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The Oncologist, Vol. 9, No. 5, 571-591, September 2004; doi:10.1634/theoncologist.9-5-571
© 2004 AlphaMed Press

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 Adjuvant Analgesics in Cancer Pain Management
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Adjuvant Analgesics in Cancer Pain Management

David Lussiera, Angela G. Huskeyb, Russell K. Portenoya

a Department of Pain Medicine and Palliative Care, Beth Israel Medical Center, New York, New York, USA; b Interdisciplinary Pain and Palliative Care and Integrative Medicine Program, H. Lee Moffitt Cancer Center, Tampa, Florida, USA

Russell K. Portenoy, M.D., Department of Pain Medicine and Palliative Care, Beth Israel Medical Center, First Avenue at 16th Street, New York, New York 10003, USA. Telephone: 212-844-1505; Fax: 212-844-1503; e-mail: rportenoy{at}bethisraelny.org; website: www.stoppain.org


   LEARNING OBJECTIVES
Top
 Learning Objectives
Abstract
 Introduction
 Types of Adjuvant Analgesics
 Combination of Adjuvant...
 Drug Interactions
 Conclusions
 References
 
After completing this course, the reader will be able to:

  1. Identify the indications of adjuvant analgesics in the treatment of cancer pain.
  2. Select an appropriate adjuvant analgesic for the treatment of pain in a specific cancer patient.
  3. Know the dosing recommendations, side effects, and drug interactions of the most common adjuvant analgesics.

Access and take the CME test online and receive 1 hour of AMA PRA category 1 credit at CME.TheOncologist.com


   ABSTRACT
Top
 Learning Objectives
 Abstract
Introduction
 Types of Adjuvant Analgesics
 Combination of Adjuvant...
 Drug Interactions
 Conclusions
 References
 
Adjuvant analgesics are defined as drugs with a primary indication other than pain that have analgesic properties in some painful conditions. The group includes numerous drugs in diverse classes. Although the widespread use of these drugs as first-line agents in chronic nonmalignant pain syndromes suggests that the term "adjuvant" is a misnomer, they usually are combined with a less-than-satisfactory opioid regimen when administered for cancer pain. Some adjuvant analgesics are useful in several painful conditions and are described as multipurpose adjuvant analgesics (antidepressants, corticosteroids, {alpha}2-adrenergic agonists, neuroleptics), whereas others are specific for neuropathic pain (anticonvulsants, local anesthetics, N-methyl-D-aspartate receptor antagonists), bone pain (calcitonin, bisphosphonates, radiopharmaceuticals), musculoskeletal pain (muscle relaxants), or pain from bowel obstruction (octreotide, anticholinergics). This article reviews the evidence supporting the use of each class of adjuvant analgesic for the treatment of pain in cancer patients and provides a comprehensive outline of dosing recommendations, side effects, and drug interactions.

Key Words. Pain • Cancer • Adjuvants • Analgesics • Anticonvulsants • Antidepressants


   INTRODUCTION
Top
 Learning Objectives
 Abstract
 Introduction
Types of Adjuvant Analgesics
 Combination of Adjuvant...
 Drug Interactions
 Conclusions
 References
 
Chronic pain is extremely prevalent among patients with cancer. Approximately one-third of patients have pain while undergoing active therapy for the disease, and more than three-quarters have pain during the last stages of illness [1, 2]. Fortunately, experience suggests that cancer pain can be relieved in more than 70% of patients using a simple opioid-based regimen [3–5]. Different types of pain vary, however, in the extent to which they can be controlled with an opioid, and some characteristics may impart a relatively lesser degree of opioid responsiveness in some patients [5]. In such cases, a variety of strategies can be implemented to improve the balance between analgesia and side effects [5]. Among these strategies is the use of adjuvant analgesics.

The term ‘adjuvant analgesic’ describes any drug with a primary indication other than pain, but with analgesic properties in some painful conditions [6]. Although they can be used alone, they are usually coadministered with analgesics (acetaminophen, nonsteroidal anti-inflammatory drugs [NSAIDS], opioids) when treating cancer pain. The term ‘coanalgesic’ is sometimes used synonymously in this setting. Adjuvant analgesics are added to an opioid to enhance pain relief provided by the opioid, address pain that has not or has insufficiently responded, and allow the reduction of the opioid dose to reduce adverse effects [6].

Adjuvant analgesics often are administered as first-line drugs in the treatment of chronic nonmalignant pain. As a result, the term ‘adjuvant’ has become a misnomer, as use of these drugs has increased. In the cancer population, however, conventional practice has evolved to view opioids as first-line drugs, and adjuvant analgesics typically are considered after opioid therapy has been optimized [6]. To better assess response and reduce the risk of additive toxicity, it usually is best to initiate treatment with one drug at a time (Table 1Go).


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  		Table 1. Using adjuvant analgesics in the management of cancer pain
 

   TYPES OF ADJUVANT ANALGESICS
Top
 Learning Objectives
 Abstract
 Introduction
 Types of Adjuvant Analgesics
Combination of Adjuvant...
 Drug Interactions
 Conclusions
 References
 
The adjuvant analgesics comprise a diverse group of medications with different primary indications. Based on conventional use, a category of nonspecific, multipurpose analgesics can be distinguished from those used for more specific indications, including neuropathic pain or bone pain (Table 2Go).


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  		Table 2. Adjuvant analgesics: major classes
 
There are very few comparative trials, and the selection of the most appropriate adjuvant analgesic cannot be based on evidence of differential efficacies. Rather, selection of a category of drugs, or a specific drug, depends on a variety of factors gleaned from the comprehensive assessment of the patient [7]. This assessment should describe the pain, clarify its etiology (including its relationship to the underlying disease), and allow inferences about the predominating type of pain pathophysiology (e.g., nociceptive or neuropathic). It also should determine the impact of pain on function and quality of life and identify any relevant comorbidities [6–9]. In some cases, the type of pain suggests the value of one category of adjuvant analgesic over another; in others, the existence of another symptom concurrent with pain favors the use of a specific drug. For example, an antidepressant is preferred for a depressed patient, an anticonvulsant is preferred for a patient with a history of seizures, and a corticosteroid is preferred for a patient with anorexia. Careful monitoring of the concurrent symptom or comorbidity is necessary as the pain is treated; the secondary condition may or may not respond, and additional treatments, such as an antidepressant selected specifically for the depression, may be needed.

