Pain and Cancer Mangement

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 oncologists 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 strategy 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 selection 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 interventions, including the use of adjuvant analgesics, psychological therapies, and physiatric techniques, and invasive 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 management, 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

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.

4-6, 1993.

Accepted for publication July 30, 1993.

Pain is among the most prevalent symptoms experienced by patients with cancer.'-3 Successful management 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 responsive to the evolving goals and needs of the ~ a t i e n t . ~ This process requires a familiarity with numerous therapeutic 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 suboptimal7 and that many oncologists are ill-prepared for the ongoing task of symptom assessment and management.7,8 Poor outcomes may contribute to physician b ~ r n o u t ~ , ~ and greatly increase patient morbidity. The American Soci- ety of Clinical Oncology recognized the need for improved 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 require other approaches."-'6

Cancer Pain Assessment

The formulation of an effective therapeutic strategy for the management of cancer pain is predicated on a comprehensive assessment of the patient. A trusting relationship 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 symptoms. 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 characteristics 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 addition, the assessment should define the nature and extent of the underlying disease; evaluate concurrent problems (physical, psychological, and social) that contribute, 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 comfort 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 begins with data collection and ends with a clinically relevant formulation (Table 2). The pain-related history should illuminate: characteristics of the pain; the responses 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 assessment. 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 disease. 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 concurrent concerns includes other symptoms and related psychosocial problems.

Additional investigations are often needed to clarify 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 compliance and reduce the distress associated with procedures. No patient should be inadequately evaluated because 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 outcomes 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

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

Available laboratory

Step 2. Provisional assessment

Provisional pain diagnosis

Syndrome identification Inferred pathophysiology

Global assessment Concurrent concerns

Extent of disease Other symptoms 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 Extent of disease

Psychological 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.


The Role of Primary Therapy

The assessment process may reveal a cause for the pain that is amenable to primary therapy. Pain that is produced by tumor infiltration may respond to antineoplas- tic treatment with surgery, radiotherapy, or chemotherapy, and pain caused by infections may be relieved with antibiotic therapy or drainage procedures. Specific analgesic 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 metastases.26 In 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 chemotherapy in responsive tumors, such as lymphoma, small cell lung cancer, germ cell tumors, and previously untreated breast cancer. Interestingly, there are isolated reports of analgesic effects from chemotherapy even in the absence of significant tumor shrinkage.33T34 In all situations, the decision to administer chemotherapy solely for the treatment of symptoms should be recon- sidered in the absence of a clearly favorable balance between relief and adverse effects.

Surgery. Surgery may have a role in the relief of symptoms caused by specific problems, such as obstruction of a hollow viscus, unstable bony structures, and compression of neural t i s s ~ e s . ~ ~ - ~ ~ In all cases, the potential benefits must be weighed against the risks of surgery, the anticipated length of hospitalization and convalescence, and the predicted duration of benefit.35 For example, large volume paracentesis (up to 5-10 1) may provide prompt and prolonged relief from the pain and discomfort of tense as cite^,^^"^ with a small risk of h y p ~ t e n s i o n ~ ~ , ~ ’ or hyp~proteinemia.~~

Antibiotics. Antibiotics may have analgesic effects when the source of the pain involves infection, as illus- trated by the treatment of chronic sinus infection, pelvic abscess, pyonephrosis, and osteitis p ~ b i s . ~ ~ , ~ ~ Occasion- ally infection may be occult and confirmed only by the symptomatic relief provided by empirical treatment with these d r ~ g s . ~ ~ , ~ ~

Systemic Analgesic Pharmacotherapy

Systemically administered analgesic drug therapy, involving the use of nonopioid, opioid, and adjuvant an-

Figure 1. The three-step ”analgesic ladder,” proposed by an expert committee convened by the Cancer Unit of the Word Health Organization. From World Health Organization. Cancer pain relief and palliative care: report of a WHO expert committee. Geneva: World Health Organization, 1990. WHO Technical Report Series, no. 804. With permission.

algesics, is the cornerstone of cancer pain management.5,6T46 Nonopioid analgesics comprise acetaminophen and the nonsteroidal anti-inflammatory drugs (NSAIDs) including aspirin. The term ”adjuvant analgesic” refers to a drug that has a primary indication other than pain, but is analgesic in selected circum- stances.

