Adjuvant Drugs
There are three main reasons to use adjuvant drugs in cancer patients: to supplement pain relief; to mitigate the adverse effects of analgesic medications (eg, antiemetics and laxatives); and to treat the psychological disturbances such as insomnia, anxiety, depression, and psychosis that so often accompany cancer and its treatment.
ANTIEMETICS
Nausea and vomiting are among the most distressing and feared toxic effects of chemotherapy and radiation therapy.1 These side effects can result in serious medical problems, increased hospital stay, and impaired quality of life.2 Chemotherapy-induced nausea and vomiting can be categorized as acute (occurring within 24 hours of therapy), delayed (persisting for 6 to 7 days after therapy), or anticipatory (occurring before chemotherapy administration).2 Breakthrough and refractory nausea and vomiting describe the symptoms of uncontrolled emesis. Failure of prophylaxis during the first 24 hours after chemotherapy is highly predictive for delayed emesis during the same cycle.3 Glaus et al.4 reported that of 247 patients and 38% who received chemotherapy and antiemetics, 13% experienced acute and 38% experienced delayed chemotherapyinduced nausea and vomiting. Of those patients with acute symptoms, 65% had recurrence of symptoms on one or more subsequent days. Thus, a highly effective antiemetic regimen should be employed at the onset of chemotherapy, as opposed to waiting until chemotherapyinduced nausea and vomiting have occurred with initially suboptimal antiemetic treatment. The emetogenicity of cancer chemotherapeutic agents varies significantly and is listed in Table 18.1.
A wide range of treatments are available for emesis prophylaxis. The most frequently used are corticosteroids (methylprednisolone, dexamethasone), 5-HT3 receptor antagonists (ondansetron, granisetron, tropisetron, dolasetron, palonosetron), and neurokinin-1 (NK-1) receptor antagonists (aprepitant).5 Metoclopramide, lorazepam and other benzodiazepines, and cannabinoids have also been used. Currently, a 5-HT3 receptor antagonist in combination with a corticosteroid and, in certain instances, an NK-1 antagonist are the treatments of choice for prophylaxis against acute emesis following chemotherapy with moderate potential for chemotherapy-induced nausea and vomiting.6 Various antiemetics and presumed mechanisms of action are listed in Table 18.2.
Even with the emergence of new 5-HT3 receptor and NK-1 antagonists, corticosteroids continue to play an important role in antiemesis for oncology patients. The mechanisms by which corticosteroids are effective as prophylaxis against chemotherapy-induced nausea and
vomiting are unknown. Antagonism of 5-HT3 receptors known to be involved in emesis may contribute to the prophylactic effects of corticosteroids in cancer patients.5 A single intravenous (I.V.) dose of dexamethasone 8 mg given prophylactically before chemotherapy with anthracyclines, carboplatin, or cyclophosphamide completely protected 89.2% of patients against nausea and 61% of patients against vomiting.7 Moderate-to-severe side effects may occur in patients receiving dexamethasone for prophylaxis against delayed chemotherapy-induced nausea and vomiting and include insomnia (45%), indigestion/epigastric discomfort (27%), agitation (27%), increased appetite (19%), weight gain (16%), and acne (15%) in the week following chemotherapy.8 Corticosteroids are seldom used as monotherapy for management of emesis and nausea induced by moderately or highly emetogenic chemotherapy.5
vomiting are unknown. Antagonism of 5-HT3 receptors known to be involved in emesis may contribute to the prophylactic effects of corticosteroids in cancer patients.5 A single intravenous (I.V.) dose of dexamethasone 8 mg given prophylactically before chemotherapy with anthracyclines, carboplatin, or cyclophosphamide completely protected 89.2% of patients against nausea and 61% of patients against vomiting.7 Moderate-to-severe side effects may occur in patients receiving dexamethasone for prophylaxis against delayed chemotherapy-induced nausea and vomiting and include insomnia (45%), indigestion/epigastric discomfort (27%), agitation (27%), increased appetite (19%), weight gain (16%), and acne (15%) in the week following chemotherapy.8 Corticosteroids are seldom used as monotherapy for management of emesis and nausea induced by moderately or highly emetogenic chemotherapy.5