Few adjuvant analgesics have been studied in cancer populations. To a large extent, therefore, drug selection, dosing, and monitoring approaches reflect extrapolation from the literature on nonmalignant pain.

Multipurpose Analgesics
Some adjuvant analgesics have been shown to have analgesic properties in diverse pain syndromes (Table 2Go). This suggests that they can be considered multipurpose analgesics.

Antidepressant Drugs

Tricyclic Antidepressants The tricyclic antidepressants have been extensively studied, and there is compelling evidence for their analgesic properties in a variety of chronic nonmalignant pain conditions [10–12]. Both the tertiary amines—amitriptyline (Elavil®; Merck & Co.; Whitehouse Station, NJ), imipramine (Tofranil®; Mallinckrodt Inc.; St. Louis, MO), doxepin (Sinequan®; Pfizer Pharmaceuticals; New York, NY), and clomipramine (Anafranil®; Mallinckrodt Inc.)—and the secondary amines—nortriptyline (Pamelor®; Mallinckrodt Inc.) and desipramine (Norpramin®; Aventis Pharmaceuticals Inc.; Bridgewater, NJ)—are analgesic. Although few clinical trials have specifically evaluated these drugs for cancer pain, partially controlled [13–15] and uncontrolled trials [16], as well as clinical experience, generally support their analgesic effects.

The use of the tricyclic antidepressants as analgesics in medically ill or elderly patients may be limited by the frequent occurrence of side effects [17, 18] (Table 4Go). Although their most serious adverse effect, cardiotoxicity, is uncommon [18], patients who have significant heart disease (conduction disorders, arrhythmias, heart failure) should not be treated with a tricyclic. An electrocardiogram might be indicated before starting a tricyclic in a patient with an increased risk of cardiac disease (e.g., elderly, diabetic, or hypertensive). Given the risk of lethal cardiotoxicity encountered with an overdose, tricyclics also should be avoided in patients who are suicidal.


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  		Table 4. Adverse effects, prescribing precautions, and potential drug interactions with adjuvant analgesics
 
Tricyclic antidepressants are far more likely to cause orthostatic hypotension, and they must be used cautiously in patients at risk of orthostasis, such as the elderly and those with autonomic neuropathy. Tricyclics are also contraindicated in patients with a known history of a narrow anterior chamber of the eye or prior attacks of acute glaucoma. They should be used cautiously in those with cognitive impairment, or a high propensity for impairment, because of the risk of drug-induced confusion.

The secondary amine tricyclic antidepressants, desipramine and nortriptyline, are less anticholinergic and, therefore, better tolerated than the tertiary amines. Patients who are predisposed to side effects from the tricyclics, or who have distressing side effects during a trial of a tertiary amine drug, should, thus, be considered for a trial of desipramine or nortriptyline.

A favorable analgesic effect is usually observed within a week after achieving an effective dose of a tricyclic. Although a typically effective dose range has been observed (Table 3Go), there is large pharmacokinetic variability, and it can be useful to monitor plasma drug concentration to clarify the safety of dose escalation or to identify a concentration associated with a favorable effect.


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  		Table 3. Dosing guidelines of adjuvant analgesics
 

Other Antidepressants There is evidence from randomized controlled trials that several other antidepressants are analgesic. In aggregate, this evidence is far less than that which supports the efficacy of the tricyclic drugs [7]. Nonetheless, the nontricyclic compounds are generally safer and better tolerated. Accordingly, the nontricyclic antidepressants should be considered for patients who have not responded satisfactorily to tricyclics, have relative contraindications to tricyclics, or have experienced adverse effects during earlier treatment with a tricyclic antidepressant [7].

There are limited data supporting the analgesic efficacy of the selective serotonin reuptake inhibitors (SSRIs). Paroxetine (Paxil®; GlaxoSmithKline; Research Triangle Park, NC) and citalopram (Celexa®; Forest Laboratories, Inc.; New York, NY) are the only ones for which controlled studies have suggested benefit [19, 20]. No studies have been done on cancer pain. The main advantage of the SSRIs is their favorable side-effect profile [21].

Venlafaxine (Effexor®; Wyeth Pharmaceuticals; Collegeville, PA), a mixed reuptake inhibitor, has been shown to be analgesic in several studies. Randomized controlled trials showed good pain relief for painful polyneuropathy [22] and for neuropathic pain following treatment of breast cancer [23]. Analgesic effects in neuropathic pain have also been suggested for a newer mixed reuptake inhibitor, duloxetine (CymbaltaTM; Eli Lilly and Company; Indianapolis, IN). Bupropion (Wellbutrin®; GlaxoSmithKline; Research Triangle Park, NC), a noradrenergic compound, also is analgesic in neuropathic pain [24, 25] and often is activating. The latter effect can be particularly helpful in the hypoactive depressed, sedated, or fatigued patient often encountered in the cancer population [26].

In summary, there is substantial evidence that antidepressant drugs have analgesic effects in diverse types of chronic nonmalignant pain. There is limited evidence for analgesic effects in cancer pain. Given the established benefit of the antidepressants in patients with diverse types of neuropathic pain, the strongest indication for their use as an adjuvant analgesic in the cancer population occurs in the patient with neuropathic pain whose response to opioids has been inadequate. Early use of antidepressants as adjuvant analgesics is also justified when pain is accompanied by depression. In that situation, the clinical response of the depression should be evaluated carefully and the treatment adjusted if necessary. The sedating tricyclic antidepressants are often added when the patient complains of insomnia, the anxiolytic SSRIs can be useful in anxious patients, and bupropion can be considered in sedated or fatigued patients.

