Pharmacotherapy for Cancer Pain: An Anaesthesiologist's Viewpoint

Richard B. Patt, M.D.

Deputy Chief, Pain and Symptom Management Section,
University of Texas M.D. Anderson Cancer Center
Houston, TX

Originally published in Ann Acad Med Singapore 1994; 23:598-609

Reprinted by permission

Introduction

The anesthesiologist with an interest in the management of cancer pain may make important contributions to the well being of the cancer patient with pain, as well as to the effectiveness of teams organized to deliver pain and symptom control. Traditionally, the role of the anesthesiologist has been somewhat narrowly conceived of as that of a skilled technician providing invasive procedures when warranted, a "job description" related in large part to the skillful adaption of regional anesthetic techniques to the management of chronic symptoms.(1,2) The practice of cancer pain management has evolved considerably over the last decade, mandating careful scrutiny of the anesthesiologist's role in contemporary cancer pain management. This article outlines a rationale for an expanded role for the anesthesiologist-pain specialist and reviews the basic aspects of the pharmacologic control of cancer pain.

Basis for Expanded Role of the Anesthesiologist

The rationale for adopting a broader view of the anesthesiologist's contribution to cancer pain control(3) relates to several fundamental concepts that have come to serve as foundations for the contemporary practice of cancer pain medicine, hospice care and palliative care. These factors can be conceived of as including: (1) the acquisition of new pharmacologic knowledge and consequently, a greater emphasis on pharmacotherapy, (2) a reappraisal of the roles of invasive versus noninvasive interventions that views them as complementary rather than mutually exclusive; and (3) an emphasis on quality of life as the end point of a broad-based therapeutic armamentarium, the goals of which include the management not just of pain, but also of other symptoms.

A New View of Opioid Pharmacotherapy

Foremost among these factors is a reappraisal of the pharmacology of chronically administered opioids, and a growing understanding of the significant differences in pharmacology that exist with chronic as opposed to acute administration.(4)

Most of the knowledge gleaned about opioid pharmacology, until recently, was derived from single or limited dose studies conducted in the presence of either experimentally induced or acute pain. In a construct that recognizes chronic and acute pain as distinct disorders, there is limited justification for applying knowledge gained from one setting to the other uncritically.

The inadequate scientific basis for prescribing practices is linked to and compounded by firmly held beliefs regarding the dangers of opioid therapy.(5) Such beliefs are now widely understood to be based more on cultural biased than medical considerations.(6-8) Recognition that the uncritical acceptance of these biases has historically impeded legitimate scientific inquiry and the dissemination and implementation of knowledge already on hand has engendered an almost unparalleled scientific activism to dispel these myths. Guidelines released by the World Health Organization,(9,10) American Pain Society,(11) American Society of Clinical Oncology,(12) Oncology Nursing Society the American Society of Anesthesiologists (pending) and U.S. government Agency for Health Care Policy Research(14) stress the importance of opioid therapy and articulate the need to overcome exaggerated concerns about its risks.

Through the Lookinglass: "Oral Opioids Are Ineffective"

In prior eras oral morphine was deemed ineffective,(15) with the first edition of the A.M.A. Drug Evaluation Manual (1971) referring to orally administered morphine simply as "not recommended." Biases against the use of oral opioids can be traced to an incomplete understanding of their clinical properties, especially the concepts of parenteral:oral bioavailability, lack of ceiling doses and a propensity for the rapid development of tolerance to most adverse effects. An illustrative study was conducted by Beecher and colleagues.(16) They compared the effectiveness of 10 mg oral morphine, aspirin and placebo in postoperative patients, and demonstrated that morphine was no more effective than placebo and was less effective than aspirin. Having administered oral morphine in doses expected to be therapeutic, they concluded that oral morphine was ineffective as an analgesic. Only in light of later studies demonstrating the limits of oral morphine's bioavailability,(16) does it become apparent that Beecher's study utilized sub-therapeutic doses of oral morphine, and as such simply provided preliminary indirect evidence of a parenteral:oral analgesic equivalency of greater than 1:1. Other contemporary research has demonstrated a lack of ceiling effect to opioid-mediated analgesia(17) and a high incidence of the rapid development of tolerance to adverse effects such as nausea(18) and sedation.(19)

