach is appropriate, where
patients and their loved ones are informed of the risks, benefits, and
variable responses typical for particular treatment options. This shared
decision making engages the patients as active participants in the treatment
process and educates them about desired and undesired effects that may be
encountered and need to be recorded. Cautious drug and dose selection is
needed for the older adult. Lower starting doses and longer dosing
intervals are justified until the patient’s response to analgesics is known.
Monitoring the patient’s response early in therapy for side effects, drug (or

2955
herbal) interactions, and toxicity is important, especially for those with
comorbid conditions that add risks. Continued monitoring for older adults
on sustained treatment is important as several late-onset toxicities (e.g., GI
bleed, hypertension, liver/renal impairment, opioid-induced hyperalgesia)
may not emerge until months or years of therapy have passed. The prudent
use of nonoperative interventions (e.g., nerve blocks) and nondrug or
complementary, integrative therapies should be considered for older adults
with persistent pain. Given the breadth of options available to treat pain,
allowing it to go untreated in older adults is a mistake. Whereas not all
treatments are good options for older adults, failing to treat pain is
unacceptable, especially for those who are so vulnerable to the harmful
effects of unrelieved pain.

*The terms chronic pain and persistent pain are often used interchangeably to denote pain that lasts
for more than 3 months. Persistent pain is used in this text to avoid negative connotation often
associated with the label chronic pain, as is recommended by the American Geriatrics Society.

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alternative medicine use among community-dwelling older adults. J Altern Complement Med
2017;23(1):41–44.
159. Bruckenthal P, Marino MA, Snelling L. Complementary and integrative therapies for
persistent pain management in older adults: a review. J Gerontol Nurs 2016;42(12):40–48.
160. Burger AJ, Lumley MA, Carty JN, et al. The effects of a novel psychological attribution and
emotional awareness and expression therapy for chronic musculoskeletal pain: a preliminary,
uncontrolled trial. J Psychosom Res 2016;81:1–8.
161. Rini C, Porter LS, Somers TJ, et al. Automated Internet-based pain coping skills training to
manage osteoarthritis pain: a randomized controlled trial. Pain 2015;156(5):837–848.
162. Rini C, Williams DA, Broderick JE, et al. Meeting them where they are: using the Internet to
deliver behavioral medicine interventions for pain. Transl Behav Med 2012;2(1):82–92.
163. Riva S, Camerini AL, Allam A, et al. Interactive sections of an Internet-based intervention
increase empowerment of chronic back pain patients: randomized controlled trial. J Med
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164. Tse MM, Yeung SS, Lee PH, et al. Effects of a peer led pain management program for nursing
home residents with chronic pain: a pilot study. Pain Med 2016;17(9):1648–1657.
165. Eccleston C, Tabor A, Edwards RT, et al. Psychological approaches to coping with pain in
later life. Clin Geriatr Med 2016;32(4):763–771.
166. Nicholas MK, Asghari A, Blyth FM, et al. Long-term outcomes from training in self-
management of chronic pain in an elderly population: a randomized controlled trial. Pain
2017;158(1):86–95.
167. Miller WR, Rose GS. Motivational interviewing and decisional balance: contrasting responses
to client ambivalence. Behav Cogn Psychother 2015;43(2):129–141.
168. Wetherell JL, Petkus AJ, Alonso-Fernandez M, et al. Age moderates response to acceptance
and commitment therapy vs. cognitive behavioral therapy for chronic pain. Int J Geriatr
Psychiatry 2016;31(3):302–308.
169. Morone NE, Greco CM, Moore CG, et al. A mind-body program for older adults with chronic
low back pain: a randomized clinical trial. JAMA Intern Med 2016;176(3):329–337.
170. Scott W, Daly A, Yu L, et al. Treatment of chronic pain for adults 65 and over: analyses of
outcomes and changes in psychological flexibility following interdisciplinary acceptance and
commitment therapy (ACT). Pain Med 2017;18(2):252–264. doi:10.1093/pm/pnw073.
171. Nahin RL, Stussman BJ, Herman PM. Out-of-pocket expenditures on complementary health
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172. Nahin RL, Boineau R, Khalsa PS, et al. Evidence-based evaluation of complementary health
approaches for pain management in the United States. Mayo Clin Proc 2016;91(9):1292–
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173. AARP, National Center for Complementary and Integrative Health. Complementary and
alternative medicine: what people aged 50 and older discuss with their health care providers.
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174. Gong G, Li J, Li X, et al. Pain experiences and self-management strategies among middle-
aged and older adults with arthritis. J Clin Nurs 2013;22(13–14):1857–1869.
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175. Herman PM, Poindexter BL, Witt CM, et al. Are complementary therapies and integrative
care cost-effective? A systematic review of economic evaluations. BMJ Open
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176. Holmberg C, Rappenecker J, Karner JJ, et al. The perspectives of older women with chronic
neck pain on perceived effects of qigong and exercise therapy on aging: a qualitative
interview study. Clin Interv Aging 2014;9:403–410.
177. Teut M, Knilli J, Daus D, et al. Qigong or yoga versus no intervention in older adults with
chronic low back pain-a randomized controlled trial. J Pain 2016;17(7):796–805.
178. Hariprasad VR, Varambally S, Shivakumar V, et al. Yoga increases the volume of the
hippocampus in elderly subjects. Indian J Psychiatry 2013;55(suppl 3):S394–S396.
179. Villemure C, Čeko M, Cotton VA, et al. Neuroprotective effects of yoga practice: age-,
experience-, and frequency-dependent plasticity. Front Hum Neurosci 2015;9:281.
180. Leininger B, McDonough C, Evans R, et al. Cost-effectiveness of spinal manipulative
therapy, supervised exercise, and home exercise for older adults with chronic neck pain. Spine
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181. Rayner JA, Bauer M. “I wouldn’t mind trying it. I’m in pain the whole time”: barriers to the
use of complementary medicines by older Australians in residential aged-care facilities. J
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182. Geisler CC, Cheung CK. Complementary/alternative therapies use in older women with
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183. McFeeters S, Pront L, Cuthbertson L, et al. Massage, a complementary therapy effectively
promoting the health and well-being of older people in residential care settings: a review of
the literature. Int J Older People Nurs 2016;11(4):266–283.
184. Leong M, Smith TJ, Rowland-Seymour A. Complementary and integrative medicine for older
adults in palliative care. Clin Geriatr Med 2015;31(2):177–191.
185. Robinson A, Lind CR, Smith RJ, et al. Atlanto-axial infection after acupuncture. Acupunct
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186. Huisma F, Konrad G, Thomas S. Pneumothorax after acupuncture. Can Fam Physician
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187. Yeh CH, Morone NE, Chien LC, et al. Auricular point acupressure to manage chronic low
back pain in older adults: a randomized controlled pilot study. Evid Based Complement
Alternat Med 2014;2014:375173.
188. Tang SK, Tse MY. Aromatherapy: does it help to relieve pain, depression, anxiety, and stress
in community-dwelling older persons? Biomed Res Int 2014;2014:430195.
189. Nasiri A, Mahmodi MA, Nobakht Z. Effect of aromatherapy massage with lavender essential
oil on pain in patients with osteoarthritis of the knee: a randomized controlled clinical trial.
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191. Kee WG, Middaugh SJ, Redpath S, et al. Age as a factor in admission to chronic pain
rehabilitation. Clin J Pain 1998;14(2):121–128.
192. Fishbain DA, Gao J, Lewis JE, et al. At completion of a multidisciplinary treatment program,
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clinically important difference, or an absolute VAS score improvement of 1.5 cm or more?
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193. Moe RH, Grotle M, Kjeken I, et al. Effectiveness of an integrated multidisciplinary
osteoarthritis outpatient program versus outpatient clinic as usual: a randomized controlled
trial. J Rheumatol 2016;43(2):411–418. doi:10.3899/jrheum.150157.
194. Hogan TM, Howell MD, Cursio JF, et al. Improving Pain Relief in Elder Patients (I-PREP):
an emergency department education and quality intervention. J Am Geriatr Soc
2016;64(12):2566–2571. doi:10.1111/jgs.14377.