TABLE 18.1 EMETOGENICITY FOR SINGLE-DOSE, INTRAVENOUS CHEMOTHERAPEUTIC AND BIOLOGIC AGENTS | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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TABLE 18.2 ANTIEMETICS | ||||||||||||||||||||||||||||||||||||||||||||||||
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Management of emesis in oncologic and surgical settings improved with the introduction of 5-HT3 receptor antagonists. Prophylactic use of these agents is recommended for the prevention of both acute chemotherapyand radiation-induced nausea and vomiting.9, 10 The 5-HT3 receptor antagonists widely used in current clinical practice are generally perceived to have comparable efficacy and safety. Although 5-HT3 receptor antagonists have similar chemical structures, they exhibit differing pharmacologic profiles that result in variations in their pharmacodynamic action. In particular, the elimination half-lives of these compounds differ considerably, with studies in adult cancer patients finding that ondansetron displays the shortest half-life (4 hours), compared with granisetron, for example, which has a mean half-life of 10.6 hours.11, 12 Hydrodolasetron, the active metabolite of dolasetron, has an intermediate elimination half-life of 7.5 hours in cancer patients. The elimination half-life of tropisetron (8 hours) is similar to that of hydrodolasetron; however, this can be increased to as much as 45 h in slow metabolizers of the drug. A further difference in pharmacology between the 5-HT3-receptor antagonists lies in the nature of their antagonism of 5-HT3 receptors. Ondansetron displays competitive antagonism at the 5-HT3 receptor and can be easily displaced by high concentrations of 5-HT3. Conversely, granisetron and tropisetron exhibit insurmountable, noncompetitive, antagonism of 5-HT3 receptors.13 This may have implications for their duration of action with prolonged antiemetic activity beyond that suggested by their plasma half life. Intractable nausea and vomiting antiemetic dosing recommendations are shown in Table 18.3.
The neurokinin-1 (NK1)-receptor antagonists block the action of substance P released in the gut following cytotoxic stimuli. Aprepitant (NK-1 antagonist), when used in combination with a 5-HT3 receptor antagonist and a corticosteroid, improves control of delayed nausea and vomiting.14 As Aprepitant is a CYP 3A4 inhibitor and can interfere with dexamethasone metabolism,
the dose of dexamethasone should be reduced when used in combination.5
the dose of dexamethasone should be reduced when used in combination.5
TABLE 18.3 INTRACTABLE NAUSEA AND VOMITING: RECOMMENDED DOSES OF ANTIEMETICS | ||||||||||||||||||||||||||||||||||||||||
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Jordan et al.15 reviewed the various guidelines for antiemetic treatment of chemotherapy-induced nausea and vomiting. Recommendations were based on guidelines from the Multinational Association of Supportive Care in Cancer, the American Society of Clinical Oncology, and the National Comprehensive Cancer Network. All patients receiving highly emetogenic chemotherapy and selected patients receiving moderately emetogenic chemotherapy should receive an NK-1 antagonist in combination with a 5-HT3 antagonist and/or corticosteroid. Dexamethasone is the preferred agent to use for delayed chemotherapyinduced nausea and vomiting. Patients receiving a lowrisk emetogenic regimen should receive a corticosteroid before treatment and no prophylaxis beyond 24 hours for acute nausea and vomiting. For minimally emetogenic chemotherapy, no antiemetic drug should be routinely administered before chemotherapy. We support the use of these guidelines for antiemetic therapy.