The Contemporary View: Oral Opioids as Treatment of First Choice

Oral morphine and its congeners were not widely used until the experience gleaned from the British hospice movement in the 1960's(20) exerted its influence during the 1970's and 1980's.(21) In large part as a result of the World Health Organization's identification of cancer pain as a major global health problem,(9,10) well controlled, cross culturally validated trials of oral pharmacotherapy have since been performed that demonstrate efficacy in 70% or more of patients with cancer pain.(22-25) Such efficacy combined with the favorable safety profile of oral opioids (reversibility, titratability, absence of long term organ toxicity) has caused cancer pain experts from multiple disciplines to advocate the use of oral opioids as the treatment of first choice for cancer pain that has not responded to antitumor therapy.(10,11,26,27) This trend establishes an imperative that the anesthesiologist develop and maintain expertise in pharmacotherapy, even if their primary focus remains neural blockade.

Changing Views on the Role of Nerve Blocks and Other Procedures

Far from eliminating the need for invasive procedures, new evidence supporting the use of oral opioids as the mainstay of therapy for patients with cancer pain has refined the role of such procedures. Although this construct dictates that invasive procedures should be confined to those 30% of cases or so where pain or side effects persist despite the judicious use of opioids, this represents a substantial population in need of invasive treatments.

Even within the realm of invasive therapies, new developments have further circumscribed their indications. Advances in microprocessor technology and the maturation of organized home care, together with the more facile use of parenteral opioids have resulted in an intermediate role for subcutaneous and intravenous opioid infusions (with or without patient controlled analgesia), especially for patients with alimentary dysfunction. These same trends, together with the introduction of intraspinal opioid therapy have made an entire set of new modalities available for both ambulatory and bedbound patients. While neural blockade remains an important option for selected patients, parenteral and intraspinal opioid therapy have the advantages of titratability, reversibility and efficacy for generalized and multifocal pain. The latter feature is particularly important in virtue of the fact that most cancer patients experience more than one distinct pain problem.(28)

Enhanced interest and knowledge about cancer pain and the more liberal use of opioids has had another important effect on the indications for neural blockade. In the context of an historical view that considered the use of opioids as being prima facie undesirable, there was a tendency to correlate the outcome of nerve blocks with whether opioid use could subsequently be discontinued or dramatically reduced. With the current emphasis on quality of life(29,30) independent of opioid doses per se,(17,27) nerve blocks are more readily viewed as occupying a role that complements rather than replaces that of opioids. Reductions in opioid use are often still sought as a means to reduce drug side effects and as indirect evidence that the correct procedure has been selected and properly executed. Nevertheless, efficacy is not generally judged directly in light of changes in dose requirements, but instead on clinical reports of pain and toxicity.

Juxtaposing opioid therapy and neural blockade as complementary rather than mutually exclusive modalities demands proficiency in pharmacologic management. Within such a construct, the likelihood increases that patients will continue to utilize opioid analgesics even after an invasive procedure, albeit with dose titration. Careful dose adjustments are perhaps most essential in the event of a highly successful procedure: reduction in the dose of systemic opioids is often necessary to circumvent toxicity when abrupt reductions in pain result in unopposed opioid effects, while downward titration must be tempered to avoid symptoms of physical withdrawal (abstinence).

Symptom Control and Quality of Life

Another lesson from the hospice movement relates to the identification of quality of life as an end point of treatment. A focus on quality of life is also a hallmark of palliative care,(31,32) a discipline that grew out of hospice and which has achieved the status of a distinct medical subspeciality in some countries.(33) Quality of life refers to the patient's overall functional status and sense of well being, and includes a focus on physical, but also psychological and spiritual aspects of the person.(20) More than an abstract concept, quality of life has been the subject of considerable research that has included the development of valid measurement tools.(29,34)

