3393
Cancer Pain Management
Current Strategy
Nathan I. Cherny, M.B.B.S., F.R.A.C.P., and Russell K. Porfenoy, M.D.
Pain is among the most prevalent symptoms experienced
by cancer patients. A strategy for the management of
cancer pain is now widely accepted, and when well im-
plemented, is usually effective. Unfortunately, many on-
cologists are ill-prepared for the task of pain assessment
and management, and the outcomes achieved in clinical
practice are often suboptimal.
The various elements in the pain management strat-
egy are described. Patient assessment, the use of primary
therapies and systemically administered nonopioid and
opioid analgesics are pivotal to the strategy. Practical
aspects of opioid pharmacotherapy encompass drug se-
lection and dosing considerations including selection of
an appropriate route of administration, dose titration,
and the management of side effects. Specific approaches
are described for the treatment of patients for whom an
acceptable balance between relief and side effects of
opioids is not achieved. These comprise noninvasive in-
terventions, including the use of adjuvant analgesics, psy-
chological therapies, and physiatric techniques, and in-
vasive interventions, such as the use of intraspinal
opioids, neural blockade, and neuroablative techniques.
Finally, the use of sedation in the treatment of patients
with pain that is refractory to other interventions is ad-
dressed.
The skilled application of this strategy can provide
adequate relief to the vast majority of patients, most of
whom will respond to systemic pharmacotherapy alone.
Patients with refractory pain should see specialists
in pain management or palliative medicine who can
address these difficult problems. Cancer 1993; 72:
3393-415.
Key words: cancer pain, pain assessment, pain manage-
ment, analgesics, opioids, adjuvant analgesics, neural
blockade, spinal opioids, sedation.
Presented at the Second National Conference on New Oncolo-
gic Agents: Practical Applications, San Diego, California, February
4-6, 1993.
From the Department of Neurology, Memorial Sloan Kettering
Cancer Center, New York, New York.
Address for reprints: Russell K. Portenoy, M.D., Pain Service,
Department of Neurology, Memorial Sloan-Kettering Cancer Center,
1275 York Avenue, New York, NY 10021.
Accepted for publication July 30, 1993.
Pain is among the most prevalent symptoms experi-
enced by patients with cancer.'-3 Successful manage-
ment depends on the ability of the clinician to assess
initial problems, identify and evaluate pain syndromes,
and formulate a plan for continuing care that is respon-
sive to the evolving goals and needs of the ~ a t i e n tThis
.~
process requires a familiarity with numerous therapeu-
tic options.
A general strategy for the management of cancer
pain is now widely accepted (Table 1). When imple-
mented well, this approach is usually eff e ~ t i v e .Unfor-
~,~
tunately, there is abundant evidence that the outcomes
achieved in routine clinical practice are suboptimal7and
that many oncologists are ill-prepared for the ongoing
task of symptom assessment and management.7,8Poor
outcomes may contribute to physician b ~ r n o u tand ~,~
greatly increase patient morbidity. The American Soci-
ety of Clinical Oncology recognized the need for im-
proved clinician education and has recently published
curriculum guidelines for cancer pain assessment and
treatment." This publication represents a necessary
first step, which must now be followed by widespread
implementation in training programs and continuing
education.
An effective strategy for the management of cancer
pain is built on a comprehensive assessment and the
skillful administration of analgesic drugs. Survey data
suggest that approximately 10-30% of patients fail to
achieve satisfactory pain relief, and subsequently re-
quire other approaches."-'6
Cancer Pain Assessment
The formulation of an effective therapeutic strategy for
the management of cancer pain is predicated on a com-
prehensive assessment of the patient. A trusting rela-
tionship with the patient is essential to this process, but
does not negate the potential for under-reporting of
symptom^.'^ A clinical posture should be adopted that
affirms relief of pain and suffering as important goals of
therapy, and encourages communication about symp-
toms. To this end, it is useful to ask an open-ended
3394 CANCER Supplement December 2, 2993, Volume 72, No. 11
Table 1. Clinical Strategies Essential in the Management
of Cancer Pain
Comprehensive assessment
Primary therapy and systemic nonopioid and opioid analgesic
therapy
Role of primary therapies
Selection of nonopioid and opioid analgesic agents
Practical aspects of administration
Routes
Dose selection and titration
Management of side effects
Noninvasive interventions for patients unable to attain an
acceptable balance between relief and side effects of systemic
opioid therapy
Reduce opioid requirement by:
Appropriate primary therapy
Addition of nonopioid analgesic
Addition of an adjuvant analgesic
Use of cognitive or behavioral techniques
Use of an orthotic device or other physical medicine approach
Switch to another opioid
Invasive interventions for patients unable to attain an acceptable
balance between relief and side effects during systemic
pharmacotherapy
Regional analgesic techniques (spinal or intraventricular opioids)
Neural blockade
Neuroablative techniques
Consider increased sedation
question about the presence of pain at each patient visit
in routine oncologic practice.
The assessment should clarify the pain characteris-
tics and syndrome, infer the putative mechanisms that
may underlie the pain, and determine the impact of the
pain on function and psychological well-being. In addi-
tion, the assessment should define the nature and ex-
tent of the underlying disease; evaluate concurrent
problems (physical, psychological, and social) that con-
tribute, or may soon contribute, to patient distress; and
clarify the goals of care. The goals of care are often
complex, but can generally be grouped into three broad
categories: (1)prolonging survival, (2) optimizing com-
fort and (3) optimizing function. The relative priority of
these goals provides an essential context for therapeutic
decision-making.
A stepwise approach to cancer pain assessment be-
gins with data collection and ends with a clinically rele-
vant formulation (Table 2). The pain-related history
should illuminate: characteristics of the pain; the re-
sponses to previous disease-modifying and analgesic
therapies; effects of the pain on activities of daily living,
psychological state, familial and professional function;
and associated symptom^.^^'^,'^ Numerous instruments,
including symptom checklists and quality-of-life mea-
sures, are available and may be useful in this evalua-
tion.’O,’l A careful review of medical history and the
chronology of the cancer is important to place the pain
complaint in context.
A physical examination, including a neurologic
evaluation, is a necessary part of the initial pain assess-
ment. The need for a thorough neurologic assessment is
justified by the high prevalence of painful neurologic
conditions in the cancer p~pulation.~’~’~ The physical
examination should attempt to identify the underlying
causes of the pain problem, clarify the extent of the
underlying disease, and discern the relation of the pain
complaint to the disease.
Careful review of previous laboratory and imaging
studies can provide important information about the
cause of the pain and the extent of the underlying dis-
ease. The treating clinician is best able to correlate this
information with the patient’s symptoms and signs,
and should personally evaluate these studies.
The information derived from these data provides
the basis for a provisional pain diagnosis that clarifies
both the status of the disease and the nature of other
concurrent concerns that may require therapeutic focus
(Table 2). The provisional pain diagnosis includes infer-
ences about the pathophysiology of the pain and an
assessment of the pain syndrome. Evaluation of concur-
rent concerns includes other symptoms and related
psychosocial problems.
Additional investigations are often needed to clar-
ify uncertainties in the provisional assessment.” The
extent of the these investigations must be appropriate to
the patient‘s general status and the overall goals of care.
For some patients, multiple studies may be needed to
evaluate the pain problem, clarify extent of disease, or
assess other symptoms. Again, the physician ordering
the diagnostic procedures should personally review
them to correlate pathologic changes with the clinical
findings. Expert assistance from physicians in other dis-
ciplines, nurses, social workers, or others may be also be
necessary to evaluate related physical or psychosocial
problems identified during the initial assessment. Pain
must be managed during this process to improve com-
pliance and reduce the distress associated with proce-
dures. No patient should be inadequately evaluated be-
cause of poorly controlled pain.
The findings of this evaluation should be reviewed
with the patient, and other appropriate persons, so that
current problems can be listed in order of priority to
reflect their importance to the patient. Potential out-
comes that would benefit from contingency planning
may also be identified, including the need for advanced
medical directives, the evaluation home care resources,
and prebereavement interventions with the family. A
multimodality treatment approach targeted to specific
problems can be developed from this assessment.
Current Strategy for Cancer Pain Management/Cherny and Portenoy 3395

Table 2. Stepwise Assessment of the Patient With Cancer Pain

Step 1. Data collection
Available laboratory
Pain-related history Other relevant history and imaging data Physical examination

Chronology Disease-related Radiographs and scans

Characteristics Other symptoms Tumor markers
Impact on function Psychiatric history Hematologic parameters
Prior treatment Social resources Biochemical parameters
Other pain history

Step 2. Provisional assessment

Provisional pain diagnosis Global assessment Concurrent concerns

Syndrome identification Extent of disease Other symptoms

Inferred pathophysiology Goals of care Untreated concurrent diseases
Prolonging survival Psychosocial needs
Optimizing function Rehabilitative needs
Optimizing comfort Financial needs

Step 3. Diagnostic investigations and other assessments

Diagnostic investigations Other assessments

Symptom-specific Psychological
Extent of disease Social
Financial
Functional

Step 4. Initial formulation and problem list

Pain syndromes and pathophysiology
Extent of disease
Concurrent concerns
Anticipated contigencies

