C A C a n c e r J C l i n 1 9 9 4 ; 4 4 : 2 6 2 - 3 0 3
The Management of Cancer Pain
Nathan I. Cherny, MBBS, FRACP
Russell K. Portenoy, MD
Abstract
Surveys indicate that clinicians are fre-
quently ill equipped to treat cancer pain.
Pain is often poorly assessed, and many
caregivers lack sufficient knowledge to op-
timize treatment. Effective management
requires an understanding of pain patho-
physiology, the ability to identify and eval-
uate pain syndromes, and familiarity with
proven therapeutic strategies. Opioid
pharmacotherapy is the mainstay of treat-
ment. Practical aspects of opioid therapy
include selection of both drug and route,
dose titration, and management of side ef-
fects. Specific strategies for the manage-
ment of patients who are unable to attain
an acceptable balance between pain relief
and side effects include both noninvasive
interventions (such as adjuvant analgesics,
psychological therapies, and physiatric
techniques) and invasive interventions
(such as the use of intraspinal opioids,
neural blockade, and neuroablative thera-
pies). Sedation is an option at the end of
life for the treatment of pain that is refrac-
Dr. Cherny, a former Fellow in the Pain Service of
Memorial Sloan-Kettering Cancer Center in New
York, New York, is now a Pain and Palliative Care
Physician in the Department of Internal Medicine of
the Shaare Zedek Medical Center in Jerusalem,
Israel.
Dr. Portenoy is the Director of Analgesic Studies in
the Pain Service, Department of Neurology of the
Memorial Sloan-Kettering Cancer Center in New
York, New York.
This article is a revised and updated version of a
paper originally published in Cancer. Adaptation
published with permission of Cancer 1993;72-
(suppl):3393-3415. Used with permission of J.B.
Lippincott Company.
262
tory to other interventions. These ap-
proaches can provide adequate relief to
the vast majority of patients, most of
whom will respond to systemic pharma-
cotherapy alone. Patients with refractory
pain should have access to specialists in
pain management or palliative medicine.
Introduction
Numerous surveys indicate that pain is
experienced by about one third of cancer
patients during active therapy and more
than two thirds of those with advanced
disease.1-7 Unrelieved pain can be inca-
pacitating and preclude a satisfying quali-
ty of life. Pain interferes with physical
functioning and social interaction and is
strongly associated with heightened psy-
chological distress.4,8-10 Relief of pain is a
compelling therapeutic goal for those
who care for this population.
Despite the widespread acceptance
of a highly effective therapeutic strategy
for the management of cancer pain (Fig.
1), surveys suggest that more than 40
to 50 percent of patients in routine prac-
tice settings fail to achieve adequate re-
lief.2,4-6,11,12 There are numerous barriers
to effective pain management (Table
1),9,13-16 among which is clinician under-
treatment. Studies have revealed that pa-
tients who complain of severe pain may
not be believed by a physician,17 pain as-
sessment is often inadequate,9,12,14,15,18,19
and knowledge of approaches to pain
management is often rudimentary.12,18 In
a survey of 1,177 cancer specialists, only
51 percent reported that patients in their
treatment setting attained adequate re-
Ca—A cancer Journal for Clinicians
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Comprehensive Assessment

Primary therapy Systemic nonopioid and opioid analgesic

Surgery Selection of agent
Chemotherapy Practical aspects of administration:
Radiation therapy Route
Antibiotic Schedule
Management of side effects

If balance between pain relief and side effects is suboptimal, consider...

Noninvasive strategies to improve balance between analgesia and side effects

Reduce opioid requirement:
Appropriate primary therapy
Addition of nonopioid analgesic
Addition of an adjuvant analgesic
Use of cognitive or behavioral techniques
Use of an orthotic device or other physical medicine approach
Switch to another opioid

If balance between pain relief and side effects is suboptimal, consider...

Invasive strategies to improve balance between analgesia and side effects

Regional analgesic techniques (spinal or intraventricular opioids)
Neural blockade
Neuroablative techniques

If balance between pain relief and side effects is suboptimal, consider...

Role of sedating pharmacotherapy

Fig. 1. A strategy for the management of cancer pain.

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 t h e M a n a g e m e n t o f C a n c e r p a i n

Table 1
The Barriers to Effective Pain Management

Clinician-Related Factors
Uncertainty about the role of opioid therapy
Patients with early disease
Patients with indolent metastatic disease
Patients with treatment-related pain
Undertreatment
Caused by deficiencies in knowledge of analgesic
pharmacotherapy
Caused by failure of assessment
Caused by overestimation of risks
–risk of adverse effects
–risk of addiction
–risk of tolerance
Caused by physician concern about regulation of controlled
prescription drugs

Patient-Related Factors
Ineffectual pain reporting
Caused by desire to focus on treatment of tumor
Caused by stoicism
Caused by desire to please the staff
Caused by use of pain to follow course of disease
Fear of opioid drugs
Fear of adverse reactions
Fear of addiction
Fear of tolerance
Poor compliance
Inability to comply with complicated program
Inadequate understanding of dosing guidelines

Other Factors
Supply
Lack of adequately skilled clinicians
Pharmacies that fail to maintain opioid supply
Economic
Excessive cost
Inadequate insurance

Adapted with permission from Portenoy.13

264 Ca—A cancer Journal for Clinicians

 C A C a n c e r J C l i n
lief.12 The small number of comprehen-
sive cancer centers that have allocated re-
sources to cancer pain and palliative care
and the limited exposure given to the
management of cancer pain at national
oncology meetings20 suggest a low priori-
ty for much of the cancer establishment.
Indeed, until recently there were no for-
mal guidelines for the education of cancer
specialists in the management of cancer
pain.21 Improved outcome can only be
achieved if the problem is recognized,
and education of clinicians in well-estab-
lished techniques of pain assessment and
management becomes commonplace.
Assessment of Cancer Pain
The assessment of patients with cancer
should routinely incorporate inquiries
about the presence and severity of pain.
A practical approach to the assessment of
cancer pain incorporates a sequence of
steps that begins with data collection and
ends with the formulation of a prioritized
problem list and a therapeutic plan
(Table 2).22
Initial data collection (Step 1) in-
volves a careful medical and psychosocial
history, physical examination, and review
of all pertinent prior investigations. Pa-
tient self-report is the gold standard for
the assessment of pain intensity.17,23-25
The use of a validated quantitative pain
assessment tool such as a 10-point verbal
scale, a 100-mm visual analogue scale,26,27
or instruments such as the Memorial Pain
Assessment Card28 or the Brief Pain In-
ventory29 can facilitate communication
between the patient and health care pro-
fessionals and be used to monitor the ad-
equacy of therapy. Routine recording of
pain intensity along with other vital signs
is recommended.26,30,31
Subsequent steps in the assessment
include the development of inferences
about the pain syndrome and pathophysi-
ology and clarification of the extent of the
disease and the goals of therapy (Step 2).
This information influences the extent of
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subsequent investigations (Step 3). Pain
must be managed during this diagnostic
evaluation.
The assessment should enable the
clinician to appreciate the nature of the
pain syndrome, its impact, and concur-
rent problems that further undermine
quality of life (Step 4). This formulation
should be reviewed with the patient so
that problems can be prioritized and the
goals of therapy can be discussed. The
goals of care provide an essential context
for therapeutic intent and, consequently,
therapeutic decision-making.22 When the
goals are both comfort and function, the
therapeutic intent is to achieve an ade-
quate degree of relief without compro-
mising cognition or physical perfor-
mance. When comfort is the overriding
goal of care, therapies that impair cogni-
tive function are occasionally required to
achieve adequate relief.
NOCICEPTION, PAIN, AND SUFFERING
The assessment process is based on the
concepts of pain, nociception, and suffer-
ing. These concepts must be understood
to interpret the information obtained.
Nociception
Nociception is the activity produced in
the nervous system by potentially tissue-
damaging stimuli. Although this process
cannot be directly observed, it is inferred
in the clinical setting when a tissue-dam-
aging stimulus impinges on a pain-sensi-
tive structure. Nociceptors are widely dis-
tributed in the somatic structures,
including skin, muscles, and connective
tissues,32 and in viscera.33 There are many
types of nociceptors, and afferent input
that originates in these neurons travels in
multiple pathways.32,33 Nociceptive input
is regulated by both segmental and
suprasegmental systems, a concept origi-
nally modeled in the Gate Control Theo-
ry.34 Segmental processes occur at the lev-
el of the dorsal horn and brainstem and
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Table 2
Stepwise Assessment of the Patient with Cancer Pain

Step 1 Step 3
Data Collection Diagnostic Investigations and Other
Assessments
Pain-related history
Other relevant history Diagnostic investigations
Disease related Symptom specific
Other symptoms Extent of disease
Psychiatric history Other assessments
Social resources Psychological
Social
Other relevant history
Financial
Disease related
Functional
Other symptoms
Psychiatric history
Step 4
Social resources
Initial Formulation and Problem List
Available laboratory and imaging data
Radiographs and scans Pain syndromes and pathophysiology
Tumor markers Extent of disease
Hematologic parameters Concurrent concerns
Biochemical parameters Anticipated contingencies

Physical examination Step 5

Patient Review and Formulation of
Step 2 Prioritized Problem Lists
Provisional Assessment
Current problems
Provisional pain diagnosis Anticipated contingencies
Syndrome identification
Inferred pathophysiology Step 6
Global assessment Multimodality Therapeutic Plan
Extent of disease
Primary anticancer treatment
Goals of care
–Chemotherapy
–Prolonging survival
–Radiation therapy
–Optimizing function
–Surgery
–Optimizing comfort
–Immunotherapy
Concurrent concerns –Other
Other symptoms Treatment of concurrent disease processes
Untreated concurrent diseases Symptom-directed pharmacotherapy
Psychosocial needs Rehabilitative approaches
Rehabilitative needs Psychological approaches
Financial needs Anesthetic approaches
Neurostimulatory approaches