Studies documenting the frequency of symptoms in patients with cancer have demonstrated that pain is one of the most common problems, present in about 2/3 of patients overall (up to 25% of those with early disease and up to 90% in the setting of advanced disease).(35) Other symptoms are, however, highly prevalent (Table 1) and if unrelieved result in high levels of distress among patients and family members. If other symptoms are not addressed, even successful pain management will fail to impact on quality of life in a meaningful way. Palliative care experts recommend bringing the same intensity of effort to bear on treating other symptoms as is applied to the management of pain.(20,36) Management of other symptoms is predominantly pharmacologic, and principles governing such management have been advanced in the same way as have guidelines for pain management.(20,36) Treatment is often relatively straightforward. It is noteworthy, however that recent developments have suggested therapeutic alternatives for symptoms resistant to standard approaches as well as to symptoms previously viewed as irremediable like cognitive failure(37), dyspnea(38), anorexia and weight loss.(39,40) Expertise in the management of related symptoms and toxicities is essential for the anesthesiologist-subspecialist, and is facilitated by their expertise in clinical pharmacology. The dictum that treatment with opioids should proceed until pain is controlled or unpleasant side effects supervene(41) implies that significant side effects will be present in a high proportion of patients referred for consultation. Treatment modalities instituted by the anesthesiologist to control pain may produce new symptoms or exacerbate preexisting symptoms. The anesthesiologist's involvement in overall symptom management is fundamental to the conceptualization of their role as a consultant rather than a technician, or the "doctor at the other end of the needle."

Trends in Pharmacologic Management

Pharmacologic management is considered the first line of therapy for patients with cancer pain and when properly applied results in adequate analgesia in the majority of cases. Treatment is effective in adults and children and across different cultures. The analgesia that is associated with systemically administered medications is titratable and suitable for pain that is multifocal and/or progressive. Effects and side effects are reversible, and widespread implementation does not depend on sophisticated technology or scarce resources.(26)

Interindividual Variability

Cancer pain, and indeed pain in general, is characterized by interindividual variability that is manifest in multiple ways.(42,43) For example, not all bone metastases result in pain.(44) Even when pain is present, self-report varies dramatically as do responses to therapy. The regular administration of an aspirin-like drug may suffice for some patients, while others will require treatment with morphine or another potent opioid. In the latter group, even patients with similar disease characteristics vary dramatically in their analgesic requirements(45) to the extent that daily doses of morphine may need to be dispensed in milligrams for some patients and grams for others.(6) Even in the same patient, one standard opioid analgesic may produce dose-limiting side effects, while a pharmacologically similar drug may be tolerated without difficulty due to incomplete cross tolerance. This high degree of interindividual variability mandates careful assessment,(46,47) and even with the likelihood of favorable treatment outcomes, makes cancer pain management a demanding and time-intensive endeavor.

Nonopioid Analgesics

A detailed description of pharmacologic properties and clinical use of these agents is beyond the scope of this paper, but is available elsewhere.(11,27,41)

Nonsteroidal Anti-inflammatory Drugs

The nonsteroidal anti-inflammatory drugs (NSAIDs) are indicated for mild pain, and combined with stronger analgesics, for moderate to severe pain.(11,48) The NSAIDs are particularly effective for pain of bony metastatic origin, as well as for pain associated with inflammation, due to their inhibitory effects on prostaglandin synthetase (cyclo-oxygenase),(44) an enzyme involved in prostaglandin synthesis. Regular (around-the-clock or a-t-c) administration is most effective. Gastrointestinal, hematologic and renal toxicity may occur, as well as masking of fever, a particular concern in patients with reduced marrow function. In contrast to opioids, the use of the NSAIDs is associated with a ceiling effect, above which dose escalations do not result in enhanced analgesia. The ceiling dose in a given individual may differ from the recommended dose by up to two-fold though, and as a result some dose-titration may still be indicated.(49) Selection is based on the patient's prior experience, minor differences in toxicity, physician experience, schedule and expense.(41,48)

Coanalgesics/Analgesic Adjuvants

The so-called "adjuvant analgesics or coanalgesics" enhance opioid-mediated analgesia, reduce opioid-mediated toxicity or help control other symptoms of cancer.(50) They are a heterogeneous group of medications developed for purposes other than relief of pain, but subsequently determined to have a complementary role in pain management. Of drugs with purported coanalgesic properties, evidence most strongly supports the clinical use of selected antidepressants, anticonvulsants, oral local anesthetics and corticosteroids (50) (see references for details).