Step 5. Patient review and formulation of prioritized problem lists

Current problems
Anticipated contingencies

Step 6. Multimodality therapeutic plan

Primary anti-cancer treatment
Chemotherapy
Radiation therapy
Surgery
Immunotherapy
Other
Treatment of concurrent disease processes
Symptom-directed pharmacotherapy
Rehabilitative approaches
Psychological approaches
Anesthetic approaches
Neurostimulatory approaches
From Chemy NI, Portenoy RKP. Cancer pain: principles of assessment and syndromes. In: Wall PD, Melzack R, eds.
Textbook of pain. Edinburgh Churchill Livingstone, 1993. With permission.
3396 CANCER Supplement December 2, 2993, Volume 72, No. 13

The Role of Primary Therapy

The assessment process may reveal a cause for the pain

that is amenable to primary therapy. Pain that is pro-
duced by tumor infiltration may respond to antineoplas-
tic treatment with surgery, radiotherapy, or chemother-
apy, and pain caused by infections may be relieved with
antibiotic therapy or drainage procedures. Specific an-
algesic treatments are usually required as an adjunct to
the primary therapy.
Radiation therapy. Radiation therapy has a pivotal
role in the treatment of cancer pain caused by bone
m e t a ~ t a s e s ,epidural
~ ~ , ~ ~ ne~plasm,’~
and cerebral me-
tastases.26In other settings, conclusive data are lacking,
but clinical observations support empirical radiation
therapy. For example, the results with perineal pain
caused by low sacral plexopathy appear to be encourag-
ing,27,28 and hepatic radiation therapy (e.g., 2000-3000
cGy) can be well tolerated and effective for the pain of
hepatic capsular distention in 50-9070 of patient^.'^-^'
Chemotherapy. There is a strong impression that
tumor shrinkage is generally associated with relief of
pain. Hence, analgesia can be anticipated after chemo-
therapy in responsive tumors, such as lymphoma, small
cell lung cancer, germ cell tumors, and previously un-
treated breast cancer. Interestingly, there are isolated
reports of analgesic effects from chemotherapy even in Figure 1. The three-step ”analgesic ladder,” proposed by an expert
committee convened by the Cancer Unit of the Word Health
the absence of significant tumor shrinkage.33T34 In all Organization. From World Health Organization. Cancer pain relief
situations, the decision to administer chemotherapy and palliative care: report of a WHO expert committee. Geneva:
solely for the treatment of symptoms should be recon- World Health Organization, 1990. WHO Technical Report Series,
sidered in the absence of a clearly favorable balance no. 804. With permission.
between relief and adverse effects.
Surgery. Surgery may have a role in the relief of algesics, is the cornerstone of cancer pain manage-
symptoms caused by specific problems, such as ob- ment.5,6T46 Nonopioid analgesics comprise acetamino-
struction of a hollow viscus, unstable bony structures, phen and the nonsteroidal anti-inflammatory drugs
and compression of neural t i s s ~ e s . In~ ~all- ~
cases,
~ the (NSAIDs) including aspirin. The term ”adjuvant anal-
potential benefits must be weighed against the risks of gesic” refers to a drug that has a primary indication
surgery, the anticipated length of hospitalization and other than pain, but is analgesic in selected circum-
convalescence, and the predicted duration of benefit.35 stances.
For example, large volume paracentesis (up to 5-10 1) The three-step ”analgesic ladder,” proposed by an
may provide prompt and prolonged relief from the pain expert committee convened by the Cancer Unit of the
and discomfort of tense as cite^,^^"^ with a small risk of World Health Organization, has emphasized that pain
h y p ~ t e n s i o n ~or~ ,hyp~proteinemia.~~
~’ intensity should be the prime consideration in the se-
Antibiotics. Antibiotics may have analgesic effects lection of these (Fig. 1). Patients with mild to
when the source of the pain involves infection, as illus- moderate cancer-related pain should be treated with a
trated by the treatment of chronic sinus infection, pelvic nonopioid analgesic, which should be combined with
abscess, pyonephrosis, and osteitis p ~ b i s .Occasion-
~~,~~ an adjuvant analgesic if a specific indication for one
ally infection may be occult and confirmed only by the exists. Patients who are relatively nontolerant and have
symptomatic relief provided by empirical treatment moderate to severe pain, or who fail to obtain adequate
with these d r ~ g s . ~ ~ , ~ ~ relief after a trial of a nonopioid analgesic, are usually
Systemic Analgesic Pharmacotherapy treated with an opioid. This treatment is typically ac-
complished using a combination product containing a
Systemically administered analgesic drug therapy, in- nonopioid (e.g., aspirin or acetaminophen) and an
volving the use of nonopioid, opioid, and adjuvant an- opioid conventionally used for this indication, such as
Current Strategy for Cancer Pain Management/Cherny and Portenoy 3397

Table 3. Nonoplioid Analgesics

Maximal
recommended
Half-life Starting dose dose
Chemical class Generic name (hr) (mg) (mg/day) Comments
Nonacidic
p-Aminophenol derivatives Acetaminophen 3-4 750 every 4 hr 6000 Available over the counter
Naphthylalkanones Nabumetone 22-30 500 every 12 hr 2000
Acidic
Salicylates Aspirin 3-12 650 every 4-6 hr 6000 Avaiiable over the counter
Diflunisal 8-12 500 every 12 hr 1500 Less GI toxicity than
aspirin
Choline magnesium 8-12 1000 every 12 hr 4000 Minimal GI toxicity
trisalicylate No effect on platelet
function at usual doses
Salsalate 8-12 1000 every 12 hr 4000 Minimal GI toxicity
No effect on platelet
function at usual doses
Proprionic acids Ibuprofen 3-4 400 every 6 hr 4200 Available over the counter
Naproxen 1-3 250 every 12 hr 1000
Fenoprofen 2-3 200 every 6 hr 3200
Ketoprofen 2-3 25 every 8 hr 200
Flurbiprofen 5-6 100 every 12 hr 300
Acetic acids lndomethacin 4-5 25 every 12 hr 200 Sustained release and
rectal preparations
Sulindac 14 150 every 12 hr 400
Diclofenac 2 25 every 8 hr 200
Ketorolac 4-7 30 every 6 hr 240 Oral or parenteral
preparation
Tolmen tin 1 200 every 8 hr 2000
Oxicams Piroxicam 45 20 every 24 hr 40
Fenamates Mefenamic acid 2 250 every 6 hr 1000
I'yranocarboxylic acids Etodolac 7 1000 every 24 2000
GI: gastrointestinal.

codeine, oxycodone, or propoxyphene. This drug of prostaglandins, inflammatory mediators known to

