(7) Caution: Methadone is much more potent than indicated in older Clonazepam is an

published literature. On average it is 10 times more potent than anticonvulsant from the
morphine. However, its potency relative to morphine is not linear. benzodiazepine class, and is
When morphine
medNewsat lower doses is switched to methadone (e.g. 30 60 commonly used for treating
mg orally per day), the potency may be 3 to 5 times; when switch lancinating or
from high doses (e.g. greater than 300 mg morphine per day paroxysmal neuropathic × NCl
orally), the potency may be 12 times or even higher. pain.[_1_29]The potential for
drowsiness and cognitive
impairment must be
monitored
"Pain" is redistributed by Universits of Bonn, TIedical Center
care&lly.
Reduced libido is a
well known Pain
phenomenon for those using heroin or in a Switching from one opioid to another requires
methadone maintenance program. familiarity with a range of opioids and the use of
208/04470
Unfortunately, clinicians prescribing opioids for opioid dose conversion tables.[_6,56]When
pain poorly understand this effect. Animal this documentusing
Getstudies via a these
secure ratios,
connection
it must be understood
confirm that : thatthe guidelines and thepatients should
opioids lower testosterone levels and suppress be monitored more closely during the switching
sexual fitnetion
Overview in males.[ ] Early case studies phase. A recent review has highlighted some
ofpersons using
Pain Assessment important issues
heroin or methadone Manazement
Pharmacologic described diminished libido, related to these tables.[½] Wide ranges in
sexual dysfitnetion, reduced testosterone
Physical And Psychosocial Interventionslevels in ratios are noted. In the case of methadone, it is
men, andAntineoplastic Interventions much more potent thanm previously thought
Invasive
amenorrhea Interventions 122]
in women.[117 (on average 10 times more potent) and its
Discharzeresolve
These effects Plaimine
after the opioid has been equianalgesic dose ratio compared to other
Treatine Elderly Patients
discontinued. opioids changes according to the dose ofthe
previous opioid; the higher the dose, the higher
the ratio. (Note thatpotency does not denote
CancerMail from the more effectiveness, rather the equivalent dose
National Cancer Institute
required to obtain the same effect).

This information is intended mainly for use by doctors and other health care professionals. Ifyou have
questions about this topic, you can ask your doctor, or call the Cancer Information Service at 1-800-4-CAVCER
(1-800-422-6237).

Information from PDQ --

for Health Professionals

OVERVIEW
Cancer pain can be managed effectively throughrelatively simple means in up to 90% of the 8 million Americans
who have cancer or a history of cancer. Unfortunately, pain associated with cancer is frequently undertreated.[_1]

Although cancer pain or associated symptoms cannot always be entirely eliminated, appropriate use of available
therapies can effectively relieve pain in the great majority of patients. Pain management improves the patient's
quality of life throughout all stages of the disease. Patients with advanced cancer experience multiple concurrent
symptoms with pain; therefore, optimal pain management necessitates a systematic symptom assessment and
appropriate management for optimal quality of life.[_2]

State and local laws often restrict the medical use of opioids to relieve cancer pain, and third-party payers may not
reimburse for noninvasive pain control treatments. Thus, clinicians should work with regulators, state cancer pain
initiatives or other vronne to eliminate these health care avstem barriers to eKeetive noin manneement These and
HHLIRLIVCD, U1 URIGl (LUUgo LU GIIMHHRLC HICDU HURIul bulC bybtCul Unil1CID LU C11CULIVC yd1H HIGHugCHIGHL. lHUDC GHU

other barriers to effective pain management are listed below. Changes in health care delivery may create additional
disineentives for clinicians to practice effective pain management.

Problems related to health care professionals:

• Inadequatelmowledge ofpainmanagement.

• Poor assessment ofpain.

• Concem about regulation of controlled substances.

. Fear ofpatient addiction.

. Concem about side effects of analgesics.

• Concem about patients becoming tolerant to analgesics.

Problems related to patients:

• Reluctance to report pain.

• Concem about distracting physicians from treatment ofunderlying disease.

. Fear that pain means disease is worse.

. Concem about not being a "good"patient.

• Reluctance to take pain medications.

• Fear of addiction or of being thoughtof as an addict.

• Worries about unmanageable side effects.

• Concem about becoming tolerant to pain medications.

. Poor adherence with the prescribed analgesic regimen.[3]

Problems related to the health care system:

• Low priority given to cancer pain treatment

• Inadequate reimbursement

• The most appropriate treatmentmay not be reimbursed or may be too costly for patients and families

• Restrictive regulation of controlled substances

. Problems of availability of treatment or access to it

. Opioids unavailable in the patient's pharmacy

Flexibility is the key to managing cancer pain. As patients vary in diagnosis, stage of disease, responses to pain and
interventions, and personal preferences, so must pain management. The recommended clinical approach outlined
below emphasizes a focus on patient involvement.
A. Ask about pain regularly. Assess pain and associated symptoms
systematically.[_2]

B. Believe the patient and family in their reports of pain and what relieves
1t.

C. Choose pain control options appropriate for the patient, family, and
settmg.

D. Deliver interventions in a timely, logical, coordinated fashion.

E. Empower patients and their families. Enable patients to control their

course to the greatest extent possible.

Highlights of Patient Management

Effective pain management is best achieved by a team approach involving patients, their families, and health care
providers. The clinician should:

• Initiate prophylactic anticonstipation measures in all patients prior to or concurrent with opiate
administration. (Refer to the Side Effects of Opioids section for more information on constipation.)

• Discuss pain and its management with patients and their families.

• Encourage patients to be active participants in their care.

• Reassure patients who are reluctant to report pain that there are many safe and effective ways to relieve pain.

. Consider the cost of proposed drugs and technologies.

. Share documented pain assessment and management with other clinicians treating the patient.

• Know state/local regulations for controlled substances.

References:

1. Weiss SC, Emanuel LL, Fairclough DL, et al.: Understanding the experience of pain in terminally ill patients.
Lancet 357(9265): 1311-1315, 2001.
2. Meuser T, Pietruck C, Radbruch L, et al.: Symptoms during cancer pain treatment following WHO-
guidelines: a longitudinal follow-up study of symptom prevalence, severity and etiology. Pain 93(3): 247-
257, 2001.
3. Miaskowski C, Dodd MJ, West C, et al.: Lack of adherence with the analgesic regimen: a significant barrier
to effective cancer pain management. Journal of Clinical Oncology 19(23): 4275-4279, 2001.

PAIN ASSESSMENT
Failure to assess pain is a critical factor leading to undertreatment. Assessment involves both the clinician and the
patient. It should occur:

• At regular intervals after initiation of treatment.

 • Ateachnentreportofpain.

• At a suitable interval aner pharmacologic or nonpharmacologic intervention, e.g., 15 to 30 minutes after

parenteral drug therapy and I hour after oral administration.

Identifying the etiology of pain is essential to its management. Clinicians treating patients with cancer should
recognize the common cancer pain syndromes (See Table 1). Prompt diagnosis and treatment ofthese syndromes
can reduce morbidity associated with unrelieved pain. Distinct cultural influences may need to be incorporated into
a multidimensional assessment ofpain.[l-_4]

Table 1. Common Cancer Pain Syndromes Due to Nerve Injury

Pain syndrome Associated signs and symptoms Affected nerves

Tomor Constant, burning pain with Peripheral

infiltration of a dysesthesia in an area of sensory
peripheral nerve loss

Pain is radicular and often

unilateral

Postradical neck Tight, burning sensation in the area Lower cranial nerves
dissection of sensory loss Cervical plexus

Dysesthesias and shocklike pain may

be present

Musculoskeletal pain may occur due to

a drooped shoulder syndrome

Postmastectomy Tight, constricting, burning pain in Intercosto-

pain the posterior arm, axilla, and brachia1
anterior chest wall

Pain exacerbated by arm movement,

possibly due to musculoskeletal
dysfunction or edema

Post-thoracotomy Aching sensation in the distribution Intercostal

pain of the incision with sensory loss
with or without autonomic changes

Often exquisite point tenderness at

the most medial and apical points of
the scar with a specific trigger
point in the muscle

Postnephrectomy Numbness, fullness, or heaviness in Superficial

pain the flank, anterior abdomen, and cutaneous nerves
groin

Dysesthesias are common

Post Persistent, severe phantom limb pain Peripheral

amputation in a minority of patients nerves and
pain their central
projections
Stump pain generally resolves with
 wound healing, although pain associated
with scar sensitivity may emerge after
months or years

Chemotherapy- Painful paresthesias and dysesthesias Peripheral nerves

induced (e.g.,
peripheral Hyporeflexia polyneuropathy)
neuropathy
Less frequently: motor and sensory
loss; Rarely: autonomic dysfunction

Commonly associated with the vinca

alkaloids, cisplatin, and Taxol

Peripheral nerve Radiation therapy may promote Peripheral nerves

tumors malignant fibrosarcoma

Painful, enlarging mass in a

previously irradiated area

Patients with neurofibromatosis more

susceptible

Cranial Severe head pain with cranial nerve Cranial V, VII,

neuropathies dysfunction IX, X, XI, XII
are most common
Leptomeningeal disease

Base of skull metastasis

Acute and Painful paresthesia and dysesthesia Thoracic and

postherpetic cranial (V) are
neuralgia Constant burning and aching pain most common

Shocklike paroxysmal pain

Immunosuppression from disease or

treatment is a risk factor;
postherpetic neuropathy incidence
increases with age

Initialikssessnient

The goal ofthe initial assessment of pain is to characterize the pathophysiology ofthe pain and to determine the
intensity of the pain and its impact on the patient's ability to function. Factors that may influence analgesic response
and result in persistent pain include changing nocieeption due to disease progression, intractable side effects,
tolerance, neuropathic pain, and opioid metabolites.[_5] Essential to initial assessment are:

• Detailed history

• Physical examination

• Psychosocialassessment

. Diagnostic evaluation

Patient Self-Report
The mainstay of pain assessment is the patient self-report. To enhance pain management across all settings,
clinicians should teach families to use pain assessment tools in their homes. The clinician should help the patient to
describe:

PAIN

Listen to the patient's descriptive words about the quality of the pain; these provide valuable clues to its etiology.
Elicit the temporal features including onset, duration, and diurnal variation. Ask about breakthrough or episodic
pain, (a transitory increase in pain that occurs in addition to persistent pain). Some patients may have episodic pain
without persistent pain.[_6]

LOCATION

Ask the patient to indicate the exact location of the pain on his or her body, or on a body diagram and whether it
radiates.

INTENSITY OR SEVERITY

Encourage the patient to keep a log of pain intensity scores to report during follow-up visits or by telephone.
Examples of simple self-report pain intensity scales include the simple, descriptive, numeric, and visual analogue
scales.

AGGRAVATING AND RELIEVING FACTORS

Ask the patient to identify factors, which cause the most pain, and also what relieves the pain.

COGNITIVE RESPONSE TO PAIN

Note behavior suggesting pain in patients who are cognitively impaired or who have communication problems
relating to education, language, ethnicity, or culture. Use appropriate (e.g., simpler or translated) pain assessment
tools.