Coanalgesics versus Opioids

In contrast to the opioids, which are relatively useful for all types of pain, the coanalgesics are indicated only in specific settings, e.g.: antidepressants,(52-56) anticonvulsants (50,57-59) and oral local anesthetics(41,60,61) for neuropathic pain and corticosteroids(62,67) for pain associated with inflammation and peritumoral edema. The dose-response relationship for these drugs and the opioids differs in important ways. The administration of a sufficient dose of an opioid invariably results in some degree of analgesia, which increases linearly with the dose in a close temporal relationship to each administration. Depending on the underlying pain mechanism and other more obscure factors, administration of the coanalgesics may or may not result in analgesia. The onset of analgesia may be delayed by days or even weeks after initiating therapy, and the quality of analgesia is less closely linked to dose increases. As a result, serial trials of each class of coanalgesics, and even of different agents within the same class are indicated.

Opioid Analgesics

Oral analgesics are the mainstay of therapy for patients with cancer pain, and are reported to control pain in 70-90% of patients when they are prescribed in accordance with contemporary guidelines.(11,22,26,27) The recent introduction of transdermal and oral transmucosal fentanyl provides alternative means to control pain noninvasively.(67-69) Pain control can be achieved in a high proportion of remaining patients when opioids are administered parenterally (subcutaneously(70) or intravenously(71)) regionally (intraspinally(72) or intraventricularly(73)) and when these techniques are combined with other more invasive approaches.(74) The World Health Organization (Figure 1) has adopted a "ladder" approach to cancer pain management that relies on the administration of oral agents.(10) Similar guidelines have been promulgated by the American Pain Society(11) and other authorities.(26,27)

Addiction Redefined

Despite widespread use, the opioids are among the most stigmatized classes of medically available drugs. Misconceptions and other nonmedical factors that detract from optimal use have been described (Table 2), and of these, issues related to the potential for habituation predominate.

Tolerance, physical dependence and psychological dependence (addiction), once considered together as part of a single syndrome are increasingly recognized as distinct phenomena (Table 3). Physical dependence and tolerance are physiologic effects that are almost invariably associated with chronic opioid use, and as such can be conceived of as independent and distinct from addiction. Addiction (psychological dependence)(75) is regarded as a psychologically-mediated disorder with possible genetic influences that occurs only rarely as a consequence of medical use, and then idiosyncratically.(76) Given acceptance of the validity of this construct, physical dependence, tolerance need not be regarded as important impediments to the successful management of cancer pain with opioid analgesics (see discussion below). Addiction exerts only an indirect negative effect, that correlates with the degree to which clinicians overestimate its risk.

Physical dependence, which also occurs with drugs other than the opioids (eg, benzodiazepines), refers to the probability that a state of withdrawal (abstinence syndrome) will occur if drug administration is abruptly discontinued or a sufficient dose of a specific antagonist is administered. If treatment with the opioids should become unnecessary, physical dependence can be readily managed (avoided) by gradually tapering opioid doses (10-25%/day) and avoiding the use of antagonists. Tolerance exists when, over time, an increased dose of a drug is required to achieve a given effect. It is usually first manifest by a decrease in the observed duration of effect of each administered dose. When tolerance is suspected to be responsible for increased reports of pain, it can usually be countered safely and effectively by simply increasing the dose, especially since tolerance also develops to many of the adverse effects of the opioids, notably nausea and sedation.

Addiction is a complex psychobehavioral syndrome characterized by overwhelming involvement in the acquisition and nonmedical use of a substance despite the threat of physiologic and/or psychological harm.(75) Although it is a rare sequelae of medical exposure and therefore should not markedly influence prescribing habits, the risk of iatrogenic addiction remains a serious concern among practitioners.(6)

Selecting an Opioid

The mainstay of treatment for cancer pain of moderate to severe intensity is with potent opioid analgesics, which occupy the highest tier of the three step ladder schema (Figure 1) recommended by the World Health Organization.(9) Patients may access this ladder at any level and may be started on potent opioids initially for severe pain. Also of note is that when patients ascend the ladder serially, less potent analgesics should not be automatically eliminated since the NSAIDs may provide additive analgesia and the mild opioids may be useful for breakthrough or incident pain.

The various opioids produce analgesia by similar mechanisms and when administered in comparable doses, the quality of analgesia and spectrum of side effects are similar.(77) Nevertheless, individuals vary idiosyncratically in their sensitivity to the analgesic effects and toxicity of the various drugs (incomplete cross tolerance), forming the basis for the clinical use of morphine alternatives. Other reasons for selecting alternate opioid preparations and routes include convenience of dosing and patient satisfaction, variable patterns of pain, gastrointestinal dysfunction, the need for concentrated formulations, and prior favorable clinician and patient experience.

