Chapter 45. Medical Management of Cancer Pain

Cancer pain is usually caused directly by neoplastic injury to pain-sensitive structures. For this reason, primary antineoplastic therapy, including radiation, chemotherapy, and palliative surgery, should be considered part of an analgesic strategy in some cases. When therapy directed at the tumor is inappropriate, is not feasible, or is ineffective, symptomatic analgesic therapies become the overriding concern. Opioid-based pharmacotherapy is the mainstay approach, but adjunctive anesthetic, surgical, psychiatric, and physical modalities may be essential in some cases (See Chapter 46, Anesthetic Interventions in Cancer Pain). Pharmacologic approaches may be systemic or regional (anesthetic). This chapter addresses only systemic pharmacologic analgesics.

The World Health Organization (WHO) proposed a three-step approach to the selection of drugs for the treatment of cancer pain (Fig. 45-1).1 The first step, for mild pain, utilizes non-opioid analgesics and adjuvant drugs. Adjuvant drugs can be either nontraditional analgesics (so-called adjuvant analgesics) or drugs added to manage the side effects of the primary analgesics. For more intense pain, an opioid is added. Some opioids are used conventionally for moderate pain and others are used for severe pain. This approach is designed to be simple to understand and useable around the world. Uncontrolled field testing has found the WHO guidelines effective for 70% to 100% of patients with cancer.2

Pain is often underrecognized in cancer patients. Cleeland et al surveyed outpatients with metastatic cancer and physicians from 54 treatment centers.3 They found that 42% of 597 patients with pain were not receiving adequate analgesia by the WHO guidelines (Fig. 45-1). Insufficient pain relief was particularly common among minorities, women, and the aged. An important barrier to effective pain management was a discrepancy between the patient’s and physician’s assessments of the extent to which pain was interfering with daily activities. The data underscore the importance of accurate pain assessment in providing adequate cancer pain relief.

The assessment should allow inferences about the pain mechanisms, identification of the pain syndrome (See Chapter 44, Cancer Pain Syndromes), and classification of the relationship between the pain and the disease. The clinician must also assess the functional impact of the pain and psychosocial comorbidities. It is essential to accept the patient’s report of pain at face value. Pain should be assessed frequently and systematically, especially when a new pain is reported or a new analgesic treatment is initiated. The location, intensity, and quality of the pain, aggravating and relieving factors, and the patient’s emotional and cognitive response to pain should be noted.

Pain Measurement Tools

Although there is no quantitative biochemical or neurophysiologic test for pain, tools have been devised to assess pain intensity 4 (See Chapter 6, Evaluating the Patient with Chronic Pain). Categorical scales, which ask patients to rate pain using adjectives such as “mild” and “excruciating,” are simple to use, but assume an understanding of the adjectives. Pain relief may also be rated with a categorical or percentage scale. The verbal numeric scale, rating pain from zero for “no pain” to 10 for “the worst imaginable pain,” is easily implemented and recorded during frequent assessments. The use of numbers removes any linguistic misunderstanding of categorical descriptors. Similarly, a 100-mm visual analog scale may be used, with or without intensity descriptors (Fig. 45-2). Although a visual analog pain score may not mean the same thing to different patients, it is reliable on repeated use with the same patient.5 This permits serial assessments by different clinicians, if necessary, over the course of treatment. Patients must be instructed in the use of these analog scales.

All of these pain scales are unidimensional. They do not reflect the complexity of the pain experience. Nonetheless, they provide a score that can be recorded, as vital signs are.6 This is useful for tracking pain intensity and can prompt intervention when pain exceeds an acceptable level.

When the patient cannot communicate, pain intensity must be evaluated by other means. Next of kin are usually able to verify the existence of pain, but they cannot accurately describe its intensity, location, and treatment.7 Non-English speakers will need a translator or a pain scale with instructions in their language. Originally designed for use in children, the faces pain scale might also be useful in some cognitively impaired adult patients (Fig. 45-3).8

Attention to nonverbal pain manifestations is also important. Autonomic changes may be present, including hypertension, tachycardia, and diaphoresis. Patients with organic brain disease may show agitation or confusion, or they may be apathetic, inactive, or irritable. They may also refuse to eat without explanation, protect the painful part, and show facial grimacing. While these manifestations are not specific for pain, empiric analgesic treatment in such situations, after ruling out more serious acute illness, will often confirm the assessment.

Several multidimensional assessment instruments incorporate pain quality, intensity, location, emotional and functional impact, and effectiveness of coping skills.9 The best known of these is the McGill Pain Questionnaire (MPQ).10 The patient chooses among 16 groups of descriptive words to characterize the sensory, affective, and evaluative qualities of his or her pain. Four additional word groups are specific to certain pain conditions. A pain intensity scale, a questionnaire on the use of analgesics and prior pain experience, and a human figure drawing on which the patient indicates his or her pain location are also included in the MPQ. A shorter instrument, the Memorial Pain Assessment Card, is designed to allow rapid assessment of cancer pain intensity, effectiveness of analgesics, and general psychological distress.11 It uses three visual analog scales and a set of eight pain intensity descriptors (Fig. 45-4). It appears to correlate with some of the more complicated instruments, yet it can be administered repeatedly without the evaluator’s assistance.