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CHAPTER 56
Obstetric Pain
CYNTHIA A. WONG

Historical Notes
Childbirth pain is arguably the most severe pain most women will endure
in their lifetimes. The modern era of childbirth analgesia began in 1847
when Dr. James Young Simpson administered ether to a woman in
childbirth and later, in the same year, chloroform. The use of analgesia for
childbirth aroused violent opposition from some physicians, the public,
and the clergy.1 Simpson was labeled a heretic, blasphemer, and an agent
of the devil. The furor died down somewhat in 1853, when John Snow
successfully administered chloroform to Queen Victoria for the birth of her
eighth child.
In the ensuing years, public opinion regarding obstetric analgesia began
to change, thus forcing the medical community to offer analgesia. Women
enthusiastically embraced labor analgesia. Fanny Longfellow, the wife of
poet Henry Wadsworth Longfellow and the first woman in the United
States to receive labor analgesia in the modern era, wrote that “this is
certainly the greatest blessing of this age.”2 Pain began to lose its theologic
connections.3 It was no longer considered punishment for sin or divine
retribution. Instead, disease and pain were considered biologic processes
that could be studied and treated.
Following this auspicious beginning in the 19th century, however,
childbirth analgesia was largely neglected by the medical community. The
next major step occurred in the early 20th century when Dämmerschlaf, or
“twilight sleep,” was introduced in Europe.4 The combination of
scopolamine and morphine was enthusiastically accepted by women but
not by the medical profession. Medical professionals expressed concern
about the effect of childbirth analgesia on the progress of labor. In
addition, with the advent of twilight sleep, physicians began to appreciate

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that anesthetics cross the placenta and had potentially adverse effects on
the newborn. This was the stimulus for Virginia Apgar, an
anesthesiologist, to develop an evaluation tool to assess neonatal well-
being in 1953.5 A salutary effect of the Apgar score was that scientific
studies comparing the effects of different anesthetic techniques on
neonatal outcome were now possible.
Regional anesthesia was first introduced in 1884, when Carl Koller
described the use of cocaine to anesthetize the eye.6 Descriptions of
regional anesthesia, including spinal, lumbar epidural, caudal,
paravertebral, and pudendal nerve blocks, were published in the obstetric
literature between 1900 and 1930.3 In the 1930s and 1940s, Cleland7
contributed to our understanding of the innervation of the uterus and
applied this knowledge to regional anesthesia in the care of the obstetric
patient. Continuous neuraxial analgesia, as it is practiced today, had its
birth in 1943, when Hingson and Edwards8 published the first report of
continuous caudal analgesia for childbirth. Flexible, disposable catheters
replaced the original malleable needles, and refinements were made, and
continue to be made, in technique, drugs, doses, and delivery techniques.
Although other regional nerve block and systemic analgesic techniques
are often used for analgesia, women continue to request neuraxial labor
analgesia for childbirth at ever-increasing rates. In the most recent survey
performed in 2012, over 85% of women in large maternity hospitals in the
United States received neuraxial analgesia during labor.9 Spinal and
epidural anesthesia accounts for over 95% of the anesthetics for elective
cesarean deliveries. Multimodal analgesic therapy, which often includes a
regional technique component, is the norm for postcesarean analgesia.
This chapter summarizes the physiology of childbirth pain, physiologic
changes of pregnancy that influence the provision of analgesic and
anesthetic care, specific labor analgesic techniques, the effects of analgesia
on the mother and infant, and the treatment of nonobstetric pain during
pregnancy and lactation.

Pain of Childbirth
Although it is a common observation that parturients vary in the amount of

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pain and suffering associated with labor and vaginal delivery, few well-
designed studies on the prevalence, intensity, and quality of labor pain
have been performed. Melzack et al.10 used the McGill Pain Questionnaire
to assess childbirth pain. The mean total pain rating index (PRI) was 34 for
nulliparous and 30 for parous women. Significant differences were also
found between nulliparas and parous women in the sensory qualities of
pain. Labor pain scores were 8 to 10 points higher than those associated
with cancer pain, phantom limb pain, and postherpetic neuralgia (Fig.
56.1A), although there was a wide range of scores ranging from mild to
excruciating (Fig. 56.1B).

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FIGURE 56.1 A: Comparison of pain scores using the McGill Pain Questionnaire obtained from
women during labor and from patients in general hospital clinics and an emergency department.
The pain rating index (PRI) represents the sum of the rank values for all words chosen from 20 sets
of pain descriptions. B: Distribution of PRI scores from nulliparous and parous women in six
intervals of the total PRI range. (Redrawn after Melzack R. The myth of painless childbirth [the
John J. Bonica lecture]. Pain 1984;19[4]:321–337, with permission.)

CHILDBIRTH PAIN MECHANISMS AND PATHWAYS

Most data support the concept that the pain of the first stage of labor
originates predominantly in the cervix and the lower uterine segment
rather than the body of the uterus. Dilation of the cervix and lower uterine

2970
segment results in distension, stretching, and tearing of tissues. During the
late first stage and second stage of labor, the descent of the fetus and
intense stretching and tearing of the tissues of the vagina and perineum
become additional sources of pain.
Based on animal and human studies, Cleland7 concluded that the
sensory afferents from the uterus and cervix that transmit pain during the
first stage of labor enter the spinal cord at T11 and T12 (Fig. 56.2). He
demonstrated that these visceral sensory afferents are intermingled with
sympathetic efferents by demonstrating that bilateral paravertebral lumbar
sympathetic blockade abolished the pain of the first stage of labor. Second-
stage pain from descent of the fetus in the birth canal is primarily somatic
in nature and is transmitted through sacral nerves to the S2–S4 segments of
the spinal cord.

FIGURE 56.2 Schematic depiction of the peripheral nociceptive pathways involved in the pain of
childbirth. A: The uterus, including the lower uterine segment and cervix, is supplied by afferents
that pass from the uterus to the spinal cord by accompanying sympathetic nerves through the
cervical plexus; the superior and inferior hypogastric plexuses (SHP, IHP); the lumbar and lower
thoracic sympathetic chain; and to the T11, T12, and L1 nerve roots. The vagina and perineum are
supplied by afferents that travel to the spinal cord via the pudendal nerve to the S2–S4 nerve roots.
B: The nerves involved in the transmission of nociceptive impulses are provoked by noxious
stimulation of pelvic structures.

Bonica11 used a series of discrete nerve blocks of various nociceptive

pathways, including paracervical, segmental epidural, caudal, and
transsacral blocks, to further refine our knowledge of the nerve pathways
that transmit labor pain to the central nervous system. He demonstrated
that the upper part of the cervix and lower uterine segment are supplied by
afferents that accompany the sympathetic nerves through the uterine and

2971
cervical plexus; the inferior, middle, and superior hypogastric plexuses;
and the aortic plexuses. The nociceptive afferents then pass to the lumbar
sympathetic chain and course cephalad through the lower thoracic
sympathetic chain via the rami communicantes of the T10, T11, T12, and
L1 spinal segments. Finally, they pass through the dorsal roots of these
nerves to make synaptic contact with the interneurons of the dorsal horn.
Typical of pain arising from viscera, the pain of the first stage of labor is
often referred to the T10–L1 dermatomes. Additionally, during the late
first stage and second stage of labor, some parturients experience referred
pain to the lower lumbar and sacral dermatomes as a result of stimulation
of pain-sensitive structures within the pelvic cavity and pressure on one or
more roots of the lumbosacral plexus. The pain may be severe if the fetus
is in an abnormal position.
Visceral C fibers transmitting pain during the first stage of labor
terminate in the spinal cord in a loose network of synapses in the
ipsilateral, superficial, and deep dorsal horn and the ventral horn as well as
cross the midline to the contralateral dorsal horn with extensive
rostrocaudal extension.12 In contrast, somatic afferent fibers tend to
terminate in the ipsilateral superficial laminae of the dorsal horn with
minimal rostrocaudal fiber extension. This explains the diffuse localization
of visceral first-stage labor pain compared to somatic second-stage labor
pain. It may also explain why the neuraxial administration of lipid-soluble
opioids in early labor provides complete analgesia, as these drugs
penetrate deeply into the spinal cord.
Understanding the anatomic basis of the transmission of labor pain
underlies the current treatment of labor pain using regional anesthesia
techniques. The visceral pain of the first stage of labor can be blocked with
bilateral cervical plexus, lumbar sympathetic blocks, or central neuraxial
blockade. The somatic pain caused by descent of the fetus in the birth
canal can be blocked with bilateral pudendal nerve blocks or neuraxial
blockade.
Our current understanding of the neurophysiologic basis of labor pain is
superficial at best. Better understanding of the pain pathways,
neurotransmitters, and receptors involved in labor pain will open up new
avenues for the treatment of labor pain in the future.