Patients undergoing chemotherapy and who are pancytopenic are at risk for significant complications from intractable opioid-induced nausea and vomiting.16, 17, 18 In patients experiencing acute nausea and/or vomiting with opioid use, we recommend the use of I.V. dexamethasone 4 to 8 mg, and/or an orally disintegrating tablet (which may also be given I.V.) ondansetron 8 mg and/or Aprepitant 40 mg for short-term control of symptoms. We do not propose these medications be used long-term for this problem as most opioid-induced vomiting will usually resolve with short-term antiemetic use, opioid dose stabilization, or a change in the type of opioid.
LAXATIVES AND OPIOID-INDUCED BOWEL DYSFUNCTION
Opioid-induced bowel dysfunction (OBD) is a distressing condition that may persist indefinitely in the clinical setting. OBD is characterized by constipation, incomplete evacuation, bloating, and increased gastric reflux. Hard, dry stool, gas distention, incomplete evacuation, and straining are common sequelae. OBD includes inhibition of gastric emptying, peristalsis, and secretions, as well as increased tone of intestinal sphincters.19 Slowed gastrointestinal (GI) transit, increased fluid absorption, and desiccation of stool can lead to constipation. Opioids induce bowel dysfunction through several effects: block of propulsive peristalsis, inhibition of the secretion of intestinal fluids, and an increase in intestinal fluid absorption.20, 21 Opioids decrease the activity of both excitatory and inhibitory neurons in the myenteric plexus. In addition, they increase smooth muscle tone and inhibit the coordinated peristalsis required for propulsion, leading to disordered, nonpropulsive contractile activity, which contributes to nausea and vomiting as well as constipation.
Constipation is often refractory to stool softeners and laxatives and may limit the ability to deliver effective pain relief by opioid medications. In cancer patients, up to 90% of patients on chronic opioid therapy develop OBD.22 Three types of receptors for opioid peptides have been identified as having effects on human GI function: δ -, κ, and µ.20 Human studies have revealed that µ receptors were more consistently distributed between the myenteric and submucosal plexi, and between the small and
large intestines.23 Because κ-receptors are more abundant in peripheral nerves than in central nerves, stimulation of these receptors may induce fewer central side effects such as euphoria and depression. δ-receptors are found predominantly in the central nervous system (CNS) but are also found in the myenteric and submucosal neurons of the gut, where activation results in inhibition of motility and secretion.19 Pharmacologic and clinical effects of opioids on different segments of the gastrointestinal tract are shown in Table 18.4.
large intestines.23 Because κ-receptors are more abundant in peripheral nerves than in central nerves, stimulation of these receptors may induce fewer central side effects such as euphoria and depression. δ-receptors are found predominantly in the central nervous system (CNS) but are also found in the myenteric and submucosal neurons of the gut, where activation results in inhibition of motility and secretion.19 Pharmacologic and clinical effects of opioids on different segments of the gastrointestinal tract are shown in Table 18.4.
Several types of pharmacologic agents have been used to treat opioid-induced constipation, including osmotic or lubricant laxatives, stimulant laxatives (oral or rectal), and prokinetics. Fiber bulking agents are organic polymers that retain water in stool. It is important that adequate water be taken concomitantly with fiber. Without sufficient water, fiber may worsen constipation. Many practitioners recommend a combination of a stool softener with a stimulant laxative for patients on chronic opioid therapy. Stool softeners, such as docusate sodium, are detergents that allow better water penetration into stool making it softer and more voluminous. Stimulant laxatives, such as senna and bisacodyl, induce peristalsis via mechanisms that are not well understood. In vitro, applying senna to intestinal mucosa leads to immediate contraction. After optimal titration of these agents, oral osmotics are commonly added to enhance laxation by pulling along water by means of osmotic forces. Osmotics include sugars such as lactulose or sorbitol, magnesium salts such as magnesium citrate, or inert substances such as polyethylene glycol. When these are unsuccessful, rescue oral and rectal interventions are also often needed. Rectal interventions include such agents as bisacodyl suppositories and phosphosoda enemas to soften, lubricate, and mobilize hard, dry distal stool. Often synergism of multiple categories of agents is required for successful laxation.