should be coadministered with an adjuvant analgesic if
needed. Finally, patients who have severe pain, or fail
to achieve adequate relief after appropriate administra-
tion of drugs on the second rung of the analgesic ladder,
should receive an opioid agonist conventionally used
for severe pain. This drug may also be combined with a
nonopioid or adjuvant analgesic.
The Use of Nonopioid Analgesics
The nonopioid analgesics are useful alone for mild to
moderate pain and provide additive analgesia when
combined with opioid drugs in the treatment of more
severe pain. These drugs constitute a heterogeneous
group of compounds that differ in chemical structure
but share many pharmacologic actions (Table 3). Unlike
opioid analgesics, all have a "ceiling" effect for analge-
sia and produce neither tolerance nor physical depen-
dence. The major site of action is presumably periph-
eral. Aspirin and the NSAIDs inhibit the enzyme cy-
clooxygenase and consequently block the biosynthesis
sensitize peripheral n o c i ~ e p t o r sA
. ~central
~ mechanism
of action is also likely to c ~ n t r i b u t e ,however,
~ ~ ' ~ ~ and
probably predominates in acetaminophen analge~ia.~'
The safe administration of nonopioid analgesics re-
quires familiarity with their potential adverse effects.51
Aspirin and the other NSAIDs have a broad spectrum
of potential toxicity. Bleeding diathesis due to inhibition
of platelet aggregation, gastroduodenopathy (including
peptic ulcer disease), and renal impairment are the most
common. The less common adverse effects include con-
fusion, precipitation of cardiac failure, and exacerba-
tion of hypertension. Particular caution is required in
the administration of these agents to patients at in-
creased risk of adverse effects, including the elderly and
those with blood clotting disorders, predilection to pep-
tic ulceration, impaired renal function, and concurrent
corticosteroid therapy. Of the NSAIDs, the nonacety-
lated salicylates ( e g , choline magnesium trisalicylate
and salsalate) are preferred for patients who have a
bleeding ulcer or ulcer diathesis; these drugs have rela-
3398 CANCER Supplement December 1, 1993, Volume 72. No. 11
Table 4. Classification of Opioid Analgesics Based on
Receptor Interactions
Partial
Agonists Agonists/antagonists agonists
Codeine Butorphanol Buprenorphine
Oxycodone Nalbuphine Dezocine
I'ropoxyphene I'entazocine
Morphine
Hydromorphone
Methadone
Meperidine
Oxymorphone
Heroin
Levorphanol
Fentanyl
tively less effect on gastric mucosa and platelet aggre-
gation, and no effect on bleeding time at routine clinical
doses5*Acetaminophen rarely produces gastrointesti-
nal toxicity, and has no adverse effects on platelet func-
tion. Hepatic toxicity is possible, however, and patients
with liver disease can develop severe hepatopathy at
the usual therapeutic dose.53
Standard recommended doses for nonopioid drugs
are derived from studies performed in populations (gen-
erally healthy patients with an inflammatory disease)
that potentially have little in common with cancer pa-
tients, who often have numerous medical problems and
may be receiving multiple other drugs. Consequently,
there is no certain knowledge of the minimal effective
analgesic dose, ceiling dose, or toxic dose for any pa-
tient with cancer pain, and doses may be higher or
lower than the usual dose ranges recommended for the
drug involved. These considerations and the observa-
tion that the effects of these drugs are (at least partially)
dose-dependent, support an approach to the adminis-
tration of NSAIDs that incorporates both low initial
doses and dose titration. With gradual dose escalation,
it may be possible to identify the ceiling dose and re-
duce the risk of significant toxicity. Clinical experience
suggests that 1week is usually adequate to evaluate the
efficacy of a dose. The potential for dose-dependent
toxicity requires the use of an empirical upper limit for
dose titration, which is usually in the range of 1.5-2
times the standard recommended dose of the drug in
question. Because failure with one NSAID can be fol-
lowed by success with another, sequential trials of sev-
eral NSAIDs may be needed to identify a drug with a
favorable balance between analgesia and side effects.
Systemically Administered Opioid Therapy
Based on their interactions with the various receptor
subtypes, opioid compounds can be divided into ago-
nist, agonist-antagonist, and antagonist classes (Table
4).The pure agonist drugs (Table 5) are most commonly
used in cancer pain management. The mixed agonist-
antagonist opioids (pentazocine, nalbuphine, and bu-
torphanol) and the partial agonist opioids (buprenor-
phine and probably dezocine) have limited usefulness
in this setting because of a ceiling effect for analgesia,
precipitation of withdrawal reactions in patients physi-
cally dependent to opioid agonists, and a high preva-
lence of dose-dependent psychotomimetic side ef-
fects.4,5
Opioid selection. A trial of opioid therapy should
be administered to all patients with pain of moderate or
greater severity, regardless of the pathophysiological
mechanism underlying the pain.5,54-57In accordance
with the analgesic ladder approach,46 patients with
moderate pain are commonly treated with a combina-
tion product, which in the United States typically con-
tains codeine, oxycodone or propoxyphene plus acet-
aminophen, or aspirin. The dose of these combination
products can be increased until the maximum dose of
the nonopioid coanalgesic is attained (e.g., 4000-6000
mg acetaminophen). If pain relief is inadequate at this
dose, the opioid contained in the combination product
can be increased as a single agent ( e g , oxycodone tab-
lets or syrup can be used to supplement an oxycodone-
aspirin combination product), or the patient can be
switched to an opioid customarily used to treat severe
pain.
Most patients with cancer pain require long-term
treatment with an opioid conventionally used to man-
age severe pain (third rung of the analgesic ladder). Po-
tentially any of these opioids could be used. Ease of
titration and convenience of administration are impor-
tant considerations, and morphine sulphate is usually
preferred because it has a short half-life, is easy to ti-
trate in its immediate release form, and is also available
as a controlled-release preparation that allows an 8-12-
hour dosing interval. The long half-life drugs, metha-
done and levorphanol, are not preferred for the elderly
or those with major organ failure, because they can be
difficult to titrate and present challenging management
problems should delayed toxicity develop as plasma
concentrations gradually rise after dose increments.
The use of meperidine is generally not recom-
mended for the management of cancer pair^.^,^,^' Me-
peridine is demethylated to normeperidine, an active
metabolite that is twice as potent as a convulsant and
has a half-life 4-5 times as longer than the parent com-
pound.59Repetitive dosing of meperidine can result in
normeperidine accumulation, which may cause central
nervous system toxicity characterized by subtle adverse
mood effects, tremulousness, multifocal myoclonus
and, occasionally, seizure^.^^-^' Naloxone does not re-
verse normeperidine-induced seizures, and indeed,
Current Strategy for Cancer Pain Management/Cherny and Portenoy 3399

Table 5. Opioid Agonist Drugs

Dose (mg) equianalgesic to 10
mg im morphine Duration
Half-life of action
Drug IM PO (hr) (hr) Comments
Opioid agonists customarily used to treat moderate pain
Codeine 130 200 2-3 2-4 Usually combined with a nonopioid
Available over the counter
Oxycodone* 15 30 2-3 2-4 Formulated as single agent or
combined with a nonopioid
Propoxyphene 50 100 2-3 2-4 Usually combined with a nonopioid
Norpropoxyphene toxicity may
cause seizures

Opioid agonists customarily used to treat severe pain

Morphine 10 30 (repeated dose) 2-3 3-4 M6G accumulation in renal failure
60 (single dose) may predispose to additional
toxicity
Oxycodone 15 30 2-3 2-4 Formulated as single agent
Hydromorphone 1.5 7.5 2-3 2-4 No known active metabolites
Methadone 10 20 15-190 4-8 Plasma accumulation may lead to
delayed toxicity
Dosing should be initiated on a
PRN basis
Meperidine 75 300 2-3 2-4 Not recommended for cancer pain
Normeperidine toxicity limits utility
Contraindicated in patients with
renal failure and those receiving
MA0 inhibitors
Oxymorphone 1 10 (PR) 2-3 3-4 No oral formulation available
Less histamine release
Heroin 5 60 0.5 3-4 High solubility morphine prodrug
Levorphanol 2 4 12-15 4-8 Plasma accumulation may lead to
delayed toxicity
Fentanyl transdermal system 48-72 Patches available to deliver 25, 50,
75, and 100 g d h r
IM: intramuscular; PO: per 0s; P R per rectum; PRN: as needed; MAO: monoamine oxidase.
* When combined with a nonoDioid.