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FACTORS THAT AFFECT THE PAIN OF CHILDBIRTH
In addition to physiologic factors such as intensity, duration, pattern of
contractions, and descent of the fetus, the amount or degree of pain and
suffering associated with childbirth is influenced by physical,
psychological, emotional, and motivational factors.
Physical factors that are associated with the severity and duration of
childbirth pain include age, parity,13 history of previous pain or
dysmenorrhea, fatigue, the condition of the cervix at the onset of labor,
and the relationship between the size and position of the fetus to the size of
the birth canal. Generally, an older nullipara experiences longer and more
painful labor than a younger nullipara.10 The cervix of parous women
begins to soften even before the onset of labor and is less sensitive than
that of the nullipara. The intensity of uterine contractions in early labor
tends to be higher in nulliparous compared to parous women, whereas the
reverse is true as labor advances. Pain is greater in the presence of dystocia
caused by a contracted pelvis, a large baby, or abnormal presentation or
position. Women who go on to require cesarean delivery following a
period of labor have more breakthrough pain14 and require more epidural14
and systemic15 analgesia during labor than women who deliver vaginally.
Psychological factors, such as fear, apprehension, and anxiety, also
influence the degree of pain and suffering during childbirth.16 The
presence of family members17 or birthing companions18 during labor and
delivery may decrease anxiety and positively affect the progress of labor.
Education, intense motivation, and cultural influences can influence the
affective and behavioral dimensions of pain, although they probably
minimally affect actual pain sensation. Bonica19 observed women who had
had predelivery training in psychoprophylaxis manifested little or no pain
behavior during childbirth, although when questioned the next day, most
of them indicated the process had been quite painful. Jewish health
providers rated the labor pain of Jewish women higher than that of
Bedouin women who were delivering in the same institution,20 whereas
the level of pain assessed by the women themselves was not different.

EFFECTS OF PAIN ON THE MOTHER AND FETUS

Labor and vaginal delivery produce tissue damage and, similar to tissue

2973
injury from other causes, result in pain and local segmental,
suprasegmental, and cortical responses. These responses include marked
stimulation of respiration and circulation as well as the hypothalamic,
autonomic centers of neuroendocrine function, limbic structures, and
psychodynamic mechanisms of anxiety and apprehension. These may have
a deleterious impact on the mother, fetus, and newborn. Many of these
responses are mitigated by effective pain relief.
The pain of childbirth is a powerful respiratory stimulus, resulting in a
marked increase in minute ventilation and oxygen consumption during
contractions.21 Compensatory periods of hypoventilation between
contractions cause transient maternal hypoxemia and, potentially, fetal
hypoxemia (Fig. 56.3). Maternal hyperventilation causes severe respiratory
alkalosis and a left shift of the maternal oxyhemoglobin dissociation curve,
thus diminishing oxygen transfer to the fetus. The pain and stress of labor
activates the sympathetic nervous system, resulting in an increase in
plasma catecholamine concentrations, cardiac output, and blood pressure
(Fig. 56.4). Epinephrine and norepinephrine levels increase by 200% to
600% during unmedicated labor,22 and this increase is associated with a
decrease in uterine blood flow (UBF). Pain and anxiety and the
accompanying increased catecholamine levels may contribute to prolonged
or dysfunctional labor.23 Epinephrine is a tocolytic, and physicians have
long observed that an apparent dysfunctional labor pattern can be corrected
with effective analgesia.24 Finally, unrelieved severe pain can produce
serious mental health disturbances that may interfere with maternal–fetal
bonding, future sexual relationships, and contribute to postpartum
depression10 and, rarely, posttraumatic stress disorder.

2974
FIGURE 56.3 Continuous recording of uterine contractions (UC), maternal thoracic impedance,
maternal transcutaneous oxygen tension (partial pressure of oxygen [Pao2]), fetal oxygen tension,
and fetal heart rate (FHR) in a nullipara breathing room air 120 minutes before spontaneous
delivery. Marked hyperventilations during UC were followed by hypoventilation or apnea between
contractions. After the first and fourth contractions, the maternal Pao2 fell to 44 and 46 mm Hg,
with a consequent decrease in fetal Pao2, and variable decelerations, which reflect fetal hypoxemia.
(Redrawn after Huch A, Huch R, Schneider H, et al. Continuous transcutaneous monitoring of fetal
oxygen tension during labour. Br J Obstet Gynaecol 1977;84[suppl 1]:1–39. Reprinted by
permission of John Wiley & Sons, Inc.)

FIGURE 56.4 Effect of noxious stimulus (application of an electric current to the skin) on
maternal arterial blood pressure, norepinephrine blood level, and uterine blood flow in a pregnant
ewe. The increase in arterial pressure is transient, and the decay in norepinephrine level is more

2975
protracted and is reflected by a mirror image decrease in uterine blood flow. (Redrawn after Shnider
SM, Wright RG, Levinson G, et al. Uterine blood flow and plasma norepinephrine changes during
maternal stress in the pregnant ewe. Anesthesiology 1979;50[6]:524–527, with permission.)

The healthy parturient easily tolerates the large increase in cardiac work,
but parturients with heart disease, severe preeclampsia, or pulmonary
hypertension may not tolerate these changes without adverse outcome.
Similarly, the healthy fetus tolerates the changes in UBF; however, these
changes may be deleterious in the setting of uteroplacental insufficiency
(e.g., preeclampsia, intrauterine growth restriction).
In summary, there is large individual variation in how women
experience childbirth pain and suffering. Pain associated responses to
noxious stimuli during childbirth are net effects of highly complex
interactions of various neural systems, modulating influences, and
psychological factors. These interactions are responsible for the complex
physiologic, behavioral, and affective responses that characterize the pain
of childbirth.

Physiologic Changes of Pregnancy

Pregnancy is associated with significant anatomic and physiologic
changes. Many of these changes impact the treatment of pain during
pregnancy, parturition, and the puerperium. Safe care of these women
requires a thorough understanding of these changes and their impact on the
treatment of pain. In addition, a thorough understanding of the fetal–
placental complex is necessary for the safe care of the fetus and neonate.
These changes and their anesthetic implications are summarized in Table
56.1 and discussed in the following text.

TABLE 56.1 Physiologic Changes of Pregnancy and Anesthetic

Implications
Physiologic Change Anesthetic Implication
Respiratory
Increase in O2 requirement and CO2 Greater risk of desaturation after induction of
production general anesthesia
Decrease in FRC Greater risk of desaturation after induction of
general anesthesia
Cardiovascular

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 Hyperdynamic: increased reliance on
sympathetic nervous system
Decreased responsiveness to vasoactive agents
Aortocaval compression
Aortocaval compression and engorgement of
azygous veins
Central Nervous System
Increased lumbar lordosis and decreased
thoracic kyphosis
Rotation of pelvis
Widening of the pelvis
Decrease in CSF volume
Decrease in CSF specific gravity
Increase in CSF pH
Increased susceptibility to all anesthetics
Increased progesterone levels
Pharmacokinetics
Altered volume of distribution
Altered protein binding of drugs
Increased renal blood flow
Altered hepatic microsomal enzyme activity
CSF, cerebrospinal fluid; FRC; functional residual capacity.
Increase in incidence and severity of
hypotension after neuraxial
analgesia/anesthesia
Require higher doses of vasopressors to correct
hypotension
More profound hypotension with parturient in
the supine position
Less epidural space and decreased egress of
drugs from the epidural space result in lower
requirement for epidural drugs
Decreased size of lumbar interspinous space
and altered movement of anesthetic agents
within CSF
Tuffier’s line more cephalad
Spine more “head-down” in lateral position
Decrease in local anesthetic dose requirements
Altered baricity of spinal anesthetic solutions
Change in proportion of un-ionized drug
Decrease in anesthetic dose requirements
Increased pain threshold
Change in drug pharmacokinetics
Change in drug pharmacokinetics
Change in drug elimination
Change in drug metabolism

RESPIRATORY CHANGES
Pregnancy is associated with anatomic and physiologic changes involving
the airway, lung volumes, ventilation, and the dynamics of breathing.
Capillary engorgement, an increase in upper airway soft tissue mass, and
enlargement of the breasts contribute to making endotracheal intubation
more difficult in pregnant compared to nonpregnant women.25 Failed
intubation and pulmonary aspiration (often associated with difficult airway
management) are the most common causes of anesthesia-related maternal
mortality.26 Therefore, in addition to the ability to provide complete
analgesia, continuous neuraxial labor analgesia has the added benefit of
avoiding the need for general anesthesia and endotracheal intubation
should emergency cesarean delivery be required.
Oxygen consumption, carbon dioxide production, and minute