Corticosteroids
Corticosteroids possess analgesic properties for a variety of cancer pain syndromes, including bone pain, neuropathic pain from infiltration or compression of neural structures, headache due to increased intracranial pressure, arthralgia, and pain due to obstruction of a hollow viscus (e.g., bowel or ureter) or to organ capsule distention. Corticosteroids are also effective in managing pain and symptoms from metastatic spinal cord compression [27, 28] while awaiting more definitive treatment, if justified by the goals of care.

The relative risks and benefits of the various corticosteroids are unknown. Dexamethasone (Decadron®; Merck and Company, Inc.; West Point, PA) is often selected, a choice that gains theoretical support from the relatively low mineralocorticoid effects of this drug. Prednisone (Deltasone®; Pfizer Pharmaceuticals; New York, NY; Orasone®; Solvay Pharmaceuticals; Marietta, GA) and methylprednisolone (Medrol®; Pfizer Pharmaceuticals; New York, NY) can also be used.

On the basis of clinical experience, corticosteroids are usually administered either in a high- or a low-dose regimen. A high-dose regimen (e.g., dexamethasone, 100 mg, followed initially by 96 mg/day in divided doses) has been used for patients who experience spinal cord compression or an acute episode of severe pain that cannot be promptly reduced with opioids [29]. The dose can be tapered over days or weeks after the initiation of other analgesic approaches (e.g., opioid therapy, radiation therapy).

A low-dose corticosteroid regimen (e.g., dexamethasone at a dose of 2–4 mg once or twice daily) can be used for patients with advanced cancer who continue to have pain despite optimal dosing of opioid drugs. In most cases, long-term therapy is then planned, and the dose should be tapered down to the lowest effective dose.

Corticosteroid drugs have several other indications. They can improve appetite, nausea, malaise, and overall quality of life [29–32]. Although the risk of adverse effects increases with both the dose and duration of therapy, long-term treatment with relatively low doses is generally well tolerated. Repeated assessments are required to ensure that benefits are sustained. Although steroids can be beneficial in patients with good prognoses for prolonged survival, as well as in patients with terminal illnesses, greater caution and monitoring for adverse effects are needed in the former group. Ineffective regimens should be tapered and discontinued and, if the therapy is beneficial, the lowest dose that yields the desired results should be sought.

Long-term corticosteroid therapy may increase the risk of peptic ulcer disease [33] and some clinicians may coadminister a gastroprotective drug (usually a proton pump inhibitor) in an effort to reduce this risk. Given the lack of evidence supporting this practice, however, many clinicians add a gastroprotective drug only if other important risk factors for peptic ulcer disease exist. The concurrent administration of an NSAID and a corticosteroid increases the risk of peptic ulcer disease substantially [34]; this combination is not desirable, and administration of a gastroprotective drug can be justified if it is used.

{alpha}2-Adrenergic Agonists
Although clonidine (Catapres®; Boehringer Ingelheim Pharmaceuticals; Ridgefield, CT; Catapres-TTS®; Boehringer Ingelheim Pharmaceuticals; Ridgefield, CT) and tizanidine (Zanaflex®; Elan Pharmaceuticals) are {alpha}2-adrenergic agonists and may be considered nonspecific multipurpose adjuvant analgesics, the supporting data are limited and the potential for side effects, most importantly somnolence and hypotension, is relatively great. For these reasons, trials of these drugs usually are considered after others have proved ineffective. Clonidine, administered either orally, transdermally, or intraspinally, has been studied in non-malignant neuropathic pain [35–37]. Fewer than one-fourth of patients are likely to respond to systemic administration of clonidine [35], and side effects are a particular concern in the medically frail. Intraspinal clonidine has been shown to reduce pain (especially neuropathic pain) in patients with severe intractable cancer pain partly responding to opioids [38]. Consideration of this therapy requires referral to an interventional pain specialist.

Tizanidine is approved as an antispasticity agent. Although the evidence of the analgesic efficacy of tizanidine is limited to the treatment of myofascial pain syndrome [39, 40] and the prophylaxis of chronic daily headache [41], a favorable clinical experience supports its use as a multipurpose adjuvant analgesic. As it is more specific for the {alpha}2-adrenergic receptor than clonidine, hypotension occurs less commonly.

Neuroleptics
The second-generation (atypical) agent olanzapine (Zyprexa®; Eli Lilly and Company; Indianapolis, IN) was reported to decrease pain intensity and opioid consumption, and improve cognitive function and anxiety, in a recent case series of cancer patients [42]. Apart from this limited observation, evidence that commercially available neuroleptic drugs have analgesic properties is very meager. Given their potential for side effects (Table 4Go) and potential risks (tardive dyskinesia, neuroleptic malignant syndrome), neuroleptics are not clinically used as adjuvant analgesics unless the primary indication of delirium or agitation is present, in which case the analgesic properties might provide better pain control and allow a decrease of opioid consumption, which might in turn be helpful in resolving the delirium [43]. Neuroleptics also sometimes tend to increase appetite, which may be desirable in some cancer patients.

Adjuvant Analgesics Specific for Neuropathic Pain
The term ‘neuropathic pain’ is applied to those pain syndromes for which the sustaining mechanisms are presumed to be related to aberrant somatosensory processes in the peripheral nervous system, central nervous system (CNS), or both [44]. Surveys have reported that up to 40%–50% of cancer pain can be categorized as exclusively or partly neuropathic [45, 46]. Neuropathic cancer pain syndromes can be related to the cancer or to therapeutic interventions (Table 5Go).