Adapted with permission from Cherny and Portenoy.22

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involve such mechanisms as activation of
inhibitory interneurons by myelinated
nonnociceptive afferent fibers. The best
characterized descending inhibitory path-
ways arise in the brainstem and project to
the dorsal horn of the spinal cord via the
dorsal longitudinal fasciculus.35,36 Neuro-
transmitters such as dopamine, serotonin,
norepinephrine, and the endogenous opi-
oid peptides (including enkephalin, -en-
dorphin, and dynorphin) play a signifi-
cant role in these modulatory systems.37,38
Pain
The International Association for the
Study of Pain has defined pain as “an un-
pleasant sensory and emotional experi-
ence associated with actual or potential
tissue damage or described in terms of
such damage.”39 Pain is the perception of
nociception, and like other perceptions, it
is determined by an interaction between
activity in sensorineural pathways and a
variety of behavioral and psychological
factors. Although psychological process-
es can strongly influence the expression
and impact of pain, organic factors that
produce activity in the sensorineural
pathways appear to predominate in the
cancer population.40
Suffering
Suffering is the perception of distress en-
gendered by all the adverse factors that
together undermine quality of life. Pain
may contribute profoundly to suffering,
but numerous other factors, such as the
experience of other symptoms, progres-
sive physical impairment, or psychosocial
disturbances, may be equally or more im-
portant.10 Suffering and pain are there-
fore best regarded as related but discrete
experiences, which have distinct clinical
implications. Analgesia alone may not
lessen suffering, and consequently, pain
therapy is not the sole objective in the
supportive care of the cancer patient.
Rather, pain therapy must be a critical
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component of a more comprehensive
therapeutic plan designed to address the
diverse factors that impair quality of
life.41,42
PAIN CHARACTERISTICS AND THE
IDENTIFICATION OF PAIN SYNDROMES
Cancer pain syndromes are defined by
the association of particular pain charac-
teristics and physical signs with specific
consequences of the underlying disease
or its treatment. Syndromes are associat-
ed with distinct etiologies and pathophys-
iologies and have important prognostic
and therapeutic implications. Pain syn-
dromes associated with cancer can be ei-
ther acute (Table 3) or chronic (Table 4).
Acute pains experienced by cancer pa-
tients are usually related to diagnostic
and therapeutic interventions, and chron-
ic pains are most commonly caused by di-
rect tumor infiltration. Adverse conse-
quences of cancer therapy account for 15
to 25 percent of chronic cancer pain prob-
lems, and a small proportion of the
chronic pains experienced by cancer pa-
tients are caused by pathology unrelated
to either the cancer or the cancer the-
rapy.5,43-45
The evaluation of pain characteris-
tics provides some of the data essential
for syndrome identification. These char-
acteristics include intensity, quality, dis-
tribution, and temporal relationships.
Pain Intensity
The evaluation of pain intensity is pivotal
to therapeutic decision-making.42,46 It in-
dicates the urgency with which relief is
needed and influences the selection of
analgesic drug, route of administration,
and rate of dose titration. Furthermore,
the assessment of pain intensity may help
characterize the pain mechanism and un-
derlying syndrome. For example, the pain
associated with radiation-induced nerve
injury is rarely severe; the occurrence of
severe pain in a previously irradiated re-
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Table 3
Acute Cancer Pain Syndromes

Acute Pain Associated with Diagnostic and Therapeutic Interventions

Acute pain associated with diagnostic interventions
Lumbar puncture headache
Arterial or venous blood
Sampling
Bone-marrow biopsy
Lumbar puncture
Acute postoperative pain
Acute pain caused by other therapeutic interventions
Pleurodesis
Tumor embolization
Acute pain associated with analgesic techniques
Injection pain
Spinal opioid hyperalgesia syndrome
Epidural injection pain

Acute Pain Associated with Anticancer Therapies

Acute pain associated with chemotherapy infusion techniques
Intravenous infusion pain
–Venous spasm
–Chemical phlebitis
–Vesicant extravasation
–Anthracycline-associated flare reaction
Hepatic artery infusion pain
Intraperitoneal chemotherapy abdominal pain
Acute pain associated with chemotherapy toxicity
Mucositis
Corticosteroid-induced perineal discomfort
Painful peripheral neuropathy
Diffuse bone pain from transretinoic acid or colony-stimulating factors
Acute Pain Associated with Hormonal Therapy
Leutenizing hormone releasing factor tumor flare in prostate cancer
Hormone-induced acute pain flare in breast cancer
Acute pain associated with radiation therapy
Incident pains
Oropharyngeal mucositis
Acute radiation enteritis and proctocolitis
Acute pain associated with infection
Acute herpetic neuralgia

Adapted with permission from Cherny and Portenoy.22

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Table 4
Chronic Cancer Pain Syndromes

Tumor-Related Pain Syndromes Chronic Pain Syndromes Associated

with Cancer Therapy
Bone pain
Multifocal or generalized bone pain Postchemotherapy pain syndromes
–Multiple bony metastases Chronic painful peripheral neuropathy
–Marrow expansion Avascular necrosis of femoral or
Vertebral syndromes humeral head
–Atlantoaxial destruction and odontoid Plexopathy associated with intra-
fractures arterial infusion
–C7-T1 syndrome Chronic pain associated with
–T12-L1 syndrome hormonal therapy
–Sacral syndrome Gynecomastia with hormonal therapy
Back pain and epidural compression for prostate cancer
Pain syndromes of the bony pelvis and hip
Chronic postsurgical pain syndromes
Headache and facial pain Postmastectomy pain syndrome
Intracerebral tumor Post-radical neck dissection pain
Leptomeningeal metastases Post-thoracotomy pain
Base of skull metastases Postoperative frozen shoulder
Painful cranial neuralgias Phantom pain syndromes
Stump pain
Tumor involvement of the peripheral
Postsurgical pelvic floor myalgia
nervous system
Tumor-related radiculopathy Chronic postradiation pain syndromes
–Postherpetic neuralgia Plexopathies
Cervical plexopathy Chronic radiation myelopathy
Brachial plexopathy Chronic radiation enteritis and proctitis
Malignant lumbosacral plexopathy Burning perineum syndrome
Tumor-related mononeuropathy Osteoradionecrosis
Paraneoplastic painful peripheral neuropathy
Pain syndromes of the viscera and
miscellaneous tumor-related syndromes
Hepatic distention syndrome
Midline retroperitoneal syndrome
Chronic intestinal obstruction
Peritoneal carcinomatosis
Malignant perineal pain
Ureteric obstruction
Paraneoplastic nociceptive pain syndromes
Tumor-related gynecomastia

Adapted with permission from Cherny and Portenoy.22

Vol. 44 No. 5 September/october 1994 269

 t h e M a n a g e m e n t
gion therefore suggests the existence of
recurrent neoplasm or a radiation-in-
duced second primary neoplasm.
Pain Quality
The quality of the pain often suggests its
pathophysiology. Somatic nociceptive
pains are usually described as sharp,
aching, throbbing, or pressure-like. Vis-
ceral nociceptive pains may be gnawing
or crampy when due to obstruction of a
hollow viscus or aching, sharp, or throb-
bing when due to involvement of organ
capsules or mesentery. Neuropathic pains
may be described as burning, tingling, or
shock-like (lancinating).
Pain Distribution
Patients with cancer pain commonly ex-
perience pain at more than one site.4 The
distinction between focal, multifocal, and
generalized pain may be important in the
selection of pain therapy. The term “fo-
cal” pain, which is used to denote a single
site, has also been used to depict pain that
is experienced in the region of the under-
lying lesion. Focal pains can be distin-
guished from those that are referred, that
is, experienced in a site remote from the
lesion. Familiarity with pain referral pat-
terns is essential to target appropriate di-
agnostic and therapeutic strategies
(Table 5).47-49 For example, a patient who
develops progressive shoulder pain and
has no evidence of focal pathology needs
to undergo evaluation of the region
above and below the diaphragm to ex-
clude the possibility of referred pain from
diaphragmatic irritation.
Temporal Relationships
Cancer-related pain may be acute or
chronic. Acute pain is defined by a recent
onset and a natural history characterized
by transience. The pain is often associat-
ed with overt pain behaviors (such as
moaning, grimacing, and splinting), anxi-
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o f C a n c e r p a i n
ety, or signs of generalized sympathetic
hyperactivity, including diaphoresis, hy-
pertension, and tachycardia.
Chronic pain has been defined by
persistence of pain for three months or
more beyond the usual course of an acute
illness or injury, a pattern of recurrence at
intervals over months or years, or by as-
sociation with a chronic pathologic
process.2 Chronic tumor-related pain is
usually insidious in onset, often increases
progressively with tumor growth, and
may regress with tumor shrinkage. Overt
pain behaviors and sympathetic hyperac-
tivity are often absent, and the pain may
be associated with affective disturbances
(anxiety and/or depression) and vegeta-
tive symptoms, such as asthenia, anorex-
ia, and sleep disturbance.3,7,50,51
Transitory exacerbations of severe
pain over a baseline of moderate pain or
less may be described as “breakthrough
pain.”52 Breakthrough pains are common
in both acute or chronic pain states.
These exacerbations may be precipitated
by volitional actions of the patient (so-
called incident pains), such as movement,
micturition, cough, or defecation, or by
nonvolitional events, such as bowel dis-
tention. Spontaneous fluctuations in pain
intensity can also occur without an identi-
fiable precipitant.
INFERRED PATHOPHYSIOLOGY
Inferences about the mechanisms that
may be responsible for the pain are valu-
able in the assessment and management
of cancer pain. The assessment process
provides the data necessary to infer a pre-
dominant pathophysiology.
Nociceptive Pain
Nociceptive pain describes pain that is
perceived to be commensurate with tis-
sue damage associated with an identifi-
able somatic or visceral lesion. The per-
sistence of pain is presumed to be related
to ongoing activation of nociceptors. No-
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 C A C a n c e r J C l i n
Table 5
Common Patterns of Pain Referral
Pain Mechanism Site of Lesion
Visceral Diaphragmatic irritation
Urothelial tract
Somatic C-7, T-1 vertebrae
L-1, L-2 vertebrae
Hip joint
Pharynx
Neuropathic Nerve or plexus
Nerve root
Central nervous system
ciceptive pain that originates from somat-
ic structures (somatic pain) is usually well
localized and described as sharp, aching,
throbbing, or pressure-like. Pain that aris-
es from visceral structures (visceral pain)
is generally more diffuse and is often de-
scribed as gnawing or cramping when due
to obstruction of a viscus and aching,
sharp, or throbbing when due to distur-
bance of organ capsules or mesentery.
From the clinical perspective, nociceptive
pains (particularly somatic pains) usually
respond to opioid drugs53,54 or to inter-
ventions that ameliorate or denervate the
peripheral lesion.
Neuropathic Pain
Neuropathic pain refers to syndromes
that may be related to damaged peripher-
al or central neural structures or are per-
ceived to be sustained by aberrant so-
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Referral Site
Shoulder
Inguinal region and genitalia
Interscapular
Sacroiliac joint and hip
Knee
Ipsilateral ear
Anywhere in the distribution
of a peripheral nerve
Anywhere in the correspond-
ing dermatome
Anywhere in the region of the
body innervated by the
damaged structure
matosensory processing at these sites.55,56
It is most strongly suggested when a
dysesthesia occurs in a region of motor,
sensory, or autonomic dysfunction that is
attributable to a discrete neurologic le-
sion. The diagnosis can be challenging,
however, and is often inferred solely from
the distribution of the pain and identifica-
tion of a lesion in neural structures that
innervate this region.
Although neuropathic pains can be
described in terms of the pain characteris-
tics (continuous or lancinating) or site of
injury (e.g., neuronopathy or plexopa-
thy), it is useful to distinguish these syn-
dromes according to the presumed site of
the aberrant neural activity (generator)
that sustains the pain.56 Peripheral neuro-
pathic pain is caused by injury to a pe-
ripheral nerve or nerve root and is pre-
sumably sustained by aberrant processes
originating in the nerve root, plexus, or
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Table 6
The Roles of the Primary Therapies in the
Management of Cancer Pain