GOALS FOR PAIN CONTROL

Document the patient's preferred pain assessment tool and the goals for pain control (such as scores on a pain
scale).

Physical Examination

A thoroughphysical examination is required to determine the pathophysiology of pain. Specific features ofthe
neurologic examination such as altered sensation (hypoesthesia, hyperesthesia, hyperpathia, allodynia) in a painful
area are suggestive ofneuropathic pain. Physical findings oftumor growth and metastasis are also important to
identify.

Continual assessment of cancer pain is crucial. Changes in pain pattern or the development ofnew pain should
trigger diagnostic evaluation and modification of the treatmentplan. Persistent pain indicates the need to consider
other etiologies (e.g., related to disease progression or treatment) and alternative (perhaps more invasive)
treatments.

Assessment of the Outcomes of Pain Management

Pain-related outcomes: Clinicians should document and be aware of outcomes of pain therapy. It is helpful to think
of pain-related outcomes as primarily measured in 2 ways: decreased pain intensity and improvement in
psychosocial Enctioning. Using rating scales of pain intensity at its worst and on average, and also using pain
interference scales can help clinicians monitor outcomes. Measurement ofthe percentage ofpain reliefis also
usefid, thoughmeasuring patient satisfaction is less useflil because ofthe low expectations patients sometimes hold
for pain control.[

Drug-taking outcomes: Clinicians prescribing chronic opioids should also monitor and document patients' dnig-
taking behaviors. Outcomes related to addiction in cancer patients are rare but nonetheless should be periodically
assessed; these assessments can be reassuring to patients. Tolerance and dependence are not addiction-related.
Documentation ofpatients' compliance withregard to changes in dosing and duration ofprescriptions is essential in
all pain practice.

The clinical assessment of drug-taking behaviors in medically ill patients with pain is complex. Aberrant drug-
taking behavior from cancer pain management is related to premorbid history of drug addiction and the likelihood of
other pain treatment.A pilot questionnaire was used to characterize drug-related behaviors and attitudes in cancer
and AIDS patients. Despite limitations this study highlights wide potential variation in different palliative care
populations in patterns of past and present aberrant drug-taking behaviors and the need for a clinically usefill
screening approach. The implications for psychosocial and pharmacological management of symptoms such as pain,
as well as any aberrant behavior, remains unclear.[_8]

Previous drug abuse is likely to lead to specific needs for appropriate dosing during cancer pain therapy. A
prospective open-label study compared morphine dosage and effectiveness in AIDS patients with and without prior
substance use. Results demonstrated that both groups benefited, but patients with a prior drug use history require
and will tolerate substantially higher morphine doses to achieve stable pain control.[_9] This study should increase
confidence in providing patients with a past history of drug use with appropriate pain management.

References:

1. Chune JW. Wone TK. Yanz JC: The lens model: assessment of cancer pain in a Chinese context. Cancer
Nursing 23(6): 454-461, 2000.
2. Cleeland CS. Nakamura Y. Mendoza TR. et al.: Dimensions of the impact of cancer pain in a four country
sample: new information from multidimensional scaling. Pain 67(2-3): 267-273, 1996.
3. Greenwald HP: Interethnic differences in pain perception. Pain 44(2): 157-163, 1991.
4. Bates MS. Edwards WT. Anderson KO: Etimocultural influences on variation in chronic pain perception.
Pain 52(1): 101-112, 1993.
5. Mercadante S. Portenov RK: Opioid poorly-responsive cancer pain. Part 1: clinical considerations. Journal
of Pain and Symptom Management 21(2): 144-150, 2001.
6. Mercadante S, Radbruch L, Caraceni A, et al.: Episodic (breakthrough) pain: consensus conference of an
expert working group ofthe European Association for Palliative Care. Cancer 94(3): 832-839, 2002.
7. Rhodes DJ. Koshy RC. Waterfield WC. et al.: Feasibility of quantitative pain assessment in outpatient
oncology practice. Journal of Clinical Oncology 19(2): 501-508, 2001.
8. 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. Journal ofPain and Symptom Management 19(4): 274-286, 2000.
9. Kaplan R. Slvwka J. Slaele S. et al.: A titrated morphine analgesic regimen comparing substance users and
non-users with AIDS-related pain. Journal of Pain and Symptom Management 19(4): 265-273, 2000.

PHARMACOLOGIC MØlAGEMENT
Basic Principles of Cancer Pain Management

The World Health Organization (WHO) has described a three-step analgesic ladder as a framework for pain
management.[ It involves a stepped approach based on the severity ofthe pain. Ifthe pain is mild, one may begin
by prescribing a Step 1 analgesic such as acetaminophen or a non-steroidal anti-inflammatory drug (NSAID).
Fotential aaverse ettects snoula De notea, particularly tne renal ana gastromtestinal aaverse ettects ot tne JmsA11RS.
Ifpain persists or worsens despite appropriate dose increases, a change to a Step 2 or 3 analgesic is indicated. The
majority ofpatients with cancer pain will require a Step 2 or 3 analgesic. Step 1 can be skipped in those patients
presenting at the onset with moderate to severe pain in favor of Steps 2 or 3. At each step, an adjuvant drug or
modality such as radiation therapy may be considered in selected patients. WHO recommendations are based on a
worldwide availability of drugs, and not strictly on pharmacology.

Analgesies should be given "by mouth, by the clock, by the ladder, and for the individual "[L This requires regular
scheduling of the analgesic, not just as needed. In addition, rescue doses for breakthrough pain need to be added.
The oral route is preferred as long as a patient is able to swallow. Each analgesic regimen should be adjusted for
each patient's individual circumstances and physical condition.

Acetaminophen and NSAIDs

NSAIDs are effective for relief of mild pain, and may have an opioid dose-sparing effect that helps reduce side
effects when given with opioids for moderate to severe pain. Acetaminophen is included with aspirin and other
NSAIDs because it has similar analgesic potency although it lacks peripheral anti-inflammatory activity. Side
effects can occur at any time, and patients who take acetaminophen or NSAIDs, especially elderly patients, should
be followed carefully.[_2-_4]

Dosage

Use patient response to determine the effective dosing interval for aspirin, acetaminophen, and other NSAIDs listed e
in Table 2. When pain relief is not attained with the maximum dosage of one NSAID, try other drugs within this
category before abandoning NSAID therapy.

Route of administration

Use readily available oral tablets, capsules, or liquid. During intervals ofnausea and vomiting, use suppositories.
Ketorolac tromethamineis the only NSAID available for parenteral use.

Contraindications

Patients taking NSAIDs (except acetaminophen) are at risk for platelet dysfunction that may impair blood clotting.
Table 2 lists NSAIDs with minimal antiplatelet activity.

Other side effects

Follow patients carefully for adverse effects, which range from mild gastrointestinal discomfort to more serious
problems including:

Renal failure.

Hepatic dysfunction.

Gastric ulceration.

Because both NSAIDs and other drugs (e.g., warfarin, methotrexate, digoxin, cyclosporine, oral antidiabetic agents,
and sulfonamide-containing drugs) are highly protein bound, there is potential for altered efficacy or toxicity when
given simultaneously.

Table 2. Dosing Data for Acetaminophen and NSAIDs

Drug Usual dose for adults Usual dose for

 and children >/= 50 kg adults and children(1)
body weight <50 kg body weight

Orally-administered acetaminophen and over-the-counter NSAIDs

ace¯ami¯«¯sle¯«¯2
650 mg q 0 mg kg q
975 mg q 6 h 15-20 mg/kg q 4 h
(rectal)

aspirin(3) 650 mg q 4 h 10-15 mg/kg q 4 h

975 mg q 6 h 15-20 mg/kg q 4 h
(rectal)

ihuprofen (Motrin, 400-600 mg q 6 h 5-10 mg/kg q 4-6 h

others)

Prescription NSAIDs

carprofen (Rimadyl) 100 mg tid

choline magnesium 1,000-1,500 mg q 6-8 h 25 mg/kg q 6-8 h

trisalicylate(4)
(Trilisate)

choline salicy1ate 870 mg q 3-4 h

(Arthropan)(4)

diflunisal (Dolobid)(5) 500 mg q 12 h

etodolac (Lodine) 200-400 mg q 6-8 h

fenoprofen calcium 300-600 mg q 6 h

(Nalfon)

ketoprofen (Orudis) 25-60 mg q 6-8 h

ketorolac 10 mg q 4-6 h to a
tromethamine(6) maximum of 40 mg/day
(Toradol) Intravenous administration
should not exceed 5 days

magnesium salicylate 650 mg q 4 h

(Doan's, Magan,
Mobidin, others)

meclofenamate sodium 50-100 mg q 6 h

(Meclomen) (7)

mefenamic acid (Ponstel) 250 mg q 6 h

naproxen (Naprosyn) 250-275 mg q 6-8 h 5 mg/kg q 8 h

naproxen sodium 275 mg q 6-8 h

(Anaprox)

sodium salicylate 325-650 mg q 3-4 h

(Generic)

Parenteral NSAIDs

ketorolac 60 mq initially, then 30

 tromethamine (6, 8) mg q 6 h
(Toradol) Intravenous administration
should not exceed 5 days

(1) Acetaminophen and NSAID dosages for adults weighing less than 50 kg
should be adjusted for weight.
(2) Acetaminophen lacks the peripheral anti-inflammatory and antiplatelet
activities of the other NSAIDs.
(3) The standard against which other NSAIDs are compared. May inhibit platelet
aggregation for greater than 1 week and may cause bleeding.
(4) May have minimal antiplatelet activity.
(5) Administration with antacids may decrease absorption.
(6) Use limited to not greater than 5 days.
(7) Coombs-positive autoimmune hemolytic anemia has been associated with
prolonged use.
(8) Rave the same GI toxic effects as oral NSAIDs.
Note: Only the above NSAIDs have FDA approval for use as simple analgesics, but
clinical experience has been gained with other drugs as well.

Codes: q=every tid=three times a day

Opioids

Opioids, the major class of analgesics used in management of moderate to severe pain, are effective, easily titrated,
and have a favorable benefit-to-risk ratio.

The predictable consequences of long-term opioid administration--tolerance and physical dependence--are often
confused with psychological dependence (addiction), that manifests as drug abuse. This misunderstanding can lead
to ineffective prescribing, administering, or dispensing of opioids for cancer pain. The result is undertreatment.

Clinicians may be reluctant to give high doses of opioids to patients with advanced disease because of a fear of
respiratory depression. Many patients with cancer pain become opioid tolerant during long-term opioid therapy.
Therefore, the clinician's fear of shortening life by increasing opioid doses is usually unfounded. The clinician's
ethical duty to benefit the patient by relieving pain supports increasing doses, even at the risk of side effects.

Opioid Types

Opioids are classified as full morphine-like agonists, partial agonists, or mixed agonist-antagonists, depending on
the specific receptors to which they bind and their activity at these receptors. The benefits ofusing opioids and the
risks associated with their use vary among individuals.