The three-step ”analgesic ladder,” proposed by an expert committee convened by the Cancer Unit of the World Health Organization, has emphasized that pain intensity should be the prime consideration in the selection of these (Fig. 1). Patients with mild to moderate cancer-related pain should be treated with a nonopioid analgesic, which should be combined with an adjuvant analgesic if a specific indication for one exists. Patients who are relatively nontolerant and have moderate to severe pain, or who fail to obtain adequate relief after a trial of a nonopioid analgesic, are usually treated with an opioid. This treatment is typically accomplished using a combination product containing a nonopioid (e.g., aspirin or acetaminophen) and an opioid conventionally used for this indication, such as


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 Naphthylalkanones Nabumetone

Salicylates Aspirin Acidic

Diflunisal

Choline magnesium trisalicylate

Salsalate

Proprionic acids

Acetic acids

Ibuprofen Naproxen Fenoprofen Ketoprofen Flurbiprofen lndomethacin

Sulindac Diclofenac Ketorolac

Tolmen tin Oxicams Piroxicam Fenamates Mefenamic acid I'yranocarboxylic acids Etodolac

3-4 22-30

3-12 8-12

8-12

8-12

3-4 1-3 2-3 2-3 5-6 4-5

14 2

4-7

1 45

2 7

750 every 4 hr 500 every 12 hr

650 every 4-6 hr 500 every 12 hr

1000 every 12 hr

1000 every 12 hr

400 every 6 hr 250 every 12 hr 200 every 6 hr



200 every 8 hr

250 every 6 hr 20 every 24 hr

1000 every 24

6000 2000

6000 1500

4000

4000

4200 1000 3200

200 300 200

400 200 240

2000 40

1000 2000

Available over the counter

Avaiiable over the counter Less GI toxicity than

Minimal GI toxicity No effect on platelet

Minimal GI toxicity No effect on platelet

function at usual doses Available over the counter

aspirin

function at usual doses

Sustained release and rectal preparations

Oral or parenteral preparation

GI: gastrointestinal.

codeine, oxycodone, or propoxyphene. This drug should be coadministered with an adjuvant analgesic if needed. Finally, patients who have severe pain, or fail to achieve adequate relief after appropriate administration 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 analgesia and produce neither tolerance nor physical dependence. The major site of action is presumably peripheral. Aspirin and the NSAIDs inhibit the enzyme cy- clooxygenase and consequently block the biosynthesis

of prostaglandins, inflammatory mediators known to sensitize peripheral noci~eptors .~~ A 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 requires 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 confusion, precipitation of cardiac failure, and exacerba- tion of hypertension. Particular caution is required in the administration of these agents to patients at increased risk of adverse effects, including the elderly and those with blood clotting disorders, predilection to peptic 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 aggregation, and no effect on bleeding time at routine clinical doses5* Acetaminophen rarely produces gastrointestinal toxicity, and has no adverse effects on platelet function. 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 (generally healthy patients with an inflammatory disease) that potentially have little in common with cancer patients, 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 patient with cancer pain, and doses may be higher or lower than the usual dose ranges recommended for the drug involved. These considerations and the observation that the effects of these drugs are (at least partially) dose-dependent, support an approach to the administration 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 reduce the risk of significant toxicity. Clinical experience suggests that 1 week 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 followed by success with another, sequential trials of several 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 agonist, 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 butorphanol) and the partial agonist opioids (buprenorphine 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 prevalence of dose-dependent psychotomimetic side effects. 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.5,54-57 In accordance with the analgesic ladder approach,46 patients with moderate pain are commonly treated with a combination product, which in the United States typically con- tains codeine, oxycodone or propoxyphene plus acetaminophen, 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 tablets 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 manage 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 important considerations, and morphine sulphate is usually preferred because it has a short half-life, is easy to titrate 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, methadone 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 recommended 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 compound.59 Repetitive 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,


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

Oxycodone*

Propoxyphene

15 30

50 100

Opioid agonists customarily used to treat severe pain

Morphine

Oxy codone Hydromorphone Methadone

Meperidine

Oxymorphone

Heroin Levorphanol

Fentanyl transdermal system

10 30 (repeated dose) 60 (single dose)

15 30

10 20 1.5 7.5

75 300

1 10 (PR)