2977
ventilation increase during pregnancy.27 Functional residual capacity
(FRC) decreases28 and closing capacity may exceed FRC in supine
pregnant women at term. Obesity, recumbency, and anesthesia (neuraxial
or general) further decrease FRC.
During parturition, minute ventilation and oxygen consumption increase
markedly, and hyperventilation results in partial pressure of carbon dioxide
(PaCO2) values as low as 10 to 15 mm Hg.29 Maternal aerobic oxygen
requirements exceed oxygen consumption resulting in a progressive
maternal lactic acidemia.30

CARDIOVASCULAR CHANGES
The cardiovascular system is hyperdynamic during pregnancy. Total blood
volume increases by approximately 50% during pregnancy,31 as does
cardiac output (Fig. 56.5).27 Plasma volume increases more than red cell
mass, resulting in the physiologic anemia of pregnancy.31 Organ perfusion
is markedly increased, particularly perfusion of the uterus. Systolic blood
pressure falls minimally, whereas diastolic pressure decreases by
approximately 20%.27 Both return to prepregnant levels at term.
Hemodynamic stability is more highly dependent on sympathetic nervous
system activity,32 and arterial responsiveness to vasopressors is reduced.33

FIGURE 56.5 Changes in heart rate, stroke volume, and cardiac output during pregnancy and in
the puerperium. (Redrawn after Bonica JJ. Obstetric Analgesia and Anesthesia. 2nd ed. Seattle,
WA: University of Washington Press; 1980:5. Reprinted by permission of World Federation of
Societies of Anaesthesiologists.)

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Aortocaval Compression
At term, compression of the aorta and vena cava by the gravid uterus in the
supine position results in decreased right ventricular preload and a 10% to
20% decrease in cardiac output compared to the standing position.34 Vena
cava compression begins as early as 13 to 16 weeks’ gestation and may be
nearly complete at term (Fig. 56.6).35 Partial aortic compression in the
supine position results in decreased blood flow to the pelvis and lower
extremities. Aortic compression is completely relieved by the lateral
position.36 Data regarding the degree of compression of the vena cava in
the lateral position are inconsistent35,37; however, in the lateral position,
collateral circulation through the azygous system maintains venous return
and cardiac output.37,38 The left lateral position is superior to the right
lateral position for maintenance of venous return.39
During labor, cardiac output increases due to increased central blood
volume secondary to autotransfusion during uterine systole and because of
increased sympathetic nervous system activity. Due to the adverse effects
of aortocaval compression, parameters of fetal well-being deteriorate when
parturients labor in the supine compared to lateral position.40 Adverse
effects may be more profound in the parturient with neuraxial blockade
induced sympathetic blockade.

2979
FIGURE 56.6 Effect of the pregnant uterus on the inferior vena cava (I.r.c.) and the aorta in the
supine position (left) and the lateral position (right). The marked aortocaval compression in the
supine position causes venous blood to be diverted to and through the vertebral venous plexus,
which becomes engorged and reduces the size of the epidural and subarachnoid spaces. (Redrawn
after Bonica JJ. Obstetric Analgesia and Anesthesia. 2nd ed. Seattle, WA: University of
Washington Press; 1980:8. Reprinted by permission of World Federation of Societies of
Anaesthesiologists.)

Implications for Labor Analgesia

Shunting of lower extremity blood through the azygous system results in
venous engorgement in the epidural space. This functionally reduces the
size of the epidural and subarachnoid spaces, thus reducing the amount of
anesthetic necessary to produce neuroblockade. Sympathetic blockade in
the term parturient (e.g., as a consequence of neuraxial
analgesia/anesthesia) results in a marked decrease in blood pressure
compared to nonpregnant control subjects.41 Pregnant women may require
higher doses of vasopressors compared to nonpregnant individuals to treat

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hypotension.33

CENTRAL NERVOUS SYSTEM CHANGES

Anatomy of the Spinal Column and Analgesic Implications
Anatomic and physiologic changes in the nervous system alter responses
to pain and susceptibility to both general and regional anesthesia.
Specifically, anatomic changes in the spinal canal may affect neuraxial
anesthesia techniques. The epidural and vertebral foraminal veins are
enlarged, resulting in an increased risk of intravascular injection.
Additionally, there is decreased nonvascular space in the spinal canal and
decreased egress of epidural anesthetic agents from the epidural space.
Engorged epidural veins42 and increases in abdominal pressure43 are
associated with a decrease cerebral lumbosacral cerebral spinal fluid (CSF)
volume.
Anatomic changes also occur to the ligamentous and bony structures of
the vertebral column. The hormonal changes of pregnancy may cause the
ligamentum flavum to feel less dense and “softer” in pregnant women
compared to nonpregnant patients; thus, it may be more difficult to feel the
passage of the epidural needle through the ligamentum flavum.
Progressive accentuation of lumbar lordosis during pregnancy alters the
relationship of surface anatomy to the vertebral column. The line joining
the iliac crests (Tuffier’s line) assumes a more cephalad relationship to the
vertebral column, and accentuated lumbar lordosis results in less space
between adjacent lumbar spinous processes. The apex of the lumbar
lordosis is shifted caudad during pregnancy, and the typical thoracic
kyphosis in women is reduced in pregnant women.44 This may influence
the spread of hypo- or hyperbaric intrathecal anesthetic solutions in supine
patients.
Subarachnoid dose requirements may also be affected by the lower
specific gravity of CSF in pregnant compared with nonpregnant women45
and the higher CSF pH.46 Widening of the pelvis may lead to a relative
head-down position in women in the lateral position, thus affecting
movement of hypo- or hyperbaric anesthetic solutions in the CSF. Because
of the gravid uterus, it may be more difficult for a pregnant woman to
achieve flexion of the lumbar spine. Finally, labor pain may make it

2981
difficult for women to assume and maintain an ideal position while the
anesthesiologist initiates neuraxial anesthesia.

Neurohormonal Changes and Analgesic Implications

Pregnancy-induced neurohumoral changes may alter responses to pain.
Lower plasma substance P concentrations47 and higher CSF progesterone
levels48 are found in pregnancy. In a rat model, the pregnancy-associated
increased concentration of plasma β-endorphin was associated with an
increased tolerance to visceral stimulation, and this effect was reversed by
naloxone.49 Pain thresholds are increased during pregnancy50 and labor.51
Both peripheral and central nervous tissue from pregnant animals
(including human) appears to be more susceptible to many different
analgesic and anesthetic agents, including local anesthetics, volatile
anesthetic agents, and thiopental. Possible mechanisms of enhanced neural
blockade during pregnancy include potentiation of the analgesic effect of
endogenous analgesic systems, hormone-related changes in the actions of
spinal cord neurotransmitters, increased permeability of the neural sheath,
or other pharmacodynamic or pharmacokinetic differences between
pregnant and nonpregnant women.
Together, these anatomic and physiologic changes result in a 25%
reduction in the segmental dose requirement for spinal anesthesia48 and a
similar segmental dose reduction for epidural anesthesia.52

PHARMACOKINETIC CHANGES
Pregnancy alters disposition of drugs by several mechanisms.53 Volume of
distribution may be altered. For example, the plasma concentration of
antibiotics and, therefore, antimicrobial efficacy are decreased in
pregnancy secondary to a large increase in the volume of distribution.53
Plasma protein concentration decreases, leading to altered drug binding.54
For example, lidocaine is less protein-bound during pregnancy, resulting in
a higher free fraction in the blood.55 Increased renal blood flow and
glomerular filtration and altered hepatic microsomal activity change renal
and hepatic drug clearance.

UTEROPLACENTAL UNIT

2982
Blood flow to the uterus increases markedly during pregnancy, from 50 to
100 mL per minute before pregnancy, to 700 to 900 mL per minute at
term. UBF is directly related to uterine perfusion pressure and indirectly
related to uterine vascular resistance.