could theoretically precipitate seizures in patients re-
ceiving meperidine by blocking the depressant action of
the parent compound and allowing the convulsant ac-
tivity of normeperidine to become manifest.62Although
normeperidine toxicity is most likely to affect the el-
derly and patients with overt renal disease (who are
unable to renally clear the metabolite), it is sometimes
observed in younger patients with normal renal func-
tion.59,63In the unusual patient who is administered
meperidine, concurrent therapy with a monoamine oxi-
dase inhibitor is specifically contraindicated because of
the risk of a severe drug reaction characterized by exci-
tation, hyperpyrexia, and convulsions.
Renal impairment may reduce the clearance of the
active metabolites of propoxyphene (norpropoxy-
phene), meperidine (normeperidine), and morphine
(morphine-6-glucuronide). Particular caution is re-
quired in the titration of these agents in this ~ e t t i n g , ~ ~tence
and alternative opioids are often recommended. Similar
care is required when prescribing meperidine, pentazo-
cine, or propoxyphene to patients with hepatic dys-
function. The clearance of these drugs is diminished
with liver disease and plasma concentrations may be-
come higher than normal.70,71 Morphine clearance is
only minimally affected by mild or moderate hepatic
i m ~ a i r m e n t ,but
~ ~may
, ~ ~ be significantly reduced in ad-
vanced disease.74
Patients who have experienced dose-limiting side
effects with one opioid may benefit from sequential
trials of other opioid For each patient, the bal-
ance between side effects and analgesic efficacy varies
among drugs in an unpredictable manner. Sequential
trials may therefore identify a more acceptable drug. An
explanation for the variability in response is lacking,
but hypotheses have been proposed based on the exis-
- ~ ~ of receptor binding difference^^^ and the occur-
3400 CANCER Supplement December 2, 2993, Volume 7 2 . No. 11
rence of incomplete cross-tolerance to the analgesic and
adverse effects of different ~ p i o i d . ~ ~
A successful switch from one opioid to another re-
quires understanding of relative analgesic potency,
which can be defined as the ratio of the dose of two
analgesics required to produce the same analgesic effect
(equianalgesia). Reference tables conventionally ex-
press these relative potencies in terms of a dose equian-
algesic to 10 mg of parenteral morphine (Table 5).77
Equianalgesic doses should not be viewed as standard
starting doses when the drug or route of administration
is changed, but rather as a useful guide for dose selec-
tion. Numerous other variables may influence the ap-
propriate dose for the individual patient, including pain
severity, prior opioid exposure (and the degree of cross-
tolerance this confers), age, route of administration,
level of consciousness, and metabolic abnormalities
(see later).
Selecting a route of systemic opioid administra-
tion, Opioids should be administered by the least inva-
sive and most convenient route capable of providing
adequate analgesia for the patient. In routine practice,
the oral route is usually the most appropriate.5r6r58 Al-
ternative noninvasive routes, including the rectal, sub-
lingual, and transdermal routes, should be used for pa-
tients who have impaired swallowing or gastrointesti-
nal obstruction.
The potency of opioids administered rectally is be-
lieved to approximate oral d ~ s i n g .Rectal
~~,~supposito-
~ fusion devices vary in complexity, cost, and ability to
ries containing oxymorphone, hydromorphone, and
morphine are available, and controlled-release mor-
phine tablets can also be administered rectally."
The bioavailability of the sublingual route is very
poor with opioid drugs that are not highly lipophilic,"
and the likelihood of an adequate analgesic response is
low. Sublingual buprenorphine, a relatively lipophilic
partial agonist, has been proven eff ective,82but is not
available in the United States. Sublingual morphine has
also been reported anecdotally to be effe~tive,'~but this
drug has poor sublingual absorption,'l and efficacy
may be related to swallowing of the dose.84Both fen-
tanyl and methadone are relatively well absorbed
through the buccal mucosa,81and sublingual adminis-
tration of an injectable formulation might be a reason-
able approach in the patient who transiently loses the
option of oral dosing.
A transdermal formulation of fentanyl is available
in systems that deliver 25, 50, 75, and 100 ~ g / h . 'The
~ an opioid when there is a need for infusion of large
transdermal system consists of a drug reservoir sepa-
rated from the skin by a rate-limiting membrane that
controls the rate of drug delivery such that the drug is
released into the skin at a nearly constant amount per
unit time. The dosing interval for each system is usually
72 hours, but interindividual pharmacokinetic variabil-
ity is and some patients require dosing inter-
vals as brief as 48 hours. Limitations of the transdermal
delivery system include its expense and the require-
ment for an alternative short-acting opioid for break-
through pain.
Parenteral routes of administration should be con-
sidered for patients who have impaired swallowing or
gastrointestinal obstruction, those who require the
rapid onset of analgesia, and highly tolerant patients
who require doses that cannot otherwise be conve-
niently administered. Repeated parenteral bolus injec-
tions, which may be administered by the intravenous
(IV), intramuscular, or subcutaneous (SC) routes, may
be useful in some patients, but are often complicated by
the occurrence of prominent "bolus" effects (toxicity at
peak concentration and/or pain breakthrough at the
trough). Although repetitive intramuscular injections
are a common practice, they are painful and offer no
pharmacokinetic advantage; their use is not recom-
mended.58Repeated bolus doses, if required, can be ac-
complished without frequent skin punctures through
the use of an indwelling IV or SC infusion device. To
deliver repeated SC injections, a 27-gauge infusion de-
vice (known as a "butterfly") can be left under the skin
for up to 1 week.
Continuous infusions avoid the problems asso-
ciated with the bolus effect and may be administered
intravenously or subcutaneously.s9-93Ambulatory in-
provide patient-controlled "rescue doses" as an adjunct
to a continuous basal infusion (see later). Opioids suit-
able for continuous SC infusion must be soluble, well
absorbed, and nonirritant. Extensive experience has
been reported with heroin, hydromorphone, oxymor-
phone, and Methadone appears to be
relatively irritating and is not preferred for SC infu-
~ i o n The . ~ ~bioavailability of SC hydromorphone is
7 8 Y 0 , ~and
~ is assumed to be similarly high with other
opioids. This bioavailability supports the recommenda-
tion that dosing with SC administration proceed in a
manner identical to continuous IV infusion. To main-
tain the comfort of an infusion site, the SC infusion rate
should not exceed 5 ml/hr. Patients who need high
doses may benefit from the use of concentrated solu-
tions, which in selected cases can be compounded spe-
cifically for continuous SC infusion. Continuous IV in-
fusion may be the most appropriate way of delivering
volume of solution, or when using methadone. If con-
tinuous IV infusion is to be continued on a long-term
basis, a permanent central venous port is recom-
mended.
Continuous infusions of drug combinations may be
indicated when pain is accompanied by nausea, anxi-
Current Strategy for Cancer Pain Management/Cherny and Portenoy
ety, or agitation. An antiemetic, neuroleptic, or anxioly-
tic agent may be combined with an opioid provided it is
nonirritant, miscible, and stable in combined solution.
Experience has been reported with infusions of an
opioid combined with metoclopromide, haloperidol,
scopolamine, cyclizine, methotrimeprazine, chlorprom-
azine, and midazolam.'00-'02
The switch between the oral and parenteral routes
requires careful attention to relative potency (see Table
5). To avoid inadvertent overdosing or underdosing, it
is useful to perform the change in steps if possible.
Slowly reducing the parenteral dose while increasing
the oral dose during a 2-3-day period can minimize the
potential problems caused by an abrupt change of
routes associated with different potencies.
Scheduling of opioid administration. Scheduled,
around-the-clock dosing can provide the patient with
continuous relief and is generally preferred when pain
is constant or frequently recurring. The initiation of
opioid therapy with an around-the-clock regimen, re-
quires particular vigilance when patients have had no
previous opioid exposure and when drugs with long
half-lives are selected. Drugs with long half-lives may
produce the delayed onset of adverse effects as plasma
concentration rises toward steady-state levels.
Breakthrough pain is highly prevalent among pa-
tients with controlled baseline pain.'03 To help manage
these episodes, all patients who receive an around-the-
clock opioid regimen should also have access to a sup-
plemental rescue dose on an as-needed basis. The "res-
cue" drug is typically identical to that administered on a
continuous basis with the exception of transdermal fen-
tanyl and methadone, for which the use of an alterna-
tive short half-life opioid is recommended. Clinical ex-
perience suggests that the size of the rescue dose should
be equivalent to approximately 5-15% of the 24-hour
baseline dose. The frequency with which the rescue
dose can be offered depends on the time to peak effect
for the drug and the route of administration. Oral res-
cue doses are offered up to every 1-2 hours and paren-
teral doses are offered up to every 15-30 minutes. The
integration of scheduled dosing with rescue doses pro-
vides a method for safe and rational stepwise dose
escalation, which is applicable to all routes of opioid
administration (Table 6).
Controlled-release preparations can lessen the in-
convenience associated around-the-clock administra-
tion of drugs with a short duration of action.'04 In the
United States, controlled-release morphine sulphate is
available in 15, 30, 60, and 100 mg tablets, and formu-
lations of controlled-release oxycodone and hydromor-
phone are under development. Controlled-release prep-
arations of morphine sulphate typically achieve peak
levels 3-5 hours after administration and have a dura-
3401
tion of effect of 8-12 hours.'05 Immediate-release mor-
phine is generally used as the rescue medication for
patients receiving these formulations'06(Table 6). Con-
trolled-release morphine should not be used to rapidly
titrate the dose in patients with severe pain'06; repeated
dose adjustments at short intervals are performed more
efficiently with an immediate-release preparation,
which may be converted on a milligram to milligram
basis to a controlled-release preparation when the ef-
fective around-the-clock dose is identified.
In some situations, an as-needed dosing regimen
alone can be recommended, This type of dosing pro-
vides additional safety during the initiation of opioid
therapy in the opioid-naive patient, particularly when
rapid dose escalation is needed. This technique is
strongly recommended when starting methadone ther-
apy. As-needed dosing may also be appropriate for pa-
tients who have rapidly decreasing analgesic require-
ment or intermittent pains separated by pain-free inter-
vals.
Patient-controlled analgesia (PCA) is a technique
of parenteral drug administration (see above) in which
the patient controls a pump that delivers bolus doses of
an analgesic according to parameters set by the physi-
~ i a n . ~ ~Use
, ' ~of
' a patient-controlled analgesia device
allows the patient to carefully titrate the opioid dose to
his or her individual analgesic needs. The technique is
most commonly applied postoperatively. For patients
with cancer pain patient-controlled analgesia is typi-
cally used in conjunction with continuous opioid infu-
sion. Long-term patient-controlled analgesia in cancer
patients is most commonly accomplished via the subcu-
taneous route using an ambulatory infusion device (see
earlier).
Dose selection and adjustment. Patients who are
opioid-naive or who have had limited exposure to an
opioid conventionally used for moderate pain should
generally begin one of the opioids used for more severe
pain at a dose equivalent to 5-10 mg intramuscular
morphine every 3-4 hours. If morphine is used, an in-
tramuscu1ar:oral relative potency ratio of 1:3 is gener-
ally recommended.
When patients receiving higher doses of opioids are
switched to an alternative opioid drug, the equianalge-
sic dose table (Table 5) is used as a guide to the starting
dose. For patients with good pain control but unaccept-
able side effects, the starting dose of the new drug
should be reduced to 50-75% of the equianalgesic dose
(and to 33-50% when the switch is to methadone) to
account for incomplete cross-tolerance. For patients
with poor pain control and unacceptable side effects,
the starting dose of the new drug can usually be 75-
100% of the equianalgesic dose (and 50-75% when the
switch is to methadone). Patients must be monitored to
3402 CANCER Supplement December 1, 1993, Volume 72, No. 11
Table 6. Examples of Stepwise Dose Escalation of Morphine Sulfate Administered as Oral Immediate Release
Preparation and Oral Controlled Release and Continuous Infusion
Oral immediate release
mg every 4 hr Rescue dose PRN
"around the every 1 hr
Step* clock" (mg)
1 10 5 30 every 12 hr
2 15 7.5
3 30 15.0
4 45 22.5
5 60 30.0
* Indications for progression from one step to the next: requirement of z 2 rescue doses in any 4-hour interval; requirement of > 6 rescue doses in 24 hours.
assess the adequacy of analgesia and to detect the devel-
opment of side effects. Subsequent dose adjustments
are usually necessary.
At any point during the course of therapy, the de-
velopment of inadequate pain relief should be ad-
dressed through a stepwise escalation of the opioid
dose. The opioid dose should be increased until ade-
quate analgesia is reported or unmanageable side ef-
fects supervene. Most patients reach plateaus that re-
main constant for a prolonged p e r i ~ d . ' Patients
~ ~ , ~ ~in~