Primary Therapy Major Pain Indications

Radiation therapy Painful bony metastases

Epidural spinal cord compression
Cerebral metastases
Tumor-related compression or infiltration of
peripheral neural structures

Chemotherapy Nociceptive or neuropathic pain syndromes caused

by tumors likely to respond to chemotherapy

Surgery Stabilization of pathologic fractures

Spinal cord decompression
Relief of remediable bowel obstructions
Drainage of symptomatic ascites

Antibiotic therapy Overt infections (e.g., pelvic abscess or pyonephrosis)

Occult infections (e.g., in head and neck tumors or
ulcerating tumors)

nerve. Neuropathic pains believed to be
sustained by a central generator include
sympathetically maintained pain (also
known as reflex sympathetic dystrophy or
causalgia) and a group of syndromes tra-
ditionally known as the deafferentation
pains (e.g., phantom pain). Sympatheti-
cally maintained pain, which may occur
following injury to soft tissue, peripheral
nerves, viscera, or the central nervous
system, is characterized by focal auto-
nomic dysregulation or trophic changes
in a painful region (e.g., vasomotor or pi-
lomotor changes, swelling, or sweating
abnormalities).57
The diagnosis of neuropathic pain
has important clinical implications. The
response of neuropathic pains to opioid
drugs is less predictable than the response
of nociceptive pains.53,54,58,59 Optimal
treatment may depend on the use of so-
called adjuvant analgesics60 or other spe-
cific approaches, such as sympathetic
nerve block.
Idiopathic Pain
Pain that is perceived to be excessive for
the extent of identifiable organic patholo-
gy can be termed idiopathic, unless the
patient presents with affective and behav-
ioral disturbances that are severe enough
to infer a predominating psychological
pathogenesis, in which case a specific psy-
chiatric diagnosis (somatoform disorder)
can be applied.61 When the latter infer-
ence cannot be made, however, the label
“idiopathic” should be retained, and as-
sessments should be repeated at appro-
priate intervals. Idiopathic pain in gener-

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 C A C a n c e r J C l i n
al and pain related to a psychiatric disor-
der specifically are uncommon in the can-
cer population, notwithstanding the im-
portance of psychological factors in
quality of life.
An Integrated Approach to
Cancer Pain
Most cancer patients can attain satisfacto-
ry relief of pain through an approach that
incorporates primary treatments, oral or
parenteral analgesic therapy, and at
times, other noninvasive psychological or
rehabilitative interventions. Occasional
patients benefit from invasive therapies.
Continuity of care is essential and re-
quires ongoing assessment and the capac-
ity to respond flexibly to the patient’s
changing needs.
PRIMARY THERAPY
The assessment may reveal a cause for
the pain that is amenable to primary ther-
apy. For pain produced by tumor infiltra-
tion or compression, antineoplastic treat-
ment with surgery, radiation therapy,
chemotherapy, or other approaches may
be considered. Pain caused by infections
may be amenable to antibiotic therapy or
drainage procedures (Table 6).
THE ‘ANALGESIC LADDER’ APPROACH
TO SYSTEMIC PHARMACOTHERAPY
The World Health Organization Three-
Step Analgesic Ladder (Fig. 2) provides a
useful approach to drug selection for can-
cer pain62:
At step 1, patients with mild to mod-
erate cancer-related pain should be treat-
ed with a nonopioid analgesic, which
should be combined with adjuvant drugs
if a specific indication for one exists.
At step 2, patients who have limited
opioid exposure and present with moder-
ate to severe pain or who fail to achieve
adequate relief after a trial of a nonopioid
analgesic should be treated with an opi-
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oid conventionally used for moderate
pain (previously termed “weak” opioids).
In the United States, these drugs include
codeine, hydrocodone, dihydrocodeine,
oxycodone, or propoxyphene. This drug
is typically combined with a nonopioid
and may be coadministered with an adju-
vant analgesic.
At step 3, patients who present with
severe pain or who fail to achieve ade-
quate relief following appropriate admin-
istration of drugs on the second step of
the analgesic ladder should receive an
opioid conventionally used for severe
pain (previously termed “strong” opi-
oids). In the United States, these drugs
include morphine, oxycodone, hydro-
morphone, methadone, levorphanol, and
fentanyl. These drugs may also be com-
bined with a nonopioid analgesic or an
adjuvant drug.
This approach has been adopted by
clinicians in numerous countries. It was
recently endorsed by the United States
Agency for Health Care Policy and Re-
search in their clinical practice guidelines
for the Management of Cancer Pain.26
The division of opioid agonists into
weak versus strong opioids, which was in-
corporated into the original analgesic lad-
der proposed by the World Health Orga-
nization,62 was not based on fundamental
differences in the pharmacology of the
pure agonist opioids, but rather reflected
the customary manner in which these
drugs were used. These terms are no
longer preferred.
SYSTEMIC ANALGESIC
PHARMACOTHERAPY
Nonopioid Analgesics
The nonopioid analgesics are useful
alone for mild to moderate pain (Step 1
of the analgesic ladder) and provide addi-
tive analgesia when combined with opi-
oid drugs in the treatment of more severe
pain. The nonopioid analgesics comprise
numerous subclasses (Table 7). Aspirin
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 t h e M a n a g e m e n t
and other nonsteroidal anti-inflammatory
drugs (NSAIDs) inhibit the enzyme cy-
clo-oxygenase and consequently block
the biosynthesis of prostaglandins, in-
flammatory mediators known to sensitize
peripheral nociceptors.63 A central mech-
anism of action is also likely to con-
tribute64,65 and presumably predominates
in acetaminophen analgesia.66
Unlike opioid analgesics, the non-
opioid analgesics have a “ceiling” effect
for analgesia and produce neither toler-
ance nor physical dependence. To reduce
the risks of therapy, it is reasonable to be-
gin treatment with a relatively low dose
and then explore the dose-response rela-
tionship through gradual dose escalation.
The safe administration of the non-
opioid analgesics also requires familiarity
with their potential adverse effects. As-
pirin and the other NSAIDs have a broad
spectrum of potential toxicity, and cau-
tion is required in the administration of
these agents to patients at increased risk,
including the elderly; patients with blood
clotting disorders, ulcer diathesis, and im-
paired renal function; and patients receiv-
ing concurrent corticosteroid therapy.67
The nonacetylated salicylates, such as
choline magnesium trisalicylate and sal-
salate, have less effect on platelet aggre-
gation and no effect on bleeding time at
usual clinical doses.68 These drugs are
preferred in patients who have a bleeding
diathesis and a strong indication for an
anti-inflammatory drug. Acetaminophen
has fewer adverse effects than the
NSAIDs. Acetaminophen-induced he-
patic toxicity is a rare occurrence, but pa-
tients with chronic alcoholism and liver
disease are at increased risk and can de-
velop severe hepatotoxicity even when
the drug is taken in usual therapeutic
doses.69
Opioid Analgesics
Based on their interactions with the vari-
ous receptor subtypes, the opioid anal-
gesics can be divided into agonist and ag-
274
o f C a n c e r p a i n
onist-antagonist classes. The pure agonist
drugs (Table 8) are most commonly used
in cancer pain management. The mixed
agonist-antagonist opioids (pentazocine,
nalbuphine, and butorphanol) and the
partial agonist opioids (buprenorphine
and probably dezocine) have limited util-
ity in this setting because of a ceiling ef-
fect for analgesia, precipitation of with-
drawal reactions in patients physically
dependent to opioid agonists, and a high
prevalence of dose-dependent psy-
chotomimetic side effects (pentazocine
and butorphanol).70
The pure agonist opioid drugs have
no clinically relevant ceiling effect to
analgesia. As the dose is raised, analgesic
effects increase in a log-linear function
until either analgesia is achieved or som-
nolence occurs. In practice, the efficacy of
any particular drug in a specific patient
will be determined by the degree of anal-
gesia produced following dose escalation
through a range limited by the develop-
ment of adverse effects.
Relative analgesic potency is the ra-
tio of the dose of two analgesics required
to produce the same analgesic effect. By
convention, relative potency is expressed
in comparison to 10 mg of parenteral
morphine. Equianalgesic dose informa-
tion provides a useful guide for dose se-
lection when the drug or route of admin-
istration is changed (see below).
Indications
A trial of opioid therapy should be ad-
ministered to all patients with pain of
moderate or greater severity, irrespective
of the pathophysiologic mechanism un-
derlying the pain.58,71-73 Patients who pre-
sent with severe pain are usually treated
with an opioid customarily used in step 3
of the analgesic ladder. Patients with
moderate pain are commonly treated
with a combination product containing
acetaminophen or aspirin plus a conven-
tional step-2 opioid (codeine, dihy-
drocodeine, hydrocodone, oxycodone,
Ca—A cancer Journal for Clinicians
 C A C a n c e r J C l i n 1 9 9 4 ; 4 4 : 2 6 2 - 3 0 3