TABLE 18.4 PHARMACOLOGIC AND CLINICAL EFFECTS OF OPIOIDS ON DIFFERENT SEGMENTS OF GASTROINTESTINAL TRACT | |||||||||||||||||||||||||||||||||||||||||||||||||||||
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Opioid antagonists have also been studied in the treatment of OBD. Oral naloxone given in doses between 2 mg to 4 mg three times per day was effective in improving bowel movement frequency, but some patients also experienced reversal of pain relief, and this reversal occurred in spite of using very low doses of naloxone relative to the total dose of opioid taken.24 In particular, patients using higher doses of opioids appear to be the most vulnerable to the antianalgesic effect of oral naloxone. Naloxone is lipid soluble and easily crosses membranes, but undergoes extensive first-pass metabolism, with only 2% systemic bioavailability.
Peripheral opioid antagonists (alvimopan, methylnaltrexone) may be helpful in this setting. McNicol and Boyce25 demonstrated that methylnaltrexone and alvimopan were better than placebo in reversing opioidinduced increased gastrointestinal transit time and constipation, and that alvimopan appears to be safe and efficacious in treating postoperative ileus. Methylnaltrexone is a µ-opioid-receptor antagonist with a quaternary amine derivative of naltrexone that prevents substantial entry into most areas of the brain, brain stem, and spinal cord, thereby preserving central analgesic actions of coadministered opioid agonists. Several small brain regions
known as the circumventricular organs lack a blood-brain barrier,26 including the vomiting center in the area postrema in the floor of the fourth ventricle. Methylnaltrexone prevents nausea and vomiting in part by gaining access to opioid receptors in the area postrema.27
known as the circumventricular organs lack a blood-brain barrier,26 including the vomiting center in the area postrema in the floor of the fourth ventricle. Methylnaltrexone prevents nausea and vomiting in part by gaining access to opioid receptors in the area postrema.27
Alvimopan has a greater affinity for the µ-receptor than the κ- or σ-opioid receptors.28 The polarity of the molecule limits gastrointestinal absorption and CNS penetration. Methylnaltrexone is approved for the treatment of opioid-induced constipation.29 As a quaternary amine, methylnaltrexone, a µ-opioid-receptor antagonist, has restricted ability to cross the blood-brain barrier. Time to peak effect is approximately 30 minutes after subcutaneous dosing and has an elimination half-life of 8 hours.30 Portenoy et al.31 demonstrated that the optimal dose of subcutaneous methylnaltrexone for reversing OBD was ≥5mg. Methylnaltrexone was also approved by the Food and Drug Administration (FDA) in April 2008 for opioidinduced constipation, administered subcutaneously once a day in doses of 8 to 12 mg. Thomas et al.32 reported on the use of methylnaltrexone in 133 patients (71 placebo, 62 methylnaltrexone) with advanced illness and opioidinduced constipation in a 2-week double-blind, randomized, placebo-controlled study with a 3-month open-label extension. In the methylnaltrexone group, 48% of patients had laxation within 4 hours after the first study dose, compared with 15% in the placebo group, and 52% had laxation without the use of a rescue laxative within 4 hours after two or more of the first four doses, compared with 8% in the placebo group (P < .001 for both comparisons). The time to laxation after the first dose was rapid; among patients in the methylnaltrexone group who had a response within 4 hours; half had a response within 30 minutes. The response rate remained consistent throughout the extension trial. The median time to laxation was significantly shorter in the methylnaltrexone group than in the placebo group. Evidence of withdrawal mediated by central nervous system opioid receptors or changes in pain scores was not observed. Abdominal pain and flatulence were the most common adverse events.