Morphine is the most commonly used opioid in cancer pain management, largely for reasons of availability and
familiarity.[_5] However, it is useful to be familiar with more than one type of opioid. Wide interindividual
variability in response to both the analgesic and adverse effects of opioids is recognized.[_6] Some patients may not
experience adequate pain control despite appropriate dose adjustments while others may develop intolerable
adverse effects to one particular opioid (see below). Alternative opioids include hydromorphone, oxycodone and
fentanyl. Knowledge of several medications and formulations give the categiver much more flexibility in tailoring a
regime to a particular patient's needs.

Short-acting opioids are generally recommended when opioid therapy is being initiated for the first time or when
patients are medically unstable or the pain intensity is highly variable. Once stable, patients can be switched to a
controlled-release or slow-release formulation. This is more convenient and promotes compliance. (See Table 3 in
the opioid switching section).

Full agonists
Morphine, hydromorphone, codeine, oxycodone, hydrocodone, methadone, levorphanol, and fentanyl, are classified
as full agonists because their effectiveness with increasing doses is not limited by a "ceiling." Full agonists will not
reverse or antagonize the effects of other full agonists given simultaneously.

Morphine

The most commonly used opioid, morphine, is readily available in several forms, including sustained-release (8-24
hours duration of effectiveness)
formulations for oral administration.

Other agonists

For the patient who experiences dose-limiting side effects with one oral opioid (e.g., hallucinations, nightmares,
dysphoria, nausea, or mental clouding), other oral opioids should be tried before abandoning one route in favor of
another.

Methadone

Given the reported clinical experience, methadone can be considered a very useful second- or third-line opioid for .

cancer pain management. However, given the high potency, a relatively long and unpredictable half-life, and a
varying equianalgesic dose associated with the degree ofpre-existing opioid tolerance resulting in an unpredictable
response at the initiation oftreatment, inexperienced clinicians should be cautious. It is recommended that
appropriate reference material is reviewed, and the support of an experienced colleague is requested when starting
a patient on methadone for the first time.

There has been a revival in interest in using methadone for the management of pain in cancer patients. Publications
have been in the form of case reports,[2-R] outcome surveys,[B-R] and reviews.[B,2] Subcutaneous methadone
has been reported to cause tissue irritation at the injection site. Success has been reported using methadone orally,
intravenously, and by suppository.

Methadone is a synthetic opioid agonist that has been reported to have a number ofunique characteristics. These
include excellent oral and rectal absorption, no loown active metabolites, prolonged duration of action resulting in
longer administration intervals, and lower cost than other opioids. The published clinical experience has
highlighted these important considerations:

1. Methadone used for chronic pain management demonstrates a much higher

potency thanthe 1:1 or 1:2 methadone to morphine ratio that is generally reported in tables of opioid equivalence.
Clinical study results have reported methadone as 5 to 15 times more potent than morphine, with this ratio varying
according to the previous opioid dose.[_2_1]

2. Patients on high opioid doses exhibiting both inadequate pain control and
significant opioid-related toxicity have achieved good pain control with switching to methadone.

3. The rate of metabolism as an individual response to methadone (because of

issues of potency, accumulation, and drug elimination) has resulted in the recommendation that this medication
should be used with extreme caution.

Several methods of switching to methadone have been proposed. Some rely on patient-controlled analgesia with
fixed doses and flexible intervals, some require fixed intervals and fixed doses, while others stagger the conversion
over a few days. One careful method is to switch to methadone over a period of 3 to 5 days.[L,B] This method
may be useful ifthe patient is being switched from relatively high doses ofmorphine or other opioids.

On day 1, the total 24-hour opioid dose ofthe original opioid is decreased by 30%. This is replaced by a dose of
methadone calculated at a ratio of 10:1 compared to a morphine-equivalent dose (methadone given at 1/10 the
morphine-equivalent dose), given on an 8-hour schedule. Patients are followed closely, with inpatient monitoring
preterred.

On day 2, the original opioid dose is further decreased by 30%, and the methadone dose is increased by 10% to
30%, based on clinical assessments ofthe patient's analgesic requirements. A patient not tolerating the conversion
should consult with a pain management expert. If one has concerns regarding drowsiness or respiratory depression,
the methadone dose should not be increased, and the original opioid dose may be further decreased by 30%. If at all
uncertain, hold the administration of methadone and consult an experienced colleague.

On day 3, if the patient is not sedated (in mental acuity) and respiration is not compromised, the original opioid is
discontinued and the methadone dose increased by 0% to 30% as determined by the clinical assessment. At this
point, the rescue dose of opioid is also switched to methadone, calculated at 10% ofthe 24-hour dose. Daily
assessment should be continued on days 4 through 7, watching for sedation, respiratory depression, and analgesic
efficacy. Despite using this cautious approach, respiratory depression has been observed, requiring intervention
with dilute parenteral or subcutaneous naloxone.[_8] Depending on the severity ofrespiratory depression, a
continuous infusion of dilute naloxone may be indicated until the methadone effect resolves.

In some countries there are restrictions that do not apply to other opioids on the ability of physicians to prescribe
methadone. In the United States, this pertains to methadone for maintenance of addiction. Methadone is not restricted
when used for pain management, however, physicians should carefully document the use ofmethadone.[2]

Meperidine (Demerol)

Useful for brief courses (few days) to treat acute pain, meperidine is not recommended in treating persistent cancer
pain due to its short duration of action (2.5-3.5 hours) and its neurotoxic metabolite, normeperidine. Accumulation
of this metabolite, particularly when renal function is impaired, causes central nervous system stimulation that may
lead to seizures. This is typically preceded by development ofmultifocal myoclonus, which can be used as a
warmng sign.

Partial agonists

Partial agonists such as buprenorphine, have less effect than full agonists at opioid receptors. They are subject to a
ceiling effect, thus are less effective analgesics.

Mixed agonist-antagonists

Mixed agonist-antagonists block or are neutral at one type of opioid receptor while activating a different opioid
receptor. Mixed agonist-antagonists are contraindicated for use in the patient receiving an opioid agonist because
they may precipitate a withdrawal syndrome and increase pain. Mixed agonist-antagonists include pentazocine
(Talwin), butorphanol tartrate (Stadol), dezocine (Dalgan), and nalbuphine hydrochloride (Nubain). Their analgesic
effectiveness is limited by a dose-related ceiling effect.

Principles of Opioid Administration

Most patients with cancer pain require fixed-schedule dosing to manage the constant pain and prevent the pain from
worsening. An as-needed rescue dose (breakthrough dose) should be combined with the regular fixed-schedule
opioid to control the episodic exacerbation of pain, often referred to as breakthrough pain. When this pain is
elicited by an action such as weight-bearing, breathing, or defecation, it is termed 'incident' pain. Rescue or
breakthrough doses can be on an hourly as-needed basis. The breakthrough dose is generally calculated to be 10%
or 1/6 of the total dose of the fixed-schedule. Adherence rates are improved when patients are prescribed around-
the-clock opioids compared with as-needed prescribing.[g

Dosage

The appropriate dosing interval is determined by the opioid and formulation used. The analgesic effects of short-
acting oral opioids such as morphine, hydromorphone, codeine, and oxycodone begin within a half-hour after
administration and usually last for approximately 4 hours. The dosing interval of these drugs is therefore usually 4
hours. In patients given controlled-release formulations of morphine, hydromorphone, codeine, or oxycodone, relief
should begin in 1 hour, peak in 2 to 3 hours, and last for 12 hours (controlled-release hydromorphone and codeine
are not available in the United States). Therefore, they are usually prescribed in 12-hour intervals. There is a small
group ofpatients (10%-20% ofthose on 12-hourly controlled-release formulations), however, who may require
administration every 8 hours. The analgesic effect of transdermal fentanyl begins approximately 12 hours after the
application of the patch, peaks in 24 to 48 hours, and lasts for about 72 hours. Patches are therefore changed every
48 to 72 hours. Transdermal fentanyl use is not recommended for control of acute pain or poorly controlled pain
because there is a delayed onset of action until reaching steady-state either with new use or a change in the dose.

Dose titration

There is no maximum dose or ceiling dose for the strong opioid agonists. The appropriate dose is the amount of
opioid that controls pain with the fewest side effects. Dose titration should continue until good pain relief is
achieved or intolerable side effects develop that cannot otherwise be controlled. The goal is to achieve a favorable
balance between analgesia and side effects throughgradual adjustments ofthe dose. If analgesic tolerance appears
to be occurring, the dose can be increased or consideration given to switching the opioid, especially ifhigher doses
are required.

The severity of the pain and the opioid formulation chosen determines the rate of titration. The dose of immediate-
release formulations can be increased on a daily basis ifnecessary until pain reliefis adequate. Patients with
uncontrolled pain of a moderate intensity require daily increases of between 25% and 50% to their previous dose,
while patients with severe uncontrolled pain may require a higher increase. This refers to lower doses. At higher
opioid doses, increases of20% to 30% would be more prudent. Rapid dose escalation should be accompanied by
close monitoring for efficacy and side effects.

Occasionally, doses may need to be reduced or, even rarely, stopped. This may occur when patients become pain
free as a result of cancer treatment, including treatments such as nerve blocks and radiation therapy. Another reason
for considering reducing the dose is when a patient experiences significant opioid-related sedation that is
accompanied by good pain control. In situations where interventions achieve complete pain relief, rapid opioid
tapering rather than abrupt discontinuation is recommended and usually adequate.

Different types of opioids

The debate whether any one opioid causes less side effects or is more effective is characterized by much
speculation but little clinical evidence. Some have suggested that, compared to morphine, fentanyl and methadone
may cause less constipation.[B,2] Studies suggesting that oxycodone and hydromorphone may cause less nausea
and hallucinations than morphine [¾] are juxtaposedwith other studies that found no significant differences
between them.[2-_29] These inconclusive findings have prompted expert working groups ofthe European
Association of Palliative Care to recommend that there is currently little evidence of the clinical superiority of one
opioid over another regarding the side effect profile and/or analgesia.[5,_6]

Tolerance

Assume that patients actively abusing heroin or prescription opioids (including methadone) have some
pharmacologic tolerance that will require higher starting doses and shorter dosing intervals.

Opioid therapy in special populations

Health professionals should check current recommendations for opioid use in older people, children, people who
are cognitively impaired, and loown or suspected drug abusers.