Freed
and propoxyphene).42,62 The doses of cancerom from
these combination products can be in- pain
creased until the maximum dose of the Opioid fo
to severer moderate
nonopioid coanalgesic is attained (e.g., + pain
N
4,000 to 6,000 mg of acetaminophen); be- + onopioid
Adjuvan
yond this dose, the opioid contained in t
Pain p
the combination product could be in- or increersisting
creased as a single agent, or the patient asing
could be switched to another opioid con- Opioid fo
ventionally used in step 3. to mode r mild
+ rate pain
N
+ onopioid
Adjuvan
t
Selecting an Opioid Pain
or incrpersisting
For the patient without major organ fail- easing
ure who is opioid-naive, any of the avail-
able agonist opioids can be selected. Non
+ opiod
Short half-life opioid agonists (e.g., mor- Adjuvan
t
phine, hydromorphone, or oxycodone)
are generally favored because they are
easier to titrate than the long half-life Pain
drugs, which require a longer period to
approach steady-state plasma concentra- Fig. 2. The three-step “analgesic ladder” pro-
tions. posed by an expert committee of the Cancer
Among the short half-life opioids, Unit of the World Health Organization. Repro-
the range of available formulations often duced with permission from the World Health
influences specific drug selection. For ex- Organization.62
ample, although oxycodone is a versatile
opioid agonist, the oral formulations cur-
rently available in the United States can- analgesic than its parent compound. Ac-
not be conveniently administered in high cumulation of normeperidine after repet-
doses, and no parenteral formulation is itive meperidine administration can re-
available. For ambulatory patients who sult in central nervous system excitability
are able to tolerate oral opioids, mor- characterized by subtle mood effects;
phine sulphate is often preferred because tremors; multifocal myoclonus; and, occa-
it is available as a controlled-release sionally, seizures.74-76
preparation that allows an eight- to 12- In selecting an opioid, it is important
hour dosing interval. The long half-life to review the response to previous trials.
drugs, methadone and levorphanol, are If the patient is receiving an opioid and
not usually considered first-line therapy tolerating it well, it is usually continued
because they can be difficult to titrate and unless difficulties in dose titration occur
present challenging management prob- or the required dose cannot be adminis-
lems if delayed toxicity develops as plas- tered conveniently. If an opioid has been
ma concentrations gradually rise follow- associated with dose-limiting side effects,
ing dose increments. a trial of an alternative opioid should be
The use of meperidine for the man- considered. In a prospective survey of 100
agement of cancer pain must be discour- consecutive inpatients treated by Pain
aged. Meperidine is N-demethylated to Service physicians at Memorial Sloan-
normeperidine, which is an active Kettering Cancer Center, 44 required tri-
metabolite that is twice as potent as a als of two or more systemically adminis-
convulsant and one half as potent as an tered opioid drugs, and 20 required

Vol. 44 No. 5 September/october 1994 275

276
Table 7
Nonopioid Analgesics

Maximum
Recommended
Half Life Starting Dose Dose
t h e

Chemical Class Generic Name (hr) (mg) (mg/day) Comments

Nonacidic

p-aminophenol derivatives Acetaminophen 3-4 650 q4hr 6,000 Available over the counter

Naphthylalkanones Nabumetone 22-30 500 q12hr 2,000

M a n a g e m e n t
o f

Acidic

Salicylates Aspirin 3-12 650 q4-6hr 6,000 Available over the counter

Diflunisal 8-12 500 q12hr 1,500 Less gastrointestinal toxicity

than aspirin
C a n c e r

Choline magnesium 8-12 500-1,000 q12hr 4,000 Minimal gastrointestinal toxicity.

trisalicylate No effect on platelet function at
p a i n

usual doses

Salsalate 8-12 500-1,000 q12hr 4,000 Minimal gastrointestinal toxicity.

No effect on platelet function at
usual doses

Ca—A cancer Journal for Clinicians

 Maximum
Recommended
Half Life Starting Dose Dose
Chemical Class Generic Name (hr) (mg) (mg/day) Comments
C A

Proprionic acids Ibuprofen 3-4 400 q6hr 4,200 Available over the counter
Naproxen 1-3 250 q12hr 1,500 Available over the counter
Fenoprofen 2-3 200 q6hr 3,200
Ketoprofen 2-3 25 q6hr 300
C a n c e r

Flurbiprofen 5-6 100 q12hr 300

J

Vol. 44 No. 5 September/october 1994

Oxaprozin 40 600 q24hr 1,800

Acetic acids Indomethacin 4-5 25 q8hr (oral) 200 Sustained release or

C l i n

rectal preparations
Sulindac 14 150 q12hr 400

Diclofenac 2 25 q8hr 200

Ketorolac 4-7 30-60 load, then 150 day 1, 120 day 2 Oral or parenteral preparation
15-30 q6hr (parenteral) and after (parental)
10 q6hr (oral) 40 (oral)

Tolmentin 1 200 q8hr 2,000

Oxicams Piroxicam 45 20 q24hr 40

1 9 9 4 ; 4 4 : 2 6 2 - 3 0 3

Fenamates Mefenamic acid 2 250 q6hr 1,000

Pyranocarboxylic acids Etodolac 7 200 q8hr 1,200

Abbreviations: q=every.