Mild Opioids

Traditionally when treatment with the NSAIDs is associated with insufficient relief of pain or is poorly tolerated, the addition of a member of the class of drugs referred to as the "weak opioids" is recommended as an analgesic of intermediate potency.(11) Most mild opioids are available only as combination analgesics (with acetaminophen or aspirin), and while there is probably no ceiling dose for the opioid component of these formulations, the number of tablets that can be taken safely is limited by the amount of simple analgesic (aspirin, acetaminophen). Given the lack of a ceiling dose for the opioid component of these preparations, the distinction between so-called weak and potent opioids is somewhat artificial, influenced more on a cultural rather than medical basis, eg: oxycodone has recently been made available in an uncombined form that can be utilized in progressively higher doses to treat even severe pain.(78) One of the most common prescribing errors relates to continuing the use of codeine-like drugs after they are no longer effective, in an ill-advised attempt to avoid prescribing more potent opioids which are also more highly regulated.(6)

Propoxyphene, a stereoisomer of methadone has relatively few indications for the management of cancer pain since it is only about « to 1/3 as potent as codeine(6) and is not more effective than aspirin or acetaminophen.(79) Although codeine is considered the prototypical drug of this class, it's emetogenic and constipating effects are disproportionate to its relatively weak analgesic properties. Oxycodone is up to 7.7 times more potent than codeine,(80) and, of this class of drugs, is preferred by many authorities.(78) The potency of hydrocodone and dihydrocodeine lies between that of codeine and oxcycodone.(81) They are typically available as combination products and their use may be less regulated than that of oxycodone in some clinical settings.

Potent Opioids: Morphine

Morphine remains the standard of reference to which other analgesics are commonly compared. The pharmacokinetic and pharmacodynamic characteristics of a single 10 mg dose of morphine administered intramuscularly forms the basis of most tables and charts compiled to describe the relative characteristics of the opioids (Table 4). Despite widespread use and extensive research, misconceptions about the use of morphine for chronic pain management continue to interfere with its optimal use (Table 2).(6)

Morphine is readily absorbed from the gastrointestinal tract and is metabolized in the liver. With chronic use, about 1/3 of the orally administered dose ultimately exerts an analgesic effect (oral bioavailability of 3:1). This is in contrast to the 6:1 parenteral:oral ratio determined from single dose studies for acute pain.(16) Since parenterally administered drug is not subject to this first-pass effect, clinicians may incorrectly perceive parenterally administered opioids as more effective than opioids administered orally. Recent research has focused on the role of morphine metabolites, once thought to be inactive. Morphine-3-glucuronide has been postulated to antagonize opioid analgesia, while morphine-6-glucuronide appears to possess potent analgesic properties and may induce persistent nausea and sedation, especially in the presence of altered renal function.(82-85) The clinical relevance of these metabolites is currently uncertain.

Morphine is available in a variety of formulations and is appropriate for administration by a variety of routes. The most important distinctions are between (1) so-called "immediate release preparations" (MSIR, Roxanol) which have a short latency to effect (about 30 min) and short duration (2-4 hr) and are usually administered every 4 or 3 hours and (2) "controlled release preparations" (MS Contin, Oramorph) which have a longer latency to effect and duration, and as a result are usually administered every twelve or sometimes eight hrs.

Practical Use of Oral Morphine

Most patients will require simultaneous treatment with two different formulations of an opioid: a long-acting (basal) analgesic administered around-the-clock (a-t-c) and a short acting analgesic, administered as needed (prn). This schema is analogous to the treatment of diabetes mellitus with long acting (NPH) and short acting (regular) formulations of insulin concurrently.

Basal (around-the-clock) Analgesia

Since most oncologic pain is constant and unremitting, a time-contingent (a-t-c) schedule for the administration of analgesics is preferable to symptom-contingent (prn) administration. This strategy promotes consistent therapeutic plasma levels and avoids "roller coaster" or sine wave kinetics and dynamics characterized by alternating bouts of pain and toxicity (Figure 2). If analgesics are withheld until pain becomes severe, sympathetic arousal occurs and even potent analgesics may be ineffective.(11) Prolonged prn administration may lead to the establishment of a pattern of anticipation and memory of pain that predisposes to persistent suffering even after a more regular administration of analgesics has been instituted (Figure 2).(86) Basal analgesia is usually provided by the administration of controlled release preparations of oral morphine every 12 or 8 hours, or alternatively with transdermal fentanyl, methadone or levorphanol (see below).