Nonsteroidal anti-inflammatory drugs (NSAIDs) and acetaminophen are routinely used in the treatment of cancer pain (See Chapter 61, NSAIDs). In general, they should be used on an around-the-clock schedule for patients with mild pain before advancing to step 2 of the pain ladder.1 At that step and beyond, they may be continued in addition to opioids. NSAIDs may be especially effective for bone pain,12 but they are probably useful in all types of pain, since they provide at least additive analgesia. They can act synergistically with opioids in the spinal cord 13 and allow reduction of opioid dose, lessening the likelihood of opioid side effects. When one NSAID is ineffective or poorly tolerated, another drug should be tried. When the oral route is not available, as in the patient with unremitting nausea, some NSAIDs and acetaminophen may be given rectally. Ketorolac is available for intramuscular and intravenous use in the United States, but is not recommended for prolonged use because of concern about gastrointestinal toxicity (Table 45-1).

NSAID Side Effects

Before initiating NSAID or acetaminophen therapy, the potential for toxicity must be considered (See Chapter 61, NSAIDs).14 Nonselective NSAIDs inhibit cyclooxygenase 1 and 2 (COX-1 and COX–2), and produce gastroduodenal irritation and ulceration, renal cortical ischemia, hepatotoxicity, and platelet dysfunction. These toxicities are believed to be primarily related to COX-1 inhibition.15 COX-2 is induced by injury or inflammation, and likely that NSAID analgesia is mainly related to inhibition of this isoenzyme. Certain NSAIDs, including choline magnesium trisalicylate, nabumetone, diclofenac, and etodolac, may be less likely to cause gastrointestinal toxicity because they show relative selectivity for COX-2.16 Celecoxib and rofecoxib cause less gastrointestinal toxicity than traditional NSAIDs.17

NSAID-induced dyspepsia is best managed prophylactically by taking the drugs with food. If this is insufficient, addition of an H2-receptor blocker, misoprostol, omeprazole, lansoprazole, sucralfate, or an oral antacid may be necessary. NSAID-induced ulcers may be prevented with H2 blockers (e.g., famotidine 40mg per day, or ranitidine 150 mg twice daily) or misoprostol (200 μg orally three times daily).18 Yeomans et al showed that omeprazole (20 mg or 40 mg taken orally every day) is somewhat more effective in preventing and healing gastric and duodenal ulcers than ranitidine.19 The same group also found that omeprazole is better than misoprostol in healing gastric and duodenal ulcers and in preventing their reappearance during NSAID therapy.20 The risk of ulceration during NSAID therapy increases with age, previous NSAID intolerance, history of peptic ulcer disease, and smoking.21 In such patients, prophylactic use of an H2 blocker, proton, pump inhibitor, or misoprostol is warranted.

Most NSAIDs interfere with platelet aggregation. Choline magnesium trisalicylate does not prevent normal platelet aggregation as measured experimentally, and appears to be associated with less occult gastrointestinal bleeding.22 COX-2 inhibitors have less platelet effects,17 but the clinical implications of this effect remain to be determined. Despite its short elimination half-life, aspirin irreversibly inhibits platelet aggregation for the lifetime of the platelet (4 to 7 days). The platelet effect of other NSAIDs lasts about 2 days after the drug is discontinued.

Renal effects of NSAIDs include reversible renal insufficiency, interstitial nephritis, and predisposition to acute tubular necrosis in the patient with low renal perfusion. NSAIDs should be prescribed with caution for patients with hypertension, renal insufficiency, or congestive heart failure. Although COX-2 inhibitors might eventually prove less nephrotoxic than conventional NSAIDs, present evidence is insufficient to draw this conclusion.23

Other toxicities are also possible: both acetaminophen and NSAIDs may cause hepatic toxicity, even at normally recommended doses.24 Confusion and inability to concentrate are possible central nervous system (CNS) effects of the NSAIDs. Patients who are allergic to aspirin or to an NSAID may be cross-reactive to other NSAIDs.

Opioids are indicated for the treatment of cancer pain because of their effectiveness, reliability and safety, and ease of administration (See Chapter 58, Opioid Pharmacology). Although neuropathic pain may be more difficult to treat with opioids, its presence does not preclude a favorable response to opioid-based analgesia.25

Steps 2 and 3 of the WHO ladder advocate the addition of opioids for moderate to severe pain, with or without an adjuvant drug.1 “Weak” and “strong” opioids (for step 2 and step 3, respectively) are not inherently different in their ability to control pain, but are customarily used in amounts appropriate for milder and stronger pain, respectively. The so-called weak opioids (codeine, hydrocodone, dihydrocodone) are commonly prepared in combination with coanalgesics (acetaminophen, aspirin, or an NSAID). The coanalgesic limits dose escalation, necessitating a change to another opioid or preparation as pain increases.

Tolerance, Physical Dependence, and Addiction

Opioids can induce tolerance and physical dependence. Addiction—defined as loss of control over drug use, compulsive use, and use despite harm—is rare in patients with no history of substance abuse.26 Although demands for opioids and dramatic pain behavior are commonly interpreted as markers of addiction, undertreatment of pain is an alternative explanation (pseudoaddiction).27

Although tolerance to opioid analgesia occurs, disease progression is usually to blame for increasing analgesic requirements.28 Tolerance to adverse effects, such as respiratory depression and somnolence, is favorable and allows dose escalation to analgesic levels. Physical dependence is another pharmacologic effect of opioid drugs, and is defined solely by the development of abstinence after abrupt discontinuation of therapy or administration of an antagonist. Physical dependence is not a clinical problem if abstinence is avoided.