UBF is not autoregulated; therefore, decreases in uterine arterial

pressure (systemic hypotension), increases in venous pressure (caval
compression, uterine contraction or increase in uterine tone, Valsalva
maneuver), or increases in uterine vascular resistance (increase in uterine
vasoconstriction relative to systemic vasoconstriction) result in decreased
UBF.
The net effect on UBF of any therapeutic intervention depends on
relative changes in systemic and uterine vessels and effect on uterine tone.
Labor analgesia may directly and indirectly affect UBF, both positively
and negatively. For example, neuraxial analgesia may increase UBF
because of decreased sympathetic outflow (secondary to both pain relief
and direct sympathetic blockade), and decreased maternal
hyperventilation. Conversely, neuraxial analgesia-induced maternal
hypotension may decrease UBF. Additionally, neuraxial analgesia may be
associated with transient uterine tachysystole secondary to an acute
decrease in circulating epinephrine levels56 and loss of its tocolytic (β2-
adrenergic agonism) effects.57 Uterine tachysystole may also result from
high concentrations of local anesthetic in uterine tissue, for example, after
a paracervical block.58

Transfer of Drugs across the Placenta

Most drugs administrated to the mother cross the placenta to the fetus to
some degree. Placental transfer depends on several factors, including
plasma drug concentration and electrochemical gradients across the
placenta, molecular weight, lipid solubility, degree of ionization,
membrane surface area and thickness (changes during pregnancy),
maternal and fetal blood flow, placental binding and metabolism, and
degree of maternal and fetal protein binding. Direct drug teratogenicity

2983
may manifest as death, structural abnormalities, growth restriction, and
functional deficiencies. Teratogenic potential is influenced by the timing
of exposure, drug dose, duration of exposure, and genetic predisposition.59
The risk of structural teratogenicity is greatest during the period of
organogenesis (day 31 to 71 after the first day of the last menstrual
period). Functional or behavioral teratogenicity may result from drug
exposure during pregnancy, and even after birth, as the central nervous
system continues to develop during this period.60 Nondrug teratogens
include hypoxia, hypercarbia, hyperthermia, hypoglycemia, and ionizing
radiation.

Nonpharmacologic Methods of Labor Analgesia

Nonpharmacologic methods to relieve the pain and suffering of childbirth
include childbirth education, emotional support, massage, aromatherapy,
audiotherapy, and therapeutic use of hot and cold. More specialized
techniques that require specialized training or equipment include
hydrotherapy, intradermal water injections, biofeedback, transcutaneous
electrical nerve stimulation (TENS), acupuncture or acupressure, and
hypnosis. Many of these techniques are inadequately studied in that study
quality is poor and sample size is small,61,62 and therefore, conclusions
about efficacy are not possible.

ANTENATAL CHILDBIRTH EDUCATION

Childbirth education is widely practiced. Unfortunately, studies of
childbirth education lack scientific rigor. Study results are inconsistent as
to whether participation in childbirth education classes influences
outcomes, such as use of analgesia, duration of labor, mode of delivery,
and incidence of nonreassuring fetal status.

LABOR SUPPORT
Emotional support is commonly provided by the parturient’s husband or a
friend. “Continuous labor support” refers to the nonmedical support of the
parturient by a trained person. Prospective, controlled trials and several
systematic analyses have concluded that women who receive continuous

2984
labor support have shorter labors, fewer operative deliveries, fewer
analgesic interventions, and greater satisfaction.63

HYDROTHERAPY
Hydrotherapy is the immersion of the parturient in warm water (deep
enough to cover the abdomen) during labor (not birth). Systematic reviews
of randomized controlled trials have concluded that women experience
less pain and use less analgesia without change in the duration of labor,
rate of operative delivery, or neonatal outcome.64

INTRADERMAL WATER INJECTIONS

Intradermal water injection consists of the injection of 0.05 to 0.1 mL of
sterile water, using an insulin or tuberculin syringe, at four sites on the
lower back: over each posterior superior iliac crest, and 1 cm medial/3 cm
caudad to these injections (Fig. 56.7). The technique is used to treat back
pain during labor. The injections themselves are acutely painful for about
20 to 30 seconds, but as the injection pain fades, so does lower back pain.
A 2012 systematic review that included seven studies and 766 study
subjects reported a greater reduction in pain scores in women who
received sterile water injections compared with women in the control
group.65 However, the authors determined that a meta-analysis of the data
was not appropriate and four studies were at high risk of bias. Further
study is warranted.

FIGURE 56.7 Placement of intradermal water blocks: four intradermal injections of 0.05 to 0.1
mL of sterile water to form four small blebs over each posterior superior iliac spine and 3 cm below

2985
and 1 cm medial to each spine. The exact locations of the injections do not appear to be critical to
the block success. (Redrawn after Simkin P, Bolding A. Update on nonpharmacologic approaches
to relieve labor pain and prevent suffering. J Midwifery Womens Health 2004;49[6]:489–504.
Copyright © 2004 American College of Nurse Midwives. Reprinted by permission of John Wiley &
Sons, Inc.)

HYPNOSIS
Self-hypnosis for treatment of childbirth pain has been practiced for
several centuries. Hypnosis requires prenatal training of the mother, and
sometimes her partner, by a trained hypnotherapist. A meta-analysis of
nine randomized controlled trials that included 2,954 women found the
overall use of pharmacologic analgesia methods was decreased in the
hypnosis compared to control groups, but neuraxial analgesia use was
not.66 Data were inconclusive or limited regarding progress of labor and
neonatal outcomes.

TRANSCUTANEOUS ELECTRICAL STIMULATION

TENS involves the application of low-intensity, high-frequency electrical
impulses to the skin of the lower back. The buzzing, electrical current
sensation caused by the TENS unit may reduce the mother’s awareness of
contraction pain. Studies of TENS are inconsistent, but in general, labor
pain does not appear to be lessened or is the use of other analgesic
modalities.67

ACUPUNCTURE AND ACUPRESSURE

Acupuncture is a component of traditional Chinese medicine that has
gained popularity in Western cultures in recent years. A 2011 systematic
review concluded that the use of acupuncture and acupressure during labor
may have a role in reducing pain and the need for pharmacologic
analgesia.68 However, authors of a 2014 review of systematic reviews of
acupuncture therapy during labor concluded that the trials included in this
and other systematic reviews differ in terms of study design and outcome
measures, and therefore, it may be inappropriate to include the studies in a
pooled analysis.62 Further study is warranted.

Systemic Analgesia

2986
INHALATIONAL ANALGESIA
Inhalation analgesia for labor and vaginal delivery, common in other
countries, is gaining popularity in the United States. The only inhaled
anesthetic agent currently in common use is nitrous oxide. It is
commercially available as a mixture of 50% nitrous oxide and 50%
oxygen. Special equipment is required to ensure the safe administration of
the drug without contamination of the labor room. The mother must be
taught to breathe the mixture correctly, so that peak brain nitrous oxide
concentrations coincide with peak contraction pain. Studies are conflicting
as to whether nitrous oxide provides benefit to the parturient; most studies
are of a poor quality.69 Although the intermittent use of nitrous oxide
appears safe for the fetus and neonate, neonatal studies are also of poor
quality.69 There is accumulating evidence that nitrous oxide use in other
settings may not be benign; neurologic, genologic, and hematologic
toxicity as well as adverse immunologic effects have been described.70
Risk may depend on genotype71; thus, further study of its use for childbirth
analgesia is warranted.71,72 The concomitant use of nitrous oxide and
systemic opioids may increase the risk of maternal hypoxemia.

PARENTERAL OPIOID ANALGESIA

Systemic opioid analgesia, administered by the subcutaneous,
intramuscular, or intravenous route, is widely used around the world either
as the sole analgesic modality or prior to the administration of regional
labor analgesia.73 The use of systemic opioids for labor analgesia lacks
rigorous scientific study. There is a high incidence of side effects (e.g.,
sedation, nausea, and vomiting), and analgesia is incomplete, at best,
during active labor.74,75 Historically, meperidine has been the most
commonly used systemic opioid; however, its use in the United States has
declined in the past decade as practitioners have come to better appreciate
its long maternal and neonatal half-life and that of its active metabolite,
normeperidine. There is little scientific evidence that any one opioid is
better than another. All have dose-related, maternal, fetal, and neonatal
side effects. Maternal side effects include nausea, vomiting, delayed
gastric emptying, dysphoria, and respiratory depression. All opioids cross
the placenta. In utero, opioids may result in a slower fetal heart rate and

2987
decreased beat-to-beat variability.76 The likelihood of neonatal respiratory
depression depends on the dose and timing of administration.