Although alvimopan was approved by the FDA in May, 2008, it was only for short-term use (15 doses) in hospitalized patients and was indicated to accelerate the time to upper and lower GI recovery following partial large or small bowel resection surgery with primary anastomosis. In addition, alvimopan should not be used in patients who have received opioids for more than 1 week. This last restriction was included because data presented to the FDA indicated that the 12-mg dose of alvimopan can actually be painful for patients receiving long-term opioid therapy. Dose recommendations for this indication are 12 mg administered 30 minutes to 5 hours before surgery followed by 12 mg bid beginning the day after surgery for a maximum of 7 days or until discharge. Alvimopan is a large polar molecule that does not easily enter the CNS and produces strong peripheral opioid antagonism without affecting central effects such as pain relief. It is available only as an oral preparation. Systemic absorption is approximately 6%.33 Gonenne et al.34 demonstrated the effectiveness of alvimopan on codeine-induced constipation in a group of 74 healthy volunteers. Alvimopan 12 mg was given twice daily in the presence and absence of codeine sulfate 30 mg four times/day, or codeine or placebo alone. Codeine delayed gastric, small-bowel, proximal, and overall colonic transit (P < .05). Alvimopan reversed codeine’s effect on small bowel and colon (ascending colon and overall colonic transit). Alvimopan also accelerated overall colonic transit compared with placebo. Thus, the mean colonic geometric center at 24 hours was 2.33 with placebo/placebo, 3.25 with alvimopan/placebo (P < .05), 1.5 with placebo/codeine (P < .05), and 2.63 with alvimopan/codeine. The mean geometric colonic center is a research technique used to evaluate colonic transit time. Regions of interest are generated around six segments of the colon to determine the geometric mean of counts in each segment. A weighted numerical value represents the center of the activity as it travels through the colon. A high geometric center implies faster colonic transit times.
In addition to standard recommendations of increasing dietary fiber content and adequate fluid intake, we routinely use a stool softener (docusate) with a bowel stimulant (senna) for opioid-induced constipation. For intractable constipation unresponsive to routine measures, we use subcutaneous methylnaltrexone.
ADJUVANT ANALGESICS
Adjuvant analgesics are medications whose principal indication is not pain relief, but which may provide or enhance pain relief under appropriate circumstances. The common adjunctive analgesics in the setting of cancer pain are corticosteroids, anticonvulsants, and antidepressants. Adjuvant analgesics include general-purpose analgesics, adjuvants used for musculoskeletal pain, and those with specific use for neuropathic, bone, or visceral pain. These drugs play an important role for patients who cannot attain an acceptable balance between pain relief and opioid side effects.
General Purpose Adjuvants
Corticosteroids are the most widely used general-purpose adjuvant analgesics.35 Steroids are most useful for increased intracranial pressure, acute spinal cord compression, superior vena cava syndrome, metastatic bone pain, neuropathic pain due to infiltration or compression, symptomatic lymphedema, and hepatic capsular distension. Standard doses are dexamethasone 4 to 8 mg/day or prednisone 30 to 60 mg/day or the equivalent in patients with advanced cancer and related symptoms.36 A very short course of relatively high doses (eg, dexamethasone 100 mg I.V. followed initially by 96 mg per day in divided doses) can help ameliorate an acute episode of severe pain related to a neuropathic lesion (eg, plexopathy or epidural spinal cord compression) or bony metastasis that does not respond adequately to opioids. Once adequate pain relief has been attained, steroid doses should be tapered to the minimum needed to sustain pain relief.
Corticosteroids can also be used to achieve such endpoints as mood elevation, for anti-inflammatory effects, as antiemetics, and as appetite stimulants. The low dose regimen outlined above is appropriate for these purposes. Side effects and toxicity such as myopathy, hyperglycemia, or psychosis may make chronic steroid administration unacceptable for the patient (Table 18.5).