Choosing an Opioid

Comparative clinical trials do not exist to differentiate opioids according to responsiveness. Hence, they are usually chosen on the basis of familiarity by the prescriber. Other factors to consider are the route of administration, cost, convenience, and availability. Individual patients vary greatly in their response to different opioids, supporting the practice of sequential opioid trials (opioid rotation) to find the most acceptable balance between analgesia and side effects (See Changing Opioids and Routes of Administration later in this chapter).29

The initial opioid should be a short-acting drug when the patient has severe pain and requires rapid dose titration, when the patient has intermittent pain, or when the patient is opioid naïve and there is concern about delayed toxicity from a long-acting preparation. In other cases, a long-acting drug may be the initial opioid. Long-acting opioids include methadone, levorphanol, and extended-release preparations of morphine, oxycodone, and fentanyl.

There are differences among opioids in toxicity. Meperidine should be avoided for cancer pain treatment, especially in patients with renal failure.30 Its active metabolite, normeperidine, has a long half-life, and causes CNS excitability, including seizures. It accumulates with high doses, prolonged use, and renal dysfunction. Morphine is metabolized to a potent opioid compound, morphine-6-glucuronide. It does not tend to cause problems in patients with normal renal function, but can lead to toxicity in those with renal failure. In these patients, morphine should be used with caution.

Partial opioid receptor agonists (buprenorphine) and mixed agonist-antagonists (pentazocine, dezocine, nalbuphine, and butorphanol) also should be avoided. They may precipitate withdrawal symptoms and pain in patients already physically dependent on opioids. When used alone, increasing amounts provide less incremental analgesia, a phenomenon known as a “ceiling effect.” Some of the mixed agonist-antagonists have relatively greater toxicity than the pure mu agonists.31

Combination analgesics, which often contain acetaminophen, should be used with caution because of the possibility of acetaminophen toxicity. Daily acetaminophen intake should be limited to 4 g. Alcohol use, coexisting hepatic disease, and starvation (which may be present in debilitated cancer patients) predispose to acetaminophen hepatotoxicity at lower doses.24

Methadone and levorphanol have long half-lives and may be considered in place of extended-release preparations for baseline opioid requirements. One advantage of these drugs is that they are absorbed easily by the gut, and may be effective in patients with bowel pathology who are unable to completely absorb the extended-release preparations.32 These drugs, particularly methadone, may be difficult to titrate, however, because the initial duration of action (4 to 6 hours) is shorter than the half-life, leading to drug accumulation with repeated dosing over 2 to 5 days. Furthermore, methadone pharmacokinetics are highly variable among patients, owing to differences in protein binding, urinary excretion, and induction of metabolism by methadone and other drugs.32,33 Methadone’s half-life is usually about 24 hours, but may be as short as 12 hours, or longer than 150 hours. Therefore, it may be prudent to use these two opioids on an as-needed basis initially, allowing an adjustment for drug accumulation by titrating to the analgesic effect and to the degree of sedation.34

Opioid Dosing

The appropriate opioid dose and interval control pain without end-of-dose failure and unacceptable side effects at peak concentration (i.e., without bolus effects). The required dose varies with the severity of pain, the type of pain, preexisting opioid exposure, psychological distress, and other factors.25 The elderly are more sensitive to opioid-induced analgesia, but may also be more susceptible to side effects.35 Large doses may be necessary as the disease progresses. Although there is no theoretical limit to the dose, a practical limit is imposed by the occurrence of intolerable side effects, a large injectate volume, numerous pills or suppositories, or excessive skin surface required for fentanyl patches.

When initiating opioid therapy, a short-acting drug may be given as needed every 2 or 3 hours (Table 45-2). After 5 or 6 half-lives (1 day for morphine), the basal daily opioid requirement is determined and a long-acting opioid preparation may be substituted. Alternatively, a long-acting opioid may be used initially when pain is constant and not severe or progressive. Long-acting opioids should be provided regularly to prevent most pain. An additional short-acting opioid (5% to 15% of the basal daily requirement) is made available for breakthrough pain every 1 to 3 hours.34 If the short-acting opioid is needed more than three times per day, the amount of long-acting opioid is usually increased. It is inconvenient and unnecessary to increase the dosing frequency of long-acting oral preparations when increasing the total daily dose. Dose changes should be in increments of one third to one half of the preceding dose, or according to the patient’s usage of breakthrough opioid. If side effects prevent dose escalation, a switch to another opioid should be considered before changing to another route of administration or abandoning opioids.29

Cessation or reduction of opioid use may be appropriate when the patient is pain-free following antitumor therapy, or after a successful anesthetic or neuroablative procedure. Based on clinical observation, reduction of the daily dose by 50% every 3 days will usually prevent symptomatic withdrawal. Withdrawal is marked by yawning, nausea, vomiting, abdominal cramps, diarrhea, insomnia, anxiety, irritability, temperature instability, diaphoresis, and salivation.