Patient-Controlled Intravenous Analgesia

Patient-controlled intravenous analgesia (PCIA) has theoretical advantages
to nurse-administered opioid analgesia, including superior analgesia with
smaller drug doses, resulting in a lower incidence of side effects. PCIA
studies have been reported using meperidine, nalbuphine, fentanyl, and,
more recently, remifentanil with and without a background infusion.
Remifentanil has the theoretical advantage of rapid onset and offset
compared to the other opioids, although its peak effect still occurs after the
contraction if the parturient self-administers a bolus dose at the beginning
of a contraction. Multiple studies have used different bolus doses, rates of
bolus-dose administration, lockout intervals, and background infusion
rates. In a 2016 review, Van de Velde and Carvalho77 suggested a fixed
bolus dose of 20 to 50 µg with a lockout interval of 1 to 3 minutes and no
background infusion. The bolus dose may require upward adjustment as
labor progresses. However, as with other systemic opioid techniques, it is
unclear whether remifentanil PCIA can provide satisfactory analgesia
without an unacceptably high incidence of side effects.78 In a randomized
trial comparing epidural to remifentanil PCIA, apnea episodes were
recorded in 53% of women in the remifentanil group.79 Monitoring oxygen
saturation (SpO2) was insufficient to identify most of the apnea episodes.79
Experts agree that remifentanil PCIA should only be used when the
parturient is under continuous observation by a midwife or labor nurse.78

Neuraxial Analgesia
Neuraxial labor analgesia is the most effective method of pain relief during
childbirth and the only method that provides complete analgesia without
maternal or fetal sedation. The use of neuraxial analgesia for childbirth has
increased dramatically in the United States over the past 40 years.9 The
most common techniques are continuous lumbar epidural analgesia and
combined spinal-epidural (CSE) analgesia. Single-shot spinal, continuous
spinal, and caudal analgesia are occasionally used.

2988
 Contraindications to neuraxial analgesia and anesthesia include patient
refusal, infection at the puncture site, preexisting coagulopathy, and lack
of experienced anesthesia providers. Relative contraindications include
hemorrhage or other causes of hypovolemia, untreated systemic infection,
preload-dependent disease states, and lumbar spine pathology. The
anesthesiologist should weigh the risk and benefits of a neuraxial
procedure for each patient, and the specific neuraxial analgesic technique
should be tailored to individual patient needs. The risks and benefits of the
procedure should be discussed with each parturient, preferably early in
labor. The advantages and disadvantages of specific neuraxial techniques
are listed in Table 56.2.

TABLE 56.2 Advantages and Disadvantages of Specific Neuraxial

Techniques for Labor Analgesia
Analgesia Technique
Combined
Continuous Spinal- Single-Shot Continuous
Epidural Epidural Spinal Spinal Caudal
Advantages Continuous Rapid Rapid onset Rapid onset Ability to
technique onset Technically Early sacral access
No dural Early easier block epidural space
puncture sacral Early sacral Low dose of in patient
Ability to block block anesthetic with lumbar
convert to Low dose Continuous epidural
epidural of technique pathology
anesthesia anesthetic Ability to
Complete convert to
early labor spinal
analgesia anesthesia
with
opioid
onlya
Disadvantages Slow onset Requires Requires Requires Requires large
Requires dural dural dural volume/mass
greater mass of puncture puncture puncture of anesthetic
anestheticb Limited with large to block T10
Delayed sacral duration of gauge dermatome
blockade/sacral analgesia needlec
sparing Potential for
accidental
intrathecal
injection of

2989
 epidural
dose of
anesthetic
agents
aLarge doses of epidural opioid may provide near-complete analgesia for early labor but at the
expense of significant systemic absorption and with accompanying side effects.
bGreater vascular absorption of anesthetic agents and greater likelihood for accidental intravascular

injection of a toxic amount of local anesthetic.

cIncreased risk of postdural puncture headache.
dMay not be able to achieve T4 sensory blockade necessary for cesarean delivery.

EPIDURAL ANALGESIA
Lumbar epidural analgesia has been the mainstay of regional labor
analgesia. Placement of an epidural catheter allows analgesia to be
maintained until after delivery. Additionally, it allows conversion to
epidural anesthesia should cesarean delivery be necessary. No dural
puncture is required. Randomized studies consistently demonstrate that
pain scores are lower and patients are more satisfied with epidural
analgesia compared to nonneuraxial analgesia.80 Injection of anesthetics in
the lumbar epidural space allows spread of the anesthetic solution both
cephalad and caudad. Neural blockade to the T10 dermatome is necessary
to relieve uterine and cervical pain, whereas blockade of the sacral
dermatomes is necessary to block the pain of vaginal and perineal
distention.
Compared to spinal analgesic techniques, the onset of epidural analgesia
is significantly slower (15 to 20 minutes compared to 2 to 5 minutes),
particularly the onset of sacral analgesia. It may take several hours of
lumbar epidural infusion, or several bolus injections of local anesthetic
into the lumbar epidural space, to achieve sacral analgesia. This is
particularly disadvantageous in a rapidly laboring parturient who requires
rapid onset of sacral analgesia for the late first and second stages of labor.
In addition, epidural compared to spinal analgesia requires significantly
more drug(s) to attain comparable analgesia, thus increasing the risk of
systemic toxicity. Finally, there is significantly more systemic absorption
of anesthetic agents, and therefore, maternal and fetal plasma drug
concentrations are higher with epidural compared to spinal analgesia.
Lumbar epidural analgesia is initiated in either the sitting or lateral

2990
position. The epidural space is identified with a 17 or 18G epidural needle,
usually using a loss-of-resistance to air of saline technique. A flexible
catheter is passed through the needle approximately 4 to 5 cm into the
epidural space, the epidural needle is removed, and the catheter is secured.
A test dose is frequently administered to rule out intrathecal or
intravascular catheter placement. The most common test dose is lidocaine
15 mg/mL with epinephrine 5 µg/mL, 3 mL. No matter whether a test dose
is injected, drugs should be injected incrementally into the epidural space,
as no test is 100% sensitive and catheters may migrate during use.
Pregnant women are very difficult to resuscitate from local anesthetic
systemic toxicity.
Analgesia is initiated by bolus injection of anesthetic(s) through the
epidural needle, catheter, or both. Analgesia is maintained with
intermittent bolus injections or a continuous infusion. The catheter is
removed after delivery when there is no further need for
analgesia/anesthesia.

Drugs for Initiation of Epidural Analgesia

Drugs commonly used for epidural labor analgesia are listed in Table 56.3.
Local anesthetics, primarily bupivacaine, have been the mainstay of
epidural analgesia for many years. The amount of epidural local anesthetic
required for satisfactory analgesia increases as labor progresses.81 Low
bupivacaine concentrations (≤1.25 mg/mL) provide excellent analgesia
with minimal motor block. The ED50 of bupivacaine 1.25 mg/mL was
lower than the ED50 of bupivacaine 2.5 mg/mL, suggesting that the use of
low concentrations is associated with less overall drug requirement.82
Bupivacaine is highly protein-bound with minimal placental transfer,83 and
duration of analgesia is approximately 2 hours. Onset to peak effect is
approximately 20 minutes. Lidocaine and 2-chloroprocaine have shorter
latency, but their duration of analgesia is shorter, limiting their usefulness
for routine labor analgesia. In addition, lidocaine is less protein-bound than
bupivacaine and therefore has a higher umbilical vein/maternal vein
ratio.84 2-Chloroprocaine is most useful for rapidly converting epidural
analgesia to epidural anesthesia for urgent operative delivery.

2991
 TABLE 56.3 Typical Drugs for Initiation of Epidural Labor
Analgesia
Drug Concentration
Local Anestheticsa Dose (Volume)
Bupivacaine 1.00–1.25 mg/mL 10–15 mL
Ropivacaine 1.0–2.0 mg/mL 10–15 mL
Opioidsa Dose (Mass)
Fentanyl — 50–100 µg
Sufentanil — 5–10 µg
Adjuvants
Epinephrine 1.25–5.00 µg/mL —
Clonidineb — 60–75 µgc
NOTE: The actual drug dose will depend on the stage of labor (women in advanced labor require
higher doses), the progress of labor (women with rapid progress of labor will require higher
doses), and whether or not an anesthetic containing test dose has been administered.
aLocal anesthetics and opioids are commonly administered together, in which case a lower dose of

each is required.
bClonidine is not approved for use in obstetric patients in the United States.
cThis dose should be combined with local anesthetics, as higher doses used alone cause sedation

and hypotension.