Opioid switching

A series of case reports have demonstrated the clinical problem of inadequate pain control with escalating opioid -
doses in the presence of doA-limiting
toxic effects incl ing halluc natio confusion hypera gesia my lonus,
sedation, and nausea.[K,¾,B-U] It was suggested that these problems could be managed by switching to an
alternative opioid with the result being improved pain management and decreased toxic effects. The improvement
with opioid switching, although predominantly demonstrated initially with morphine, has also been reported with
other opioids.[E-g] A series of outcome surveys has demonstrated that the toxic effects of an opioid can be
relieved by opioid switching with substitution of a different opioid in a reduced equianalgesic dose of 50% to 70%.
[ ,¾-R] The major area of concern has been with the conversion to methadone. Methadone has been
demonstrated to be much more potent than previously described. It has been reported that the equianalgesic dose can
be 5 to 10 times or even higher than the previously quoted oral methadone to morphine ratio of l:1. It should be
noted that ratios are different for switching from methadone to a morphine-like opioid.[ ]

Table 3. Dose Equivalents for Opioid Analgesics in Opioid-Naive Adults

Drug Approximate equianalgesic Usual starting dose for

dose moderate to severe pain

Oral Parenteral Oral Parenteral

Opioid agonist (2)

morphine (3)
10mg q 4 h 3-5 mg q 4 h 5-10 mg q 4 h 2.5-5mg q 4 h
(repeat
around-the-
clock dosing)

morphine, 30 mg q 12 h N/A 15 mg q 12 h N/A

controlled
release (3, 4)
(MS Contin,
Oramorph)

hydromorphone (3)
(Dilaudid) 2 mg q 4 h 1 mg q 4 h 1-2mg q 4 h 0 5-1mg
.
q 4 h

hydromorphone, 6mg q 12 h N/A 3-6 mg ql2 h N/A

controlled-release
(not available in the US)

levorphanol
(Levo- 2 mg q 4 h 1 mg q 4 h 1-2mg q 4 h 0 5-1
. mg q 4 h
Dromoran)

methadone The conversion ratio of methadone and other opioids is

(Dolophine, variable depending on tolerance. Please refer to the
other) methadone section.

oxymorphone (3) N/A in US 1 mg q 3-4 h N/A 1 mg q 3-4 h

(Numorphan)

Combination opioid/NSAID preparations (6)

codeine(7) (with 180-200 mg q 130 mg q 60 mg q 3-4 h 60 mg q 2 h

aspirin or 3-4 h 3-4 h
acetaminophen)

hydrocodone (in 30 mg q 3-4 h N/A 10 mg q 3-4 h N/A

Lorcet, Lortah,
oxycodone 5-7.5 mg q 4 h 2.5mg q 4 h 5mg q 4 h 2.5mg q 4 h
(Roxicodone, (N/A in US)
also in Percocet,
Percodan, Tylox,
others)

oxycodone 10-15 mg q 12 h N/A 10 mg q 12 h N/A

controlled-release

(1) Caution: Recommended doses do not apply for adult patients with body weight
less than 50 kg. Smaller doses may be required in adults weighing less than 50
kg.

(2) Caution: Recommended doses do not apply to patients with renal or hepatic
insufficiency or other conditions affecting drug metabolism and kinetics.

(3) Caution: For morphine, hydromorphone, and oxymorphone, rectal

administration is an alternate route for patients unable to take oral
medications. Equianalgesic doses may differ from oral and parenteral doses
because of pharmacokinetic differences. Note: A short-acting opioid should
normally be used for initial therapy of moderate to severe pain.

(4) Transdermal fentany1 (Duragesic) is an alternative option. Transdermal

fentany1 dosage is not calculated as equianalgesic to a single morphine dosage.
See the package insert for dosing calculations. Doses above 25 mcg/hr should
not be used in opioid-naive patients.

(5) Not recommended. Doses listed are for brief therapy. Switch to another
opioid for long-term therapy.

(6) Caution: Doses of aspirin and acetaminophen in combination opioid/NSAID

preparations must also be adjusted to the patient's body weight.

(7) Caution: Methadone is much more potent than indicated in older published
literature. On average it is 10 times more potent than morphine. However, its
potency relative to morphine is not linear. When morphine at lower doses is
switched to methadone (e.g. 30-60 mq orally per day), the potency may be 3 to 5
times; when switched from high doses (e.g. greater than 300 mq morphine per day
orally), the potency may be 12 times or even higher.

(8) Caution: The oral to intravenous dose ratio of methadone is not well
established. The intravenous route is very seldom used. Subcutaneous
administration may be too irritating.

Note: Published tables vary in the suggested doses that

are equianalgesic to
morphine. Clinical response is the criterion that must
be applied for each
patient; titration to clinical responses is necessary. Because there is not
complete cross-tolerance among these drugs, it is usually necessary to use a
lower than equianalgesic dose when changing drugs and to retitrate to response.

Codes: q=every. N/A=not available. N/R=not recommended.

IM=intramuscular. SC=subcutaneous.

It has been suggested that rather than opioid switching, a less complicated approach would be to reassess the
clinical situation and use of adjuvant analgesics, decrease the opioid dose if possible, use medical management for
the opioid-related side effects, and correct any contributing metabolic abnormalities.[B, ] Nevertheless, there
does appear to be an emerging consensus that opioid switching does have a useful role when pain control remains
inadequate with escalating opioid doses, and the opioid results in unacceptable opioid-related side effects.[39-421 -
Morphine, as the strong opioid metabolite of choice for the management of cancer pain, was used increasingly
during the 1970s and 1980s.[g] Associated with this increasing experience was the clinical observation that there
was also a risk of accumulation of morphine metabolites, particularly in the presence ofrenal impairment.
Morphine-6-glucuronide, an analgesic metabolite, was recognized as having a usetal role in enhancing analgesia. A
number ofreports, however, have described seizures, cognitive impairment, nausea, and problems ofmyoclonus
that were associated with accumulation ofmorphine-6-glucuronide.[E-X]

The potential role of morphine metabolites, in particular the ratio of 3-glucuronide to 6-glucuronide in the
development of opioid-related toxicity, has been reported. The literature on this issue has been somewhat
controversial There is certainly no disagreement that morphine metabolites increase in the presence of deteriorating
renal fimetion, however, there has been conflicting evidence regarding the role and ratios ofthe metabolites in
patients exhibiting both a poor response to increasing morphine doses and associated toxicity.[5_1-55]

Switching from one opioid to another requires familiarity with a range of opioids and the use of opioid dose
conversion tables.[_6,56]When using these ratios, it must be understood that the guidelines and the patients should
be monitored more closely during the switching phase. A recent review has highlighted some important issues
related to these tables.[½] Wide ranges in ratios are noted. In the case of methadone, it is much more potent than
previously thought (on average 10 times more potent) and its equianalgesic dose ratio compared to other opioids
changes according to the dose ofthe previous opioid; the higher the dose, the higher the ratio. (Note that potency
does not denote more effectiveness, rather the equivalent dose required to obtain the same effect).

Following a switch, the dose should be further decreased by 25% to 40% to account for the lack of complete cross-
tolerance between opioids and patients should be monitored closely.

Route of Administration

Oral administration is preferred because it is convenient and usually inexpensive. When patients cannot take oral
medications, other less invasive routes (e.g., rectal or transdermal) should be offered. Parenteral methods should be
used only when simpler, less demanding, and less costly methods are inappropriate, ineffective, or unacceptable to
the patient. In general, assessing the patient's response to several different oral opioids is advisable before
abandoning the oral route in favor of anesthetic, neurosurgical, or other invasive approaches.

Rectal

Use this safe, inexpensive, effective route for delivery of opioids as well as nonopioids when patients have nausea
or vomiting. Rectal administration is inappropriate for the patient who has diarrhea, anal/rectal lesions, or
mucositis; who is thrombocytopenicor neutropenic; who is physically unable to place the suppository in the rectum;
or who prefers other routes. When changing kom the oral to the rectal route, begin with the same dosage as had
been given orally, then titrate as needed. The use of suppositories is not always culturally acceptable and may not
be practical in some instances (e.g., obese patients, patients with factures).

Transdermal (fentanyl)

Patches currently available are formulated to provide analgesia lasting up to 72 hours. This preparation is not
suitable for rapid dose titration and should be used for relatively stable analgesic requirements when rapid
increases or decreases in dosage are not likely to be needed.[E,2] Although other opioids are sometimes
compounded into gel form for transdermal application, there is insuñicient evidence at this point to support this
practice.

Transmucosal (fentanyl)

Oral transmucosal fentanyl citrate (OTFC) is used for the relief of breakthrough pain. The lipid solubility of
fentanyl allows rapid onset ofpain relief In a large, open-label multicenter study, 92% of patients received relief
irout urenKuirougu pHIH. 0100 CHCULE WCTC CUHSlSLCHL W1UI OUICT OplUlu UICIHyles, lHClüGlHy SCUNGUH, COHSupHUUH,

and nausea.[59] There is growing interest in the use ofrapidly-acting, highly lipophilie opioids such as fentanyl for
the management of difficult breakthrough pain syndromes. Recently an oral transmucosal fentanyl citrate compound
for buccal administration has become available for this purpose.[_60,_61] Other opioids such as morphine,
hydromorphone, and oxycodone are not very lipophilie and therefore not suited for buccal or sublingual
administration. While in the home setting, opioids are sometimes administered buccally or sublingually with erratic
absorption that is likely via the lower gastrointestinal tract.

Parenteral: intravenous and subcutaneous

Intravenous administration provides a rapid onset of analgesia within 2 to 10 minutes. The duration of action after a
bolus dose may be shorter than with other routes. This route may be useful if a patient cannot swallow and
intravenous access is established.

The subcutaneous route is as effective as the intravenous route.[_5] In some situations, it may even be more
convenient, especially if patients are being cared for at home or in a hospice. To facilitate administration via this
route, a 25- or 27-gauge butterfly needle can be inserted subeutaneously and left in place for up to 7 days at a time.
The anterior thighs, abdomen, upper arms, and upper back are possible areas for needle insertion. The site should
be monitored for signs of infection or irritation and should be changed if these are noted.

The bioavailability of parenterally administered opioids (morphine, hydromorphone, oxycodone, and codeine) is
generally 2 to 3 times that ofthe oral route. The dose therefore needs to be halved or decreased by a third when
switching from the oral to the subcutaneous and intravenous routes respectively (See Table 3). Opioids
administered parenterally may be given either intermittently (usually on a every 4 hour basis) or by a continuous
infusion. With some exceptions, these two methods appear to be as effective.

Other routes

Some studies suggest that the use of inhaled opioids for the management of pain and cancer-related shortness of
breath are, with some exceptions, not more effective than systemic administration.[G,63]Their absorption via this
route is unpredictable.

The intramuscular administration of opioids is not recommended.

Patient-Controlled Analgesia (PCA)

PCA may be used to determine the opioid dose needs when initiating opioid therapy. Once the pain is well
controlled, a regular opioid dose can be instituted on the basis ofthe PCA doses required. This method is
contraindicated in patients with cognitive impairment or patients with significant psychological undercurrents to
their pain experience.

Intraspinal

The intraspinal administration of opioids (epidural or intrathecal), especially when combined with a local
anesthetic, can be helpful in a very small select group ofpatients with intractable pain. Use ofthe epidural or
intrathecal route requires skill and expertise that may not be available in all settings. Table 4 presents the
advantages and disadvantages of intraspinal administration. The main indication for long-term administration of
intraspinal opioids is intractable pain in the lower part ofthe body, particularly bilateral or midline pain. Analgesia
is possible without motor, sensory, or sympathetic blockade. Local anesthetics may be combined with opioids for
intraspinal administration.