5 60 2 4

2-3 2-4

2-3 2-4

2-3 2-4

2-3 3-4

2-3 2-4 2-3 2-4

15-190 4-8

2-3

2-3

0.5 12-15

2-4

3-4

3-4 4-8

48-72

Usually combined with a nonopioid Available over the counter Formulated as single agent or

combined with a nonopioid Usually combined with a nonopioid Norpropoxyphene toxicity may

cause seizures

M6G accumulation in renal failure may predispose to additional toxicity

Formulated as single agent No known active metabolites Plasma accumulation may lead to

Dosing should be initiated on a

Not recommended for cancer pain Normeperidine toxicity limits utility Contraindicated in patients with

renal failure and those receiving MA0 inhibitors

delayed toxicity

PRN basis

No oral formulation available Less histamine release High solubility morphine prodrug Plasma accumulation may lead to

Patches available to deliver 25, 50, delayed toxicity

75, and 100 g d h r IM: intramuscular; PO: per 0s; PR per rectum; PRN: as needed; MAO: monoamine oxidase. * When combined with a nonoDioid.

could theoretically precipitate seizures in patients receiving meperidine by blocking the depressant action of the parent compound and allowing the convulsant activity of normeperidine to become manifest.62 Although normeperidine toxicity is most likely to affect the elderly and patients with overt renal disease (who are unable to renally clear the metabolite), it is sometimes observed in younger patients with normal renal function.59,63 In the unusual patient who is administered meperidine, concurrent therapy with a monoamine oxidase 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 (norpropoxyphene), meperidine (normeperidine), and morphine (morphine-6-glucuronide). Particular caution is required in the titration of these agents in this ~ e t t i n g , ~ ~ - ~ ~

and alternative opioids are often recommended. Similar care is required when prescribing meperidine, pentazocine, or propoxyphene to patients with hepatic dysfunction. The clearance of these drugs is diminished with liver disease and plasma concentrations may become 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 advanced 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 balance 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- tence of receptor binding difference^^^ and the occur-

3400 CANCER Supplement December 2, 2993, Volume 72. 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 requires 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 equianalgesic 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 selection. Numerous other variables may influence the appropriate 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 administration, Opioids should be administered by the least invasive and most convenient route capable of providing adequate analgesia for the patient. In routine practice, the oral route is usually the most appropriate.5r6r58 Al- ternative noninvasive routes, including the rectal, sublingual, and transdermal routes, should be used for patients who have impaired swallowing or gastrointestinal obstruction.

The potency of opioids administered rectally is be- lieved to approximate oral d ~ s i n g . ~ ~ , ~ ~ Rectal supposito- ries containing oxymorphone, hydromorphone, and morphine are available, and controlled-release morphine 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,82 but 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.84 Both fentanyl and methadone are relatively well absorbed through the buccal mucosa,81 and sublingual administration of an injectable formulation might be a reasonable 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 transdermal system consists of a drug reservoir separated 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 intervals as brief as 48 hours. Limitations of the transdermal delivery system include its expense and the requirement for an alternative short-acting opioid for breakthrough pain.

Parenteral routes of administration should be considered 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 injections, 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 recommended.58 Repeated bolus doses, if required, can be accomplished without frequent skin punctures through the use of an indwelling IV or SC infusion device. To deliver repeated SC injections, a 27-gauge infusion device (known as a "butterfly") can be left under the skin for up to 1 week.

Continuous infusions avoid the problems associated with the bolus effect and may be administered intravenously or subcutaneously.s9-93 Ambulatory infusion devices vary in complexity, cost, and ability to 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, oxymorphone, 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 specifically for continuous SC infusion. Continuous IV infusion may be the most appropriate way of delivering an opioid when there is a need for infusion of large volume of solution, or when using methadone. If continuous IV infusion is to be continued on a long-term basis, a permanent central venous port is recommended.

Continuous infusions of drug combinations may be indicated when pain is accompanied by nausea, anxi-


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, chlorpromazine, 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, requires 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 patients 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 "rescue" drug is typically identical to that administered on a continuous basis with the exception of transdermal fentanyl and methadone, for which the use of an alternative short half-life opioid is recommended. Clinical experience 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 rescue doses are offered up to every 1-2 hours and parenteral doses are offered up to every 15-30 minutes. The integration of scheduled dosing with rescue doses provides 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 administration 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 formulations of controlled-release oxycodone and hydromorphone are under development. Controlled-release preparations of morphine sulphate typically achieve peak levels 3-5 hours after administration and have a dura-

tion of effect of 8-12 hours.'05 Immediate-release morphine 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 effective around-the-clock dose is identified.