277
 t h e M a n a g e m e n t
sequential trials of three or more opioids
to optimize the balance between analge-
sia and side effects. The existence of dif-
ferent degrees of incomplete cross-toler-
ance to various receptor-mediated opioid
effects (analgesia and side effects) may
explain the utility of these sequential tri-
als.77-80 To safely implement the tech-
nique of sequential opioid trials, the clini-
cian must be familiar with at least three
opioid drugs used in the management of
severe pain and have the ability to calcu-
late appropriate starting doses using
equianalgesic dosing data.
Patients with renal impairment may
accumulate the active metabolites of
propoxyphene (norpropoxyphene), me-
peridine (normeperidine), and morphine
(morphine-6-glucuronide). Particular
caution is required in the administration
of these drugs.81-86
Selecting an Appropriate Route
Opioids should be administered by the
least invasive and most convenient route
capable of providing adequate analgesia
for the patient. In routine practice, the
oral route is usually the most appropriate.
Alternative noninvasive routes, including
rectal, sublingual, and transdermal, are
sometimes feasible for patients who have
impaired swallowing or gastrointestinal
obstruction. In the United States, rectal
suppositories containing morphine, hy-
dromorphone, and oxymorphone are
available, and controlled-release mor-
phine tablets can also be administered
rectally.87 The potency of opioids admin-
istered rectally is believed to approximate
oral dosing.88,89
A sublingual preparation of bupre-
norphine is available in some countries,
but not in the United States.90 Nonethe-
less, all opioids are absorbed sublingually
to some extent, and fentanyl and meth-
adone are relatively well absorbed.91 Sub-
lingual administration of an injectable
formulation may be a useful approach in
some patients who transiently lose the
278
o f C a n c e r p a i n
option of oral dosing.
A transdermal formulation of fen-
tanyl that delivers 25, 50, 75, or 100 g
per hour is now commercially available.
The dosing interval for each system is
usually 72 hours, but interindividual
pharmacokinetic variability is large,92-94
and some patients require a dosing inter-
val of 48 hours. A limitation of the trans-
dermal delivery system is the require-
ment of an alternative short-acting opioid
for breakthrough pain.
Parenteral routes of administration
should be considered for patients who
have impaired swallowing or gastroin-
testinal obstruction, those who require
the rapid onset of analgesia, and patients
who require high doses that cannot other-
wise be conveniently administered. Re-
peated parenteral bolus injections, which
can be delivered by the intravenous (IV),
intramuscular (IM), or subcutaneous
(SC) routes, may be appropriate in some
situations but are often complicated by
the occurrence of untoward bolus effects
(toxicity at peak concentration and/or
pain breakthrough at the trough). Al-
though repetitive IM injections are com-
monly prescribed, they are painful, they
offer no pharmacokinetic advantage, and
their use is not recommended. Repeated
bolus doses, if required, can be accom-
plished without frequent skin punctures
through the use of an indwelling IV or SC
infusion device. To deliver repeated SC
injections, a 27-gauge infusion device (a
“butterfly”) can be left under the skin for
up to a week.95-97
Continuous infusions avoid the
problems associated with the bolus effect
and may be administered IV or SC.95-100
Ambulatory infusion devices vary in
complexity, cost, and ability to provide
patient-controlled “rescue doses” as an
adjunct to a continuous basal infusion
(see below). Opioids suitable for continu-
ous SC infusion must be soluble, well ab-
sorbed, and nonirritant. Extensive expe-
rience has been reported with heroin,
hydromorphone, oxymorphone, and
Ca—A cancer Journal for Clinicians
 C A C a n c e r J C l i n
morphine.97,99-104 Methadone appears to
be relatively irritating and is not pre-
ferred for SC infusion.105 Studies suggest
that dosing with SC administration can
proceed in a manner identical to continu-
ous IV infusion. A postoperative study
that compared patients who received an
identical dose of morphine by either IV
or SC infusion found no difference in
blood levels,106 and a controlled study of
hydromorphone calculated a bioavail-
ability of 78 percent for the SC route and
observed that analgesic outcome was
identical during IV or SC infusion.103 To
maintain the comfort of an infusion site,
the SC infusion rate should not exceed 5
ml/hr. Patients who require high doses
may benefit from the use of concentrated
solutions, which, in selected cases, can be
Until recently there were no formal
guidelines for the education of cancer specialists in
the management of cancer pain.
compounded specifically for continuous
SC infusion.
Continuous IV infusion may be the
most appropriate way of delivering an
opioid when there is a need for infusion
of a large volume of solution or when us-
ing methadone. If continuous IV infusion
must be continued on a long-term basis, a
permanent central venous port is recom-
mended.
Continuous infusions of drug combi-
nations may be indicated when pain is
accompanied by nausea, anxiety, or agita-
tion. In such cases, an antiemetic, neu-
roleptic, or anxiolytic may be combined
with an opioid, provided it is nonirritant,
miscible, and stable in combined solution.
Experience has been reported with infu-
sions of an opioid combined with meto-
clopramide, haloperidol, scopolamine,
cyclizine, methotrimeprazine, chlorpro-
mazine, or midazolam.97,107-109
Vol. 44 No. 5 September/october 1994
1 9 9 4 ; 4 4 : 2 6 2 - 3 0 3
Switching Routes
During long-term treatment, it is often
necessary to switch routes of administra-
tion. All such changes require careful at-
tention to relative potency (Table 8). It is
generally prudent to perform the switch
in a gradual stepwise manner over a two-
to three-day period.
Selecting a Dosing Schedule
Patients with continuous or frequently re-
curring pain generally benefit from
scheduled “around-the-clock” dosing.
When using immediate-release formula-
tions of short half-life opioids, such as
morphine, hydromorphone, and oxy-
codone, there is a close approximation
between the plasma half-life of the drug
and the duration of action. Most patients
will require dosing every three to four
hours.
Clinical vigilance is required, howev-
er, in patients with no previous opioid ex-
posure and those administered drugs with
long half-lives. With long half-life drugs,
such as methadone, delayed toxicity may
develop as plasma concentration rises
slowly toward steady-state levels.110 In
most patients, methadone must be ad-
ministered at a dosing interval far shorter
than its half-life,111 which increases the
potential for clinically significant accumu-
lation.
All patients who receive an around-
the-clock opioid regimen should also be
offered a “rescue” dose, a supplemental
dose given on an as-needed basis to treat
pain that breaks through the regular
schedule. The integration of scheduled
dosing with rescue doses provides a
279
 t h e M a n a g e m e n t
method for safe and rational stepwise
dose escalation and is applicable to all
routes of opioid administration (Table 9).
The rescue drug is typically identical to
that administered on a continuous basis,
with the exception of transdermal fen-
tanyl and methadone. An alternative
short half-life opioid is recommended for
the rescue dose when these drugs are
used. The frequency with which the res-
cue dose can be offered depends on the
time to peak effect for the drug and the
route of administration. Oral rescue dos-
es can be offered up to every one to two
hours, and parenteral rescue doses can be
offered up to every 15 to 30 minutes.
Clinical experience suggests that the size
of the rescue dose should be equivalent to
about five to 15 percent of the 24-hour
baseline dose.
Controlled-release formulations can
lessen the inconvenience associated with
around-the-clock drug administration.112
These formulations should not be used
to rapidly titrate the dose in patients with
severe pain. Controlled-release oral
morphine sulphate and transdermal fen-
tanyl are now widely used, and new con-
trolled-release formulations of oxy-
codone and hydromorphone are under
development.113,114 Controlled-release
preparations of morphine sulphate typi-
cally achieve peak plasma levels three to
five hours after a dose and have a dura-
tion of effect of eight to 12 hours.115 An
immediate-release formulation of a short
half-life opioid (usually the same drug) is
generally used as the rescue medication
(Table 9). Controlled-release and imme-
diate-release formulations of oral mor-
phine are dose equivalent; a switch from
one to the other is done on a milligram to
milligram basis.
In some limited situations, an as-
needed dosing regimen alone can be rec-
ommended. This type of dosing provides
additional safety during the initiation of
opioid therapy in the opioid-naive pa-
tient, particularly when rapid dose escala-
tion is needed or a long half-life drug is
280
o f C a n c e r p a i n
administered. This technique is strongly
recommended when starting methadone
therapy.
Patient-controlled analgesia (PCA)
is a technique of parenteral drug adminis-
tration in which the patient controls a
pump that delivers bolus doses of an anal-
gesic according to parameters set by the
physician. Use of a PCA device allows
the patient to carefully titrate the opioid
dose to his or her individual analgesic
needs. The technique is most commonly
used to manage acute postoperative pain.
Long-term PCA in cancer patients is ac-
complished via the subcutaneous or intra-
venous route using an ambulatory infu-
sion device. The more technologically
advanced devices have programmable
variables, including infusion rate, rescue
dose, and lock-out interval.95 The option
for bolus dosing is typically administered
in conjunction with a continuous opioid
infusion.100,116
Initial Dose Selection
Patients in severe pain who are opioid-
naive should generally begin one of the
opioids conventionally used for severe
pain at a dose equivalent to 5 to 10 mg IM
morphine every three to four hours. If a
switch from one opioid drug to another is
required, the equianalgesic dose table
(Table 8) is used as a guide to the starting
dose. For patients with good pain control
but unacceptable side effects, the starting
dose of the new drug should be reduced
to 50 to 75 percent of the equianalgesic
dose to account for incomplete cross-tol-
erance. For patients with poor pain con-
trol and moderate, unacceptable side
effects, the starting dose of the new drug
can usually be 75 to 100 percent of the
equianalgesic dose. Clinical experience
suggests that additional caution is needed
when the change is to methadone; a
reduction of 66 to 75 percent of the
equianalgesic dose is prudent. When
morphine is used, an IM:oral relative po-
tency ratio of 1:3 is generally recom-
Ca—A cancer Journal for Clinicians
 C A C a n c e r J C l i n
mended. After any change from one
opioid to another, patients must be mon-
itored to assess the adequacy of analgesia
and to detect the development of side ef-
fects. Subsequent dose adjustments are
usually necessary.
Dose Titration
The persistence of inadequate pain relief
should be addressed through a stepwise
escalation of the opioid dose until ade-
quate analgesia is reported or unmanage-
able side effects supervene. Clinical expe-
rience indicates that a dose increment of
30 to 50 percent is safe and large enough
to observe a meaningful change in effects.
In most cases, gradual dose escalation
identifies a favorable balance between
analgesia and side effects that remains
stable for a prolonged period.117,118 While
doses can become extremely large during
this process, the absolute dose is immate-
rial as long as the balance between anal-
gesia and side effects remains favorable.
For example, in a retrospective study of
100 patients with advanced cancer, the
average daily opioid requirement was
equivalent to 400 to 600 mg of intramus-
cular morphine, but about 10 percent of
patients required greater than 2,000 mg,
and one patient required over 30,000 mg
per 24 hours.3 Patients who develop dose-
limiting side effects during dose titration
require the use of another analgesic ap-
proach or a technique to reduce opioid
toxicity (see below).
The severity of the pain should de-
termine the rate of dose titration. Patients
with very severe pain can be managed by
repeated parenteral dosing every 15 to 30
minutes until pain is partially relieved.
Guidelines have been proposed for the
calculation of hourly maintenance dosing
after parenteral loading with a short half-
life opioid.119 These guidelines recom-
mend that the starting hourly mainte-
nance dose be approximated by dividing
the total loading dose by twice the elimi-
nation half-life of the drug. For example,
Vol. 44 No. 5 September/october 1994
1 9 9 4 ; 4 4 : 2 6 2 - 3 0 3
the starting maintenance dose for a pa-
tient who has required an intravenous
loading dose of morphine sulphate 30 mg
(half-life of about three hours) would be
5 mg per hour. Patients with less severe
pain can undergo more gradual dose es-
calation.
It is important to recognize that
analgesic tolerance is seldom the domi-
nant factor in the need for opioid dose es-
calation. Rather, most patients who re-
quire an escalation in dose to manage
increasing pain have demonstrable pro-
gression of disease.118,120 True pharmaco-
logic tolerance to the analgesic effect of
an opioid, in which exposure to the opi-
oid is inferred to be the driving force for
dose escalation, can only be said to occur
if a patient manifests the need for increas-
ing opioid doses in the absence of other
factors that would be capable of explain-
ing the increase in opioid requirement
(e.g., progressive disease, psychological
factors, or pharmacokinetic factors).
Such an occurrence appears to be very
uncommon. This observation suggests,
first, that concerns about tolerance
should not impede the use of opioids ear-
ly in the course of the disease and, sec-
ond, that worsening pain in a patient re-
ceiving a stable dose of opioids should
generally be assessed as presumptive evi-
dence of disease progression or, rarely,
increasing psychological distress or deliri-
um.121
Adverse Effects of Opioids and Their
Management
A detailed understanding of the strate-
gies used to prevent or manage common
opioid toxicities is needed to optimize the
balance between analgesia and side ef-
fects. The most common adverse effects
are constipation, nausea and vomiting,
and somnolence or cognitive impairment.
Other important dose-limiting adverse
effects include dysphoria, myoclonus, and
respiratory depression.
The likelihood of opioid-induced
281
282
Table 8
Opioid Agonist Drugs

Dose (mg)
equianalgesic to
10 mg I.M. morphine Duration of
t h e

Half Life Action

Drug I.M. Oral (hr) (hr) Comments

Opioid Agonist Drugs Customarily Used To Treat Moderate Pain (Formerly Called "Weak Opioids")

Codeine 130 200 2-3 2-4 Usually combined with a nonopioid.

Available over the counter

Oxycodone* 15 30 2-3 2-4 Used for step 2 of the analgesic ladder when
M a n a g e m e n t

formulated in combination with a nonopioid

o f

Propoxyphene – 50 2-3 2-4 Usually combined with nonopioid.

Norpropoxyphene accumulation with renal
impairment may cause seizures
C a n c e r

Opioid Agonist Drugs Customarily Used To Treat Severe Pain (Formerly Called "Strong Opioids")
Morphine 10 30 2-3 3-4 Morphine-6-glucuronide in renal failure may predis-
(repeated dose) pose to additional toxicity. Wide range of formula
p a i n

tions. On World Health Organization essential drug list

Oxycodone 15 30 2-3 2-4 Formulated as single agent. Can be used for severe
pain

Ca—A cancer Journal for Clinicians

 Dose (mg)
equianalgesic to
10 mg I.M. morphine Duration of
Half Life Action
Drug I.M. Oral (hr) (hr) Comments
C A

Hydromorphone 1.5 7.5 2-3 2-4

Methadone 10 20 15-190 4-8 Plasma accumulation may lead to delayed

toxicity. Dosing should be initiated on an as
needed basis
C a n c e r

Meperidine 75 300 2-3 2-4 Not recommended for cancer pain. Normeperidine
J

Vol. 44 No. 5 September/october 1994

toxicity limits utility. Contraindicated in patients
with renal failure and those receiving monoamine
oxidase (MAO) inhibitors
C l i n

Oxymorphone 1 10 (rectal) 2-3 3-4 No oral formulation available. Less histamine

release

Levorphanol 2 4 12-15 4-8 Plasma accumulation may lead to delayed toxicity

Fentanyl Transdermal ** 48-72 Patches available to deliver 25, 50, 75, and 100
System g/hr
1 9 9 4 ; 4 4 : 2 6 2 - 3 0 3

*When combined with a nonopioid.

**Transdermal fentanyl 100 g/hr = morphine 2 mg/hr.
Abbreviations: I.M. = intramuscular.

283
284
Table 9
Examples of Stepwise Dose Escalation of Morphine Sulphate

Oral Controlled Release

(With Immediate Release Subcutaneous Infusion
Oral Immediate Release Rescue Dosing) (With Subcutaneous Rescue Doses)
t h e

Around-the- Around-the- Around-the-

Clock Dose Rescue Dose Clock Dose Rescue Dose Clock Infusion Rescue Dose
Step* (mg q4hr) (mg q1hr prn) (mg) (mg q1hr prn) (mg/hr) (mg q20min prn)

1 10 5 30 q12hr 7.5 3 2.0

2 15 7.5 30 q8hr 15.0 5 2.5

M a n a g e m e n t

3 30 15.0 60 q12hr 15.0 7 3.5

o f

4 45 22.5 100 q12hr 30.0 10 5.0

5 60 30.0 100 q8hr 30.0 15 7.5

C a n c e r

6 90 45.0 200 q12hr 45.0 20 10

7 120 60.0 200 q8hr 60.0 30 15

p a i n

*Indications for progression from one step to the next:

1. Requirement of greater than two rescue doses in any four-hour interval.
2. Requirement of greater than six rescue doses in 24 hours.
Abbreviations: q = every; prn = as needed.