Ropivacaine is a homologue of bupivacaine, formulated as a single

levorotatory enantiomer. Its onset and duration of action are similar to
bupivacaine,85 but it has less potential for cardiac toxicity. Although
potency studies suggest that ropivacaine is approximately 40% less potent
than bupivacaine,86 clinical studies comparing low concentrations of
ropivacaine and bupivacaine for labor analgesia suggest that they are
equipotent in terms of sensory blockade for labor analgesia.87,88 However,
ropivacaine may be associated with less motor blockade than equipotent
doses of bupivacaine.89 Levobupivacaine, the S-enantiomer of
bupivacaine, is not available in the United States. Similar to ropivacaine
and bupivacaine in its onset and duration of action, it is less cardiotoxic
than bupivacaine and is associated with less motor blockade compared to
bupivacaine.87,89
Opioids, particularly the lipid-soluble opioids, fentanyl and sufentanil,
are commonly added to local anesthetics for epidural analgesia. Epidural
opioids and local anesthetics interact synergistically to provide
analgesia.90,91 The addition of opioids shortens latency; allows for

2992
decreased concentration of local anesthetic, thus decreasing motor block;
and prolongs analgesia. Although epidural opioids alone can provide
moderate analgesia for early labor, analgesia is incomplete, and the
necessary dose is accompanied by bothersome side effects (e.g., pruritus,
nausea, vomiting, maternal sedation, neonatal respiratory depression).
Combining local anesthetics with opioids allows for effective analgesia
while minimizing the side effects of both drugs.
Fentanyl and sufentanil are ideal for labor analgesia because of their
rapid onset (5 to 10 minutes). Their short duration of action (60 to 90
minutes) is overcome by maintaining analgesia with a continuous epidural
infusion. Doses commonly used for epidural analgesia initiation and
maintenance have been shown to be safe for both the mother and
neonate.92,93 Morphine has a much slower onset (30 to 60 minutes) and
longer duration of action (12 to 24 hours) than fentanyl or sufentanil. The
long duration of action is not beneficial, as the bothersome side effects of
morphine (pruritus, nausea, and vomiting) continue to be present after
delivery.
Adjuvants for epidural labor analgesia include epinephrine and
clonidine. Epidural epinephrine may contribute to analgesia by decreasing
the uptake of local anesthetics and opioids from the epidural space
secondary to vasoconstriction and by binding to spinal cord α2-adrenergic
receptors.94 Clonidine also binds to α2-adrenergic receptors and has been
shown to supplement epidural labor analgesia. The U.S. Food and Drug
Administration (FDA) has not approved neuraxial clonidine for use in
obstetric patients because of the risks of sedation and hypotension.
However, it is useful for the treatment of breakthrough pain (75 to 100 µg)
when the administration of additional local anesthetic is likely to
contribute to worsening motor block; any resulting hypotension is usually
readily treated.95

COMBINED SPINAL-EPIDURAL ANALGESIA

CSE analgesia has become increasingly popular for labor analgesia. There
are advantages and disadvantages to CSE compared to traditional epidural
analgesia (see Table 56.2). Onset of analgesia is significantly faster
compared to epidural analgesia.96 Complete analgesia for early labor can

2993
be accomplished with the intrathecal injection of lipid-soluble opioids
without the addition of local anesthetics, thus avoiding motor blockade and
decreasing the risk of hypotension. This is ideal for patients who wish to
ambulate, or for those with preload-dependent conditions such as stenotic
heart lesions. The effective opioid dose is significantly less than for
systemic or epidural administration. Therefore, systemic drug absorption is
minimal, as are direct fetal effects. The addition of local anesthetic to a
lipid-soluble opioid results in sacral analgesia within several minutes. This
is a decided advantage compared to lumbar epidural analgesia, as sacral
analgesia is difficult to accomplish after a single lumbar epidural dose of
local anesthetic. Therefore, CSE analgesia provides more complete
analgesia for women in advanced stages of labor or women whose labor is
progressing rapidly. Finally, use of the CSE technique may decrease the
incidence of failed epidural analgesia (e.g., a nonfunctioning epidural
catheter).97
There are several undesirable side effects of CSE analgesia. The
incidence of pruritus is higher with intrathecal versus epidural opioids.96
Dural puncture is required to initiate CSE analgesia. The risk of postdural
puncture headache (PDPH) may be minimally higher with the CSE
compared to pure epidural technique (estimated excess rate of 3 in
1,000).98 However, a more serious concern is that dural puncture in the
obstetric patient may be a risk factor for postpartum neuraxial infection, a
rare but potentially life-threatening complication.99
Several techniques for CSE analgesia/anesthesia have been described,
including using two skin punctures in two interspaces, two punctures in
one interspace, and the needle-through-needle technique.98 The most
common CSE technique for labor analgesia is the needle-through-needle
technique in a midlumbar interspinous space. The epidural space is
identified with an epidural needle in the standard fashion. The epidural
needle then functions as an introducer needle as a long spinal needle is
passed through it until the dura is punctured. The intrathecal drug(s) is
injected through the spinal needle, the spinal needle is withdrawn, and an
epidural catheter is threaded through the epidural needle. Analgesia is
maintained via the epidural catheter, as with traditional epidural analgesia.

2994
Drugs for Initiation of Combined Spinal-Epidural Analgesia
CSE labor analgesia is usually initiated with a lipid-soluble opioid
(fentanyl or sufentanil) or a combination of opioid and local anesthetic
(Table 56.4). Morphine is not commonly used because of its long latency
and long duration of action (a disadvantage, as women usually deliver
before regression of side effects). However, morphine has been
successfully combined with intrathecal bupivacaine and fentanyl in order
to shorten latency and increase duration of analgesia.100 This combination
of drugs may be particularly useful in settings where continuous epidural
infusion techniques are impractical.100 Meperidine is unique among the
opioids in that it has weak local anesthetic properties. However,
meperidine was associated with a significantly higher incidence of nausea
and vomiting compared to combined fentanyl and bupivacaine.101

TABLE 56.4 Drugs for the Initiation of Intrathecal Labor

Analgesia
Drug(s)a Opioid Dose (μg) Bupivacaine Dose (mg)
Fentanyl 15–25 —
Sufentanil 5–7.5 —
Bupivacaine-fentanyl 10–15 1.25–2.5
Bupivacaine-sufentanil 1–2.5 1.25–2.5
Bupivacaine-fentanyl-morphineb Fentanyl 12.5–25 2.0–2.5
Morphine 200–250 2.0–2.5
a
Opioids alone provide complete analgesia for early labor, but the addition of local anesthetics is
required for late first-stage and second-stage analgesia.
b The combination of bupivacaine-fentanyl-morphine may be advantageous in the settings where

continuous epidural infusions for maintenance of analgesia are impractical and single-shot
techniques are an alternative.

Intrathecal opioids can provide complete analgesia early in labor when

the pain stimuli are primarily visceral. Onset of analgesia occurs within 5
minutes and lasts 70 to 100 minutes.102 The reported ED95 of intrathecal
fentanyl varies from 14 to 23 µg.103,104 The relative potency ratio of
intrathecal sufentanil to fentanyl for labor analgesia is 4.4:1.102 When
administered at twice the ED50, the duration of sufentanil analgesia was 25
minutes longer than fentanyl, although the incidence of side effects was
not different.102 The duration of action of intrathecal opioids is dose-

2995
related, although fentanyl doses greater than 25 µg do not increase
duration of analgesia and are associated with a higher incidence of side
effects.103
In the late first stage and second stage of labor, local anesthetic must be
added to the opioid to block somatic stimuli from the vagina and
perineum. The local anesthetic works synergistically with the opioid; thus,
lower doses of both drugs can be used.105 Bupivacaine is most commonly
combined with fentanyl or sufentanil. The ED95 of bupivacaine combined
with sufentanil 1.5 µg was 3.3 mg106 and was 1.66 mg when combined
with fentanyl 15 µg.107 Bupivacaine doses between 1.25 to 2.5 mg are
commonly used. Levobupivacaine and ropivacaine are not approved for
intrathecal use in the United States. They are less potent than bupivacaine
for intrathecal labor analgesia.106
Bupivacaine without opioid is not commonly used for labor analgesia.
Doses high enough to provide analgesia are associated with significant
motor blockade, and lower doses either do not provide satisfactory
analgesia or are associated with an unacceptably short duration of
action.108

MAINTENANCE OF EPIDURAL ANALGESIA

Epidural analgesia may be maintained with intermittent bolus injection,
continuous epidural infusion, patient-controlled epidural analgesia
(PCEA), with or without a background infusion or programmed
intermittent epidural bolus injections. Continuous epidural infusions result
in less need for bolus injections109,110 and increased patient satisfaction111
but higher total drug dose109,111 compared to intermittent injections.
However, the infusion of lower concentration bupivacaine at a higher rate
may result in similar analgesia with less motor block and no increase in
total dose.111,112 Common infusion solutions and protocols are listed in
Table 56.5.