In some situations, an as-needed dosing regimen alone can be recommended, This type of dosing provides 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 therapy. As-needed dosing may also be appropriate for patients who have rapidly decreasing analgesic requirement or intermittent pains separated by pain-free intervals.

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 typically used in conjunction with continuous opioid infusion. Long-term patient-controlled analgesia in cancer patients is most commonly accomplished via the subcutaneous 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 generally recommended.

When patients receiving higher doses of opioids are switched to an alternative opioid drug, the equianalgesic dose table (Table 5) is used as a guide to the starting dose. For patients with good pain control but unacceptable side effects, the starting dose of the new drug should be reduced to 50-75% 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


Table 6. Examples of Stepwise Dose Escalation of Morphine Sulfate Administered as Oral Immediate Release Preparation and Oral Controlled Release and Continuous Infusion

Oral controlled release (with SC infusion with SC rescue Oral immediate release immediate release rescue dosing) doses

mg every 4 hr Rescue dose PRN Rescue dose PRN Rescue dose PRN "around the every 1 hr mg "around every 1 hr q15-30 min

Step* clock" (mg) the c l o c k (mg) m g l h r (mg)

1 10 5 30 every 12 hr 7.5 3 2.0

3 30 15.0 60 every 12 hr 15.0 7 3.5

5 60 30.0 100 every 8 hr 45.0 15 7.5

2 15 7.5 30 every 8 hr 15.0 5 2.5

4 45 22.5 100 every 12 hr 30.0 10 5.0

* 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 development of side effects. Subsequent dose adjustments are usually necessary.

At any point during the course of therapy, the development of inadequate pain relief should be ad- dressed through a stepwise escalation of the opioid dose. The opioid dose should be increased until adequate analgesia is reported or unmanageable side effects 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 become 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 requirement 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 minutes until pain is partially relieved. Guidelines have been proposed for the calculation of hourly maintenance dosing after parenteral loading with a short half- life opioid.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 maintenance 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

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 increments as often as twice daily. The dose of controlled-release preparations of oral morphine or transdermal fentanyl 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 suggests that most patients who require an escalation in dose to manage increasing pain have demonstrable progression of d i s e a ~ e . ' ~ ~ ~ " ' - ~ ~ ~ True pharmacologic tolerance 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 factors (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 potential 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 depression.

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.,


Table 7. Putative Mechanisms of Opioid-Induced Nausea and Vomiting and Their Management Mechanism Suggestive clinical features Antiemetic drugs

Stimulation of the medullary Nausea and or vomiting shortly after Metoclopramide, prochlorperazine, chlorpromazine, chemoreceptor trigger opioid administration haloperidol, corticosteroid, or lorazepam zone

sensitivity and vomiting, or vertigo Enhanced vestibular Prominent movement-induced nausea Scopolamine, meclizine, or lorazepam

Increased gastric antral tone Early satiety, postprandial bloating, or Metoclopramide vomi tine.

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 patients 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 withdrawal 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 adverse effect develop^."^

The incidence of opioid-induced nausea and vomiting 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 escalation is often associated with sedation that may persist for days to weeks. Although tolerance to this effect usually develops, some patients have a persistent problem, particularly if other contributing factors exist. A stepwise strategy for the management of persistent sedation 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 occurs, most patients with persistent delirium have several contributing factors, including electrolyte disorders, neoplastic involvement of the central nervous system, sepsis, vital organ failure, or hypoxemia."* Again a stepwise approach to management is appropriate (Table 9). Myoclonus is also a common dose-related adverse effect of opioids, and may similarly re- solve spontaneously. If the myoclonus is symptomatic

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 tolerance 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 respiratory 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*'22 An intercurrent cardiac or pulmonary process can precipitate respiratory depression in patients receiving chronic opioid therapy that is

Table 8. Stepwise Management of Opioid-Induced Sedation Eliminate nonessential central nervous system depressant

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)

medications

If somnolence persists, consider: Addition of a nonopioid or adjuvant that will allow reduction in