Supplemental (prn) Analgesia

In addition to the above regimen, potent short-acting opioids with minimal potential for accumulation (immediate release morphine, hydromorphone, oxycodone) are generally made available on an as-needed basis, usually at intervals of two to four hours for exacerbations of pain. Such exacerbations, referred to as breakthrough pain(87) may be spontaneous, related to specific activities (incident pain(88)) or, if the dose of the basal analgesic is insufficient, may occur regularly just prior to the next scheduled dose (end of dose failure). When incident pain has been identified, patients should be instructed to utilize rescue doses prior to activity, and in the case of end of dose failure, the dose of long acting analgesic should be raised. When frequent use of these rescue doses or escape doses is observed, the dose of basal analgesic should be increased accordingly. In such cases, relatively tolerant patients generally tolerate increments of 25-50% or more of their basal dose readily.

Initiating Therapy

Since dose response and side effects vary widely based on a number of physiologic and behavioral factors (eg: age, previous drug history, extent of disease, etc),(89,90) therapy should be individualized to suit the patient's needs.(91) Effective doses often dramatically exceed guidelines recommended in standard texts (10 mg I.M., 30 mg p.o.), which for the most part are derived from experience with acute or postoperative pain in opioid naive patients.

Treatment with oral morphine can be started several ways. In cases of severe pain it may be desirable to initiate therapy with parenteral morphine which can later be converted to an oral drug regimen using a 3:1 ratio. More commonly, immediate release oral morphine is administered every three to four hours to determine opioid requirements, following which the sum of the daily dose is halved and administered as a controlled release preparation and supplemented by rescue doses of immediate release morphine, each aliquot of which should equal 1/6 to 1/10 of the 24 hour dose. Alternatively, treatment can be initiated with an empirically selected dose of controlled release morphine, supplemented by appropriate doses of immediate release morphine. Regardless of the regimen that is selected, low starting doses with rapid upward titration are preferred to limit the frequency of side effects and enhance compliance.

Dose Titration

The correct dose of morphine (or a morphine-line drug) for the management of cancer pain is the dose that effectively relieves the pain without inducing intolerable side effects. Daily doses of morphine required to adequately relieve cancer pain may vary from 60 to 3000 mg in divided doses.(22) There is no ceiling effect for morphine, i.e., an increase in the dose will always produce a concomitant increase in pain relief. The starting dose is gradually and steadily titrated upward until either pain control is achieved or side effects occur. If dose increases result in worsening side effects and only small increments in analgesia, the pain syndrome may be relatively opioid-resistant (eg: neuropathic pain or movement-related incident pain).(17,92), Relatively opioid-resistant pain may require alterative therapeutic approaches.

Side Effects and their Management

Treatment with the opioids may be associated with side effects although in many cases these are transient and in most cases, manageable. Prompt identification, assessment and management of side effects is a cornerstone to treatment. Adverse effects are often perceived of as barriers to the provision of analgesics in doses required to relieve pain effectively (dose-limiting side effects). Most drug-related side effects can be effectively relieved with careful management, but the same attention and skill required to tailor a pain management program needs to be applied to selecting and titrating drugs to minimize the impact of side effects. Patient education is essential to ensure the best outcome and to avoid confusion between manageable side effects and allergy.(93)

A detailed account of the management of opioid side effects is beyond the scope of this article, and is available elsewhere.(36,94-96) The potential for side effects should be carefully explained and patients should be encouraged to report problems as they occur. Constipation is almost invariable and requires prophylactic and continued management with laxatives(97)on a "sliding scale" regimen that provides successively stronger laxatives until a regular bowel habit ensues.(93) The clinician should monitor for the presence of bowel obstruction and fecal impaction.

Transient nausea and sedation are relatively common when opioid therapy is initiated,(96) but with continued use, usually resolve within a few days to one week.(6,93) Patients should be reassured and encouraged to adhere to their prescribed regimen of analgesics while symptomatic treatment is instituted and, as tolerance to these effects develops, later tapered.