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  		Table 5. Classification of neuropathic cancer pain syndromes (adapted from Portenoy [146] and Martin and Hagen [147])
 

Role of Opioids in the Treatment of Neuropathic Pain
As noted previously, the focus on neuropathic pain as a target for adjuvant analgesics in the palliative care setting derives from the observation that pain of this type may be relatively less responsive to opioid drugs than other types of pain (e.g., nociceptive). It is important to emphasize, however, that this observation does not imply that these pains are "opioid resistant" or that the conventional role of opioid drugs as first-line analgesics should be abandoned when pain is neuropathic [7]. Randomized controlled trials have established the potential efficacy of both morphine (MSir®; Purdue Pharmaceutical Products L.P; Stamford, CT; MS-Contin®; Purdue Pharmaceutical Products L.P and oxycodone (OxyContin®; Purdue Pharmaceutical Products; Roxicodone®; Elan Pharmaceuticals; South San Francisco, CA) in nonmalignant neuropathic pain syndromes [47–51].

Anticonvulsant Drugs
There is good evidence that the anticonvulsant drugs are useful in the management of neuropathic pain [52–54]. The older drugs, which have been used for decades, are now complemented by a rapidly increasing number of newer agents (Tables 2Go and 3Go).

An expanding role for the anticonvulsants began with the introduction of gabapentin (Neurontin®; Pfizer Pharmaceuticals; New York, NY). The analgesic efficacy of gabapentin has been established in several types of nonmalignant neuropathic pain [55–60], and it is now widely used to treat cancer-related neuropathic pain [61, 62]. Due to its proven analgesic effect in several types of neuropathic pain, its good tolerability, and a rarity of drug-drug interactions, gabapentin is now recommended as a first-line agent for the treatment of neuropathic pain of diverse etiologies, especially in the medically ill population [7]. It should be initiated at a daily dose of 100–300 mg at bedtime and can be increased every 3 days. The usual maximum dose is 3,600 mg daily, but occasionally patients report benefits at higher doses. An adequate trial should include 1–2 weeks at the maximum-tolerated dose. The most common adverse effects are somnolence, dizziness, and unsteadiness. If titrated carefully, gabapentin is usually well tolerated, but in medically ill patients, somnolence can be a limiting factor [61].

Lamotrigine (Lamictal®; GlaxoSmithKline; Research Triangle Park, NC) was reported to relieve nonmalignant neuropathic pain in several randomized trials [63–66]. Its adverse effects (e.g., somnolence, dizziness, ataxia), however, require a slow titration and, although uncommon, the potential for severe rash and Stevens-Johnson syndrome poses some concerns. Oxcarbazepine (Trileptal®; Novartis Pharmaceuticals Corp.; East Hanover, NJ) is a metabolite of carbamazepine (Carbatrol®; Shire US Inc.; Florence, KY; Tegretol®; Novartis Pharmaceuticals Corp.) and has a similar spectrum of effects, with better tolerability. Although the current evidence is limited to a few case series and open-label trials, it appears promising [67]. Pregabalin (Pfizer Pharmaceuticals) is a new anticonvulsant with a mechanism identical to that of gabapentin and strong evidence of analgesic efficacy [68]; this drug will soon be available in the U.S. and other countries and will be specifically indicated for varied types of neuropathic pain. Topiramate (Topamax®; Ortho-McNeil Pharmaceutical Corp.; Raritan, NJ), tiagabine (Gabitril®; Cephalon, Inc.; West Chester, PA), and zonisamide (Zonegran®; Elan Pharmaceuticals; South San Francisco, CA) have some evidence of efficacy [52], and there is some favorable clinical experience with levetiracetam (Keppra®; UCB Pharma, Inc.; Atlanta, GA) [69, 70]. Like gabapentin and pregabalin, levetiracetam lacks any significant drug-drug interactions.

Among the older drugs, evidence of efficacy is best for carbamazepine and phenytoin (Dilantin®; Pfizer Pharmaceuticals; New York, NY), and both valproate (Depacon®; Abbott Pharmaceuticals; Abbott Park, IL) and clonazepam (Klonopin®; Roche Laboratories, Inc.; Nutley, NJ) have been widely used [52]. The classic indication for carbamazepine is trigeminal neuralgia [52], and the use of phenytoin in cancer pain has been described [71]. Due to their frequent side effects (sedation, dizziness, nausea, unsteadiness) and potential for drug-drug interactions, the use of these drugs has declined with the introduction of the newer analgesic anticonvulsants. In summary, selected anticonvulsant drugs may be effective for diverse types of neuropathic pain. Although earlier studies suggested that there might be a preferential role for these drugs in the treatment of neuropathic pain characterized by lancinating or paroxysmal components, this has not been confirmed in trials, and anticonvulsants are now routinely tried for any type of neuropathic pain. Among the anticonvulsants, gabapentin should be administered first due to its proven efficacy in different neuropathic pain syndromes and its good tolerability. Other newer anticonvulsants can be tried successively in patients who either have not responded satisfactorily to, have contraindications to, or have experienced adverse effects to gabapentin and other first-line adjuvant analgesics.

Oral and Parenteral Local Anesthetics
Local anesthetics have analgesic properties in neuropathic pain [6]. Due to their potential for serious side effects, they have been conventionally positioned as second-line therapies, reserved for the treatment of severe intractable or ‘crescendo’ neuropathic pain.

A brief intravenous infusion of lidocaine (Xylocaine®; AstraZeneca; Wayne, PA) has been shown to be effective in nonmalignant neuropathic pain [72, 73]. Despite negative results obtained in randomized controlled trials in neuropathic cancer pain [74, 75], clinical experience justifies considering its use. Brief infusions can be administered at varying doses within the range of 1–5 mg/kg infused over 20–30 minutes. In the medically frail patient, it is prudent to start at the lower end of this range and provide repeated infusions at successively higher doses. A history of significant cardiac disease may relatively contraindicate this approach and should be evaluated before it is administered. An electrocardiogram should be done before starting the infusion or increasing the dose, and careful monitoring of vital signs is necessary during the period of the infusion and immediately thereafter.