Change to an alternative opioid drug Change to the intraspinal opioid (+local anesthetic) Consider invasive anesthetic or neurosurtzical techniques

opioid dose


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 response 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-'27 This confusion derives, in part, from misunderstanding of the nomenclature used to describe drug use. For example, the term dependence is commonly used but is often misappre- hended. Patients who require a specific pharmacotherapy to control a symptom or disease process are dependent on the therapeutic efficacy of the drugs in question. Examples of this therapeutic dependence include the requirements of patients with congestive cardiac 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 consequences, the fear of which can induce aberrant psychological 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) syndrome after either abrupt dose reduction or administration 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 problem if patients are warned to avoid abrupt discontinuation of the drug, a tapering schedule is used if treatment cessation is indicated, and opioid antagonist drugs (including 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 addiction could be identified among 11,882 patients with no history of addiction who received at least one opioid preparation in the hospital ~ett ing."~ 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 providers, patients, and families often require vigorous and repeated reassurance that the risk of addiction is extremely small.

Pseudoaddiction. The distress engendered in patients 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 concern about opioid availability and unsanctioned dose escalation. Pain relief, usually produced by dose escalation, eliminates these aberrant behaviors and distinguishes 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-patient relationship. In the setting of unrelieved pain, aberrant drug-related behaviors require careful assessment, 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 between pain relief and the side effects of an opioid. Nu- merous noninvasive interventions (Table 1) can improve this balance by reducing the opioid requirement. These include the concurrent use of an appropriate primary therapy, alternative pharmacologic approaches (nonopioid analgesic or an adjuvant analgesic) and the use of psychological, rehabilitative, or neurostimulatory techniques (e.g., transcutaneous electrical nerve

Current Strategy for Cancer Pain ManagementlCherny and Portenoy 3405

stimulation). A switch to another opioid, as described previously, may also improve the therapeutic outcome.75

Adjuvant Analgesics

Adjuvant analgesics can be broadly divided into general purpose analgesics, and drugs with specific utility for either neuropathic or bone pain. There is a large interindividual and intraindividual variability in the responses to these agents (including those within the same class), and sequential trials are frequently needed to identify optimal therapy.

General-purpose adjuvant analgesics. Corticoste- roids are the most widely used general-purpose adjuvant These drugs may ameliorate pain and produce beneficial effects on appetite, nausea, mood, and malai~e. '~~- '~ ' The painful conditions that commonly respond to corticosteroids include raised in- tracranial pressure, acute spinal cord compression, supe- rior vena cava syndrome, metastatic bone pain, neuropathic pain due to infiltration or compression by tumor, symptomatic lymphedema, and hepatic capsular dis- t e n t i ~ n . ' ~ ~ , ' ~ ~ Patients with advanced cancer who experience pain and other symptoms that may respond to steroids are usually given a small dose (e.g., dexamethasone 1-2 mg twice daily). An acute episode of very severe pain that is related to a neuropathic lesion ( e g , plexopathy or epidural spinal cord compression) or bony metastasis and cannot be promptly reduced with opioids may respond dramatically to a short course of relatively high doses ( e g , dexamethasone 100 mg IV followed initially by 96 mg/day in divided doses). In all cases, the dose should be gradually lowered after pain reduction to the minimum needed to sustain relief.

Adjuvant analgesics used for neuropathic pain. Neuropathic pain such as brachial or lumbosacral plexopathy can be a major therapeutic challenge, and adjuvant drugs can play an important role in the management of these problems. For purpose of drug selection, it is useful to distinguish between continuous, lancinating, and sympathetically-maintained neuropathic pain based on the patient's history and physical examination (Table

The tricyclic antidepressants are truly multipurpose analgesics, but are generally prescribed for neuropathic pain in cancer patients. They are typically used to manage continuous dysesthesias that have not responded adequately to an opioid, and lancinating neuropathic pains refractory to other specific adjuvant d r ~ g s . ' ~ ~ , ' ~ ~ These compounds are also useful in patients with pain complicated by depression and i n s ~ m n i a . ' ~ ~ , ' ~ ~ Al- though the evidence for analgesic efficacy is greatest for the tertiary amine tricyclic drugs, such as amitriptyline, doxepin, and i m i ~ r a r n i n e , ' ~ ~ - ' ~ ~ the secondary amine

Table 10. Selection of Adjuvant Analgesics for Neuropathic Pain Based on Clinical Characteristics of the Pain