Reversible central nervous system (CNS) changes associated with opioid therapy range from mild sedation to somnolence, confusion and delirium. Mild cognitive dysfunction is relatively common but usually manageable, while severe CNS toxicity can usually be avoided. Toxicity occurs most commonly after the initiation of treatment or a dose escalation, and is usually transient.(19) Sudden cognitive changes in patients taking opioids chronically are unlikely to be related to opioid therapy, and other potential causes such as brain metastases or electrolyte disturbances should be considered.(98) Sedation is most likely to emerge as a dose-limiting side effect in the elderly and in patients with relatively opioid-resistant pain problems (incident pain, bone metastases, nerve injury).(92,17) Sedation can often be minimized by initiating opioid therapy at low doses and titrating upwards gradually. Persistent sedative effects can usually be managed by initiating symptomatic treatment with a psychostimulant (methylphenidate(37) or dextroamphetamine(99)), instituting trials of an alternate opioid or an adjuvant analgesic or consideration of an alternate therapeutic modality such as a nerve block or percutaneous cordotomy.

Other Potent Opioids

The pharmacokinetics and pharmacodynamics of other opioid drugs are similar to those noted for morphine, and are described in detail elsewhere.(6,41)

A formulation of transdermal fentanyl has recently been introduced which, once treatment has been established provides relatively steady plasma levels for up to 72 hours following a single application of a 25, 50, 75 or 100 ug/hr patch.(67-69) The patch's design effectively converts fentanyl to a long acting agent,(100) although consistent, near-peak levels are not obtained for a period of 12-18 hours after the first application(101) and effects persist for 12-18 hours after system removal. Although a useful alternative for maintaining around-the-clock basal analgesia, because of its long latency to effect, transdermal fentanyl it is not recommended when rapid titration is required for unstable pain.

Methadone is equipotent with morphine when administered intramuscularly, and is slightly more potent when administered orally. It possesses a long and variable half life (13-51 hrs) that may lead to drug accumulation, especially in patients who are elderly or who have renal failure. Although inexpensive, most authorities recommend its use only as a second line drug and then call for careful monitoring during the initiation of therapy and after dose increases.(7) Treatment may best be initiated by prn administration until steady state is achieved, following which the interval between a-t-c administration may vary between 4 hr and 12 hr. Levorphanol (Levodromoran) resembles methadone, in that due to its relatively long half life (11 hrs), accumulation may occur, dosing intervals may vary from 4-8 or even 12 hrs, and as a result the same precautions described for methadone apply to its use.(102) A parenteral dose of 2 mg and oral dose of 4 mg is usually equianalgesic to 10 mg of parenteral morphine.

Hydromorphone (Dilaudid) is available in a variety of formulations and can be administered by the oral, rectal, subcutaneous and intravenous routes. It is 7-8 times more potent than morphine when administered parenterally and enterally is about four times as potent as oral morphine (parenteral to oral dose ratio of about 5:1).(97) Administered by either route, it's latency to effect and duration are relatively short (about 30 minutes and 2-4 hrs respectively). The main uses of hydromorphone are for subcutaneous infusions (in view of its solubility of up to 200 mg/ml), oral breakthrough dosing and in patients who are intolerant to morphine.

Drugs to be Avoided

Meperidine, although extensively used for postoperative pain, is not recommended for chronic administration. Its oral bioavailability is relatively low (4:1) and its duration of action is relatively short (2-3 hr). The most serious drawback to chronic administration is the potential for accumulation of normeperidine, a toxic metabolite with a long half life that may cause tremors, myoclonus and seizures, especially in patients with renal failure.(103, 104)

Brompton's cocktail one of the first preparations of an oral opioid to gain clinical acceptance is now used only infrequently. Developed at Brompton's Chest Hospital in the United Kingdom it consisted of a mixture of morphine hydrochloride (or heroin), cocaine hydrochloride, alcohol, syrup and chloroform water. In blinded trials it has not been shown to produce analgesia that is superior to an oral opioid administered alone,(24) and its use should be discouraged because of the problems associated with titrating fixed dose combinations. Likewise, no advantage has been demonstrated for treatment with heroin,(105) although it is still sometimes used in the United Kingdom and Canada, predominantly for subcutaneous infusions in virtue of its high solubility.