Although prolonged relief of pain following a brief local anesthetic infusion may occur, relief usually is transitory. If lidocaine appears to be effective but pain recurs, long-term systemic local anesthetic therapy can be accomplished using an oral local anesthetic, typically mexiletine (Mexitil®; Boehringer Ingelheim Pharmaceuticals, Inc.; Ridgefield, CT). For rare patients with refractory neuropathic cancer pain who respond only to intravenous lidocaine infusion, long-term subcutaneous administration has been reported to provide sustained relief [76].

The predictive value of a brief lidocaine infusion for the subsequent effectiveness of an oral local anesthetic has not been established for pain. Many patients are treated from the start with an oral agent, such as mexiletine. Given the limited number of supportive studies, mexiletine and other oral local anesthetics are used as second-line agents for neuropathic pain that has not responded to trials of anticonvulsant or antidepressant analgesics. Controlled studies of mexiletine have demonstrated a relatively high rate of adverse effects (nausea, vomiting, tremor, dizziness, unsteadiness, and paresthesias) and discontinuation due to toxicity in almost one-half of patients [77].

N-methyl-D-Aspartate Receptor Blockers
Interactions at the N-methyl-D-aspartate (NMDA) receptor are involved in the development of CNS changes that may underlie chronic pain and modulate opioid mechanisms, specifically tolerance [78]. Antagonists at the NMDA receptor may offer another novel approach to the treatment of neuropathic pain in cancer patients.

At the present time, there are four commercially available NMDA receptor antagonists in the U.S.—the antitussive, dextromethorphan; the dissociative anesthetic, ketamine; the antiviral drug, amantadine (Symmetrel®; Endo Laboratories; Chadds Ford, PA); and a drug approved for the treatment of Alzheimer’s disease, memantine (Namenda®; Forest Laboratories, Inc.; New York, NY). Most of these drugs have been shown to have analgesic effects in nonmalignant neuropathic pain [78].

Ketamine, administered by intravenous infusion or orally, is effective in relieving cancer pain [79–82] and reducing opioid requirements [83]. Clinicians who are experienced in the use of parenteral ketamine may, therefore, consider this option in patients with refractory pain. The side-effect profile of ketamine (Table 4Go) can be daunting, however, particularly in the medically frail. Typically, ketamine therapy for pain has been initiated at low doses given subcutaneously or intravenously, such as a starting dose of 0.1–0.15 mg/kg by brief infusion or 0.1–0.15 mg/kg/hour by continuous infusion. The dose can be gradually escalated, with close monitoring of pain and side effects. For patients with refractory pain and limited life expectancies, long-term therapy can be maintained using continuous subcutaneous infusion or repeated subcutaneous injections. Oral administration also has been used, but experience is more limited with that approach. The ratio of doses needed to maintain effects when converting from parenteral to oral dosing is uncertain. Based on anecdotal data, some authors have suggested a 1:1 ratio [84], or an oral dose equivalent to 30%–40% of the parenteral dose [85]. It is also recommended to lower the opioid dose when starting ketamine [85].

In patients undergoing surgery for bone malignancy, dextromethorphan was shown to augment analgesia and lessen analgesic requirements [86]. Other studies and clinical experience have yielded mixed results. If prescribed, a prudent starting dose is 45–60 mg/day, which can be gradually escalated until favorable effects occur, side effects supervene, or a conventional maximal dose of 1 g is achieved.

Amantadine is a noncompetitive NMDA antagonist, and limited data suggest that it might reduce pain, allodynia, and hyperalgesia in chronic neuropathic pain [87, 88] and surgical neuropathic cancer pain [89]. Currently available data are, however, too meager to support recommending its use.

Memantine is an NMDA antagonist recently marketed in the U.S. for the treatment of Alzheimer’s disease. Although it could theoretically possess some analgesic properties, controlled trials published so far have been disappointing [90, 91].

The d-isomer of the opioid methadone also blocks the NMDA receptor [92]. In the U.S., methadone is available as the racemic mixture, 50% of which is the d-isomer. The contribution of this nonopioid molecule to the analgesia produced by methadone is uncertain, but growing clinical experience with this drug suggests that it may play a role. There are no data, however, to support the conclusion that methadone is better than other opioids for the treatment of neuropathic pain.

New NMDA receptor antagonists are in development and may ultimately prove useful for a variety of medical indications. Advances in this area have occurred rapidly, and it is likely that the role of these agents in the management of pain will be much better defined within a few years.

Other Systemic Drugs
Other drugs also may be considered for trials of adjuvant analgesics. Some, such as baclofen (Lioresal®; Novartis Pharmaceuticals, Corp.), have a long history in clinical practice despite a paucity of studies. Others, such as the cannabinoids, are undergoing investigation now and are likely to have an expanded role in the future. In the population with cancer pain, most of these drugs are tried conventionally in the setting of refractory neuropathic pain.

Baclofen Baclofen, an agonist at the gamma aminobutyric acid type B (GABAB) receptor, has established efficacy in trigeminal neuralgia [93] and is often considered for a trial in any type of neuropathic pain. The effective dose range is very wide (20 mg/day to >200 mg/day orally), and titration from a low initial dose is necessary. The possibility of a serious withdrawal syndrome on abrupt discontinuation must be avoided by a gradual dose taper.

Cannabinoids Cannabinoids have antinociceptive effects in animal models and oral delta-9-tetrahydrocannabinol (dronabinol; Marinol®; Roxane Laboratories; Columbus, OH) has been shown to be effective in cancer pain [94]. Not all data are positive [95], and more studies on the various cannabinoids are needed.

Benzodiazepines The evidence for analgesic effects from benzodiazepines is limited and conflicting, and overall provides little support for the conclusion that these drugs are analgesic for neuropathic pain [96, 97]. Nonetheless, a trial of clonazepam can still be justified in refractory neuropathic pain on the basis of anecdotal experience, especially in the case of the common coexistence of pain and anxiety.