whom develop dose-limiting side effects during dose
titration require the use of another analgesic approach
or a technique to reduce toxicity (see later).
Because analgesia increases linearly with the log of
the opioid dose, necessary dose escalations should
usually be in the range of 30-50°% of the previous dose.
Smaller dose increments are not likely to significantly
improve analgesia. The absolute dose, which may be-
come very large, is immaterial as long as the balance
between analgesia and side effects remains favorable.
For example, in a retrospective study of 100 patients
with advanced cancer, the average daily opioid require-
ment was equivalent to 400-600 mg of intramuscular
morphine, but approximately 10% of patients needed
more than 2000 mg and one patient needed more than
30,000 mg every 24 hours3
The severity of the pain should determine the rate
of dose titration. Patients with very severe pain can be
treated by repeated parenteral dosing every 15-30 min-
utes until pain is partially relieved. Guidelines have
been proposed for the calculation of hourly mainte-
nance dosing after parenteral loading with a short half-
life opioid.l10 These guidelines recommend that the
starting hourly maintenance dose be approximated by
dividing the total loading dose by twice the elimination
half-life of the drug. For example, the starting mainte-
nance dose for a patient who requires an intravenous
loading dose of morphine sulphate 120 mg (half-life
approximately 3 hours) would be 20 mg/h. Patients
Oral controlled release (with SC infusion with SC rescue
immediate release rescue dosing) doses
Rescue dose PRN Rescue dose PRN
mg "around every 1 hr q15-30 min
the c l o c k (mg) mglhr (mg)
7.5 3 2.0
30 every 8 hr 15.0 5 2.5
60 every 12 hr 15.0 7 3.5
100 every 12 hr 30.0 10 5.0
100 every 8 hr 45.0 15 7.5
with less severe pain may not require a loading dose of
the opioid. In this situation, patients who are treated
with short half-life opioids can undergo dose incre-
ments as often as twice daily. The dose of controlled-re-
lease preparations of oral morphine or transdermal fen-
tanyl can be increased every 24-48 hours.
The need for escalating doses is a complex phenom-
enon that may be precipitated by any of a variety of
distinct processes. Extensive clinical experience sug-
gests that most patients who require an escalation in
dose to manage increasing pain have demonstrable pro-
gression of d i s e a ~ e . ' ~ ~ ~True
" ' - ~pharmacologic
~~ toler-
ance to the analgesic effect of an opioid, which could
potentially compromise the usefulness of treatment,
can only be said to occur if a patient manifests the need
for increasing opioid doses in the absence of other fac-
tors (e.g., progressive disease, psychological factors, or
pharmacokinetic factors) that would be capable of ex-
plaining the increase in opioid requirement. This phe-
nomenon is distinctly uncommon in the clinical setting.
This observation suggests, first, that the concern about
tolerance should not impede the use of opioids early in
the course of the disease, and second, that worsening
pain in a patient receiving a stable dose of opioids
should generally be assessed as presumptive evidence
of disease progression or, less commonly, increasing
psychological distress.
Managing side effects. Management of the poten-
tial adverse effects of opioids is necessary to optimize
the therapeutic index of these drugs. The most common
adverse effects are constipation, nausea, and vomiting.
Other important dose-limiting adverse effects include
sedation, delirium, myoclonus, and respiratory depres-
sion.
The likelihood of opioid-induced constipation is so
great that laxative medications should be prescribed
prophylactically to most patients. Recommendations
for laxative therapy are empirical. A combination of a
softening agent (docusate) and a cathartic agent (e.g.,
Current Strategy for Cancer Pain Management/Cherny and Portenoy
Table 7. Putative Mechanisms of Opioid-Induced Nausea and Vomiting and Their Management
Mechanism Suggestive clinical features
Stimulation of the medullary Nausea and or vomiting shortly after
chemoreceptor trigger opioid administration
zone
Enhanced vestibular Prominent movement-induced nausea
sensitivity and vomiting, or vertigo
Increased gastric antral tone Early satiety, postprandial bloating, or
vomitine.
senna, bisocodyl, or phenophthalein) is frequently
used. The doses of these drugs should be increased as
necessary, and an osmotic laxative (e.g., lactulose or
milk of magnesia) can be added if needed. Occasionally
patients are managed with intermittent colonic lavage
using an oral bowel preparation such as Golytely
(Braintree Laboratories, Braintree, MA), and rarely pa-
tients with refractory constipation can undergo a trial of
oral naloxone, which has a bioavailability less than 3%
and presumably acts selectively on opioid receptors in
the gut.'14 Because there is a small risk of systemic with-
drawal from oral nal~xone,"~ the initial dose should be
conservative (0.8-1.2 mg once or twice daily); this dose
can be escalated slowly until either favorable effects
occur or abdominal cramps, diarrhea, or any other ad-
verse effect develop^."^
The incidence of opioid-induced nausea and vomit-
ing has been estimated to be 10-40% and 15-40%, re-
spectively."6 Three putative mechanisms may produce
these symptoms, and their respective recommended
therapies are summarized in Table 7. Tolerance to these
effects usually develops within weeks, and routine pro-
phylactic administration of an antiemetic is not usually
indicated except in patients with a history of severe
opioid-induced nausea and vomiting.
Initiation of opioid therapy or significant dose esca-
lation is often associated with sedation that may persist
for days to weeks. Although tolerance to this effect
usually develops, some patients have a persistent prob-
lem, particularly if other contributing factors exist. A
stepwise strategy for the management of persistent se-
dation is most useful (Table 8).
Opioid-induced cognitive impairment also appears
to be transient in most patient^."^ Although persistent
cognitive impairment attributable to opioid alone oc-
curs, most patients with persistent delirium have sev-
eral contributing factors, including electrolyte dis-
orders, neoplastic involvement of the central nervous
system, sepsis, vital organ failure, or hypoxemia."*
Again a stepwise approach to management is appro-
priate (Table 9). Myoclonus is also a common dose-re-
lated adverse effect of opioids, and may similarly re-
solve spontaneously. If the myoclonus is symptomatic
3403
Antiemetic drugs
Metoclopramide, prochlorperazine, chlorpromazine,
haloperidol, corticosteroid, or lorazepam
Scopolamine, meclizine, or lorazepam
Metoclopramide
and distressing, it can be treated empirically with a ben-
zodiazepine (particularly clonazepam"'), barbiturate,
or valproate.
Respiratory depression, the most serious adverse
effect of opioid therapy, is uncommon in the cancer
patient for whom opioid doses are carefully titrated.
Continued opioid administration rapidly induces toler-
ance to this effect.12' Clinically significant respiratory
depression is always accompanied by other signs of
central nervous system depression, including sedation
and mental clouding. Respiratory distress associated
with tachypnea and anxiety is never a primary opioid
event and alternative explanations (e.g., pneumonia or
pulmonary embolism) should be sought.
Because of the risk of systemic withdrawal and the
return of pain, naloxone should only be administered
for symptomatic respiratory depression. If the patient is
arousable, and the peak plasma levels of the opioid
have already been reached, the opioid dose should be
withheld and the patient monitored until their condi-
tion is improved. If the patient is unarousable or respira-
tory depression is severe, naloxone should be used to
improve ventilation using small bolus injections of di-
lute solution (0.4 mg in 10 ml saline), which are titrated
against respiratory rate.'21*'22An intercurrent cardiac or
pulmonary process can precipitate respiratory depres-
sion in patients receiving chronic opioid therapy that is
Table 8. Stepwise Management of
Opioid-Induced Sedation
Eliminate nonessential central nervous system depressant
medications
If analgesia is satisfactory, reduce opioid dose by 25%
If analgesia is unsatisfactory, try addition of a psychostimulant
(starting dose: methylphenidate 5 mg twice daily,
dextroamphetamine 5 mg twice daily, or pemoline 18.75 mg
twice daily)
If somnolence persists, consider:
Addition of a nonopioid or adjuvant that will allow reduction in
opioid dose
Change to an alternative opioid drug
Change to the intraspinal opioid (+local anesthetic)
Consider invasive anesthetic or neurosurtzical techniques
3404 CANCER Supplement December 1, 2993, Volume 72, No. 11
Table 9. Management of Cognitive Impairment in
Cancer Patients Receiving Opioid Therapy
Eliminate nonessential centrally acting medications
If analgesia is satisfactory, reduce opioid dose by 25%
Evaluate patient for concurrent causes (e.g., sepsis, metabolic
derangement, intracerebral or leptomeningeal metastases) and
treat if possible
If delirium persists, consider
Trial of neuroleptic (e.g., haloperidol)
Change to an alternative opioid drug
Change to the intraspinal opioid (flocal anesthetic)
Consider invasive anesthetic or neurosurgical techniques
similarly responsive to naloxone. Hence, a naloxone re-
sponse does not obviate the need for subsequent careful
patient evaluation for a concurrent cardiopulmonary
process.
Dependence and Addiction
Confusion about physical dependence and addiction
augment the fear of opioid drugs and contribute to the
undertreatment of pain.'7,'23-'27This confusion derives,
in part, from misunderstanding of the nomenclature
used to describe drug use. For example, the term de-
pendence is commonly used but is often misappre-
hended. Patients who require a specific pharmacother-
apy to control a symptom or disease process are depen-
dent on the therapeutic efficacy of the drugs in
question. Examples of this therapeutic dependence in-
clude the requirements of patients with congestive car-
diac failure for cardiotonic and diuretic medications, or
the reliance of insulin-dependent diabetics on insulin
therapy. Undermedication or withdrawal of treatment
from these patients can result in serious untoward con-
sequences, the fear of which can induce aberrant psy-
chological responses and drug-seeking behaviors. In
this sense, most patients with chronic cancer pain are
therapeutically dependent on an opioid; this response
may or may not be associated with the development of
physical dependence, but is virtually never associated
with addiction.
Physical dependence. Physical dependence is a
pharmacologic property of opioid drugs solely defined
by the development of an abstinence (withdrawal) syn-
drome after either abrupt dose reduction or administra-
tion of an antagonist. Although physical dependence is
most commonly observed in patients taking large doses
for a prolonged period of time, withdrawal can also
occur in patients after low doses or short duration of
treatment. Physical dependence is not a clinical prob-
lem if patients are warned to avoid abrupt discontinua-
tion of the drug, a tapering schedule is used if treatment
cessation is indicated, and opioid antagonist drugs (in-
cluding agonist-antagonist analgesics) are avoided.
Addiction. The term addiction should never be
used when physical dependence is meant. Addiction
refers to a psychological and behavioral syndrome
characterized by a continued craving for an opioid drug
to achieve a psychic effect (psychological dependence)
and associated aberrant drug-related behaviors (e.g.,
compulsive use, or continued use despite harm to self or
others). Addiction should be suspected if patients dem-
onstrate compulsive use, loss of control over drug use,
and continuing use despite harm.
The medical use of opioids is very rarely associated
with the development of addiction."2~'24~'28 In the larg-
est prospective study, only four cases of iatrogenic ad-
diction could be identified among 11,882 patients with
no history of addiction who received at least one opioid
preparation in the hospital ~etting."~ Although there
are no prospective studies in patients with chronic
cancer pain, there is an extensive clinical experience
that affirms the extremely low risk of addiction in this
popU~ation~5,6,46,58,94,11Z,lZ3,1Z5,1Z8,130-13Z H ealth care pro-
viders, patients, and families often require vigorous and
repeated reassurance that the risk of addiction is ex-
tremely small.
Pseudoaddiction. The distress engendered in pa-
tients who are therapeutically dependent on analgesic
pharmacotherapy but who continue to experience
unrelieved pain is occasionally expressed in behaviors
that are reminiscent of addiction, such as intense con-
cern about opioid availability and unsanctioned dose
escalation. Pain relief, usually produced by dose escala-
tion, eliminates these aberrant behaviors and distin-
guishes the patient from the true addict. This syndrome
has been termed pseud~addiction.'~~ Misunderstand-
ing these phenomena may lead the clinician to inappro-
priately stigmatize the patient with the label "addict,"
which may compromise care and erode the doctor-pa-
tient relationship. In the setting of unrelieved pain,
aberrant drug-related behaviors require careful assess-
ment, renewed efforts to manage pain, and avoidance
of stigmatizing labels.
Noninvasive Interventions for Patients Unable to
Attain an Acceptable Balance Between Relief
and Side Effects of Systemic Opioids
Even with optimal management of adverse effects,
some patients fail to attain an acceptable balance be-
tween pain relief and the side effects of an opioid. Nu-
merous noninvasive interventions (Table 1) can im-
prove this balance by reducing the opioid requirement.
These include the concurrent use of an appropriate pri-
mary therapy, alternative pharmacologic approaches
(nonopioid analgesic or an adjuvant analgesic) and the
use of psychological, rehabilitative, or neurostimula-
tory techniques (e.g., transcutaneous electrical nerve
Current Strategy for Cancer Pain ManagementlCherny and Portenoy 3405