Ca—A cancer Journal for Clinicians

 C A C a n c e r J C l i n
constipation is so great that laxative med-
ications should be prescribed prophylac-
tically to most patients, particularly those
who are elderly or have coexisting gas-
trointestinal pathology. Recommenda-
tions for laxative therapy are empirical.122
A combination of a softening agent (do-
cusate) and a cathartic (e.g., senna,
bisacodyl, or phenolphthalein) is fre-
quently used. The doses of these drugs
should be increased as necessary, and an
osmotic laxative (e.g., lactulose or a mag-
nesium-containing product) can be added
if needed. Occasional patients are man-
aged with intermittent colonic lavage us-
ing an oral bowel preparation such as
Golytely. Rare patients who are refracto-
ry to laxative therapy can undergo a trial
of oral naloxone, which has a bioavail-
ability less than three percent and pre-
sumably acts selectively on opioid recep-
tors in the gut.123,124 Because there is a
small risk of systemic withdrawal from
oral naloxone,124 the initial dose should
be conservative (0.8 to 1.2 mg once or
twice daily). This dose can be escalated
slowly until either favorable effects occur
or the patient develops abdominal
cramps, diarrhea, or any other adverse ef-
fect. Naloxone should not be used in any
patient with bowel obstruction.
The incidence of opioid-induced
nausea has been estimated to be 10 to 40
percent.125 Tolerance to these effects of-
ten develops rapidly, and routine prophy-
lactic administration of an antiemetic is
not usually indicated except in patients
with a history of severe opioid-induced
nausea. Three different mechanisms may
produce nausea and vomiting. These in-
clude a direct effect on the chemorecep-
tor trigger zone, an enhanced vestibular
sensitivity, and delayed gastric emptying.
If nausea is associated with early satiety,
bloating, or postprandial vomiting, all of
which are features of delayed gastric
emptying, metoclopramide is the most
reasonable initial treatment. Patients
with vertigo or prominent movement-in-
duced nausea may benefit from the use of
Vol. 44 No. 5 September/october 1994
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an antivertiginous drug, such as scopo-
lamine or meclizine. If neither signs of
gastroparesis nor vestibular dysfunction
are prominent, treatment is usually began
with a neuroleptic, such as prochlorper-
azine or metoclopromide. If these drugs
are ineffective at relatively high doses,
other options include a trial of an alterna-
tive opioid or treatment with an antihista-
mine (e.g., diphenhydramine or hydrox-
yzine), alternate neuroleptic (e.g.,
haloperidol or chlorpromazine), benzodi-
azepine (e.g., lorazepam), steroid (e.g.,
dexamethasone), or serotonin antagonist
(e.g., ondansetron).
The initiation of opioid therapy or
significant dose escalation is often associ-
ated with somnolence or cognitive im-
pairment that usually persists for days to
weeks.126 Although tolerance usually de-
velops, some patients continue to have in-
tolerable effects, particularly if other
contributing factors exist. A stepwise
management strategy is useful: (1) elimi-
nate nonessential medications that de-
press the central nervous system and
evaluate the patient for concurrent caus-
es, including sepsis, metabolic derange-
ment, or intracerebral or leptomeningeal
metastases; (2) if analgesia is satisfactory,
reduce the opioid dose by 25 percent; (3)
if analgesia is unsatisfactory and the pa-
tient is somnolent or has mild cognitive
impairment, consider the addition of a
psychostimulant, such as methylphen-
idate (starting dose 5 to 10 mg twice dai-
ly), dextroamphetamine (starting dose 5
to 10 mg twice daily), or pemoline (start-
ing dose 18.75 to 37.5 mg twice daily); (4)
if the patient is hallucinating or delirious,
consider a trial of haloperidol (starting
dose 0.5 mg two to three times daily); and
(5) if these problems persist, consider the
addition of a nonopioid or adjuvant anal-
gesic (which may allow reduction in opi-
oid dose), a switch to a different opioid
drug, or an anesthetic or neurolytic tech-
nique.
Myoclonus is a common dose-relat-
ed adverse effect of opioids, which, like
285
286
Table 10
A Guide to the Selection of Adjuvant Analgesics for
Neuropathic Pain Based on Clinical Characteristics

Continuous Neuropathic Pain

t h e

Antidepressants Also useful for lancinating neuropathic pains that are refractory to other specific adjuvant agents
Amitriptyline Useful in patients with pain complicated by depression and insomnia
Doxepin
Imipramine Starting doses should be low and can be increased every few days until usual effective range
Desipramine or dose-limiting toxicity
Nortriptyline
Paroxetine
Maprotiline
M a n a g e m e n t

Local anesthetics Also useful for lancinating neuropathic pains that are refractory to other specific adjuvant agents
Mexiletine Mexiletine has the safest toxicity spectrum of oral agents
o f

Lidocaine
Experience is reported with continual subcutaneous lidocaine infusion

Clonidine alpha-2 adrenergic agonist

C a n c e r

Oral or transdermal

Capsaicin cream Depletes peptides in small primary afferent neurons

p a i n

Occasionally useful in postherpetic neuralgia and postmastectomy pain

Calcitonin Reported efficacy for phantom limb and sympathetically maintained pain

Ca—A cancer Journal for Clinicians

 Lancinating Neuropathic Pain
Anticonvulsant drugs First-line therapy for lancinating pain
Carbamazepine
Phenytoin Also useful for episodic neuropathic pains that are nonlancinating
Clonazepam Carbamazepine may cause marrow toxicity
C A

Valproate Dosing guidelines employed in the treatment of pain are customarily identical to those employed in
the treatment of seizures

Baclofen A GABA-agonist effective for trigeminal neuralgia

Often employed in the management of lancinating pains due to neural injury of any type
C a n c e r
J

Starting dose of 5 mg two to three times per day

Vol. 44 No. 5 September/october 1994

Dose may be increased to side effects, which are usually sedation or confusion

somnolence and cognitive impairment, is

C l i n

Pimozide A neuroleptic with efficacy against trigeminal neuralgia

Antidepressants See above

Local anesthetics See above

Sympathetically Maintained Pain

Phenoxybenzamine Second-line therapy after sympathectomy
Prazosin
1 9 9 4 ; 4 4 : 2 6 2 - 3 0 3