TABLE 56.5 Drug Solutions for Maintenance of Epidural Labor

Analgesia
Local Anesthetic
Concentration Opioid Concentration

2996
 Drug Solution (mg/mL) (μg/mL)
Bupivacaine-fentanyl 0.625–1.25 2–4
Bupivacaine-sufentanil 0.625–1.25 0.20–0.33
Ropivacaine-fentanyl 0.8–1.5 2–4
Ropivacaine 2.0 —
NOTE: Continuous infusions rate: 10 to 15 mL/hour. Patient-controlled epidural analgesia (PCEA)
parameters: PCEA bolus 5 to 10 mL, lockout interval 10 to 20 minutes, background infusion 0 to
15 mL/hour (commonly 30% to 50% of hourly dose requirement).

PCEA allows for both a continuous epidural infusion and patient-titrated

bolus injections. PCEA results in greater patient satisfaction and a lower
average hourly dose of bupivacaine (and therefore less motor block) and
less need for physician intervention.113,114 The protocols for PCEA vary
widely, and it is unclear whether this affects analgesia and outcome. At
one extreme, most of the hourly dose is administered via a background
infusion which the parturient may supplement with self-administered
boluses. At the other extreme, there is no background infusion and the
entire dose is self-administered via intermittent boluses. Bupivacaine
consumption is higher with background infusions compared to a pure
PCEA technique without a background infusion.115 Although data are
conflicting as to whether a background infusion improves analgesia,114,116
it may be helpful in selected parturients (e.g., nulliparas with long
labors).114 Solutions for PCEA generally mimic those used for continuous
infusions (see Table 56.5). The parturient administered bolus dose is 5 to
10 mL, the lockout interval is 10 to 20 minutes, and the background
infusion varies from 0 to 15 mL. Commonly, 30% to 50% of the hourly
dose is administered as a background infusion.
The bolus administration of epidural anesthetic solution appears to
result in improved analgesia with a lower total drug dose compared with
continuous infusion administration. Historically, the anesthesia provider or
the patient (PCEA) administered a bolus dose, whereas an infusion pump
delivered a continuous infusion. In a new mode for maintaining epidural
analgesia, the infusion pump is programmed to intermittently administer a
bolus dose rather than a continuous infusion. Compared with continuous
infusion analgesia or PCEA, programmed intermittent epidural bolus
analgesia results in improved parturient satisfaction, less drug use, longer
duration of analgesia, and less breakthrough pain compared to a

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continuous infusion of the same mass of drug per unit time.117,118 There
may be better distribution of anesthetic solution within the epidural space
when large volumes are injected as a bolus compared to a slow infusion.
The optimal bolus volume, interval, and administration rate have yet to be
determined. Most clinicians are currently using programmed bolus
volumes between 5 and 10 mL, administered every 30 to 60 minutes.117

OTHER CENTRAL NEURAXIAL TECHNIQUES

Single-Shot and Continuous Spinal Analgesia
In general, single-shot spinal analgesia is not useful for most laboring
patients because of its limited duration of action. It may be indicated in
parturients who require analgesia or anesthesia shortly before anticipated
delivery or in settings where continuous epidural analgesia is not possible.
Drugs for single-shot spinal analgesia mimic those used for the initiation
of CSE analgesia (see Table 56.4).
Continuous spinal analgesia is currently not practical for most
parturients. The 23G spinal catheter that is available in the United States is
inserted using a “catheter-over-needle” technique. An initial observational
trial reported that the catheter may have clinical utility119; however, further
study is required to characterize ease of use and complications, particularly
the rate of PDPH. The placement of a continuous spinal catheter is a
management option in patients with unintentional dural puncture with an
epidural needle or when rapid analgesia is necessary in an obese patient. In
this case, the “epidural” catheter is threaded into the subarachnoid space.
Care must be taken not to confuse a catheter sited in the subarachnoid
space with one sited in the epidural space, given the much larger anesthetic
dose required for epidural analgesia. Continuous spinal labor analgesia is
commonly maintained with the same solution used for epidural analgesia
but at a rate of 1 to 2 mL per hour.

Dural Puncture Epidural Analgesia

Dural puncture epidural (DPE) analgesia is a modification of CSE
analgesia that aims to exploit the advantages of the CSE analgesia without
its attendant disadvantages. The technique mimics that of CSE analgesia,
except that no drug is injected into the subarachnoid space after puncturing

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the dura with a spinal needle. It is hypothesized that the dural puncture
made by the spinal needle augments transdural migration of the local
anesthetic/opioid solution injected into the epidural space, resulting in
faster onset and improved sacral analgesia compared with epidural
analgesia. Studies are conflicting as to whether DPE offers an advantage
compared to epidural or CSE analgesia120–123; further investigation is
warranted.

Caudal Analgesia
Continuous caudal epidural analgesia is used infrequently in the practice of
modern obstetric anesthesia. Large volumes of local anesthetic are
required for first-stage analgesia and result in higher maternal plasma
concentrations of drug. There is a risk of needle/catheter misplacement and
direct injection into the fetus. However, this technique is an option in
patients in whom access to the lumbar neuraxial canal is not possible (e.g.,
fused lumbar spine).

SIDE EFFECTS OF NEURAXIAL ANALGESIA

Common side effects of neuraxial labor analgesia include hypotension and
pruritus. Other side effects include urinary retention, delayed gastric
emptying (after opioid techniques but not pure local anesthetic
techniques), oral herpes simplex virus recrudescence, shivering, maternal
hyperthermia, and fetal bradycardia.

Hypotension
Blockade of the sympathetic nervous system by local anesthetics causes
vasodilation, increased venous capacitance, and decreased afterload.
Hypotension may result in decreased uteroplacental perfusion and fetal
heart rate decelerations or bradycardia. Therefore, maternal blood pressure
and fetal heart rate should be monitored for 15 to 30 minutes after the
induction of neuroblockade. Although intravenous volume expansion prior
to initiating neuraxial analgesia has traditionally been used to reduce the
incidence and degree of hypotension, it is not clear that this has any real
benefit with modern low-dose neuraxial labor analgesia techniques.124 The
mother should be positioned in the full lateral position after initiation of

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neuraxial blockade, and hypotension should be treated with small bolus
doses of intravenous vasopressor.

Pruritus
Pruritus is common side effect of neuraxial opioid administration. It is
more common after intrathecal (as high as 100%) than epidural
administration, and the incidence and severity are dose-related.104,108 The
cause is unknown, but it is not thought to be histamine-related. Pruritus
may be generalized or localized to the nose, face, or chest and is typically
self-limited. Concomitant local anesthetic administration decreased the
incidence and severity of pruritus compared to fentanyl alone,125 whereas
the addition of epinephrine worsened the pruritus.126 The one-time
administration of naloxone (40 to 80 µg) or nalbuphine (2.5 to 5 mg) is
usually effective for the treatment of pruritus induced by fentanyl or
sufentanil. A naloxone infusion may be required for the treatment of
morphine-induced pruritus.

Fetal Bradycardia
Fetal bradycardia, not associated with maternal hypotension, occurs after
initiation of both epidural and CSE analgesia, although the incidence is
likely higher after CSE analgesia.127 Clarke and colleagues128
hypothesized that fetal bradycardia may be due to the acute decrease in
plasma epinephrine levels following the initiation of neuraxial analgesia.56
Epinephrine is a tocolytic, and the acute decrease in maternal plasma
concentration may result in temporary imbalance of uterine
tocolytic/tocodynamic forces, resulting in uterine tachysystole, decreased
uterine perfusion, and, ultimately, fetal bradycardia. Nitroglycerin has
been used successfully to treat uterine tachysystole associated with the
initiation of neuraxial analgesia.129

Maternal Hyperthermia
Epidural labor analgesia is associated with maternal fever (temperature
≥38° C) in some women.130 In randomized controlled trials, the incidence
ranges between 20% and 30%.130 The mechanism is unclear; current
evidence supports a noninfectious inflammatory mechanism. It is also not

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