stimulation). A switch to another opioid, as described Table 10. Selection of Adjuvant Analgesics for
previously, may also improve the therapeutic out- Neuropathic Pain Based on Clinical Characteristics of
come.75 the Pain
Sympathetically
Adjuvant Analgesics Continuous pain Lancinating pain maintained pain
Adjuvant analgesics can be broadly divided into gen- Antidepressants Anticonvulsant drugs Phenoxybenzamine
eral purpose analgesics, and drugs with specific utility Amitript yline Carbamazepine Prazosin
for either neuropathic or bone pain. There is a large Doxepin Phen ytoin Corticosteroid
interindividual and intraindividual variability in the re- Imipramine Clonazepam Nifedipine
sponses to these agents (including those within the Desipramine Valproate Propranolol
Notriptyline Baclofen Calcitonin
same class), and sequential trials are frequently needed
Trazodone Local anesthetics
to identify optimal therapy. Maprotiline Mexiletine
General-purpose adjuvant analgesics. Corticoste- Local anesthetics Lidocaine
roids are the most widely used general-purpose adju- Mexiletine Pimozide
vant These drugs may ameliorate pain Lidocaine Antidepressants
and produce beneficial effects on appetite, nausea, Clonidine
mood, and m a l a i ~ e . ' ~ ~ The
- ' ~ ' painful conditions that Capsaicin
commonly respond to corticosteroids include raised in- Calcitonin
tracranial pressure, acute spinal cord compression, supe-
rior vena cava syndrome, metastatic bone pain, neuro-
pathic pain due to infiltration or compression by tumor, drugs, such as desipramine and nortryptyline may be
symptomatic lymphedema, and hepatic capsular dis- preferred when concern about sedation, anticholinergic
t e n t i ~ n . ' ~Patients
~ , ' ~ ~ with advanced cancer who expe- effects, or cardiovascular toxicity is high. There is lim-
rience pain and other symptoms that may respond to ited evidence that the newer antidepressants, trazo-
steroids are usually given a small dose (e.g., dexametha- done and maprotiline, are analgesic and virtually no
sone 1-2 mg twice daily). An acute episode of very se- data in support of f l ~ o x e t i n e . The
' ~ ~ starting dose of a
vere pain that is related to a neuropathic lesion ( e g , tricyclic antidepressant should be low (e.g., amitripty-
plexopathy or epidural spinal cord compression) or line 10 mg in the elderly and 25 mg in younger pa-
bony metastasis and cannot be promptly reduced with tients). Doses can be increased every few days by incre-
opioids may respond dramatically to a short course of ments the same size as the starting dose. The usual ef-
relatively high doses ( e g , dexamethasone 100 mg IV fective dose for the most widely used of these drugs,
followed initially by 96 mg/day in divided doses). In all amitriptyline, is 50-150 mg per day. It is reasonable to
cases, the dose should be gradually lowered after pain continue upward dose titration beyond this range, how-
reduction to the minimum needed to sustain relief. ever, when patients fail to achieve benefit and have no
Adjuvant analgesics used for neuropathic pain. limiting side effects. Plasma drug concentration, if avail-
Neuropathic pain such as brachial or lumbosacral plex- able, may provide useful information and should be
opathy can be a major therapeutic challenge, and adju- followed during the course of therapy. Very low levels
vant drugs can play an important role in the manage- in nonresponders suggest either poor compliance or an
ment of these problems. For purpose of drug selection, unusually rapid metabolism. In the latter case, doses
it is useful to distinguish between continuous, lancinat- can be increased while repeatedly monitoring the
ing, and sympathetically-maintained neuropathic pain plasma drug level. Likewise, nonresponders whose
based on the patient's history and physical examination plasma concentration is not very low, but is lower than
(Table the antidepressant range, should be considered for a
The tricyclic antidepressants are truly multipurpose trial of higher doses if side effects are not a problem.
analgesics, but are generally prescribed for neuropathic Anticonvulsant drugs appear to be analgesic for di-
pain in cancer patients. They are typically used to man- verse types of lancinating (shooting) neuropathic
age continuous dysesthesias that have not responded pain.'42,'49Clinical experience also supports the use of
adequately to an opioid, and lancinating neuropathic these drugs for patients with paroxysmal (but not lan-
pains refractory to other specific adjuvant d r ~ g s . ' ~ ~ ,cinating) '~~ pains, and for those with continuous neuro-
These compounds are also useful in patients with pain pathic pains that have not responded to other agents.
complicated by depression and i n s ~ m n i a . ' ~ ~ Al-
, ' ~ ~ Although carbamazepine is often preferred because of
though the evidence for analgesic efficacy is greatest for the high response rate observed in trigeminal neural-
the tertiary amine tricyclic drugs, such as amitriptyline, gia,150-153 caution is required in cancer patients with
doxepin, and i m i ~ r a r n i n e , ' ~ ~ the
- ' ~secondary
~ amine thrombocytopenia, those at risk for marrow failure
3406 CANCER Supplement December 2 , 2993, Volume 7 2 , No. 11
(e.g., after chemotherapy), and those whose blood
counts must be monitored to determine disease status.
If carbamazepine is used, a complete blood count
should be obtained before the start of therapy, after 2
and 4 weeks, and then every 3-4 months thereafter. A
leukocyte count below 4000 is usually considered to be
a contraindication to treatment, and a decline to less
than 3000, or an absolute neutrophil count of less than
1500 during therapy, should prompt discontinuation of
the drug. Published reports and clinical experience also
support trials with other anticonvulsant drugs, includ-
ing p h e n y t ~ i n , ' ~ ~ , '~~l~o -n'a~z~e p a m , ' ~ ~and
- ' ~ ~val-
p r ~ a t e . ' ~ ~ Dosing
,'~' guidelines for the use of these
drugs as adjuvant analgesics are customarily identical
to those employed in the treatment of seizures. Low
initial doses are appropriate for carbamazepine, val-
proate, and clonazepam, and the administration of phe-
nytoin often begins with the presumed therapeutic dose
(e.g., 300 mg/day) or a prudent oral loading regimen
( e g , 500 mg twice, separated by 4 hours). When low
initial doses are used, dose escalation should ensue un-
til a favorable effect occurs, intolerable side effects su-
pervene, or the plasma drug concentration has reached
a predetermined level, which is customarily at the up-
per end of the therapeutic range for seizure manage-
ment.
Baclofen, a gamma-aminobutyric acid-agonist ef-
fective for trigeminal n e ~ r a l g i a , ' ~is~often
, ' ~ ~ employed
in the management of lancinating pains due to neural
injury of any type. A starting dose of 5 mg two to three
times per day is gradually escalated until analgesia is
achieved or adverse effects of sedation or confusion
emerge.
Oral local anesthetic drugs may be considered in
the management of neuropathic pains characterized by
either continuous or lancinating dyse~thesias.'~~ The
supporting evidence for this therapy is less abundant
than that available for other drug classes; it is, there-
fore, reasonable to undertake a trial with an oral local
anesthetic in patients with continuous dysesthesias
who fail to respond to tricyclic antidepressants, and in
patients with lancinating pains refractory to trials of
anticonvulsant drugs and baclofen. Mexiletine is the
safest of these drugs and is preferred over flecainide
and t ~ c a i n i d e . ' ~ ~Dosing
, ' ~ ~ with mexiletine should
usually start at 100-150 mg/day. If intolerable side ef-
fects do not occur, the dose can be increased by a like
amount every few days, until the usual maximum dose
of 300 mg three times per day is reached. Plasma drug
concentrations, if available, can be helpful in monitor-
ing the progress of the patient.
Topical administration of capsaicin cream depletes
peptides in small primary afferent neurons, including
compounds that are putative mediators of nociceptive
transmission (e.g., substance P).176,177 Analgesic effects
have been observed in postherpetic neuralgia,
painful peripheral neuropathies, and postmastectomy
~ - o' ~concentrations
~ a i n . ' ~ Tw ~ (0.025% and 0.075%)
are commercially available. Although the dose-re-
sponse relationship has not been evaluated in con-
trolled studies, it is reasonable to use the higher concen-
tration for either the initial trial or a subsequent trial
after failure of the lower concentration product. A
burning sensation can follow topical application of cap-
saicin. This wanes spontaneously in some patients and
others can reduce it through the prior use of an oral
analgesic or cutaneous application of lidocaine 5%
ointment. Some patients report intolerable burning and
cannot continue therapy. In those who can tolerate the
drug, an adequate trial should be considered at least
four applications every day for 4 weeks.
Experience with other drugs in the treatment of
cancer-related neuropathic pain is very limited. Cloni-
dine, an alpha-2 adrenergic agonist available in oral or
transdermal formulations, has antinociceptive effects in
the management of diverse pains, but like the tricyclic
antidepressants, is conventionally used for continuous
neuropathic pain in the cancer p ~ p u l a t i o n . Calci- '~~
tonin (200 IU/day) has been shown to be an active
analgesic in the management of some neuropathic
pains,'83 and pimozide, a phenothiazine neuroleptic,
has activity against lancinating neuropathic pain. The
latter drug is not preferred because of a high incidence
of adverse effects, including physical and mental slow-
ing, tremor, and parkinsonian symptoms.
Some drugs are used specifically in the manage-
ment of sympathetically-maintained pain (pain asso-
ciated with local signs of autonomic dysregulation, such
as edema, vasomotor instability, or sweating abnormali-
ties). Although the preferred approach for this type of
pain includes sympathetic nerve blocks, blocks may oc-
casionally be contraindicated or fail. In this situation,
several specific adjuvant analgesics have been advo-
cated. Phenoxybenzamine, 60-1 20 mg per day, has
been reported to be effective in a survey of patients
with ~ a u s a l g i a , 'and
~ ~ there is similar limited evidence
for the efficacy of p r a z o ~ i n , 'p~r~~ p r a n o l o l , ' ~and
~*'~~
nifedipine. A recent controlled trial suggests that cal-
citonin may also be useful in some patients with sym-
pathetically maintained pain.'89
Adjuvant analgesics used for bone pain. Manage-
ment of bone pain frequently requires the integration of
opioid therapy with multiple ancillary approaches (Ta-
ble 11).Anecdotally, NSAIDs appear to be particularly
efficacious in pain of this type, and corticosteroids are
often advocated in difficult cases.'90 The bisphospho-
nate drugs, pamidronate and clodronate, inhibit osteo-
clast activity and have been demonstrated to relieve
Current Strategy for Cancer Pain ManagementlCherny and Portenoy
Table 11. Nonopioid Therapies for Bone Fain
Primary therapy Psychiatric
Radiation therapy Orthotics
Chemotherapy Assistive devices
Hormonal therapy
Surgical stabilization
malignant bone pain in several recent surveys and con-
trolled trial^.'^'-'^^ A trial of one of these agents can be
recommended for patients with refractory bone pain.
Serum calcium, phosphate, magnesium, and potassium
should be monitored regularly during bisphosphonate
therapy. Clinical experience also suggests that calci-
tonin may occasionally provide significant relief of re-
fractory bone pain, and a trial should be considered in
patients who do not respond to a bisphosphonate. Fi-
nally, newly developed radiopharmaceuticals that are
absorbed at areas of high bone turnover may provide
an important means of treating metastatic bone pain.
These compounds, which include ~ t r o n t i u m - 8 9 , ~ ~ ~ * ~ ~ ' an Acceptable Balance Between Relief
samarium-153-ethylenediaminetetramethylenephos-
- ~ " rhenium-186-hydroxyethyli-
phonic a ~ i d , l ~ ~and
dene diphosphonate,200~20z~zo3 are likely to become avail- ance between analgesia and side effects from systemic
able in the near future. Further studies are needed to
identify the risks and benefits of each agent and the
durability of the effects produced.
Other Noninvasive Analgesic Techniques
Psychological therapies. While all cancer patients
benefit from psychological assessment and support,
some will benefit from specific psychological interven-
tions used in the management of pain. Cognitive-beha-
vioral interventions can help reduce the perception of
distress caused by the pain through the development of
coping skills and the modification of thoughts, feelings,
and behavior^.^^^,^^^ Some patients may be able to use
relaxation techniques to reduce muscular tension and
emotional arousal, or enhance pain Other
approaches reduce anticipatory anxiety that may lead
to avoidant behavior^."^ Successful application of
these therapies requires a cognitively intact patient and
a dedicated, well-trained clinician.204
Physiatric techniques. Physiatric techniques can
be used to enhance analgesia and optimize the function
of the patient with chronic cancer pain. Therapeutic
3407
Drug therapy
Anti-inflammatory drugs
Nonstimulatory anti-inflammatory drugs
Corticosteroids
Bisphosphonates
Pamidronate
Clodronate
Calcitonin
Radiopharmaceuticals
Strontium-89
Samarium-153-ethylenediaminetetramethylene
phosphonic acid
Rhenium-186-hydroxyethylidene diphosphonate
modalities such as electrical stimulation (including
transcutaneous electrical nerve stimulation), heat, or
cryotherapy can be useful adjuncts to standard analge-
sic therapy. The treatment of lymphedema by use of
wraps, pressure stockings, or pneumatic pump devices
can both improve function and relieve pain and heavi-
ness.208Orthotic devices can immobilize and support
painful or weakened structures, and assistive devices
can enhance comfort for patients with pain precipitated
by weight bearing or ambulation.
lnvasive Interventions for Patients Unable to
Attain
and Side Effects of Systemic Pharmacotherapy
Patients who are unable to achieve a satisfactory bal-
analgesic therapies may be candidates for the use of
invasive analgesictechniques. Anesthetic and neurosur-
gical approaches (Table 12) may reduce or eliminate the
requirement for systemically administered opioids.
Techniques such as intraspinal opioid and local anes-
thetic administration were developed to achieve this
end without need for compromising neurologic integ-
rity. The use of neurodestructive procedures should be
based on a careful evaluation of the likelihood and dura-
tion of analgesic benefit, the immediate and long-term
risks, the anticipated duration of survival of the patient,
and the anticipated length of hospitalization.
Regional Opioid Analgesia
Epidural and intrathecal opioids. The delivery of
low opioid doses near the sites of action in the spinal
cord may decrease supraspinally mediated adverse ef-
fects. Compared to neuroablative therapies, spinal
opioids have the advantage of preserving sensation,
strength, and sympathetic function. Contraindications
include bleeding diathesis, profound leukopenia, and
sepsis. A temporary trial of spinal opioid therapy
3408 CANCER Supplement December 1, 2993, Volume 72, No. 11