Psychostimulants There is substantial evidence that psychostimulant drugs dextroamphetamine (Dexedrine®; GlaxoSmithKline; Research Triangle Park, NC), methylphenidate Metadate CD®; CellTech Pharmaceuticals; Rochester, NY; Methylin®; Mallinckrodt Inc.; St. Louis, MO; Ritalin®; Novartis Pharmaceuticals Corp.), and caffeine have analgesic effects [98]. Although pain is not considered a primary indication for these drugs, the potential for analgesic effects may influence the decision to recommend a trial. In cancer patients, methylphenidate can reduce opioid-induced somnolence, improve cognition, treat depression, and alleviate fatigue [99]. Treatment is typically begun at 2.5–5 mg in the morning and again at midday, if necessary, to keep the patient alert during the day and not interfere with sleep at night. Doses are increased gradually until efficacy is established. Modafinil (Provigil®; Cephalon, Inc.), a newer psychostimulant with a unique mechanism, is also used to reduce opioid-induced somnolence in cancer patients [100]. It is usually started at 100 mg/day and then increased. Although there are currently no scientific data supporting its use to reduce opioid-induced sedation, atomoxetine (Strattera®; Eli Lilly and Company), a selective norepinephrine reuptake inhibitor approved for the treatment of attention-deficit/hyperactivity disorder [101], has been used successfully in clinical practice. The analgesic properties of modafinil and atomoxetine have not yet been studied.

Topical Analgesics
The development of a lidocaine 5% patch (Lidoderm®; Endo Laboratories; Chadds Ford, PA) has facilitated the topical application of local anesthetics. This formulation is approved in the U.S. for the treatment of postherpetic neuralgia [102], and clinical experience supports its use for other neuropathic pain conditions. There is minimal systemic absorption. The patch is usually applied 12 hours per day, but a few studies indicate a high level of safety with up to three patches for periods up to 24 hours [103]. An adequate trial may require several weeks of observation. The most frequently reported adverse event is mild to moderate skin redness, rash, or irritation at the patch application site.

EMLA® (AstraZeneca), an eutectic mixture of local anesthetics (prilocaine and lidocaine), can produce dense local cutaneous anesthesia, which can be useful to prevent pain from needle punctures. Although it may be applied to larger areas for the treatment of neuropathic pain, its use typically is limited by cost. Topical lidocaine may be tried in various concentrations (up to a compounded formulation of 10%) as an alternative.

Capsaicin is the ingredient in chili pepper that produces its pungent taste. When applied topically, it causes the depolarization of the nociceptors and release of substance P. Regular use eventually leads to depletion of substance P from the terminals of afferent C-fibers, potentially leading to decreased pain perception. In cancer patients, capsaicin cream (Zostrix®; Rodlen Laboratories; Vernon Hills, IL) has been shown to be effective in reducing neuropathic postsurgical pain (such as postmastectomy pain) [104]. There are two commercially available concentrations (0.025% and 0.075%), and an initial trial usually involves application of the higher concentration three to four times daily. A trial of several weeks is needed to adequately judge effects. Many patients experience severe burning pain after the first applications (related to the initial release of substance P), which usually decreases gradually over a few days if the cream is applied regularly. Some patients tolerate the lower concentration cream better, or tolerate application only if preceded by a topical local anesthetic or ingestion of an analgesic.

Numerous anti-inflammatory drugs have been investigated for topical use in populations with neuropathic pain, and results have generally been mixed. These formulations have established effectiveness for musculoskeletal pains.

Adjuvant Analgesics Specific for Bone Pain
Bone pain is a common problem in the palliative care setting. Radiation therapy is usually considered when bone pain is focal and poorly controlled with an opioid, or is associated with a lesion that appears prone to fracture on radiographic examination. Multifocal bone pain may benefit from treatment with an NSAID or a corticosteroid. Other adjuvant analgesics that are potentially useful in this setting include calcitonin (Miacalcin®; Novartis Pharmaceuticals Corp.), bisphosphonate compounds, and selected radiopharmaceuticals.

Calcitonin
Calcitonin may have several pain-related indications in the palliative care setting, including pain from bone metastasis [105–107]. The most frequent routes of administration are subcutaneous and intranasal. If subcutaneous boluses are used, they should be preceded by skin testing with 1 IU to screen for hypersensitivity reactions, especially in patients with a history of reactions to salmon or seafood. The optimal dose is not known. A trial may be initiated at a relatively low dose, which then can be gradually increased if tolerated. The intranasal formulation avoids the need for subcutaneous injections, facilitating the use of this drug in home care. It is administered once daily, with an initial dose of 200 IU in one nostril, alternating nostrils every day. There are no data from which to judge the dose-response relationship for pain; escalation of the dose once or twice is reasonable if the first response is unfavorable. Apart from infrequent hypersensitivity reactions associated with subcutaneous injections, the main side effect is nausea. The likelihood and severity of this effect may be reduced by gradual escalation from a low starting dose. It usually subsides after a few days and is less frequent with the intranasal form. Periodic monitoring of calcium and phosphorus is prudent during treatment.

Bisphosphonates
Bisphosphonates are analogues of inorganic pyrophosphate that inhibit osteoclast activity and, consequently, reduce bone resorption in a variety of illnesses. The analgesic efficacy of these compounds, particularly pamidronate (Aredia®; Novartis Pharmaceuticals Corp.), has been well established.

Pamidronate has been extensively studied in populations with bone metastases [108]. Its analgesic effects have been shown in breast cancer [109–111] and multiple myeloma [112]. The dose usually recommended is 60–90 mg i.v. (infused over 2–4 hours) every 3–4 weeks [111]. There are dose-dependent effects, and a poor response at 60 mg can be followed by a trial of 90 or 120 mg. The reduction of skeletal morbidity (pathological fractures, need for bone radiation or surgery, spinal cord compression, hypercalcemia) described with the administration of pamidronate in multiple myeloma and breast cancer patients is another incentive to use it as an adjuvant [113–114]. Adverse effects, including hypocalcemia and a flu-like syndrome, are dose related and typically transitory. Nephrotoxicity occurs rarely, usually following relatively rapid infusions, and typically is transitory; the drug can be used in those with impaired renal function.