Propranolol Limited anecdotal reports of efficacy

Nifedipine
Calcitonin

287
 t h e M a n a g e m e n t
often determined by multiple factors
other than the opioid. If myoclonus is
symptomatic and distressing, it can be
treated empirically with a benzodi-
azepine (specifically clonazepam),127 a
barbiturate, or valproate.
Among cancer patients whose opi-
oid dose is carefully titrated, respiratory
depression is a rare occurrence. Although
tolerance may develop rapidly to this ef-
fect,128 the observation that some patients
on stable opioid therapy develop seda-
tion or respiratory depression after anes-
thetic or neurodestructive procedures
suggests that other pain-related factors
may also play a role in the ability to toler-
ate high-dose opioid therapy.128 Indeed,
reduction of the opioid dose is usually
necessary after anesthetic or neurolytic
techniques.
Clinically significant respiratory de-
pression is always accompanied by other
signs of central nervous system depres-
sion, including somnolence and mental
clouding. Respiratory distress associated
with tachypnea and anxiety is never a pri-
mary opioid event, and alternative expla-
nations (e.g., pneumonia or pulmonary
embolism) should be sought. Due to the
risk of systemic withdrawal and the re-
turn of pain, naloxone should only be ad-
ministered for symptomatic respiratory
depression. If the patient is arousable and
the peak plasma levels of the opioid have
already been reached, naloxone should
not be administered; instead, the opioid
dose should be withheld and the patient
monitored until improved. If the patient
is becoming progressively obtunded, is
unarousable, or has respiratory depres-
sion, naloxone should be administered
using small bolus injections of dilute solu-
tion (0.4 mg in 10 ml saline), which are
titrated against respiratory rate.129,130 Par-
tial reversal of respiratory depression
with naloxone does not prove that the
opioid was the primary cause of the
event. In patients receiving chronic opi-
oid therapy, an intercurrent cardiac or
pulmonary process can precipitate respi-
288
o f C a n c e r p a i n
ratory depression that partially remits
with naloxone. Hence, a naloxone re-
sponse does not obviate the need for a
careful patient evaluation. Because nal-
oxone has a short half-life, patients re-
ceiving slow-release morphine, transder-
mal fentanyl, or methadone may require
repeated doses of naloxone or an infusion
to prevent recurrence of respiratory de-
pression.
Physical and Psychological
Dependence
Confusion about physical dependence
and addiction augments the fear of opioid
drugs and contributes to physician reluc-
tance to prescribe opioids and patient
reluctance to use them. 19,131,132 This
confusion derives, in part, from a mis-
understanding of the nomenclature used
to describe drug use.
Physical dependence is a pharmaco-
logic property of opioid drugs that is de-
fined by the development of an absti-
nence (withdrawal) syndrome following
either abrupt dose reduction or adminis-
tration of an antagonist. Physical depen-
dence is not a clinical problem if patients
are warned to avoid abrupt discontinua-
tion of the drug, a tapering schedule is
used if treatment cessation is indicated,
and opioid antagonist drugs (inclu-
ding agonist-antagonist analgesics) are
avoided.
Addiction refers to a psychological
and behavioral syndrome characterized
by loss of control over drug use, compul-
sive use, and continued use despite harm
to self or others. Addicts crave the opioid
to achieve a psychic effect and manifest
aberrant drug-related behaviors, such as
unsanctioned dose escalation, acquisition
of drugs from multiple providers, or use
of illicit drugs.
The medical use of opioids is very
rarely associated with the development of
addiction.131,133,134 In the largest prospec-
tive study, only four cases of iatrogenic
addiction could be identified among
Ca—A cancer Journal for Clinicians
 C A C a n c e r J C l i n
11,882 patients with no prior history of
addiction who received at least one opi-
oid dose in the hospital setting.134 Exten-
sive clinical experience in the use of opi-
oids for patients with chronic cancer pain
affirms that the risk of addiction in this
population is extremely low.42,62,133,135,136
Some cancer patients who continue
to experience unrelieved pain manifest
drug-seeking behaviors that are similar to
addiction but cease once pain is relieved,
often through opioid dose escalation.
These behaviors have been termed pseu-
do-addiction.137 Misunderstanding of this
phenomenon may lead the clinician to in-
appropriately stigmatize the patient with
the label addict, which may compromise
care and erode the doctor-patient rela-
tionship. In the setting of unrelieved pain,
the request for increases in drug dose re-
quires careful assessment, renewed ef-
forts to manage pain, and avoidance of
stigmatizing labels.
ADJUNCTIVE TECHNIQUES:
NONINVASIVE INTERVENTIONS
Even with optimal management of ad-
verse effects, some patients do not attain
an acceptable balance between pain relief
and side effects. Several types of noninva-
sive interventions should be considered
for their potential to improve this balance
by reducing the opioid requirement.
These include the concurrent use of ap-
propriate primary therapy, alternative
pharmacologic approaches (nonopioid
analgesics, adjuvant analgesics, or a
switch to another opioid), and the use of
psychological, physiatric, or noninvasive
neurostimulatory techniques.
Adjuvant Analgesics
Adjuvant analgesics are drugs that have a
primary indication other than pain, but
have analgesic effects in some painful
conditions. These drugs play an impor-
tant role for some patients who cannot
otherwise attain an acceptable balance
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between relief and opioid side effects.
Adjuvant analgesics can be broadly divid-
ed into general purpose analgesics and
those with specific utility for neuropathic,
bone, or visceral pain.
Corticosteroids
Corticosteroids are the most widely used
general purpose adjuvant analgesics.138
These drugs may ameliorate pain and
produce beneficial effects on appetite,
nausea, mood, and malaise.139-144 The
painful conditions that commonly re-
spond to corticosteroids include raised in-
tracranial pressure, acute spinal cord
compression, superior vena cava syn-
drome, metastatic bone pain, neuropathic
pain due to infiltration or compression by
tumor, symptomatic lymphedema, and
hepatic capsular distention. Patients with
advanced cancer who experience pain
and other symptoms that may respond to
steroids are usually given relatively small
doses (e.g., dexamethasone 1 to 2 mg
twice daily). A very short course of rela-
tively high doses (e.g., dexamethasone
100 mg IV followed initially by 96 mg per
day in divided doses) can be used to man-
age an acute episode of very severe pain
that is related to a neuropathic lesion
(e.g., plexopathy or epidural spinal cord
compression) or bony metastasis that
cannot be promptly reduced with opioids.
In all cases, the dose should be gradually
lowered following pain reduction to the
minimum needed to sustain relief.
Topical Local Anesthetics
Topical local anesthetics can be used in
the management of painful cutaneous
and mucosal lesions and as a premedica-
tion prior to skin puncture. Controlled
studies have demonstrated the effective-
ness of eutectic mixture of 2.5-percent li-
docaine and 2.5-percent prilocaine
(EMLA) in reducing pain associated with
venipuncture, 145-149 lumbar punc-
ture,146,150 and arterial puncture.151 For
289
 t h e M a n a g e m e n t o f
Table 11
Common Anesthetic and Neurosurgical Analgesic Techniques
for Pain Refractory to Systemic Pharmacotherapy
Class Technique
Regional analgesia Spinal opioids and/or
local anesthetics
Intraventricular
Intrapleural
Sympathetic blockade Celiac plexus block
and neurolysis
Lumbar sympathetic
blockade
Stellate ganglion blockade
Somatic neurolysis or Chemical or surgical
pathway ablation rhizotomy
Trigeminal neurolysis
Transacral S-4 neurolysis
Cordotomy
Other Cingulotomy
Pituitary ablation
290
C a n c e r p a i n
Clinical Situation
Systemic opioid analgesia complicated
by unmanageable supraspinally
mediated adverse affects
Limited reported experience, no
well-defined indication
Reported efficacy with both upper
body and generalized pain
Reported efficacy for pain arising
from head and neck, chest wall,
upper limbs, and upper abdominal
viscera
Refractory malignant pain involving
the upper abdominal viscera
including the upper retroperi-
toneum, liver, small bowel, and
proximal colon
Sympathetically maintained pain
involving the legs
Sympathetically maintained pain
involving the head, neck, or arms
Refractory brachial plexopathy or
arm pain
Intercostal nerve pain, chest wall
pain
Refractory bilateral pelvic or
lubosacral plexus pain in a bed-
ridden patient with urinary
diversion
Refractory unilateral facial pain
Refractory pain limited to the per-
ineum
Refractory unilateral pain arising
in the torso or lower extremity
Little reported experience, no
well-defined indications
Has been used for refractory
multifocal pain
Refractory multifocal pain
Ca—A cancer Journal for Clinicians
 C A C a n c e r J C l i n
optimal effect, the cream should be ap-
plied thickly one hour prior to the proce-
dure and covered with an occlusive dress-
ing (plastic wrap can be used). EMLA
can also be applied to painful cutaneous
lesions such as postherpetic neuralgia and
painful ulcers. Lidocaine viscous is fre-
quently used in the management of
oropharyngeal ulceration.152-155 Although
the risk of aspiration appears to be very
small, caution with eating is required af-
ter oropharyngeal anesthesia.
Adjuvants for Neuropathic Pain
The use of adjuvant analgesics can con-
tribute substantially to the successful
management of neuropathic pain. Nu-
merous drugs are used empirically for this
indication, including selected antidepres-
sants, oral local anesthetics, anticonvul-
sants, and others. For the purpose of drug
selection, it is useful to distinguish be-
tween continuous, lancinating, and sym-
pathetically maintained neuropathic pain
(Table 10).60 Given the great interpatient
and intrapatient variability in the re-
sponse to adjuvants in this setting (includ-
ing those within the same class), sequen-
tial trials are frequently required.
Adjuvants for Bone Pain
The management of bone pain frequently
requires the integration of opioid therapy
with multiple ancillary approaches. Al-
though a meta-analysis of NSAID thera-
py in cancer pain that reviewed data from
1,615 patients in 21 trials found no specif-
ic efficacy in bone pain and analgesic ef-
fects equivalent only to “weak” opi-
oids,156 some patients appear to benefit
greatly from the addition of such a drug.
The radiopharmaceutical strontium-
89 has recently been approved for the
treatment of bone pain caused by
metastatic disease.157-162 Strontium-89 is
absorbed into areas of high bone
turnover and can reduce pain, generally
without causing significant bone marrow
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depression. Because treatment with this
agent can compromise marrow reserve
and irreversibly lower platelet count, its
use is not recommended if future myelo-
suppressive chemotherapy is under
consideration or if significant throm-
bocytopenia is present. Other radio-
pharmaceuticals currently under in-
vestigation include samarium-153
ethylenediaminetetramethylene phos-
phonic acid163,164 and rhenium-186 hy-
droxyethylidene diphosphonate.165,166
The bisphosphonate drugs, pami-
dronate and clodronate, inhibit osteoclast
activity and have also been demonstrated
to relieve malignant bone pain.167-173 Par-
enteral administration of pamidronate
every two weeks is generally well tolerat-
ed, and the risk of symptomatic hypo-
calcemia is low. Other agents worthy of
consideration include corticosteroids, cal-
citonin,174 and gallium nitrate.175
Adjuvants for Visceral Pain
There are limited data that support the
potential efficacy of a range of adjuvant
agents for the management of bladder
spasm, tenesmoid pain, and colicky in-
testinal pain. Based on limited clinical ex-
perience and in vitro evidence that
prostaglandins play a role in bladder
smooth-muscle contraction, a trial of
NSAIDs may be justified for patients
with painful bladder spasms.176-178 Al-
though there is no well-established phar-
macotherapy for painful rectal spasms,
diltiazem, a calcium channel blocker that
reduces smooth-muscle contraction, has
been effective in the management of
proctalgia fugax,179 and chlorpro-
mazine180 and benzodiazepines181 have
been used anecdotally. Pain due to inop-
erable bowel obstruction has been treat-
ed empirically with intravenous scopo-
lamine (hyoscine) butylbromide,182-184
sublingual scopolamine (hyoscine) hy-
drobromide,185 and, most recently, the so-
matostatin analogue, octreotide. Despite
the theoretical advantages of antimus-
291
 t h e M a n a g e m e n t
carinic drugs in these conditions and
some limited support for the use of eme-
pronium bromide,186 dicyclomine, and
flavoxate,187 anticholinergic adverse ef-
fects are frequent and benefit is rarely ob-
served.178
In the management of pain due to
pancreas cancer, there is limited evidence
supporting the effectiveness of oc-
treotide,188 as well as the oral administra-
tion of trypsin.189 It is speculated that
these effects are mediated by reduction in
pancreatic exocrine secretion.
Other Noninvasive Techniques
Psychological Therapies
All cancer patients benefit from psycho-
logical assessment and support. Some
also will benefit from specific psychologi-
cal interventions used in the management
of pain.
Cognitive interventions can help re-
duce pain-related distress through the
modification of thoughts, feelings, and
behaviors.190 These interventions require
that patients have the ability to observe