Table 12. Commonly Performed Anesthetic and Neurosurgical Analgesic Techniques

for Pain Refractory to Systemic Pharmacotherapy
Class Technique
Regional analgesia Spinal opioids and/or local
anesthetics
Intraventricular
Sympathetic blockade and neurolysis Celiac plexus block
Lumbar sympathetic
blockade
Stellate ganglion blockade
Somatic neurolysis or pathway Chemical or surgical
ablation rhizotomy
Trigeminal neurolysis
Transacral neurolysis
Cordotomy
Other Cingulotomy
Pituitarv ablation
Clinical situation
Systemic opioid analgesia complicated by unmanageable supraspinally
mediated adverse effects
Little reported experience, no well-defined indications
Reported efficacy with both upper body and generalized pain
Refractory malignant pain involving the upper abdominal viscera
including the upper retroperitoneum, liver, small bowel, and
proximal colon
Sympathetically maintained pain involving the legs
Sympathetically maintained pain involving the head, neck, or arms
Refractory brachial plexopathy or arm pain
Intercostal nerve pain, chest wall pain
Refractory bilateral pelvic or lumbosacral plexus pain in a bedridden
patient with urinary diversion
Refractory unilateral facial pain
Refractory pain limited to the perineum
Refractory unilateral pain arising in the torso or lower extremity
Little reported experience, no well-defined indications
Has been used for refractory multifocal pain
Refractorv multifocal pain