Opioids with mixed agonist/antagonist activity and partial agonists are not usually recommended for the treatment of chronic cancer pain.(10,11,27) Differential binding to opioid receptor sites, which may confer favorable properties for acute pain management are responsible for a relatively high incidence of psychotomimetic effects,(106) and there is usually a ceiling dose above which further dose increases are not associated with additional analgesia. Patients should not be treated concurrently with a pure agonist drug, and conversion from treatment with one class of drugs to another should be performed only cautiously because of the risk of precipitating a withdrawal reaction.

Alternate Routes of Administration

Between 1/3 and 2/3 of patients will benefit from at least the transient use of an alternate route sometime before death.(107) There is no evidence that parenteral administration produces superior analgesia to oral administration, so treatment should be reserved for conditions that render oral administration unreliable, such as weakness, dry mouth, dysphagia, nausea, vomiting, malabsorption or obstruction. Alternate routes may also be considered when an impractical numbers of tablets must be ingested or, acutely when rapid induction of analgesia is required to treat a pain emergency.

Rectal Administration is reliable and effective, but is usually only considered practical for short term use.(108,109) A continuous subcutaneous infusion (CSCI) or continuous intravenous infusion (CII) is usually instituted when parenteral opioids need to be administered chronically.(70,107,109,110) With adequate home care support, treatment can be initiated and maintained safely and conveniently without hospitalization. An appropriate home infusion device should be flow-calibrated, portable, battery-driven, inexpensively-leased, easily-taught, suitable for the addition of patient controlled analgesia and equipped with alarms.

Except in selected circumstances (pre-existing indwelling catheter, severe cachexia, pain emergencies) subcutaneous administration is preferred to intravenous administration because it is easier to maintain in the home and is as reliable as intravenous administration.(109) Absorption of subcutaneously administered opioids is rapid and steady state plasma levels are generally approached within one hour.(111) Morphine and hydromorphone are most commonly employed for subcutaneous infusions, and should ideally be concentrated to permit infusion at volumes of under 1-2 ml/hr in order to minimize tissue irritation. The interested reader is referred elsewhere for a detailed commentary on instituting and maintaining therapy.(70,107,109,110)

Investigational Routes

Morphine elixir has been successfully administered by the buccal and sublingual routes in preterminal patients for short periods of time.(112) In addition, a preparation of transmucosal fentanyl lozenge has recently been approved for preoperative sedation and is now in clinical trials for the treatment of cancer pain.(113) Preliminary results of treatment with opioids by these and other routes (intranasal, inhalatory, transdermal iontophoretic, vaginal and stomal) are described elsewhere.(109)

Invasive and Procedural Approaches

This review has emphasized the importance of pharmacotherapy as a means to ensure the anesthesiologist's continued role in the management of cancer pain. Ready access to anesthetic-based interventions remains an essential component of comprehensive cancer pain management, although they are best regarded as a component of a therapeutic matrix that includes antitumor therapy, various pharmacologic strategies, neurosurgical and neuroaugmentative procedures, behavioral and psychiatric approaches. The role of diagnostic local anesthetic blocks, therapeutic neurolysis and regional opioid analgesia is amply reviewed elsewhere. These modalities remain an essential focus for the anesthesiologist with specialized training in pain management, and when applied judiciously, are invaluable in selected populations of patients. While this author has argued for the need of anesthesiologists to develop and maintain expertise in pharmacologic management, the ubiquitous application of these approaches engenders a parallel demand for a renewed emphasis on training and teaching classic anesthetic techniques that might otherwise become obscure. While more outcome data regarding the timing of invasive approaches and their respective indications for various populations of patients is needed, their role for patients with otherwise intractable pain remains unquestioned.

Conclusion

Interest in cancer pain management on the part of medical professionals, the lay public, professional societies and governmental and quasi-governmental institutions has intensified considerably in recent years. There is a trend toward emphasis of the central role of pharmacotherapy due to its overall safety, efficacy, simplicity and applicability. The principles outlined here are readily instituted and should constitute an essential and fundamental component of the anesthesiologist-pain specialist's armamentarium, complementing rather than replacing established expertise in instituting invasive approaches.

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