Table 4 . Advantages and Disadvantages of Intraspinal Drug Administration

.System Advantages Disadvantages

Percutaneous Used extensively both Mechanical problems
temporary catheter intraoperative and include catheter
postoperatively. dislodgment, kinking or
migration. Increased risk of
infection.
Useful when prognosis is
limited (<1 month).

Permanent Catheter implantation is a

silicone-rubber minor procedure.
epidural
Dislodgment and infection
less common than with
temporary catheters.

Can deliver bolus

injections, continuous
infusions, or PCA (with or
without continuous
delivery).

Subcutaneous Increased stability, less Implantation more

implanted risk of dislodgment. invasive than external
injection port catheters.
Can deliver bolus injections
or continuous infusions Approved only for
(with or without PCA). epidural catheter in United
States

Potential for infection

increases with frequent
injections.

Subcutaneous Potentially, reduced Difficult to access, and

reservoir infection in comparison to fibrosis may occur after
external system. repeated injection.

Implanted pumps Potentially, decreased risk Need for more extensive

(continuous and of infection. operative procedure.
programmable)
Need for specialized
equipment with
programmable systems.

Drugs and Routes Not Recommended

Table 5 presents data on drugs and routes of administration not recommended for the management of cancer pain.

Table 5. Drugs and Routes of Administration Not Recommended for Treatment

of Cancer Pain

Class Drug Rationale for not recommending

Opioids meperidine Short (2-3 hour) duration of analgesia.

Repeated Administration may lead to CNS toxicity
(tremor, confusion, or seizures).

Opioid agonist- pentazocine Risk of precipitating withdrawal in

antagoniËts butorphano1 opioid-dependent patients. Analgesic
nalbuphine ceiling. Possible production of
unpleasant psychotomimetic effects
(e.g., dysphoria, delusions,
hallucinations).

Partial agonist buprenorphine Analgesic ceiling. Can precipitate

withdrawal.

Antagonists naloxone May precipitate withdrawal. Limit use

naltrexone to treatment of life-threatening
respiratory depression.

Combination Brompton's No evidence of analgesic benefit to

preparations cocktails using Brompton's cocktail over single
opioid analgesics.

DPT (meperidine, Efficacy is poor compared with that of

promethazine, other analgesics. High incidence of
and adverse effects.
chlorpromazine)

Anxiolytics benzodiazepine Analgesic properties not demonstrated

alone (e.g., except for instances
some of neuropathic
alprazolam) pain. Added sedation from anxiolytics
may compromise neurologic assessment in
patients receiving opioids.

Sedative/ barbiturates Analgesic properties not demonstrated.

hypnotic drugs benzodiazepine Added sedation from sedative/hypnotic
alone drugs limits opioid dosing.

Routes of administration Rationale for not recommending

Intramuscular (IM) Painful. Absorption unreliable. should

not be used for children or patients
prone to develop dependent edema or in
patients with thrombocytopenia.

Transnasal The only drug approved by the FDA for

transnasal administration at this time
is butorphano1, an agonist-antagonist
drug, which generally is not recommended.
(see opioid agonist-antagonists above).

Side Effects of Opioids

Clinicians should anticipate and monitor for side effects. The more common adverse effects include nausea,
somnolence, and constipation. These should be discussed with patients before starting. Somnolence and nausea are
more often encountered with initiation of opioid treatment, but tend to resolve within a few days. Clinicians who
follow patients during long-term opioid treatment should watch for potential side effects and manage them as the
needm·ises.

Constipation

Anticipate the constipating effects of analgesics. Opioids compromise gastrointestinal tract peristaltic function (a
nearly universal side effect). Consequently, stool within the gut lumen becomes excessively dehydrated. The
cornerstone of effective prophylaxis, therefore, is measurement aimed at keeping the patient well hydrated in order .
to maintain well-hydrated stool. All patients using opioid medications should be prescribed a scheduled regimen of
stool softening agents (e.g., docusate sodium) at the time opioid treatment commences. Patients who do not
adequately respond to an aggressive regimen with stool softeners may benefit kom the addition ofmild osmotic
agents (e.g., 70% sorbitol solution, lactulose, milk of magnesia), lubricants (e.g., mineral oil), bulk-forming
laxatives (e.g., psyllium) with appropriate orally-administered hydration, or mild cathartic laxatives (e.g.,
casanthrol, senna). Stimulant catharties (e.g., senna, bisacodyl) may be usefid in severely constipated patients,
however, they may be relatively ineffective in situations where stool has become desiccated. Opioid-induced
constipation is a Requent cause of chronic nausea and is observed in 40% to 70% of patients receiving opioids.[g]
It appears to be dose related, characterized by large variability in individuals and is opioid-receptor mediated via
both central and peripheral mechanisms. Opioids extend the gastrointestinal transit time and desiccate the
intraluminal content.[6_4] Unlike nausea, complete tolerance to this effect does not generally develop, and most
patients require laxative/stool softener therapy for as long as theytake opioids. A plain x-ray ofthe abdomen may
be helpnil in assessing the extent of fecal load.[65]

Initiating a regular laxative regimen emphasizes prevention of opioid-induced constipation. Recommendations

regarding laxative treatment have been largely based on clinical experiences and observations. Combinations of a
sennoside and a stool softener such as docusate are generally suggested.[_66] Reports that fentanyl causes less
constipation than oral morphine are interesting, but need to be confirmed in flirther prospective studies.[M,65,62]A
recent study demonstrated decreased laxative use in patients on transdermal fentanyl as compared to patients on oral
morphine treatment.[B]Whether this decrease is clinically significant or not, however, and whether the decrease in
laxative usage relates to the route of administration instead ofthe opioid type, needs to be demonstrated. In one
small series, opioid switching ofmorphine to methadone resulted in a reduction in constipation.[_6_8] Severe opioid-
induced constipation may occur. At an extreme it may be present as a severe ileus and pseudo-bowel obstruction.
[69] Management, as is the case with opioid-induced nausea and constipation, relies on the use of gastrointestinal
prokinetic agents. The use of orally administered opioid-antagonists such as naloxone is being studied.[D,R]
Although the oral bioavailability of these medications is very limited, opioid withdrawal syndromes have been
noted when higher doses have been used. Methylnaltrexone, a quaternary derivative ofnaltrexone, is an opioid
antagonist that does not cross the blood-brain barrier. Preliminary studies suggest that it may be effective in the
management of opioid-associated constipation without causing opioid withdrawal.[2] (Refer to the PDQ
summaries on Constipation, Impaction, and Bowel Obstruction, Nausea and Vomiting, and Nutrition for more
information.)

Nausea and vomiting

Nausea and vomiting occurs in approximately one-third to two-thirds of patients taking opioids.[B-2] It is a
common complication of early exposure to opioids and usually disappears within the first week of treatment.
Appropriate antiemetic coverage during the opioid-initiation phase is usually effective in limiting this adverse
effect. Nausea alone does not represent an allergic reaction to the opioid. Occasionally, nausea may be experienced
when an opioid dose is significantly increased. An antiemetic should be available on an as-needed basis to address
this.

Three main mechanisms underlie this opioid-related adverse effect.[2] The predominant mechanism appears to be
stimulation of the chemoreceptor trigger zone, where dopamine is the main neurotransmitter. Another is reduced
gastrointestinal motility, including delayed gastric emptying. Nausea via increased vestibular sensitivity is
uncommon.

Multiple antiemetic regimens have been proposed for the management of opioid-induced emesis but prospective
studies comparing one regimen over another are lacking.[] Metoclopramide or domperidone are generally
recommended as first-line agents because they improve gastrointestinal motility and are antidopaminergic.[¾,2]
Metoclopramide can be administered orally or subeutaneously at doses of 10 mg 4 times a day or on an every 4
hour basis, depending on the severity ofthe nausea. Rescue doses should also be ordered on an as-needed basis.
Extrapyramidal-related adverse effects are a potential complication ofthese medications. The incidence of
extrapyramidal reactions is low with domperidone, but this drug is not available in a parenteral formulation. The
antihistamines act on the histamine receptors in the vomiting center and on vestibular afferents. They are generally
reserved for cases where vestibular sensitivity, often manifesting as motion-induced nausea, is suspected or where
bowel obstruction precludes the use of gastrointestinal prokinetic agents. Haloperidol may also be used under the -

latter circumstances. The phenothiazines are an alternative group of antiemetics but extrapyramidal and
anticholinergic adverse effects may be dose-limiting. Chlorpromazine has modest antiemetic activity but a high
incidence of sedation, postural hypotension and anticholinergic adverse effects, while piperazine derivatives such
as prochlorperazine are stronger antiemetics but cause more extrapyramidal side effects. Anticholinergic side
effects also limit the use of anticholinergic agents such as hyoscine hydrobromide (scopolamine) in opioid-induced
nausea, particularly in patients with advanced cancer. These patients seem to be more vulnerable to these adverse
effects. The role of 5-HT3 receptor antagonists such as ondansetron in ameliorating opioid-induced nausea is not
clear.[2]

There appear to be differences between individual patients in the extent to which different opioids cause nausea.
[3] This forms the basis for the strategy of switching kom one opioid to another when a particular opioid produces
persistent nausea.[¾,B] Switching the route, specifically Rom the oral to the parenteral, has also been suggested,
but the studies supporting this strategy are small.[g]

Nausea and vomiting can sometimes persist beyond the opioid-initiation phase or occur de novo in patients on long-
term opioid treatment. It may become chronic in nature. The multicausal nature of the problem needs to be
recognized since management is directed at identifying and addressing the various causes.[83] Chronic nausea has
been associated with the accumulation of active opioid metabolites.[_49] A number of strategies are suggested to
manage this including switching the opioid or decreasing the dose where pain is well controlled. (Refer to the PDQ
summary on Nausea and Vomiting for more information.)