should be performed to assess the potential benefits of
this approach before implantation of a permanent cath-
eter.
Opioid selection for intraspinal delivery is in-
fluenced by several factors. Hydrophilic drugs, such as
morphine and hydromorphone, have a prolonged half-
life in cerebrospinal fluid and significant rostral redis-
t r i b ~ t i o n . ~ ' Lipophilic
~-~~' opioids, such as fentanyl and
sufentanil, have less rostral redistribution212and may
be preferable for segmental analgesia at the level of
spinal infusion. In some patients, the addition of a low
concentration of a local anesthetic, such as 0.125-
0.25% bupivacaine, to an epidural opioid has been dem-
onstrated to increase analgesic effect without increasing
t o x i ~ i t y . ~The ~ ~ -potential
~'~ morbidity for these proce-
dures indicates the need for a well-trained clinician and
long-term monitoring.
Intraventricular opioids. Limited experience exists
with the administration of an opioid into the cerebral
ventricles via an Ommaya r e ~ e r v o i r . ~ ~ This ' - ~ ' ~tech-
nique has been used for patients with upper body or
head pain, or severe diffuse pain. In relatively nontoler-
ant patients, the analgesia produced by a dose of mor-
phine has a rapid onset and a long duration of
Anesthetic Techniques for Sympathetically-
maintained Pain and Visceral Pain
Celiac plexus block. Neurolytic celiac plexus
blockade can be considered in the management of pain
caused by neoplastic infiltration of the upper abdomi-
nal viscera, including the pancreas, upper retroperiton-
e m , liver, gall bladder, and proximal small b o ~ e 1 . ~ ~ ~ - ~
Reported analgesic response rates in patients with pan-
creatic cancer are 50-90%, with the duration of effect
lasting from 1 to 1 2 month^.'*^-^^^ Given the generally
favorable response to this approach, most clinicians will
recommend it as the next intervention for patients with
an appropriate pain syndrome who fail to obtain an
adequate balance between analgesia and side effects
from an oral opioid. Common transient complications
include postural hypotension and diarrhea.224-226 Poste-
rior spread of neurolytic solution can lead to involve-
ment of lower thoracic and lumbar somatic nerves and
potentially result in neuropathic pain in the region of
the lower rib cage or upper thigh. Uncommon compli-
cations include pneumothorax, retroperitoneal hema-
toma, and paraparesis.
Sympathetic blockade of somatic structures.
Sympathetically maintained pain syndromes may be
relieved by interruption of sympathetic outflow to the
affected region of the body. Lumbar sympathetic block-
ade should be considered for sympathetically main-
tained pain involving the legs, and stellate ganglion
blockade may be useful for sympathetically maintained
pain involving the face or arms.
Neuroablative Techniques for Somatic and
Neuropathic Pain
Chemical rhizotomy. Chemical rhizotomy, which
may be produced by the instillation of a neurolytic so-
lution into either the epidural or intrathecal space, can
be an effective method of pain control for patients with
Current Strategy for Cancer Pain Management/Cherny and Portenoy
otherwise refractory localized pain syndrome^.^^^,^^^
The technique is most commonly used in the manage-
ment of chest wall pain due to tumor invasion of so-
matic and neural structures. Other indications include
refractory upper limb, lower limb, pelvic, or perineal
pain.
Satisfactory analgesia is achieved in about 50% of
patients who undergo epidural or intrathecal neuroly-
is."^ Adverse effects can be related to the injection
technique (e.g., spinal headache, infection, and arach-
noiditis) or to the destruction of non-nociceptive nerve
fibers. Specific complications of the procedure depend
on the site of neurolysis. Complications of lumbosacral
neurolysis include paresis (5-20%), sphincter dysfunc-
tion (5-60%), impairment of touch and proprioception,
and dysesthesias. Fortunately, neurologic deficits are
usually transient, although fatal meningitis, paraplegia,
and permanent impairment of sphincter function have
been re~orded.”~ Because of the risk of increased dis-
ability through weakness, sphincter incompetence, and
loss of positional sense, chemical rhizotomy of lumbo-
sacral nerve roots is best reserved for patients with lim-
ited function and preexistent urinary diversion. It is es-
sential that patients be counseled about the risks in-
volved with these techniques.
Other chemical neurolyses. Neurolysis of primary
afferent nerves may provide significant relief for se-
lected patients with localized pain. Refractory unilateral
facial or pharyngeal pain may be amenable to trigemi-
nal neurolysis, Gasserian gangliolysis, or glossopha-
ryngeal neurolysis. Intercostal or paravertebral neuro-
lysis are alternatives to rhizotomy for patients with
chest wall pain. Severe pain limited to the perineum
may be treated by neurolysis of the 54 nerve root via
the ipsilateral posterior sacral foramen, a procedure that
carries a minimal risk of motor or sphincter impair-
men^"^
Cordotomy. During cordotomy, the anterolateral
spinothalamic tract is ablated to produce contralateral
loss of pain and temperature s e n ~ i b i l i t y .The
~ ~ ~pa-
, ~ ~ ~apy while continuing trials of analgesic approaches. Al-
tient with severe unilateral pain arising in the torso or
lower extremity is most likely to benefit from this pro-
cedure.228The percutaneous technique is generally pre-
ferredZ3’; open cordotomy is usually reserved for pa-
tients who are unable to lie in the supine position or are
not cooperative enough to undergo a percutaneous pro-
cedure,230
Significant pain relief is achieved in more than 90%
of patients during the period immediately following
ord do to my.^^^^^^^-^^^ Fifty percent of surviving patients
have recurrent pain after 1 year, and repeat cordotomy
can sometimes be effective. The neurologic complica-
tions of cordotomy include paresis, ataxia, and bladder
dysfunction.232The complications are usually transient,
3409
but are protracted and disabling in approximately 5%
of cases. Rarely, patients with a long duration of sur-
vival (> 12 months) develop a delayed-onset dysesthe-
tic pain. The most serious potential complication is re-
spiratory dysfunction, which may result from phrenic
nerve paralysis or occur as sleep-induced apnea (in pa-
tients who undergo bilateral high c~rdotomy).’~~ The
potential for this complication relatively contraindi-
cates bilateral high cervical cordotomies or a unilateral
cervical cordotomy ipsilateral to the site of the only
functioning lung.
Other Techniques
Pituitary ablation. Pituitary ablation, by chemical
or surgical hypophysectomy, has been reported to re-
lieve diffuse and multifocal pain syndromes that have
been refractory to opioid therapy and are unsuitable for
any regional neuroablative p r o c e d ~ r e .Pain
~ ~ ~relief
,~~~
has been observed from pain due to both hormone-de-
pendent and hormone-independent t ~ m o r s . ~ ~ ~ , ~ ~ ~
Cingulotomy. Anecdotal reports also support the
efficacy of c i n g u l ~ t o m yin~ the
~ ~ management of dif-
fuse pain syndromes that have been refractory to opioid
therapy. The mode of action is unknown and the proce-
dure is considered rarely.
Therapy for Patients with Refractory Pain: The
Role of Sedation
The use of sedation therapy to manage intractable pain
and suffering in the small population that fails to bene-
fit from optimal therapy has recently received increas-
ing at ten ti or^.^^^*^^' In one study, 52% of terminally ill
patients developed otherwise unendurable symptoms
that required deep sedation for adequate relief; in just
under half of these patients, pain was the predominant
symptom.”
The patient with advanced cancer and uncontrolled
symptoms may choose transitory use of sedating ther-
ternatively, a strategy can be designed to provide ade-
quate sedation until death. The ethical basis of the latter
approach is predicated on informed consent and an ac-
knowledgment of the ”principle of double effect,”
which distinguishes between the compelling primary
therapeutic intent (to relieve suffering) and unavoid-
able untoward consequences (the potential for accelerat-
ing death).238The use of this approach must recognize
the right of dying patients to adequate relief of pain and
the right of all patients to choose among appropriate
therapeutic option^.'^^-'^^ No patient should have to
ask to be killed because of persistently unrelieved pain,
and on the contrary, no patient should be sedated with-
out appropriate informed consent of the patient or
3410 CANCER Supplement December 1, 1993, Volume 72, No. 11
proxy. The process of informed decision making re-
quires candid discussion that clarifies the prevailing
clinical predicament and presents the alternative anal-
gesic options (including sedation). The potentially con-
flicting goals of comfort versus function may need to be
made explicit. Other relevant considerations, including
existential, ethical, religious, and familial concerns, may
benefit from the participation of a religious counselor,
social worker, or clinical ethics specialist.
Sedation can potentially be accomplished through
the use of systemic opioids, with either a benzodiaze-
pine (e.g., lorazepam or midazolam), a neuroleptic (e.g.,
chlorpromazine or methotrimeprazine), or a barbiturate
(e.g., thiopental). Experience has been reported in the
use of an opioid in conjunction with a continuous infu-
sion of m i d a ~ o l a m
or~t h~ i~~ p e n t a l . ~It ~is~the
, *respon-
~~
sibility of the physician to ensure that the patient, fam-
ily, and staff have a comprehensive understanding of
this intervention.
Conclusion
Currently available techniques can provide adequate
pain relief to the vast majority of cancer patients, most
of whom will respond to systemic pharmacotherapy
alone. Successfullong-term management requires com-
prehensive assessment and a continuity of care that
provides an appropriate level of monitoring and re-
sponds quickly, flexibly, and expertly to the changing
needs of the patient. Patients with refractory pain, or
unremitting suffering related to other losses or distress-
ing symptoms should have access to specialists in pain
management, palliative medicine and psychooncology,
who can provide an approach capable of addressing
these complex problems.
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