Zoledronic acid (Zometa®; Novartis Pharmaceuticals Corp.) is a new bisphosphonate that is approximately two to three times more potent than pamidronate. It has been shown to reduce pain and the occurrence of skeletal-related events in breast cancer [112, 115, 116], prostate cancer [117], and multiple myeloma [112], as well as a variety of solid tumors, including lung cancer [118]. It is effective in both osteoblastic and osteolytic lesions [116]. It is as effective as pamidronate [112, 116], and its use is more convenient, as it can be infused safely over 15 minutes at a dose of 4 mg every 3 weeks. The side effects are similar to those encountered with pamidronate, and the dose does not have to be adjusted in patients with mild-to-moderate renal failure [119].

Data on the analgesic effect of clodronate are conflicting, but it has been shown to be effective in prostate cancer and multiple myeloma [108]. The main advantage of clodronate over pamidronate is its good oral bioavailability, which avoids the need for i.v. administration. An oral dose of 1,600 mg daily seems to be optimal [108]. Clodronate is not available in the U.S.

Scarce data exist on the efficacy of the other newer bisphosphonates alendronate (Fosamax®; Merck and Company, Inc.; West Point, PA) and ibandronate (BonivaTM; Hoffman-La Roche Inc.). These drugs, which are very potent, are likely to be analgesic.

Radiopharmaceuticals
Radionuclides that are absorbed at areas of high bone turnover have been evaluated as potential therapies for metastatic bone disease. Strontium-89 and samarium-153, which are commercially available in the U.S., may be effective as monotherapy or as an adjunct to conventional radiation therapy [120–124]. Given the potential for myelosuppression associated with their use, these drugs usually are considered when pain is refractory to other modalities.

Adjuvant Analgesics Used for Musculoskeletal Pain
Pain that originates from injury to muscle or connective tissue is frequent in patients with cancer [125]. The efficacy of so-called muscle relaxants and other drugs commonly used for the treatment of musculoskeletal pain has not been evaluated in cancer patients.

The so-called muscle relaxants include drugs in a variety of classes, including antihistamines (e.g., orphenadrine; Norflex®; 3M Pharmaceuticals; St. Paul, MN [126, 127]), tricyclic compounds structurally similar to the tricyclic antidepressants (e.g., cyclobenzaprine; Flexeril®; McNeil Consumer and Specialty Pharmaceuticals; Fort Washington, PA [128, 129]), and others (e.g., carisoprodol; Soma®; Wallace Laboratories; Cranbury, NJ [130], metaxalone; Skelaxin®; King Pharmaceuticals; Bristol, TN [131], methocarbamol; Robaxin®; Schwarz Pharma; Milwaukee, WI [132]). Although these drugs can relieve musculoskeletal pain, these effects may not be specific, and there is no evidence that they relax skeletal muscle in the clinical setting. Although they have been shown to reduce musculoskeletal pains [129–133], their risk:benefit ratio relative to the NSAIDs or opioids is unknown [133]. The most common adverse effect is sedation, which can be additive to other centrally acting drugs, including opioids. Treatment should be initiated with relatively low initial doses. The potential for abstinence, as well as abuse by predisposed patients, warrants caution when discontinuing therapy or administering these drugs to those with a substance abuse history [127].

If a muscle spasm is present and is believed to be responsible for the pain, drugs with established effects on skeletal muscle should be tried in place of the muscle relaxants. These include diazepam (Valium®; Roche Laboratories, Inc.) or other benzodiazepines, the {alpha}2-adrenergic agonist tizanidine or the GABAB agonist baclofen. Injections of botulinum toxin can be considered for refractory musculoskeletal pain related to muscle spasms [134], including those occurring after radiation therapy [135].

Adjuvant Analgesics Used for Pain Caused by Bowel Obstruction
The management of symptoms associated with malignant bowel obstruction may be challenging. If surgical decompression is not feasible, the need to control pain and other obstructive symptoms, including distension, nausea, and vomiting, becomes paramount. The use of opioids may be problematic due to dose-limiting toxicity (including gastrointestinal toxicity) or the intensity of breakthrough pain. Anecdotal reports suggest that anticholinergic drugs, the somatostatin analogue octreotide (Sandostatin®; Novartis Pharmaceuticals Corp.), and corticosteroids may be useful adjuvant analgesics in this setting. The use of these drugs may also ameliorate nonpainful symptoms and minimize the number of patients who must be considered for chronic drainage using nasogastric percutaneous catheters.

Octreotide
The somatostatin analogue octreotide inhibits the secretion of gastric, pancreatic, and intestinal secretions, and reduces gastrointestinal motility. These actions, which can occur more rapidly than similar effects produced by anticholinergic drugs [136], probably underlie the analgesia and other favorable outcomes that have been reported in case series [137] and one randomized trial [138] in patients with bowel obstruction. Octreotide has a good safety profile, and its considerable expense may be offset in some situations by the avoidance of gastrointestinal drainage procedures.

Anticholinergic Drugs
Anticholinergic drugs could theoretically relieve the symptoms of bowel obstruction by reducing propulsive and nonpropulsive gut motility and decreasing intraluminal secretions. Two small series demonstrated that a continuous infusion of hyoscine butylbromide (scopolamine) at a dose of 60 mg daily can control symptoms from nonoperable malignant bowel obstruction, including pain [137, 139]. Glycopyrrolate (Robinul®; First Horizon Pharmaceutical Corp.; Roswell, GA) has a pharmacological profile similar to that of hyoscine butylbromide, but may produce fewer side effects because of a relatively low penetration through the blood-brain barrier; this drug, however, has not been systematically evaluated in a population with symptomatic bowel obstruction.