Cognitive and other neurotoxic side effects of opioids

Opioid-related neurotoxicity may manifest as cognitive impairment, hallucinations, delirium, generalized

myoclonus, hyperalgesia and/or allodynia. Patients who have renal impairment or who are taking higher doses of
opioids are at greater risk of developing these side effects. The mechanisms underlying these are unclear, but the
opioid metabolites are implicated. The etiological contribution of opioids to cognitive impairment and delirium in
the cancer patient is often difficult to determine. This is the case particularly in patients with advanced disease,
where the baseline vulnerability is associated with multisystem impairment, and the concurrent administration of
other psychotropic agents can complicate the assessment of etiology. Nonetheless opioid-induced cognitive
problems have been reported with increasing frequency in the last decade.[B,M,¾] Cognitive impairment within
the context of delirium is one of several effects, which also include myoclonus, hyperalgesia, perceptual
disturbance, and seizures.[¾] Although the remarkable characteristics, potential severity, and impact of delirium
contribute to its dominance in the spectrum of opioid-related cognitive dysfimetion, more subtle psychomotor and
cognitive opioid effects have been described. Neuropsychological testing has been used to study these more subtle
disease,[8_¯]
effects in less advanced cancer chronic nonmalignant pain,[B,88] or in healthy volunteers.[89]
Collectively, studies ofneuropsychological testing have demonstrated somewhat mixed findings, some detecting
opioid associated impairment in certain aspects ofpsychomotor or cognitive fonction,[g,B] while others detected
minimal or no impairment.[L,E] Clinical experience and some studies suggest that patients become tolerant of the
sedating effects that accompany either the initiation of opioid therapy or dose increases,[90] thereby allowing
patients who are otherwise physically able, and on stable opioid doses, to safely engage in activities such as
driving.[E,S]

Decreased brain cholinergic activity is recognized as one ofthe potential underlying pathophysiological
mechanisms of delirium.[B-B] In the case of meperidine, the anticholinergic activity associated with its active
metabolite normeperidine, is suspected to be the basis ofthe cognitive impairment and delirium occurring in
association with this opioid.[¾,¾] Other opioid metabolites have been studied in relation to the generation of
neuroexcitatory states in animal laboratory models and delirium in human subjects. A series of animal studies have
demonstrated neuroexcitatory states in association with morphine metabolites, morphine-3-glucuronide (M-3-G)
[2] and normorphine-3-glucuronide,[g] and the hydromorphone metabolite, hydromorphone-3-glucuronide.[R] In
a hospice study of36 patients with advanced cancer receiving morphine, both M-3-G and morphine-6-glucuronide
(M-6-G) levels were studied in relation to the development of side effects, which included nausea and vomiting in
10 and cognitive impairment in 9 patients.[ ] Creatinine levels, and plasma levels of M-3-G, M-6-G, and dose
corrected M-3-G and M-6-G, were higher in the 19 patients with side effects, suggesting that the elevation of
morphine metabolites in association with renal impairment was associated with opioid toxicity, including cognitive -

impairment. There is extensive evidence demonstrating elevation of opioid metabolite levels in the setting of renal
impairment,[ ,@,100-102] and some studies have noted an association with features ofneurotoxicity including
cognitive impairment.[85,_100] An accumulation of opioid metabolites possibly also occurs during dehydration,
which was suggested as a contributory factor in a prospective study ofpredominantly opioid-related delirium.[g]
Switching to another opioid is one strategy for abating the side effects in cases when accumulation of active
metabolites is considered responsible for side effects such as generalized myoclonus, sedation, connision, or
chronic nausea.[2]

Managing cognitive and other neurotoxic effects of opioids

The general management approach to opioid-induced delirium requires a multidimensional assessment to determine
the presence of other potentially treatable contributory factors such as dehydration, other centrally acting
medications, sepsis, and hypercalcemia.[_8_4,M,2]Clinical experience suggests that the presence oftactile
hallucinations and myoclonus,[_40] although not exclusively associated with opioid toxicity, raise the suspicion of
this cause. A carenil assessment can also identify prognostic factors associated with greater difficulty in achieving
pain control, the need for higher opioid doses, and consequently greater risk of opioid-induced delirium. These
factors include neuropathic pain, incidental pain, tolerance, somatization of psychological distress, and a positive
history of drug or alcohol abuse.[g]

In addition to searching for underlying reversible causes of delirium, the symptomatic management of delirium
requires the addition of a neuroleptic agent to control agitation and perceptual or delusional disturbance.
Haloperidol is regarded as the drug of choice in this context,[g] while methotrimeprazine and chlorpromazine are
considered useflil alternatives,[W,M] especially when a greater level ofsedation is required. Midazolam, a
sedating and short acting benzodiazepine given by continuous infosion is sometimes necessary, especially in the
case ofnonreversible delirium.[g]

The specific management approach to opioid-induced cognitive and other neurotoxic side effects involves either a
dose reduction or an opioid switch. Ifthe pain is well controlled, and the cognitive and neurotoxic side effects are
not severe, modest opioid dose reduction may be effective. The rationale for switching opioids, commonly referred
to as opioid switching, is that a more favorable balance between analgesia and side effects can be achieved, often
with a lower dose thanthat predicted by the conventional analgesic table.[U,8_4,U0]This can reflect incomplete
cross-tolerance among opioids in relation to analgesic and other effects.[H1]It is also possible that switching to a
new opioid could allow for the elimination ofpotentially toxic opioid metabolites.[M,2,84]Reduction in opioid
dose in the context of an opioid-induced delirium has not been systematically evaluated but is also likely to have
beneficial results. Although there is growing evidence to suggest a beneficial role for opioid switching,[M,2,U]
contoversy persists over the relative value of opioid switching versus dose reduction.[R]

Cognitive benefit has been reported with the use of methylphenidate in patients receiving a continuous inínsion of
opioids for cancer pain.[ ] The psychostimulant benefit is likely to relate to mitigation of sedation associated
with upward dose titration of opioid.[m] Although psychostimulants have been advocated for hypoactive
delirium,[B] any evidence ofperceptual or delusional disturbance is considered a contraindication.

Respiratory depression

Patients receiving long-term opioid therapy generally develop tolerance to the respiratory depressant effects of
these agents. When indicated for reversal of opioid-induced respiratory depression, administer naloxone titrated in
small increments to improve respiratory nmetion without reversing analgesia. Monitor the patient carenilly until the
episode ofrespiratory depression resolves. Note that the opioid antagonists have a short half-life and may have to
be given repeatedly until the agonist drug is sufficiently cleared.[g]

Subacute overdose

Perhaps more common than acute respiratory depression, subacute overdose may manifest as slowly progressive
(hours to days) somnolence and respiratory depression. Before reducing analgesic doses, advancing disease must
be considered, especially in the dying patient. Generally, withholding 1 or 2 doses of an opioid analgesic is -

adequate to assess whether mental and respiratory depression are opioid-related. If symptoms resolve after
temporary opioid withdrawal, reduce the scheduled opioid dosage by 25%. If symptoms do not abate, but the
patient complains of or exhibits signs of increased pain, or if symptoms referable to opioid withdrawal occur,
consider alternative causes for CNS depression and reinstitute analgesic treatment. Ongoing assessment is essential
to maintain adequate pain relief

Effects of opioids on sexual timetion

Reduced libido is a well-known phenomenon for those using heroin or in a methadone maintenance program.
Unfortunately, clinicians prescribing opioids for pain poorly understand this effect. Animal studies confirm that :

opioids lower testosterone levels and suppress sexual fitnetion in males.[ ] Early case studies ofpersons using
heroin or methadone described diminished libido, sexual dysfitnetion, reduced testosterone levels in men, and
amenorrhea in women.[117-122] These effects resolve after the opioid has been discontinued. More recent case
reports of patients receiving opioids for relief of chronic pain suggest these same findings.[G,m] The long-term
effects ofreduced testosterone and amenorrhea are not well known. Sexuality is an essential component of one's
quality of life, especially for cancer survivors, but also for some people with advanced disease. Patients should be
assessed for changes in libido and sexual dysflinction. Ifthese changes are distressing to the patient, serum
testosterone levels may be obtained. Should the patient seek improvement in libido and performance, treatment is
often empirical, keeping in mind that there are many potential causes of changes in sexual fimetion. Treatment
includes using nonopioids for pain, adding adjuvant analgesies in the hope the opioid dose may be reduced, or
replacing testosterone through injections or a patch (ifnot contraindicated). More research is needed to understand
the relationship between opioids and sexual fimetion, as well as the most effective treatment strategies. (Refer to the
PDQsummary on Sexuality and Reproductive Issues for more information).
Other opioid side effects

Dry mouth, urinary retention, pruritus, dysphoria, euphoria, sleep disturbances, and inappropriate secretion of
antidiuretic hormone are less common.

Adjuvant Drugs

Table 6. Adjuvant Analgesics

Class Drug Daily Dose Range

Antidepressants amitriptyline 10-150 mg

desipramine 10-150 mg
maprotiline 50-300 mg
paroxetine 10-60 mq
nortriptyline 10-100 mg

Anticonvulsants carhamazepine 100 mq tid-400 mg tid

valproate 500 mq tid-1000mg tid
gabapentin 100 mg tid-1000mg tid
clonazepam 0 5
. mg bid- 4 mg bid

Local Anesthetics mexiletine 100 mq bid-300 mq tid

lidocaine patch

Corticosteroids dexamethasone See Text

prednisone See text

Bisphosphonates clodronate see text

pamidronate See text
zoledronic acid See text
Miscellaneous hac10fen 5 mg tid-20 mg tid
calcitonin 100-200 IU (subcutaneous or
intranasal)
clonidine 0.1 mg bid-0.3 mg bid
methylphenidate 2 5 mg bid-20
. mg bid
ketamine See text

Adjuvant drugs are valuable during all phases ofpain management to enhance analgesic efficacy, treat concurrent
symptoms, and provide independent analgesia for specific types of pain.[ g] We need to keep in mind, however,
that adverse drug reactions are common and that there are wide interindividual and ethnic differences in drug
metabolism.[2] A survey on symptom severity and management in 593 cancer patients treated for an average of
51 days, reported that during this time anticonvulsants were used in 11.8% of patients, antidepressants in 16%,
corticosteroids in 28%, and bisphosphonates in 7.3%.[ ] Patients with advanced cancer on palliative medicine
services are reported to receive on average 5 medications for symptom relief and as a result are at high risk of drug
interactions.[2] A flirther note of caution appears in another study that questioned the concept of opioid-sparing
effects of co-analgesics.[g] Nevertheless, adjuvant analgesies have been extensively studied and reviewed in
noncancer settings, and are generally endorsed as an important intervention in the provision of adequate pain
management.[129-132] There are very few trials overall in the cancer setting and even fewer trials comparing
adjuvant drugs in the cancer setting.

Antidepressants

The analgesic benefits oftricyclic antidepressants has been well established and is generally considered first-line
therapy for many neuropathic pain syndromes.[2-m] Supporting evidence is strong for amitriptyline and
desipramine, and there is endorsement of other newer antidepressants such as maprotiline and paroxetine.
Neuropathic pain characterized by continuous dysesthesias is generally believed to be the most likely to benefit
from antidepressant management.

The most common side effects oftricyclic antidepressants are constipation, dry mouth, blurred vision, cognitive
changes, tachycardia, and urinary retention. Caution has also been advised in treating patients with cardiae disease
and an electrocardiogram is sometimes recommended as a prudent measure. A slow upward titration is suggested as
a good way to avoid side effects.

Anticonvulsants

The group of commonly used anticonvulsants as adjuvant analgesics for neuropathic pain includes carbamazepine,
valproate, phenytoin, and clonazepam.[_1_29- ]

There is extensive clinical experience with carbamazepine, but use ofthis drug is limited in the cancer population
because of concern that it causes bone marrow suppression, in particular leukopenia. Other common adverse effects
include nystagmus, dizziness, diplopia, cognitive impairment, and mood and sleep disturbance.

Dosing guidelines for phenytoin are similar to the treatmentfor seizures [m] and can be administered using a
loading dose, which may be particularly usekl in patients with severe pain.

Gabapentin is increasingly reported as usekl for the management ofneuropathic cancer pain.[134-136] Commonly
reported side effects include somnolence, dizziness, ataxia, and fatigue.[m]

Clonazepam is an anticonvulsant from the benzodiazepine class, and is commonly used for treating lancinating or
paroxysmal neuropathic pain.[_1_29] The potential for drowsiness and cognitive impairment must be monitored
care&lly.