TABLE 18.5 STEROID TOXICITY | ||||||||||||||||||||||||
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Painful cutaneous and mucosal lesions can be managed with topical local anesthetics, such as EMLA cream (eutectic mixture of 2.5% lidocaine and 2.5% prilocaine. EMLA cream should be applied thickly and should be covered with an occlusive dressing. Lidocaine viscous may ameliorate pain associated with oropharyngeal ulceration. A topical lidocaine 5% patch (Lidoderm) may provide pain relief for patients who have failed other topical local anesthetic preparations such as EMLA cream. Besides its pain-relieving abilities, an important characteristic of the topical lidocaine patch is its lack of systemic activity. Studies have shown that Lidoderm results in serum levels approximately one tenth those needed to treat cardiac arrhythmias.37 Gammaitoni and Davis38 showed that with the application of four 5% lidocaine patches for 18 hours/day for 3 consecutive days, steady-state plasma concentrations were achieved within 3 days and that maximum plasma concentrations of lidocaine were similar to those reported with 3 lidocaine patches (5%) applied for 12 hours/day for 3 consecutive days. Lidoderm does not appear to cause any systemic side effects or any drug-drug interactions. The lidocaine patch consists of a 10 × 14-cm, nonwoven, polyethylene-backed, and medication-containing adhesive of 5% lidocaine (700 mg/patch) and other inactive ingredients. Patients apply a maximum of three lidocaine patches to intact skin, covering as much of the painful area as possible. The patch is typically left in place for 12 hours but use may also be extended to 24 hours.38 Unlike other formulations of lidocaine, the lidocaine patch exerts an analgesic effect without causing local anesthesia; the skin underlying its application continues to have normal sensation (ie, no “numbness”). The exact mechanism behind this effect is not known. Theoretically, the formulation may deliver sufficient amounts of lidocaine to block sodium channels on small damaged or dysfunctional pain fibers but insufficient amounts to block sodium channels on large myelinated A-β sensory fibers. The amount of drug absorbed is directly proportional to the skin surface area covered and the duration of patch application. In 1999, the patch was the first agent approved by the FDA for the treatment of PHN. There are also several anecdotal reports of their use in osteoarthritic knee pain and myofascial trigger points. A Cochrane database review reported insufficient evidence to recommend topical lidocaine as a first-line agent in the treatment of postherpetic neuralgia (PHN) with allodynia39 although Dworkin et al. recommend the agent for first-line treatment.40 The use of lidocaine patches is very safe with a very low systemic absorption and only local adverse effects (mild skin reactions) have been reported.41 Up to four patches per day for a maximum of 12 hours may be used to cover the painful area. Titration is not necessary.
We have found that the use of Lidoderm patches is safe and can be effective under certain circumstances in the oncology patient. We routinely use this patch in patients suffering from postherpetic neuralgia. We have also used the Lidoderm patch in chemotherapy-induced peripheral neuropathy, particularly of the lower extremities. In our experience, the results in this situation have been variable. Patients often report difficulty in maintaining patch adhesion in the feet. However, side effects are minimal and there does not appear to be a problem tolerating this medication in the oncology population.