Route of Administration

The usual route of systemic opioid administration is oral. Peak effect is typically in 20 to 90 minutes, and duration is 3 to 6 hours.38 Extended-release oral preparations (morphine and oxycodone) are available for maintenance of steady analgesia, with peak effect at 2 to 3 hours, and a duration of 8 to 24 hours.39,40,41 The clear advantages of oral administration are the numerous drugs available and their ease of use. However, some patients may not be able to use oral medications, including those with oral mucositis, dysphagia, bowel obstruction, and severe nausea.42

Fentanyl is the only opioid prepared for transdermal use, which is especially important when the oral route is made unavailable by dysphagia or impaired gastrointestinal function.43 Transdermal fentanyl might also be selected if patient compliance with oral analgesics has been a problem. The onset of analgesia is 12 to 14 hours from initial patch application, and continues for 16 to 24 hours after removal. A comparative trial against extended-release morphine suggests that transdermal fentanyl is associated with less constipation.44

Morphine, oxymorphone, and hydromorphone are manufactured for rectal use. Injectable methadone and sustained-release morphine have also been used rectally.42,45 A disadvantage of rectal administration is the inter-patient variability in absorption and degree of first-pass metabolism. Partial avoidance of the portal circulation may result in slightly increased bioavailability compared to oral opioids. Whereas morphine suppositories are slowly absorbed,42 morphine microenema (10 mg in 1mL) has a more rapid onset and longer duration than the same dose given orally.46 Mucositis or transmucosal lesions, diarrhea, thrombocytopenia, and neutropenia contraindicate the rectal route.

Fentanyl is newly available in an oral transmucosal form (Actiq) for breakthrough pain, but experience is limited. Some pharmacies can compound concentrated solutions of morphine, oxycodone, and hydromorphone (up to 50 mg/mL) for sublingual use. These preparations might be useful for patients with dysphagia or gastrointestinal dysfunction.

Injected opioids may be useful for patients who cannot take opioids by the oral, sublingual, or rectal routes, for those who need rapid dose titration, and for those whose high opioid needs cannot be easily met by other routes. Subcutaneous injection is preferred over intramuscular, as the latter is more painful. Intravenous injection of most opioids provides peak effect in 5 to 15 minutes, with similarly shortened duration of effect. Continuous infusion (subcutaneous or intravenous) or frequent redosing is usually necessary to maintain analgesia with injected opioids. Subcutaneous infusion volume should be limited, especially in cachectic patients, to permit stable absorption.47 Moulin et al compared subcutaneous to intravenous opioid infusion in 15 patients with cancer pain in a double-blind, randomized, crossover trial.48 The mean bioavailability was 78% with subcutaneous infusion, but pain scores and the need for breakthrough medication were no different from intravenous infusion.

Patient-controlled analgesia (PCA) may be useful for initiation of parenteral opioid therapy, rapid opioid titration with changing pain intensity, and treatment of incident pain.49 Since the patient controls the delivery of opioid, individual differences in pain intensity, drug clearance, and effectiveness are less likely to interfere with therapy. In a study of 26 patients with oral mucositis following bone marrow transplantation, psychological dependence was no more likely, total opioid consumption and side effects were less, and analgesia was the same or better with PCA as with nurse-administered opioids.50 PCA devices are individually programmed for the size of the dose, the minimum time between doses (lockout interval), and the cumulative dose allowed in 1 or 4 hours (several times higher than the anticipated need). Continuous infusion may be programmed in addition to the demand doses to allow sleep and to cover baseline pain. An important safety feature of PCA is that the patient will not request additional medication when overly sedated. Those attending to the patient must not circumvent this safety feature by pressing the demand button.

Recommended PCA settings for morphine, hydromorphone, and fentanyl are shown in Table 45-3. Much larger doses may be needed for the opioid-tolerant patient. To limit the total volume of injectate, hydromorphone may be chosen over fentanyl and morphine because of its potency and solubility. Fentanyl is commercially available only at 50 μg/mL, whereas morphine and hydromorphone can be compounded to 50 mg/mL for injection.

PCA is an efficient means of determining a patient’s opioid requirement when initiating or changing opioids. The pump records the amount of drug used, which is then converted to continuous infusion, transdermal fentanyl, or a sustained-release oral preparation. PCA is available for use in the home as well as the hospital. Patients without intravenous access may use subcutaneous PCA.49

Changing Opioids and Routes of Administration

Dose-limiting side effects and the loss of the previous route of administration are the usual reasons for changing drugs or routes. Trials of several opioids should be considered before abandoning systemic opioids for treatment of cancer pain, as patients may respond differently to different drugs. Incomplete cross-tolerance between opioids may account for the apparent decrease in required dose when changing analgesic drugs.29,51 When changing one opioid to another drug or route of administration, conversion is made with the assistance of opioid conversion charts (Table 45-2).