Local Anesthetics
Management with mexiletine has become an accepted approach for chronic neuropathic pain.[m,m,m] Side
effects are reported as common and include gastrointestinal toxicity, in particular nausea, and central nervous
system side effects such as dizziness. Patients with a history of cardiac disease or those on higher doses are at
increased risk of adverse effects and it is recommended that they receive appropriate cardiac evaluation including
an electrocardiogram.

Corticosteroids

These drugs have achieved wide acceptance in the management of patients with cancer pain. They are indicated as
adjuvant analgesies for cancer pain ofbone, visceral and neuropathic origin. Adverse effects include
neuropsychiatric syndromes, gastrointestinal disturbances, and immunosuppression. The risk of adverse effects
increases with the duration ofuse. As a result, use is often restricted to patients with a limited life expectancy, and
in addition, once effective pain control is obtained it is commonly recommended that the dose be tapered as much as
possible. Dosage recommendations vary from a trial of low-dose therapy such as dexamethasone 1 mg to 2 mg or
prednisone 5 mg to 10 mg once or twice daily [ ] to a starting dose of dexamethasone 10mg twice daily with
subsequent tapering to the minimal effective dose.[ ]

Another suggested use of corticosteroidsis in high doses for short periods in patients with severe pain. This
empirical approach recommends a regime of a single bolus of dexamethasone 100 mg intravenously followed by a
small amount given 4 times per day and thentapered over the next few weeks.[ g]

Although there is widespread acceptance of steroid therapy, mostly via the oral route, but also subeutaneously and
intravenously, data remain inadequate for definitive conclusions regarding efficacy and dosing guidelines.[m-

Bisphosphonates

These drugs are recommended for the management of bone pain, as well as the prevention of skeletal complications
in patients with metastatic bone disease.[m-R,N-M_4] The bisphosphonates most frequently used are
clodronate, pamidronate, and zoledronic acid.

Clodronate can be given orally or intravenously. Dosage recommendations are oral clodronate 1600 mg per day or
intravenous clodronate 600 mg to 1500 mg every 2 to 3 weeks. Clodronate is not available in the United States.

Pamidronate is recommended in the dose range of 60 mg to 90 mg intravenously over 2 hours every 3 to 4 weeks.

Zoledronic acid is a potent bisphosphonate that can be given as an intravenous bolus over 15 to 30 minutes in the
dose range of4 mg to 8 mg.[B5,M6] The few studies to date suggest administration at 3- to 4-week intervals.

Miscellaneous

Baclofen

This drug is generally used for spasticity but may also be used in neuropathic pain.[g, , ] Side effects
include drowsiness, dizziness, ataxia, contosion, and nausea and vomiting.

Calcitonin

Although the mechanism by which calcitonin produces analgesia is unknown, it has been recommended for the
treatment of both bone and neuropathic pain.[m,m,m,N,N] The most common side effects relate to local
reactions at the site of administration or gastrointestinal problems. Optimal dose, frequency, and length of
administration are unloown.

Clonidine
This traditional antihypertensive can be given via the oral or transdermal route, and has been recommended as a
trial for the management ofneuropathic pain. Reported side effects include dry mouth, dizziness and hypotension,
sedation, and constipation.[ , ,2] The maximum recommended dose is 2.4 mg per day.

Psychostimulants

Psychostimulants such as dextroamphetamine, methylphenidate and modafinil may enhance the analgesic effects of
opioids.[m] They may also be used to diminish opioid-induced sedation when reducing the dose is not possible.

N-methyl-D-aspartate (NMDA) Receptor Antagonists

There is increasing interest in the evidence for the importance ofNMDA receptors, and the possibility that NMDA
antagonists may have a role in refractory cancer pain management.[O, ] Ketamine in subanesthetic doses has
been used in this setting. Co-administration of a neuroleptic or benzodiazepine is given to limit the emergence of
side effects. Ketamine is generally given subeutaneously at a low starting dose, such as 0.1 mg per kg of body
weight per hour with a gradual escalation. It has been suggested that oral ketamine may be a more potent analgesic
and have a more favorable side effect profile than parenteral ketamine.[2] A recent novel approach suggested
short duration therapy of a continuous subcutaneous infusion ofketamine over 3 to 5 days. The initial dose is 100 .

mg per day, and ifpain control is inadequate, the dose is escalated to 300 mg per day and thento a maximum dose
^

of 500 mg per day. Treatment is continued for three days at either the lowest effective dose or 500 mg per day and
then discontinued.[K]

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108. Breitbart W. Bruera E. Chochinov H. et al.: Neuropsychiatric syndromes and psychological symptoms in
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109. Burke AL. Diamond PL. Hulbert J. et al.: Terminal restlessness--its management and the role ofmidazolam.
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117. De Leon G. Wexler HK: Heroin addiction: its relation to sexual behavior and sexual experience. Journal of
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PHYSICAL AND PSYCHOSOCIAL INTERVENTIONS

Patients should be encouraged to remain active and participate in self-care when possible. Noninvasive physical
and psychosocial modalities can be used concurrently with drugs and other interventions to manage pain during all
phases of treatment. The effectiveness of these modalities depends on the patient's participation and communication
of which methods best alleviate pain.

Physical Modalities

Generalized weakness, deconditioning, and musculoskeletal pain associated with cancer diagnosis and therapy may
be treated by:

Heat

Avoid burns by wrapping the heat source (e.g., hot pack or heating pad) in a towel. A timing device is usefid to
prevent burns from an electrical heating pad. The use ofheat on recently irradiated tissue is contraindicated, and
diathermy and ultrasound are not recommended for use over tumor sites.

Cold

Apply flexible ice packs that conform to body contours for periods not to exceed 15 minutes. Cold treatment
reduces swelling and may provide longer-lasting relief than heat but should be used cautiously in patients with
peripheral vascular disease and on tissue damaged by radiation therapy.

Massage, Pressure, and Vibration

Physical stimulation techniques have direct mechanical effects on tissues and enhance relaxation when applied
gently. Tumor masses should not be aggressively manipulated. Massage is not a substitute for active exercise in
ambulatory patients.

Exercise

Exercise strengthens weak muscles, mobilizes stiff joints, helps restore coordination and balance, and provides
cardiovascular conditioning. Therapists and trained family or other caregivers can assist the fimetionally-limited
patient with range-of-motion exercises to help preserve strength and joint timetion.During acute pain, exercise
should be limited to self-administered range-of-motion. Weight-bearing exercise should be avoided when bone
Racture is likely.

Repositioning

Reposition the immobilized patient Requently to maintain correct body alignment, to prevent or alleviate pain, and
to prevent pressure ulcers.

Immobilization

Use restriction ofmovement to manage acute pain or to stabilize factures or otherwise compromised limbs or
joints. Use adjustable elastic or thermoplastic braces to help maintain correct body alignment. Keep joints in
positions of maximal function rather than maximal range. Avoid prolonged immobilization.

Stimulation Techniques
Transcutaneous Electrical Nerve Stimulation (TENS)

Controlled, low-voltage electrical stimulation applied to large myelinated peripheral nerve fibers via cutaneous
electrodes to inhibit pain transmission. Patients with mild to moderate pain may benefit from a trial of TENS to see
if it is effective in reducing the pain. TENS is a low-risk intervention.

Acupuncture

Pain is treated by inserting small, solid needles into the skin, with or without the application of electrical current.
Needle placement follows the Eastern theory of vital energy flow.

Cognitive-Behavioral Interventions

Cognitive-behavioral interventions are an important part of a multimodal approach to pain management. They help
to give the patient a sense of control and to develop coping skills to deal with the disease and its symptoms.
Guidelines by a National Institutes of Health assessment panel exist suggesting integration of pharmacologic and
behavioral approaches for treatment of pain and insomnia.[_1]

Interventions introduced early in the course of illness are more likely to succeed because they can be learned and
practiced by patients while they have sufficient strength and energy. Patients and their families should be given
information about and encouraged to try several strategies, and to select 1 or more ofthese cognitive-behavioral
techniques to use regularly:

Relaxation and Imagery

Simple relaxation techniques (see examples listed below) should be used for episodes ofbriefpain (e.g., during
procedures). Brief simple techniques are preferred when the patient's ability to concentrate is compromised by
severe pain, a high level of anxiety, or fatigue.

Hypnosis

Hypnotic techniques may be used to induce relaxation and may be combined with other cognitive-behavioral
strategies. Hypnosis is en'ective in relieving pain in individuals who can concentrate well, use imagery, and who
are motivated to practice.

Cognitive Distraction and Reframing

Focusing attention on stimuli other than pain or negative emotions accompanying pain may involve distractions that
are internal (e.g., counting, praying, or making self-statements such as "I can cope,"), external (e.g., music,
television, talking, listening to someone read, or the use of a visual focal point). In the related technique, cognitive
reappraisal, patients learn to monitor and evaluate negative thoughtsand replace them with more positive thoughts
and images.

Patient Education

Both oral and written information and instructions should be provided about pain, pain assessment, and the use of
drugs and other methods of pain relie£[_2] Patient education should emphasize that almost all pain can be effectively
managed. Major barriers to effective pain management should be discussed to correct patient and family
misconceptions. (Refer to the list of Barriers to Effective Cancer Pain Management in the Overview section for
more information.) Health care providers need to take into consideration family members' interpretation of patient
pain when providing pain management education services as some caregivers overestimate patient pain.[3]

Psychotherapy and Structured Support

Some patients benefit from short-term psychotherapy provided by trained professionals. Patients whose pain is
^

particularly difficult to manage and who develop symptoms of clinical depression or adjustment disorder should be
referred to a psychiatrist for diagnosis. The relationship between poorly controlled pain, depression, and thoughts
of suicide should not be ignored.

Support Groups and Pastoral Counseling

Because many patients benefit from peer support groups, clinicians should be aware of locally active groups and
offer this information to patients and their families. Pastoral counseling members of the health care team should
participate in meetings to discuss patients' needs and treatment. They should be a source of information on
community resources for spiritual care and social support.

RELAXATION EXERCISES

Exercise 1. Slow Rhytlunic Breathing for Relaxation *

1. Breathe in slowly and deeply, keeping your stomach relaxed and your
shoulders relaxed.

2. As you breathe out slowly, feel yourself beginning to relax; feel the
tension leaving your body.

3. Now breathe in and out slowly and regularly, at whatever rate is

comfortable for you. Let the breath come all the way down to your stomach, as it completely relaxes.

4. To help you focus on your breathing and breathe slowly and rhythmically:
(a) breathe in as you say silently to yourself "in, two, three"; (b) breathe out as you say silently to yourself "out,
two, three." OR

Each time you breathe out, say silently to yourself a word such as "peace" or "relax."

5. Do steps 1 through 4 only once or repeat steps 3 and 4 for up to 20

mmutes.

6. End with a slow deep breath. As you breathe out say to yourself "I feel
alert and relaxed."

Exercise 2. Simple Touch, Massage, or Warmth for Relaxation

Touch and massage are age-old methods ofhelping others relax. Some examples are:

(1) Brief touch or massage, e.g., handholding or briefly touching or rubbing a person's shoulder.