Sympathetically Continuous pain Lancinating pain maintained pain

Antidepressants Anticonvulsant drugs Phenoxybenzamine Amitript yline Carbamazepine Prazosin Doxepin Phen ytoin Corticosteroid Imipramine Clonazepam Nifedipine Desipramine Valproate Propranolol Notriptyline Baclofen Calcitonin Trazodone Local anesthetics Maprotiline Mexiletine

Local anesthetics Lidocaine Mexiletine Pimozide Lidocaine Antidepressants

Clonidine Capsaicin Calcitonin

drugs, such as desipramine and nortryptyline may be preferred when concern about sedation, anticholinergic effects, or cardiovascular toxicity is high. There is limited evidence that the newer antidepressants, trazodone and maprotiline, are analgesic and virtually no data in support of f l~oxet ine . '~~ The starting dose of a tricyclic antidepressant should be low (e.g., amitriptyline 10 mg in the elderly and 25 mg in younger patients). Doses can be increased every few days by increments the same size as the starting dose. The usual effective dose for the most widely used of these drugs, amitriptyline, is 50-150 mg per day. It is reasonable to continue upward dose titration beyond this range, however, when patients fail to achieve benefit and have no limiting side effects. Plasma drug concentration, if available, may provide useful information and should be followed during the course of therapy. Very low levels in nonresponders suggest either poor compliance or an unusually rapid metabolism. In the latter case, doses can be increased while repeatedly monitoring the plasma drug level. Likewise, nonresponders whose plasma concentration is not very low, but is lower than the antidepressant range, should be considered for a trial of higher doses if side effects are not a problem.

Anticonvulsant drugs appear to be analgesic for diverse types of lancinating (shooting) neuropathic pain.'42,'49 Clinical experience also supports the use of these drugs for patients with paroxysmal (but not lancinating) pains, and for those with continuous neuropathic pains that have not responded to other agents. Although carbamazepine is often preferred because of the high response rate observed in trigeminal neuralgia,150-153 caution is required in cancer patients with 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, including 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, valproate, and clonazepam, and the administration of phenytoin 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 until a favorable effect occurs, intolerable side effects supervene, or the plasma drug concentration has reached a predetermined level, which is customarily at the upper end of the therapeutic range for seizure management.

Baclofen, a gamma-aminobutyric acid-agonist effective 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, therefore, 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 effects 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 monitoring 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 ~ a i n . ' ~ ~ - ' ~ ~ Tw o concentrations (0.025% and 0.075%) are commercially available. Although the dose-response relationship has not been evaluated in controlled studies, it is reasonable to use the higher concentration for either the initial trial or a subsequent trial after failure of the lower concentration product. A burning sensation can follow topical application of capsaicin. 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 management of sympathetically-maintained pain (pain associated with local signs of autonomic dysregulation, such as edema, vasomotor instability, or sweating abnormalities). Although the preferred approach for this type of pain includes sympathetic nerve blocks, blocks may occasionally be contraindicated or fail. In this situation, several specific adjuvant analgesics have been advocated. Phenoxybenzamine, 60-1 20 mg per day, has been reported to be effective in a survey of patients with ~ausalgia , '~~ 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 calcitonin may also be useful in some patients with sympathetically 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 bisphosphonate drugs, pamidronate and clodronate, inhibit osteo- clast activity and have been demonstrated to relieve


Table 11. Nonopioid Therapies for Bone Fain Primary therapy Psychiatric Drug therapy

Radiation therapy Orthotics Anti-inflammatory drugs Chemotherapy Assistive devices Nonstimulatory anti-inflammatory drugs Hormonal therapy Corticosteroids Surgical stabilization Bisphosphonates

Pamidronate Clodronate

Calcitonin Radiopharmaceuticals

Strontium-89 Samarium-153-ethylenediaminetetramethylene

Rhenium-1 86-hydroxyethylidene diphosphonate phosphonic acid

malignant bone pain in several recent surveys and controlled trial^.'^'-'^^ A tr ial 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 calcitonin may occasionally provide significant relief of refractory 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 , ~ ~ ~ * ~ ~ ' samarium-153-ethylenediaminetetramethylene phosphonic a ~ i d , l ~ ~ - ~ " and rhenium-186-hydroxyethylidene diphosphonate,200~20z~zo3 are likely to become available 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 interventions used in the management of pain. Cognitive-behavioral 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

modalities such as electrical stimulation (including transcutaneous electrical nerve stimulation), heat, or cryotherapy can be useful adjuncts to standard analgesic 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.208 Orthotic 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 an Acceptable Balance Between Relief and Side Effects of Systemic Pharmacotherapy