All opioid doses can be expressed as equianalgesic doses. Typically, 10 mg of parenteral morphine is considered the unit dose, and doses of other drugs for oral or parenteral administration are listed in equianalgesic amounts. The conversion tables (Table 45-2) contain approximations based largely on short-term use of smaller opioid doses. When converting large opioid doses, caution dictates dose reduction by one third to one half to account for incomplete cross-tolerance.29,51 When changing to methadone, a 75% to 90% initial dose reduction is indicated because of the greater potential for drug accumulation and the possibility of unexpectedly high potency.29 If inadequate analgesia necessitates the conversion, and there are no significant side effects, the new drug may be started closer to the equianalgesic dose.34 Additional short-acting opioid is made available while titrating the new drug to achieve stable analgesia. When any change in opioid or route is made, frequent assessments are needed to keep pain controlled and to prevent side effects.

Analgesic adjuvants are rarely adequate analgesics when used alone for cancer pain. They are used especially to relieve neuropathic pain and to provide an opioid-sparing effect, thus lessening opioid-related side effects. Many patients with neuropathic pain, however, can be treated with opioids alone.25

Antidepressants

Tricyclic antidepressants (TCAs) were used as analgesics shortly after their introduction.52,53,54 The mechanism of their analgesic action is not certain, but probably includes enhancement of monoamine concentrations in the dorsal horn,55 and stimulation of alpha2 receptors56 (See Chapter 62, Adjuvant Analgesics). They are useful in treating neuropathic pain, and have been proven analgesic in well-designed trials for postherpetic neuralgia, diabetic neuropathy, atypical facial pain, migraine headache, fibrositis, and central poststroke pain.53,54 There are few controlled trials of TCAs for the treatment of cancer pain, perhaps because cancer pain encompasses so many somatic, visceral, and neuropathic entities (See Chapter 44, Cancer Pain Syndromes). Amitriptyline has been shown effective in a placebo-controlled study of 20 patients with neuropathic postmastectomy pain.57 The analgesic effect of the TCAs on neuropathic pain seems to be separate from their antidepressant or sedative effects.57–61

TCAs are most appropriate for cancer patients with neuropathic pain, which is often described as burning, searing, aching, or dysesthetic, and occurs in the setting of known or probable nerve injury. The choice of drug is empiric; there is no clearly superior drug. A patient having difficulty with sleep may benefit from a more sedating drug, such as amitriptyline, imipramine, or doxepin. Nortriptyline is less sedating, and desipramine has the fewest side effects.58,62 Trazodone is not an effective analgesic for neuropathic pain, but may be indicated in the cancer pain patient with a sleep disturbance. Probably fewer than half of patients with neuropathic pain achieve greater than 50% pain relief with an antidepressant,54 and a lack of complete relief should not be interpreted as treatment failure.

Suggested dosing for the TCAs is shown in Table 45-4. Because these drugs are usually sedating, they are best given in the evening. If the initial low dose is not effective, it should be increased every few days until an effect is seen or side effects become intolerable. As with opioids, greater analgesia is seen with higher doses.59

Adverse effects with TCAs are common.54 They are primarily anticholinergic, including sedation, constipation, urinary retention and overflow incontinence, tachycardia, dry mouth, blurred vision, dysphoria, and agitation. Antihistaminergic effects are responsible for sedation and weight gain, and may exacerbate hypotension. Alpha1 and alpha2 blockade contribute to orthostatic hypotension and tachycardia. Most of these side effects are not life-threatening and diminish with time. Dry mouth tends to persist. The side effects are troubling, however, and often prevent the continued use of TCAs. Cardiac conduction abnormalities and seizures are more concerning effects. A history of seizure is a relative contraindication to TCA use.63 An electrocardiogram should be obtained prior to TCA initiation to rule out bundle branch block and bifascicular block, which are also relative contraindications.64 Dose adjustment according to drug levels may help to prevent these consequences of antidepressant therapy.63 When a patient experiences unwanted side effects, it is wise to switch to another TCA, since patient responses are variable and often idiosyncratic. Persistence in treatment is essential, as analgesic response may take 4 weeks to achieve.53

Selective serotonin reuptake inhibitors (SSRIs) are newer antidepressants than TCAs. They are usually better tolerated than TCAs, but there is little evidence to support their use in cancer pain. Although SSRIs are commonly used to treat fibromyalgia and migraine headaches, most studies have found them to be less effective in neuropathic pain.54,61,62 SSRIs should be tried when TCAs are not tolerated or relatively contraindicated.

Anticonvulsants

Carbamazepine has long been used for treatment of trigeminal neuralgia.65 Several anticonvulsants are now commonly employed to treat lancinating and burning dysesthesias complicating nerve injury (See also Chapter 62, Adjuvant Analgesics). In addition to trigeminal neuralgia, glossopharyngeal neuralgia, tabes dorsalis, diabetic neuropathy, postherpetic neuralgia, postamputation pain, migraines, central pain, and other conditions have been reported to respond to anticonvulsants in case reports, case series, and poorly controlled trials.66 Two randomized, double-blind, placebo-controlled studies support the use of gabapentin for diabetic neuropathy and postherpetic neuralgia.67,68

Swerdlow studied 200 patients with lancinating pain in an open-label, uncontrolled trial of carbamazepine, phenytoin, valproate, and clonazepam.66 Patients were switched from one drug to another if they failed to obtain relief. Most patients did respond to one of the drugs, but there was no clearly superior medication in general or for any particular condition. McQuay et al conducted a recent systematic review of 20 randomized, controlled anticonvulsant trials.69 Trigeminal neuralgia responded to carbamazepine, and diabetic neuropathy responded to both carbamazepine and phenytoin. Valproate and carbamazepine were effective for migraine prophylaxis. While there are few prospective, controlled trials of anticonvulsants for patients with cancer pain, individual patients may respond dramatically, and these medications should not be withheld from patients in pain, pending definitive evidence of their efficacy. Yajnik et al compared phenytoin with buprenorphine and the combination in three groups of 25 patients with cancer pain resulting from various causes.70 A low dose of phenytoin (100 mg twice daily) provided greater than 50% pain relief in most patients, and enhanced the effect of buprenorphine without increasing side effects.