Musculoskeletal Pain Adjuvants
Pain that originates from injury to muscle or connective tissue is not unusual in patients with cancer. Muscle relaxant medications are used primarily to treat spasticity from upper motor neuron syndromes and muscular pain or spasms from peripheral musculoskeletal conditions. Common painful musculoskeletal conditions include fibromyalgia, chronic tension headaches, myofascial pain syndrome, and mechanical low back or neck pain. The efficacy of socalled muscle relaxants and other drugs commonly used for the treatment of musculoskeletal pain has not been evaluated in cancer patients. Various drug categories are considered muscle relaxants such as antihistamines (eg, orphenadrine, Norflex), tricyclic compounds structurally similar to the tricyclic antidepressants (eg, cyclobenzaprine, Flexeril), and others (eg, carisoprodol, Soma, metaxalone, Skelaxin, and methocarbamol, Robaxin). The effects of these drugs are nonspecific and there is no evidence that they relax skeletal muscle in the clinical setting. The most common adverse effect is sedation, which can be additive to other centrally acting drugs, including opioids. The potential for abstinence syndrome, as well as abuse by predisposed patients, suggest caution when discontinuing therapy or when administering these drugs to those patients with a substance abuse history. In particular, we advise particular care when prescribing carisoprodol (Soma) for either short-term or long-term use. This drug is commonly used in the treatment of low back pain. It is a drug of abuse and has been implicated as a cause of impairment in drivers.42 Clinically, with impairment, patients may display signs similar to those of benzodiazepines with some important differences such as tachycardia, involuntary movements, hand tremor and horizontal gaze nystagmus.42
Some studies suggest that patients using carisoprodol for over three months may abuse the medication, especially those individuals with a history of substance abuse.43 Carisoprodol’s active metabolite meprobamate is thought to act through the gamma-aminobutyric acid (GABA) (A)-receptor complex and produces an impairing effect. As the formation of meprobamate from carisoprodol is catalyzed by CYP2C19, patients with impairment of this enzyme system have a lower capacity to metabolize carisoprodol and may therefore have an increased risk of developing concentration dependent side-effects such as drowsiness and hypotension, if treated with ordinary doses of carisoprodol.44
Some studies suggest that patients using carisoprodol for over three months may abuse the medication, especially those individuals with a history of substance abuse.43 Carisoprodol’s active metabolite meprobamate is thought to act through the gamma-aminobutyric acid (GABA) (A)-receptor complex and produces an impairing effect. As the formation of meprobamate from carisoprodol is catalyzed by CYP2C19, patients with impairment of this enzyme system have a lower capacity to metabolize carisoprodol and may therefore have an increased risk of developing concentration dependent side-effects such as drowsiness and hypotension, if treated with ordinary doses of carisoprodol.44
Other agents that have been tried for muscle spasms include diazepam, the α2-adrenergic agonist tizanidine or the GABA (B)-agonist baclofen. Injections of botulinum toxin can be considered for refractory musculoskeletal pain related to muscle spasms. Its duration of action is usually several months.
Tizanidine hydrochloride (Zanaflex) is a centrallyacting α2-adrenergic receptor agonist used for the treatment of muscle spasticity related to central nervous system diseases.45, 46 Activity at the α2-receptor results in direct inhibition of excitatory release of amino acids from spinal interneurons and a concomitant inhibition of facilitatory coeruleospinal pathways.47 Although primarily indicated in the treatment of spasticity, it has been suggested to be helpful in the treatment of chronic neck and lower back pain in patients who have a myofascial component to their pain.48 However, it should be noted that well controlled studies of the use of tizanidine in the treatment of myofascial pain are lacking. A Cochrane review of skeletal muscle relaxants to treat low back pain (through 2001) showed favorable outcomes for cyclobenzaprine and tizanidine in managing acute but not chronic low back pain.49 Common side effects of the drug include sedation, dry mouth, asthenia, and dizziness. Tizanidine may produce hypotension in up to 16% of patients.50 Doses are typically started at 2 to 4 mg and night and titrated slowly. Daily doses should not exceed 36 mg and are administered in divided doses three to four times daily.
Metaxalone (Skelaxin) is an oxazolidone derivative that may be useful for the acute management of peripheral musculoskeletal complaints, but is not effective in treatment of spasticity related to neurological disorders. Typical doses are 800 mg tid or qid. Chou et al.51 compared the efficacy and safety of a variety of skeletal muscle relaxants for the treatment of spasticity and painful musculoskeletal conditions and concluded that the evidence in favor of metaxalone was fair at best. The benefits of this agent in acute musculoskeletal syndromes may be primarily related to its sedative effects. Of note, Chou et al. also reported that there was very limited or inconsistent data regarding the effectiveness of metaxalone, methocarbamol, chlorzoxazone, baclofen, or dantrolene compared to placebo in patients with musculoskeletal conditions.