their emotional and behavioral responses
in a relatively objective manner and iden-
tify dysfunctional reactions and interac-
tions. Specific cognitive techniques, in-
cluding relaxation, distraction, and
focusing, may be useful in reducing pain
and pain-related distress.190-192 Behav-
ioral techniques also seek to enhance
coping skills. Behavioral interventions
can be designed to discourage maladap-
tive actions and increase the frequency of
“well” behavior.193
Successful application of these ther-
apies requires a cognitively intact patient
and a dedicated, well-trained clinician. In
a controlled study, a structured nondrug
program in which elderly patients were
educated in the use of various strategies,
including heat, cold, massage/vibration,
distraction, and relaxation, was shown to
diminish pain and enhance patient satis-
faction.194
292
o f C a n c e r p a i n
Physiatric Techniques
Physiatric techniques can be used to en-
hance analgesia and optimize the func-
tion of the patient with chronic cancer
pain. Therapeutic modalities, such as
electrical stimulation (including transcu-
taneous electrical neurostimulation),
heat, or cryotherapy, can be useful ad-
juncts to standard analgesic therapy. The
treatment of lymphedema by use of
wraps, pressure stockings, or pneumatic
pump devices may both improve function
and relieve pain and heaviness.195 Orthot-
ic devices can immobilize and support
painful or weakened structures, and assis-
tive devices can enhance comfort for pa-
tients with pain precipitated by weight
bearing or ambulation.
ADJUNCTIVE TECHNIQUES: INVASIVE
INTERVENTIONS
Patients who are unable to achieve a sat-
isfactory balance between analgesia and
side effects from systemic analgesic thera-
pies may be candidates for the use of in-
vasive anesthetic and neurosurgical tech-
niques (Table 11).
Regional Analgesic Techniques
Intraspinal (Epidural and Intrathecal)
Opioids
The delivery of low opioid doses near the
sites of action in the spinal cord may de-
crease supraspinally mediated adverse ef-
fects. In the absence of randomized trials
that compare the various intraspinal tech-
niques with other analgesic approaches,
the indications for the spinal route re-
main empirical.196 A recent survey re-
ported that only 16 of 1,205 cancer pa-
tients with pain required intraspinal
therapy.197 Compared to neuroablative
therapies, spinal opioids have the advan-
tage of preserving sensation, strength,
and sympathetic function. Contraindica-
tions include bleeding diathesis, profound
leukopenia, and sepsis. A temporary trial
of spinal opioid therapy should be per-
Ca—A cancer Journal for Clinicians
 C A C a n c e r J C l i n
formed to assess the potential benefits of
this approach before implantation of a
permanent catheter.
Opioid selection for intraspinal de-
livery is influenced by several factors. Hy-
drophilic drugs, such as morphine and hy-
dromorphone, have a prolonged half-life
in cerebrospinal fluid and significant ros-
tral redistribution.198-200 Lipophilic opi-
oids, such as fentanyl and sufentanil, have
less rostral redistribution201 and may be
preferable for segmental analgesia at the
level of spinal infusion. The addition of a
low concentration of a local anesthetic,
such as 0.125- to 0.25-percent bupiva-
caine, to an epidural opioid has been
demonstrated to increase analgesic effect
without increasing toxicity.197,202-204 The
The assessment of patients with cancer should
routinely incorporate inquiries about
the presence and severity of pain.
potential morbidity for these procedures
indicates the need for a well-trained clini-
cian and long-term monitoring.
Intraventricular Opioids
Limited experience suggests that the ad-
ministration of an opioid into the cerebral
ventricles can provide long-term analge-
sia in selected patients.205-212 This tech-
nique has been used for patients with up-
per body or head pain or severe diffuse
pain. Schedules have included both inter-
mittent injection via an Ommaya reser-
voir205,206,211 and continual infusion using
an implanted pump.212
Intrapleural Local Anesthetic
Several authors have described the use of
intrapleural local anesthetics in the man-
agement of chronic postthoracotomy
pain213 and cancer-related pains involving
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the head, neck, chest, arms, and upper ab-
dominal viscera.214-216 Although a single
bolus may provide a prolonged analgesia,
continuous infusion of local anesthetic
has been recommended for patients with
chronic pain due to advanced cancer.214
Anesthetic Techniques for
Sympathetically Maintained Pain
And Visceral Pain
Celiac Plexus Block
Neurolytic celiac plexus blockade can be
considered in the management of pain
caused by neoplastic infiltration of the
upper abdominal viscera, including the
pancreas, upper retroperitoneum, liver,
gall bladder, and proximal small bow-
el.217-219 In addition to extensive anec-
dotal experience, this technique is sup-
ported by a small controlled study of the
percutaneous approach220 and a con-
trolled trial of intraoperative neuroly-
sis.221 Reported analgesic response rates
in patients with pancreatic cancer are 50
to 90 percent, and the reported dura-
tion of effect is generally one to 12
months.217-220 Given the generally favor-
able response to this approach, most clin-
icians will recommend it as the next inter-
vention for patients with an appropriate
pain syndrome who fail to obtain an ade-
quate balance between analgesia and side
effects from an oral opioid. Common
transient complications include postural
hypotension and diarrhea.217-219 Posterior
spread of neurolytic solution can occa-
sionally lead to involvement of lower tho-
racic and lumbar somatic nerves, which
can potentially result in a neuropathic
pain syndrome. Other uncommon
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 t h e M a n a g e m e n t
complications include pneumothorax,
retroperitoneal hematoma, and para-
paresis.
Sympathetic Blockade of Somatic
Structures
Sympathetically maintained pain syn-
dromes may be relieved by interruption
of sympathetic outflow to the affected re-
gion of the body. Lumbar sympathetic
blockade should be considered for sym-
pathetically maintained pain involving
the legs, and stellate ganglion blockade
may be useful for sympathetically main-
tained pain involving the face or arms.
Neuroablative Techniques for Somatic
And Neuropathic Pain
Rhizotomy
Chemical rhizotomy, which may be pro-
duced by the instillation of a neurolytic
solution into either the epidural or in-
trathecal space, can be an effective
method of pain control for patients with
otherwise refractory localized pain syn-
dromes.222,223 The technique is most com-
monly used in the management of chest
wall pain due to tumor invasion of somat-
ic and neural structures. Other indica-
tions include refractory upper limb, lower
limb, pelvic, or perineal pain. Satisfactory
analgesia is achieved in about 50 percent
of patients.218 Adverse effects can be re-
lated to the injection technique (e.g.,
spinal headache, infection, and arach-
noiditis) or to the destruction of nonnoci-
ceptive nerve fibers. Complications of
lumbosacral neurolysis include paresis
(five to 20 percent), sphincter dysfunction
(five to 60 percent), impairment of touch
and proprioception, and dysesthesias. Al-
though neurologic deficits are usually
transient, the risk of increased disability
suggests that these techniques should be
reserved for patients with limited func-
tion and preexistent urinary diversion.
Rhizotomy can also be achieved
surgically using either open or percuta-
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o f C a n c e r p a i n
neous techniques.224 Patients with refrac-
tory head and neck pain, for example,
may be candidates for an open cranial
rhizotomy, which incorporates transec-
tion of the trigeminal and glossopharyn-
geal nerves and the dorsal roots of C-2
and C-3.
Neurolysis of Primary Afferent Nerves
Or Their Ganglia
Neurolysis of primary afferent nerves
may also provide significant relief for se-
lected patients with localized pain. Re-
fractory unilateral facial or pharyngeal
pain may be amenable to trigeminal neu-
rolysis, Gasserian gangliolysis, or glos-
sopharyngeal neurolysis. Intercostal or
paravertebral neurolysis is an alternative
to rhizotomy for patients with chest wall
pain. Severe pain limited to the perineum
may be treated by neurolysis of the S-4
nerve root via the ipsilateral posterior
sacral foramen, a procedure that carries a
minimal risk of motor or sphincter im-
pairment.225
Cordotomy
During cordotomy, the anterolateral
spinothalamic tract is interrupted to pro-
duce contralateral loss of pain and tem-
perature sensibility.226,227 Patients with se-
vere unilateral pain arising in the torso or
lower extremity are most likely to benefit
from this procedure.223 Impressive results
have also been observed in patients with
chest wall pain.228 The percutaneous tech-
nique is generally preferred.226 Open cor-
dotomy is usually reserved for patients
who are unable to lie in the supine posi-
tion or are not cooperative enough to un-
dergo a percutaneous procedure.226
Significant pain relief is achieved in
more than 90 percent of patients during
the period immediately following cordo-
tomy.223,226-229 Fifty percent of surviving
patients have recurrent pain after one
year, and repeat cordotomy can some-
times be effective. The neurologic com-
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 C A C a n c e r J C l i n
plications of the procedure include pare-
sis, ataxia, and bladder dysfunction.229
These complications are usually tran-
sient, but are protracted and disabling in
about five percent of cases. Rarely, pa-
tients with a long duration of survival de-
velop a delayed-onset dysesthetic pain.
The most serious potential complication
is respiratory dysfunction, which mani-
fests as phrenic nerve paralysis or sleep-
induced apnea (in patients who undergo
bilateral high cordotomy).230 The poten-
tial for this complication relatively con-
traindicates bilateral high-cervical cordo-
tomies or a unilateral cervical cordotomy
ipsilateral to the site of the only function-
ing lung.
Other Techniques
Pituitary ablation by chemical or surgical
hypophysectomy has been reported to re-
lieve diffuse and multifocal pain syn-
dromes that have been refractory to opi-
oid therapy and are unsuitable for any
regional neuroablative procedure.219,231
Pain relief has been observed in patients
with hormone-dependent and hormone-
independent tumors.219,231
Anecdotal reports also support the
efficacy of cingulotomy in the manage-
ment of diffuse pain syndromes that have
been refractory to opioid therapy.232 The
mode of action is unknown and the pro-
cedure is rarely considered.
PATIENTS WITH REFRACTORY PAIN:
THE ROLE OF SEDATION
For some patients with advanced disease,
adequate relief of physical symptoms
may only be achieved at the cost of pro-
found sedation.7,233-236 Increasing atten-
tion has been focused on the use of seda-
tion to manage intractable pain and
suffering at the end of life in patients who
fail to benefit from optimal palliative
therapy.233,234,236 Sedation can be accom-
plished through the use of a systemic opi-
oid, benzodiazepine (e.g., lorazepam,
Vol. 44 No. 5 September/october 1994
1 9 9 4 ; 4 4 : 2 6 2 - 3 0 3
midazolam, or flunitrazepam),237,238 neu-
roleptic (e.g., chlorpromazine or metho-
trimeprazine), or barbiturate (e.g., thio-
pental).233,234 The prevalence of otherwise
refractory symptoms severe enough to
necessitate sedation is controversial and
has been variably estimated at five to 52
percent of patients with far-advanced
cancer.7,235,239-241 In one study, 52 percent
of terminally ill patients developed other-
wise unendurable symptoms that re-
quired deep sedation for adequate relief;
in just under half of these patients, pain
was the predominant symptom.7
The ethical acceptability of sedation
at the end of life is predicated upon in-
formed consent and an acknowledgment
of the “principle of double effect,” which
distinguishes between the compelling pri-
mary therapeutic intent (to relieve suffer-
ing) and unavoidable, untoward conse-
quences (the potential for accelerating
death).242 This approach recognizes the
right of dying patients to adequate relief
of pain, and the right of all patients to
choose between appropriate therapeutic
options.243-245 No patient should have to
ask to be killed because of persistently
unrelieved pain, and contrariwise, no pa-
tient should be sedated without appropri-
ate informed consent of the patient or
proxy. The process of informed decision-
making requires candid discussion that
clarifies the prevailing clinical predica-
ment and presents the alternative anal-
gesic options (including sedation). Dis-
cussions of other relevant considerations,
including existential, ethical, religious,
and familial concerns, may benefit from
the participation of a religious counselor,
social worker, or clinical ethics specialist.
Conclusion
Improving the standard of care for cancer
patients with pain is an important clinical
challenge. Research has highlighted ma-
jor problems in the assessment and treat-
ment of these patients. Initiatives are re-
quired to remedy this situation. Pain
295
 t h e M a n a g e m e n t
assessment must be incorporated into the
routine care of cancer patients. The relief
of pain must be emphasized as a cardinal
goal of cancer therapy, and patients need
reassurance that efforts to secure comfort
will not be at the expense of efforts to
control the underlying cancer. The indi-
vidual practitioner can effectively treat
most pain problems by attending to care-
ful pain assessment and implementing
analgesic therapy. Successful long-term
management requires continuity of care
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