Gabapentin is receiving considerable attention in pain management, and there is now convincing evidence to support its use in diabetic neuropathy and postherpetic neuralgia.67,68 It has not been studied in cancer pain, but it is commonly used because of its few side effects and relative absence of drug interactions. It is usually started at 300 mg at bed time, and increased as high as 3600 mg/day in divided doses. Dosage should be reduced in patients with renal failure. Side effects (somnolence, ataxia, and dizziness) are not life-threatening and plasma concentrations are not monitored, making this an easy anticonvulsant to use.71 Other new anticonvulsants, lamotrigine, tiagabine, oxcarbazepine, and topiramate are also being investigated for analgesic activity.

Carbamazepine is started at 100 mg twice daily, and is escalated until toxicity occurs, pain is relieved, or the safe plasma level is exceeded (12 μg/mL). Bone marrow suppression often manifests as mild leukopenia or thrombocytopenia, and rarely aplastic anemia. If bone marrow suppression is anticipated from radiation, chemotherapy, or tumor replacement, carbamazepine should be avoided. Patients receiving carbamazepine should have their complete blood counts and hepatic transaminases monitored. Reversible hepatotoxicity, resembling viral hepatitis, occurs rarely, and fatal hepatic necrosis is less common.72 Cutaneous reactions may also occur, and require cessation of the medication. Sedation, vertigo, ataxia, hyponatremia, and nausea are more common effects.66

Phenytoin and valproate are available in oral and intravenous forms. A new form of phenytoin, fosphenytoin, may be administered intramuscularly. Treatment with phenytoin begins with an oral loading dose, and maintenance therapy, starting at 100 mg three times daily, is adjusted to control pain with a plasma concentration of less than 20 μg/mL. Side effects may include anemia, anorexia, nausea, somnolence, and ataxia. Bone marrow suppression is less likely with phenytoin than carbamazepine. The potential for hepatotoxicity mandates periodic monitoring of liver function tests.66 Hypersensitivity to phenytoin is rare but potentially fatal, and manifests with rash, fever, and hepatitis. Up to 19% of patients on phenytoin develop cutaneous reactions, usually without hypersensitivity.73 Oral valproate therapy usually starts at 125 mg twice daily. The most common side effects are nausea and epigastric pain,which are reduced by taking it with food and with enteric-coated tablets. Hepatotoxicity is rare.66

Clonazepam is available for oral or parenteral use, and is started at 0.25 to 0.5 mg daily. It is the most sedating anticonvulsant, and may be useful for patients with anxiety and insomnia. The dose is increased as needed. Plasma concentrations are not measured and the principal toxicity is sedation.

Systemic Local Anesthetics

Systemic local anesthetics are often used to treat neuropathic pain (See also Chapter 62, Adjuvant Analgesics). Intravenous lidocaine (5 mg/kg over 30 minutes) has been found effective for postherpetic neuralgia (PHN) and diabetic neuropathy.74,75 Painful peripheral neuropathies may also respond to oral mexilitine (10 mg/kg/day).76,77 Systemic local anesthetics have not been studied for cancer pain.

Topical Analgesics

Topical local anesthetics are often used in the treatment of mucocutaneous pain states. Topical lidocaine and benzocaine provide temporary relief of pain from oral mucositis. This is necessary to allow the patient to eat and for oral hygiene. Likewise, Rowbotham et al showed that topical application of 5% lidocaine gel relieves the pain of PHN for up to 24 hours in a blinded, placebo and site-controlled trial.78 The effect is greatest when lidocaine is applied in the painful dermatome. A lidocaine patch was recently approved in the United States for treatment of PHN.

Capsaicin is the compound in chili peppers that makes them taste hot. When it is applied to the skin or a mucus membrane, it produces a burning sensation as a result of C fiber activation. Repeated application causes desensitization.79 Although it is promoted for relief of arthritis pain, topical capsaicin has been found useful for some types of neuropathic pain.79,80 Postmastectomy pain, diabetic neuropathy, and postherpetic neuralgia may respond. Studies have been complicated by difficulty in blinding because only the active preparation causes a burning sensation. Capsaicin is available over the counter in 0.25% and 0.75% concentrations in a cream vehicle and a roll-on. The cream should be used four to five times daily. Unfortunately, many patients do not persist in applying the cream after the first few treatments because of the uncomfortable burning.80

Corticosteroids

Corticosteroids are used as coanalgesics when inflammation or the mass effect of vasogenic edema causes pain.81 They reduce inflammation by inhibiting phospholipase activity, and thus prostaglandin synthesis. In addition, they may reduce axonal sprouting and neurokinin concentration in sensory fibers near injured tissue.82 Regenerating axons in neuromas discharge spontaneously or with minimal tactile stimulation because of high sodium channel expression83; locally injected corticosteroids reduce neuroma discharge in animal models, and appear to be effective in humans as well. Acute neural compression, intracranial hypertension, bony and soft tissue infiltration, and visceral distention cause pain that may respond to steroids.