In summary, the evidence regarding the clinical use of skeletal muscle relaxants is limited because of poor methodologic design, inadequate assessment methods, and small numbers of patients. Most active comparator trials of patients with spasticity indicated that tizanidine, baclofen, dantrolene, and diazepam improved spasticity equally. There is some evidence to support the use of tizanidine, orphenadrine, carisoprodol, and cyclobenzaprine, but only in the treatment of acute low back pain; the evidence for their long-term use is poor. In general, we rarely prescribe these medications and, if used, they are prescribed only for short-term (less than 1 week) use.
Neuropathic Pain Adjuvants
Patients who suffer from chronic neuropathic pain rarely experience a complete resolution of their symptoms or complete functional restoration with any form of treatment. Neuropathic pain usually has multiple potential etiologies that include non-tumor causes such as central pain from stroke or spinal cord injury, peripheral nerve injury (CRPS Type 2), as well as metabolic causes such as diabetic neuropathy. Clinicians specializing in oncology pain management are likely to encounter diverse sources of neuropathic pain which will also include non-cancerrelated issues. The spectrum of problems likely to be encountered includes chemotherapy-induced peripheral neuropathy, postherpetic neuralgia, phantom limb pain, and tumor infiltration of nerves or nerve plexuses. Frequently, treatment strategies for cancer-related neuropathic pain are extrapolated from non-cancer-related neuropathic pain and may not necessarily be efficacious for cancer pain. In the treatment of neuropathic pain that is nonmalignant in origin, most of the randomized controlled trials have been conducted for PHN and painful polyneuropathy whereas there are relatively few trials in other peripheral neuropathic pains (including trigeminal neuralgia), and central pain, and no randomized trials in painful radiculopathies.41
Because neuropathic pain represents a complex array of symptoms and heterogeneous group of disorders and medical syndromes, clinicians must be accurate in making a diagnosis of neuropathic pain and not misdiagnosis other conditions that may mimic neuropathic pain such as musculoskeletal pain. Bennett et al.52 showed that the accuracy in diagnosing neuropathic pain was improved if signs and symptoms such as dysesthesia, tenderness or numbness, evoked pain, evidence of autonomic dysfunction, paroxysmal pain, thermal pain, or allodynia were present. Failure to accurately diagnose neuropathic pain will inevitably lead to less-than-optimal treatment strategies.
The use of adjuvants can contribute substantially to the management of neuropathic pain. The drugs used empirically for this indication include selected antidepressants, anticonvulsants, opioids, tramadol, N-methyl-D-aspartate (NMDA) antagonists, topical lidocaine, cannabinoids, and capsaicin (Table 18.6 and 18.7). Given the great interpatient and intrapatient variability in the response to adjuvants in this setting (including those within the same class), many patients require sequential trials to optimize pain management.
Antiepileptic drugs (AEDs) have been used extensively for the treatment of neuropathic pain but effective pain relief has been achieved in fewer than half of the patients who received this class of drug.53 Such outcomes may be partially attributable to the large variability in the presentation of each neuropathic pain syndrome and to the lack of a clear understanding of the precise neural mechanisms underlying each clinical symptom. In addition, the
relatively high treatment failures with AEDs are associated with the high prevalence of toxicity associated with their use. However, trials indicate that various AEDs, including carbamazepine, oxcarbazepine, valproate, phenytoin, lamotrigine, topiramate, levetiracetam, gabapentin, zonisamide, and tiagabine, are somewhat effective in treating neuropathic pain.54
relatively high treatment failures with AEDs are associated with the high prevalence of toxicity associated with their use. However, trials indicate that various AEDs, including carbamazepine, oxcarbazepine, valproate, phenytoin, lamotrigine, topiramate, levetiracetam, gabapentin, zonisamide, and tiagabine, are somewhat effective in treating neuropathic pain.54
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