Corticosteroids
The symptoms associated with bowel obstruction may improve with corticosteroid therapy. The mode of action is unclear, and the most effective drug, dose, and dosing regimen are unknown. Dexamethasone has been used in a dose range of 8–60 mg/day [140], and methylprednisolone has been administered in a dose range of 30–50 mg/day [31]. The potential for complications during long-term therapy, including an increased risk of bowel perforation [141, 142], may limit this approach to patients with short life expectancies.


   COMBINATION OF ADJUVANT ANALGESICS
Top
 Learning Objectives
 Abstract
 Introduction
 Types of Adjuvant Analgesics
 Combination of Adjuvant...
Drug Interactions
 Conclusions
 References
 
Specialists in pain management often undertake combination therapy with multiple analgesics, including two or more adjuvant analgesics, during the treatment of severe, refractory pain. The treatment of a patient with severe cancer-related neuropathic pain, for example, ultimately may require the addition of an antidepressant, an anticonvulsant, and a lidocaine patch to an opioid regimen. In the setting of advanced disease, a corticosteroid also is commonly added. Combination therapy of this type, like that used to treat other disorders, such as epilepsy [143], must be undertaken cautiously. In most cases, drugs are added sequentially, starting with low initial doses. If meaningful analgesia is observed during dose titration, the dose is optimized and the drug is continued as another is tried. If therapy is ineffective because of side effects or the administration of a maximum safe dose without benefit, the drug should be discontinued (usually with a tapering of the dose). Although this approach to combination therapy has received very little study, one open-label trial reported that the addition of levetiracetam to gabapentin provided synergistic relief [70], and one small randomized controlled trial suggested that adding lamotrigine to phenytoin or carbamazepine was beneficial [63].

Data are insufficient to posit recommendations for preferred drug combinations, or the sequence in which various adjuvant analgesics should be tried. Unfortunately, drug selection during these trials is based on clinical judgment and is executed in a trial-and-error fashion. Some clinicians prefer to choose drugs in different classes, but there is no specific evidence to support this approach. In all cases, however, careful attention should be given to potential interactions between drugs during sequential trials.


   DRUG INTERACTIONS
Top
 Learning Objectives
 Abstract
 Introduction
 Types of Adjuvant Analgesics
 Combination of Adjuvant...
 Drug Interactions
Conclusions
 References
 
Cancer patients with pain often require multiple drugs, analgesic and otherwise, and are therefore at increased risk for drug-drug interactions. An understanding of the types of drug interactions can help a clinician anticipate and minimize risk.

Drug interactions can be classified as being either pharmacodynamic or pharmacokinetic. Pharmacodynamic interactions involve drug actions independent of pharmacokinetics and may relate to competition for the same receptor, or to additive or inhibitory effects on effects other than analgesia. For example, an opioid and a benzodiazepine both cause CNS depression, and their concomitant use can result in additive sedation without a change in the plasma concentrations of either drug.

In contrast, pharmacokinetic interactions imply that one drug interferes with the absorption, distribution, metabolism, or elimination of another, resulting in alterations in the concentration of one or both. Many pharmacokinetic drug interactions are mediated through the hepatic cytochrome P450 (CYP450) enzyme system, which is responsible for the metabolism of numerous drugs, including analgesics, antidepressants, anticonvulsants, steroids, anticoagulants, chemotherapeutic agents, and others. Within the CYP450 system, drugs can be further classified as substrates, inducers, or inhibitors. Substrates are agents that are metabolized by a particular enzyme, while inducers and inhibitors increase or decrease, respectively, the metabolism of other agents that are substrates of the same enzyme. For example, carbamazepine, phenytoin, and methadone are well-known inducers of the 2D6 isoenzyme (CYP2D6) and can decrease serum levels of drugs that are substrates for that enzyme, such as amitriptyline, dextromethorphan, modafinil, and sertraline (Zoloft®; Pfizer Pharmaceuticals). Likewise, paroxetine is a well-known inhibitor of CYP2D6 and may lead to higher or toxic levels of drugs that are substrates for that enzyme.

Interpatient variability (e.g., age, genetics, disease state, race) can make it difficult to predict the extent to which a pharmacokinetic interaction will affect a specific patient. Genetic polymorphism exists most commonly with CYP2D6, leading to some patients being classified as poor metabolizers. In Caucasian populations, approximately 10% are poor metabolizers of substrates for CYP2D6. This may result in increased levels of a poorly metabolized parent compound, or decreased levels of an active metabolite. Codeine is metabolized to morphine via CYP2D6, for example, and it is reasonable to assume that as many as 10% of Caucasian patients may experience relatively reduced effectiveness from codeine as a result of genetically impaired metabolism. The same problem could arise if codeine is administered with a drug that inhibits CYP2D6.

Table 6Go is a quick reference for potential drug interactions involving the CYP450 system. A further discussion of the CYP450 system and the interaction of medications can be found in Bernard [144].


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  		Table 6. Potential drug interactions for selected pharmacologic agents used in pain and cancer managementa
 

   CONCLUSIONS
Top
 Learning Objectives
 Abstract
 Introduction
 Types of Adjuvant Analgesics
 Combination of Adjuvant...
 Drug Interactions
 Conclusions
References
 
The potential utility of adjuvant analgesics in the management of cancer pain has grown as new drug development, and translational research yields a firmer scientific foundation for the use of drugs in diverse classes. These drugs can be extremely important for those patients whose pain is only partially responsive to opioids. Some adjuvant analgesics possess analgesic properties in several types of pain, whereas others are specific for neuropathic, bone, musculoskeletal, or bowel obstruction-related pain.

Unfortunately, the use of adjuvant analgesics in cancer patients is still often guided solely by anecdotal experience or derived from data on nonmalignant pain. Future studies focused on the cancer population are needed to expand and improve the use of these drugs.


   REFERENCES
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 Learning Objectives
 Abstract
 Introduction
 Types of Adjuvant Analgesics
 Combination of Adjuvant...
 Drug Interactions
 Conclusions
 References
 

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