Corticosteroid therapy for cancer pain usually includes dexamethasone, 4 to 8 mg, methylprednisolone, 8 to 40 mg, or prednisone 10 to 50 mg. Multiple daily doses are not needed, except for hydrocortisone.81 High initial doses are continued until a response is seen, then tapered to the minimum effective dose. Concurrent use of phenytoin, carbamazepine, or phenobarbital induces hepatic metabolism of corticosteroids, increasing the required dose. Dexamethasone may be given in very high doses (40 to 100 mg intravenously) for the initial treatment of spinal cord compression and for selected patients with other causes of crescendo pain.

Corticosteroids have numerous toxicities when taken chronically.81 These include fluid retention and electrolyte disturbances, hypertension, proximal myopathy, osteoporosis and aseptic necrosis, insomnia, psychosis, gastritis, hyperglycemia, and impaired cellular immunity. These adverse effects may be undesirable in cancer patients who are expected to survive for more than several months. Mood elevation, antiemesis, and appetite stimulation are often desirable side effects of corticosteroids, but they may diminish with prolonged use.81

Sedatives and Tranquilizers

Most benzodiazepines and barbiturates have no significant primary analgesic effect, but may reduce anxiety associated with uncontrolled pain and cancer. Clonazepam, when used for lancinating neuropathic pain and myoclonus, may be an effective coanalgesic (See Sections entitled Anticonvulsants, and Myoclonus and Hyperalgesia). Benzodiazepines may also be effective for reducing muscle spasm, which may accompany pain and spinal cord injury, and have a coanalgesic role in these conditions. Lorazepam has been used to prevent nausea associated with chemotherapy.

Phenothiazines have been used commonly in conjunction with opioids for acute pain management. Although they have a tranquilizing effect, only methotrimeprazine, which is no longer marketed, is analgesic when used alone.84 Extrapyramidal side effects, sedation, and hypotension make chronic phenothiazine use impractical for cancer pain treatment. They are more often indicated in the treatment of nausea and anxiety.

Most antihistamines are mild analgesics. The mechanism of analgesic activity is unknown. Hydroxyzine (50 to 100 mg intramuscularly) is commonly used in conjunction with opioids for acute pain. It is also effective in cancer pain.85 These drugs are most useful for their sedative, muscle relaxing, and antiemetic properties, though opioids are more effective analgesics.

Calcitonin and Bisphosphonates

Pain from osteolytic metastases may be caused by bony destruction alone or by neural or soft tissue compression by pathologic fracture. Bisphosphonates and calcitonin are noncytotoxic agents that inhibit osteoclast activity. They are often used for the management of hypercalcemia of malignancy.86 They have also been found to reduce bone pain from metastases, and may induce healing of lytic lesions.87 Calcitonin also inhibits malignant osteolysis, and reduces bone pain in patients with advanced, progressive disease.88

Calcitonin has also been investigated for the treatment of neuropathic pain. The mechanism of analgesia is uncertain, but binding of calcitonin in the hypothalamus and limbic system, areas rich in serotonin, may have a role. A double-blind crossover study of intravenous salmon calcitonin (200 μg) in 21 patients with acute phantom limb pain showed a decrease in pain intensity and frequency with calcitonin.89

Alpha2 Agonists

Clonidine, an alpha2 receptor agonist, may contribute to analgesia by stimulating presynaptic or postsynaptic receptors in the superficial dorsal horn, decreasing sympathetic outflow, and enhancing noradrenergic inhibitory fibers from the brain stem.90 These mechanisms may make clonidine a useful analgesic adjuvant for opioids, especially in the setting of neuropathic pain.91,92 Max et al found a single dose of oral clonidine (200 μg) superior to placebo, ibuprofen (800 mg), and codeine (120 mg) in the treatment of postherpetic neuralgia.90 The epidural route appears to be more effective than the systemic route for clonidine.92 Side effects associated with clonidine include orthostatic hypotension, sedation, dry mouth, and constipation. Clonidine does not appear to aggravate opioid-induced respiratory depression, however.

Tizanidine is a newer alpha2 agonist that has been used to treat pain associated with muscle spasm,93,94 and neuropathic pain.95 Because it causes less hemodynamic disturbance than clonidine, it may be more useful in treating debilitated patients. Animal studies suggest that tizanidine is also effective when administered intrathecally.96 Tizanidine, like clonidine, produces sedation.

Many of the analgesics described produce dose-limiting side effects. Unfortunately, patients and their families are often asked to accept a compromise between pain and these other symptoms. As the use of opioids and other analgesics becomes more widespread for cancer pain, control of side effects is receiving increased attention.