(2) Warm foot soak in a basin of warm water, or wrap the feet in a warm, wet towel.

(3) Massage (3-10 minutes) may consist of whole body or be restricted to back, feet, or hands. If the patient is
modest or cannot move or turn easily in bed, consider massage of the hands and feet.

• Use a warm lubricant, e.g., a small bowl ofhand lotion may be warmed in the microwave oven, or a bottle of
lotion may be warmed by placing it in a sink ofhot water for about 10 minutes.

• Massage for relaxation is usually done with smooth, long, slow strokes. (Rapid strokes, circular movements,
and squeezing oftissues tend to stimulate circulation and increase arousal.) However, try several degrees of
pressure along with different types of massage, e.g., loeading and stroking. Determine which is preferred. .
Especially for the older person, a back rub that effectively produces relaxation may consist ofno more than 3
minutes of slow, rhythmic stroking (about 60 strokes per minute) on both sides of the spinous process from the
crown ofthe head to the lower back. Continuous hand contact is maintained by starting one hand down the back as
the other hand stops at the lower back and is raised. Set aside a regular time for the massage. This gives the patient
something to look forward to and depend on.

Exercise 3. Peacefill Past Experiences

Something may have happened to you a while ago that brought you peace and comfort. You may be able to draw on
that past experience to bring you peace or comfort now. Think about these questions:

1. Can you remember any situation, even when you were a child, when you felt
calm, peacenil, secure, hopenil, or comfortable?

2. Have you ever daydreamed about something peacenil? What were you thinking
of?

3. Do you get a dreamy feeling when you listen to music? Do you have any
favorite music?

4. Do you have any favorite poetry that you find uplifting or reassuring?

5. Have you ever been religiously active? Do you have favorite readings,
hymns, or prayers? Even if you haven't heard or thoughtof them for many years, childhood religious experiences
may still be very soothing.

Additional points: Very likely some ofthe things you think ofin answer to these questions can be recorded for you,
such as your favorite music or a prayer. Then, you can listen to the tape whenever you wish. Or, ifyour memory is
strong, you may simply close your eyes and recall the events or words.

Exercise 4. Active Listening to Recorded Music

1. Obtain the following:

. A cassette player or tape recorder. (Small, battery-operated ones are more convenient.)

• Earphone or headset. (This is a more compelling stimulus than a speaker a few feet away, and it avoids
disturbing others.)

• Cassette ofmusic you like. (Most people prefer fast, lively music, but some select relaxing music. Other
options are comedy routines, sporting events, old radio shows, or stories.)

2. Mark time to the music, e.g., tap out the rhythm with your finger or nod your head. This helps you concentrate on
the music rather than your discomfort.

3. Keep your eyes open and focus steadily on one stationary spot or object. If you wish to close your eyes, picture
something about the music.

4. Listen to the music at a comfortable volume. If the discomfort increases, try increasing the volume; decrease the
volume when the discomfort decreases.

5. If this is not effective enough, try adding or changing one or more of the following: massage your body in rhythm
to the music; try other music; mark time to the music in more than one manner, e.g., tap your foot and finger at the ,
same time.

Additional points: Many patients have found this technique to be helptol. It tends to be very popular, probably
because the equipment is usually readily available and is a part of daily life. Other advantages are that it is easy to
learn and is not physically or mentally demanding. If you are very tired, you may simply listen to the music and omit
marking time or focusing on a spot.

• Adapted and reprinted with permission from McCaffery M, Beebe A: Pain:

Clinical Manual for Nursing Practice. St. Louis, Mo: CV Mosby Co, 1989.

References:

1. Inteeration of behavioral and relaxation approaches into the treatment of chronic vain and insomnia. NIH
Technoloev Assessment Panel on Integration of Behavioral and Relaxation Approaches into the Treatment of
Chronic Pain and Insomnia. JAMA: Journal of the American Medical Association 276(4): 313-318, 1996. =

2. Oliver JW. Kravitz RL. Kaplan SH. et al.: Individualized patient education and coaching to improve pain
control among cancer outpatients. Journal of Clinical Oncology 19(8): 2206-2212, 2001.
3. Redinbaugh EM, Baum A, DeMoss C, et al.: Factors associated with the accuracy offamily caregiver
estimates ofpatient pain. Journal ofPain and Symptom Management 23(1): 31-38, 2002.

ANTINEOPLASTIC INTERVENTIONS
Radiation therapy and surgery are discussed as pain reliefmeasures rather than as eures for primary disease.

Radiation Therapy

Local, half-body, or whole-body radiation enhances the effectiveness of analgesic drug and other noninvasive
therapy by directly affecting the cause of pain (i.e., reducing primary and metastatic tumor bulk).[_1]Dosage must be
chosen to achieve a balance between the amount of radiation required to kill tumor cells and that which would
adversely affect normal cells or allow the repair of damaged tissue.

A single intravenous injection ofbeta particle-emitting agents such as iodine-131, phosphorus-32-orthophosphate,

and strontium-89, as well as the investigational new drugs rhenium-186 and samarium-153, can relieve pain of -

widespread bony metastases. Half the patients so treated respond to a second treatment if pain recurs.

Surgery

Curative excision or palliative debulking of a tumor has potential to reduce pain directly, relieve symptoms of
obstruction or compression, and improve prognosis, even increasing long-term survival Oncologic surgeons and
other health care providers should be familiar with the interactions of chemotherapy, radiation therapy, and surgical
interventions to avoid or anticipate iatrogenic complications. They should also recognize characteristic pain
syndromes that follow specific surgical procedures.

References:

1. Salazar OM, Sandhu T, da Motta NW, et al.: Fractionated half-body irradiation (HBI) for the rapid palliation
of widespread, symptomatic, metastatic bone disease: a randomized Phase III trial of the International Atomic
Energy Agency (IAEA). International Journal ofRadiation Oncology, Biology, Physics 50(3): 765-775, 2001.
INVASIVE INTERVENTIONS
Less invasive analgesic approaches should precede invasive palliative approaches, however, for a minority of
patients in whom behavioral, physical, and drug therapy do not alleviate pain, invasive therapies are useful.

Nerve Blocks

Control of otherwise intractable pain can be achieved by the application of a local anesthetic or neurolytic agent.
Nerve blocks are performed for several reasons:

Diagnostic

To determine the source ofpain (e.g., somatic versus sympathetic pathways)

Therapeutic

To treat painful conditions that respond to nerve blocks (e.g., celiac block for pain of pancreatic cancer)

Prognostic

To predict the outcome of long-lasting interventions (e.g., infusions, neurolysis, rhizotomy)

Preemptive

To prevent procedure-related pain.

A single injection of a nondestructive agent such as lidocaine or bupivacaine, alone or in combination with an anti-
inflammatory corticosteroid for a longer-lasting effect, can provide local relief from nerve or root compression.
Placement of an infusion catheter at a sympathetic ganglion extends the sympathetic blockade from hours to days or
weeks. Destructive agents such as ethanol or phenol can be used to effect neurolysis at sites identified by local
anesthesia as appropriate for permanent pain relief, and may also be used to cause destruction of central nervous
system structures.

Neurologic Interventions

Neurosurgery can be performed to implant devices to deliver drugs or to electrically stimulate neural structures.
Surgical ablation of pain pathways should, like neurolytic blockade, be reserved for situations in which other
therapies are ineffective or poorly tolerated. In general, the choice ofneurosurgical procedure is based on location
and type of pain (somatic, visceral, deafferentation), the patient's general condition and life expectancy, and the
expertise and follow-up available.

Management of Procedural Pain

Many diagnostic and therapeutic procedures are painful to patients. Treat anticipated procedure-related pain
prophylactically and integrate pharmacologic and nonpharmacologic interventions in a complementary style.

Use local anesthetics and short-acting opioids to manage procedure-related pain, allowing adequate time for the
drug to achieve full therapeutic effect. Anxiolytics and sedatives may be used to reduce anxiety or to produce
sedation.

Cognitive-behavioral interventions, such as imagery or relaxation, are useful in managing procedure-related pain
and anxiety. (Refer to the Cognitive-Behavioral Interventions section for examples ofrelaxation exercises). Patients
generally tolerate procedures better when they are informed of what to expect.
On'er the option for a relative or fiend to accompany the patient for support.

DISCHARGE PLANNING
Patients and families may have diñiculty remembering details of the pain management plan. Therefore, they should
be given a written pain management plan. The patient and family should receive clear instructions regarding
telephone contact for more urgent questions relating to pain management.

TREATING ELDERLY PATIENTS

Like other adults, older patients require comprehensive assessment and aggressive management of cancer pain.
Older patients are at risk for undertreatment of pain, however, because ofunderestimation oftheir sensitivity to
pain, the expectation that theytolerate pain well, and misconceptions about their ability to benefit kom the use of
opioids. Issues in assessing and treating cancer pain in older patients include:

Multiple Chronic Diseases and Sources of Pain

Age and complex medication regimens place them at increased risk for drug-drug and drug-disease interactions.

Visual, Hearing, Motor, and Cognitive Impairments

The use of simple descriptive, numeric, and visual analog pain assessment instruments may be impeded. Cognitively
impaired patients may require simpler scales and more Requent pain assessment.

NSAID Side Effects

Although effective alone or as adjuncts to opioids, NSAIDs are more likely to cause gastric and renal toxicity and
other drug reactions such as cognitive impairment, constipation, and headaches in older patients. Alternative
NSAIDs (e.g., choline magnesium trisalicylate) or co-administration ofmisoprostol with NSAIDs should be
considered to reduce gastric toxicity.

Opioid Effectiveness

Older persons tend to be more sensitive to the analgesic and CNS depressant effects of opioids. Peak opioid effects
are generally greater and the duration of pain relief may be longer.

Patient-Controlled Analgesia (PCA)

Slower drug clearance and increased sensitivity to undesirable drug effects (e.g., cognitive impairment) indicate the
need for cautious initial dosing and subsequent titration and monitoring of continuous parenteral infilsions.

Alternative Routes of Administration

Although useful for patients who have nausea or vomiting, the rectal route may be inappropriate for elderly or
infirm patients who are physically unable to place the suppository in the rectum.

Postoperative Pain Control

Following surgery, surgeons and other health care team members should maintain frequent direct contact with the
elderly patient to reassess ttie quality ot pam management.

Change of Setting

Reassessment of pain management and appropriate changes should be made whenever the elderly patient moves
(e.g., from hospital to home or nursing home).

Date Last Modified: 11/2002

This information fromPDQis reviewed regularly by members ofthe PDQEditorial Boards. Ifyou have specific
comments on the content of this information, direct them to: PDQEditorial Board CIPS/NCL 6116 Erecutive
Boulevard Suite 3002B, MSC-8321, 20892-8321, far: 301-480-8105. * * The PDQdatabase also contains

listings of clinical trial protocols and directories of organizations and pipesicians who treat cancer patients, but
this information is not available through CancerMail. For more information on accessing PDQ,consult the
CancerMail Contents List.

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