Patients who are unable to achieve a satisfactory balance between analgesia and side effects from systemic analgesic therapies may be candidates for the use of invasive analgesic techniques. Anesthetic and neurosurgical approaches (Table 12) may reduce or eliminate the requirement for systemically administered opioids. Techniques such as intraspinal opioid and local anesthetic 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 duration 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 effects. 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


Table 12. Commonly Performed Anesthetic and Neurosurgical Analgesic Techniques for Pain Refractory to Systemic Pharmacotherapy

Class Technique Clinical situation

Regional analgesia

Sympathetic blockade and neurolysis

Somatic neurolysis or pathway ablation

Other

Spinal opioids and/or local anesthetics

Intraventricular

Celiac plexus block

Lumbar sympathetic

Stellate ganglion blockade Chemical or surgical

blockade

rhizotomy

Trigeminal neurolysis Transacral neurolysis Cordotomy Cingulotomy

Pituitarv ablation

Systemic opioid analgesia complicated by unmanageable supraspinally

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

mediated adverse effects

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 redistribution212 and 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 demonstrated to increase analgesic effect without increasing t o x i ~ i t y . ~ ~ ~ - ~ ' ~ The potential morbidity for these procedures 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 re~ervoi r .~~ ' -~ '~ This technique has been used for patients with upper body or head pain, or severe diffuse pain. In relatively nontolerant patients, the analgesia produced by a dose of morphine 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 abdominal 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 pancreatic cancer are 50-90%, with the duration of effect lasting from 1 to 12 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 involvement 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 complications 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 blockade should be considered for sympathetically maintained 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 solution into either the epidural or intrathecal space, can be an effective method of pain control for patients with


otherwise refractory localized pain syndrome^.^^^,^^^ The technique is most commonly used in the management of chest wall pain due to tumor invasion of somatic 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 dysfunction (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 lumbosacral nerve roots is best reserved for patients with limited function and preexistent urinary diversion. It is essential that patients be counseled about the risks involved with these techniques.

Other chemical neurolyses. Neurolysis of primary afferent nerves may provide significant relief for selected patients with localized pain. Refractory unilateral facial or pharyngeal pain may be amenable to trigeminal neurolysis, Gasserian gangliolysis, or glossopharyngeal neurolysis. Intercostal or paravertebral neurolysis 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 patient with severe unilateral pain arising in the torso or lower extremity is most likely to benefit from this procedure.228 The percutaneous technique is generally pre- ferredZ3’; open cordotomy is usually reserved for patients who are unable to lie in the supine position or are not cooperative enough to undergo a percutaneous procedure, 230

Significant pain relief is achieved in more than 90% of patients during the period immediately following ord do to my.^^^^^^^-^^^ F ifty percent of surviving patients have recurrent pain after 1 year, and repeat cordotomy can sometimes be effective. The neurologic complications of cordotomy include paresis, ataxia, and bladder dysfunction.232 The complications are usually transient,

but are protracted and disabling in approximately 5% of cases. Rarely, patients with a long duration of survival (> 12 months) develop a delayed-onset dysesthe- tic pain. The most serious potential complication is respiratory dysfunction, which may result from phrenic nerve paralysis or occur as sleep-induced apnea (in patients 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 relieve 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-dependent 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 y ~ ~ ~ in the management of diffuse pain syndromes that have been refractory to opioid therapy. The mode of action is unknown and the procedure 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 benefit from optimal therapy has recently received increasing 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 therapy while continuing trials of analgesic approaches. Al- ternatively, a strategy can be designed to provide adequate 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).238 The 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 without appropriate informed consent of the patient or


proxy. The process of informed decision making requires candid discussion that clarifies the prevailing clinical predicament and presents the alternative analgesic 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 infusion of m i d a ~ o l a m ~ ~ ~ or t h i ~ p e n t a l . ~ ~ ~ , * ~ ~ It is the responsibility of the physician to ensure that the patient, family, 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. Successful long-term management requires comprehensive 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 distressing 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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