Nausea and Vomiting

Opioids have three emetogenic mechanisms: a direct effect on the chemoreceptor trigger zone, an enhancing effect on vestibular sensitivity, and a slowing effect on gastric emptying. Although nausea is common with opioids, tolerance to this effect occurs quickly. Treatment is therefore given as needed.34 When evaluating opioid-induced nausea, refractory constipation and impaction of stool must be considered and treated first. If nausea follows meals or is accompanied by postprandial vomiting, metoclopramide is an appropriate choice. If it occurs with movement, meclizine may be more effective. In the absence of these associations, a phenothiazine, butyrophenone, antihistamine, or serotonin antagonist is appropriate (Table 45-5). If these are ineffective, a corticosteroid81 or benzodiazepine may also be useful.

Constipation

Opioids bind to specific receptors in the gastrointestinal tract and central nervous system to produce constipation by direct and anticholinergic effects.97 Increased gastrointestinal transit time causes excessive water and electrolyte reabsorption from the feces. Decreased biliary and pancreatic secretion further dehydrates the stool. Tricyclic antidepressants, clonidine, dehydration, surgical procedures, and bowel obstruction by tumor contribute to constipation as well. Elderly patients are particularly susceptible to constipation and impaction of stool.98

Opioid-induced constipation is so common that cathartic and stool-softening medications should be routinely initiated with around-the-clock opioid orders in predisposed patients, such as the elderly. The coadministration of docusate (100 mg taken orally twice daily) and senna (2 to 6 tablets twice daily) is appropriate for most patients. Adequate hydration, physical activity, and regular toileting are also helpful. If constipation develops or persists with this regimen, then an osmotic laxative, such as lactulose (15 to 30 mL) or magnesium citrate (200 mL), is added after ruling out fecal impaction. Bisacodyl suppository or sodium phosphate/biphosphate enema is used for patients who are too nauseated to take oral cathartics. Disimpaction may be facilitated with mineral oil or saline enemas. Refractory constipation may respond to oral naloxone (1 to 12 mg), which acts at enteric opioid receptors. Because naloxone is only about 3% bioavailable, systemic opioid withdrawal and recrudescence of pain may be avoided with low doses. Oral naloxone should be avoided in patients with bowel obstruction.99,100 Methylnaltrexone, a peripherally acting opioid antagonist, shows promise as a treatment for opioid-induced constipation.101

Sedation

Somnolence and mental clouding are common complaints when opioids are initiated or escalated. Some patients continue to have these problems, especially when certain coanalgesics (antidepressants, anticonvulsants, benzodiazepines, antihistamines, and phenothiazines) are being used. After ruling out primary central nervous system abnormalities and metabolic derangement, unnecessary sedative medications should be gradually eliminated. If symptoms persist, and analgesia is adequate, the opioid dose may be reduced or the opioid drug may be changed. If analgesia is unsatisfactory, coanalgesics may be initiated or increased to achieve an opioid-sparing effect. An anesthetic or neuroablative procedure may be necessary if the patient finds sedation particularly troubling.34

Psychostimulants, such as caffeine (100 to 200 mg orally per day), dextroamphetamine (2.5 to 10 mg orally twice daily), and methylphenidate (5 to 10 mg orally twice daily), are commonly used to offset the sedative effects of opioids.102 Bruera et al studied the cognitive effects of methylphenidate versus placebo in a double-blind, crossover trial involving 20 patients with cancer pain who were receiving continuous infusions of opioids.103 Cognitive function was improved by methylphenidate, and most patients preferred it to placebo. Amphetamines, like antidepressants, have mood elevating and analgesic properties as well.102

Respiratory Depression

Respiratory depression occurs with sedation when opioids are given systemically, and tolerance to this effect occurs quickly. All opioids affect the medullary respiratory center directly. No pure opioid agonist is less likely to cause respiratory depression than any other when given at an equianalgesic dose. For most patients, mild respiratory depression (respiratory rate of 8 to 12 per minute) is well tolerated. For those with limited ventilatory or respiratory reserve, it may be problematic. If a low respiratory rate and moderate sedation occur after the expected peak of opioid activity, it is best to withhold further opioids until the respiratory rate rises or pain returns. If necessary, ventilatory support and a small dose of dilute naloxone (20 to 80 μg intravenously) may be given and repeated as necessary. Because naloxone’s effects are shorter than those of most opioids, continued close monitoring for recurrence of respiratory depression is necessary.34

Myoclonus and Hyperalgesia

Myoclonus, uncontrollable spasms of certain muscle groups, and hyperalgesia, excessive sensitivity to mildly noxious stimuli, are sometimes seen at very high doses of opioids. Their occurrence, separately or together, may limit the ability of opioids to control pain at the end of life.104 The mechanisms of these conditions are not certain, but may include the inhibition of non-opioid CNS inhibitory systems,105 and the potentiation of glutamate activity at NMDA receptors.106 Morphine-3-glucuronide accumulates with chronic morphine administration, and also may play a role in these hyperexcitability conditions by stimulating non-opioid receptors in the CNS.107 A change to another opioid and the addition of coanalgesics and adjuvants may allow a reduction in the opioid dose, relieving either condition.51 Clonazepam (0.5 to 2 mg orally three times daily), and perhaps other anticonvulsants, may also be used to suppress myoclonus.51,108 Finally, an anesthetic or neuroablative procedure may be indicated for the rare patient with a more favorable prognosis.