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Complications of nonopiate pharmacotherapy
Complications of Nonopiate Pharmacotherapy W. David Mauck, MD, and Mark-Friedrich B. Hurdle, MD The intention of this article is to review complications associated with the more commonly used nonopioid medications prescribed for pain control. The medications discussed are limited to those commonly prescribed to the adult patient in the outpatient setting and include nonsteroidal antiinflammatory drugs, acetaminophen, anticonvulsants, tricyclic antidepressants, and topical agents. Only limited discussion is given to medication administered intravenously, intramuscularly, epidurally, intrathecally, or injected. Emphasis is placed on common reactions, life-threatening reactions, drug interactions, and safety in pregnancy. Semin Pain Med 2:220-227 © 2004 Elsevier Inc. All rights reserved.
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ccording to the World Health Organization (WHO), analgesic nonopioid analgesics are recommended as first line agents in the treatment of mild to moderate pain. Traditionally these analgesics have consisted of acetaminophen, acetylsalicylic acid, and nonsteroidal antiinflammatory drugs (NSAIDs) alone and in conjunction with anticonvulsants, antidepressants, local anesthetics, and other adjuvants. The algorithm indicates that these nonopioid pharmacotherapies can be titrated for increasing pain intensity as stronger opioids are added. While the WHO analgesic ladder was developed for cancer pain management, the principles and use of nonopioid medications as a first-line approach to pain control apply to many pain states. The reluctance of health care providers in prescribing opioids to cancer patients due to fear of addiction and tolerance lead to the WHOs analgesic recommendations. However, nonopioid medications can have equal or worse deleterious effects. Nonopioid medications used in the treatment and alleviation of pain are diverse and varied in their mechanism of action and efficacy. The risks associated with these medications are also diverse and must be carefully weighed against the potential benefits. This is a review of complications associated with the more commonly used nonopioid medications prescribed for pain control. Table 1 contains the common dosages and adverse reactions of the medications discussed. Many of the medications are not approved by the Food and Drug Administration (FDA) for the treatment of pain. The medications discussed are limited to those commonly prescribed in the outpatient setting with limited discussion on the intravenous, intramus-
Division of Pain Medicine, Mayo Clinic College of Medicine, Rochester MN. Address reprint requests to W. David Mauck, MD, Division of Pain Medicine, Mayo Clinic College of Medicine, 200 First Street SW, Rochester MN 55905. E-mail: [email protected]
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1537-5897/04/$-see front matter © 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.spmd.2004.09.009
cular, injectable, epidural, or intrathecal route. Emphasis is placed on common reactions, life-threatening reactions, drug interactions, and safety in pregnancy. Data cited are based on adult studies, usage, and doses. Complications not discussed are certainly possible, and we refer the reader to a pharmacology reference book or database for a complete drug monograph.
Acetaminophen Acetaminophen is indicated for pain and fever but possesses no antiinflammatory activity. Its mechanism of action remains poorly defined. The maximum daily dose of 4 g per day is recommended for patients with normal liver function. Hepatotoxicity is a serious complication of monotherapy. Acetaminophen overdose is the most common cause of acute liver failure in the United States.1 It usually occurs after a large, single, short-term dose or after chronic exposure of a low dose (less than 4 g). Age, malnutrition, and alcohol abuse are all independent risk factors for hepatotoxicity with acetaminophen.2,3 According to one study, a daily dose of greater than 2 g of acetaminophen is associated with an increased risk of an upper gastrointestinal bleed.4 Occasional to moderate intake of acetaminophen does not appear to increase the risk for nephrotoxicity in healthy individuals.5,6 However, concomitant use of aspirin has lead to nephrotoxicity.7 It is a pregnancy category B medication.
NSAIDs (Nonsteroidal Antiinflammatory Drugs) Nonsteroidal antiinflammatory drugs (NSAIDs) are one of the most prescribed classes of drugs in the United States. More than 30 billion over-the-counter tablets are sold each
Complications of nonopiate pharmacotherapy
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Table 1 Nonopioid Oral Pain Medication Dosing and Side-Effects Drug Nonsteroidal antiinflammatory drugs (NSAID) Acetaminophen Baclofen Tizanidine Carbamazepine
Oxcarbazepine
Clonazepam
Gabapentin
Lamotrigine
Levetiracetam
Phenytoin
Tiagabine
Topiramate
Valproic acid
Zonisamide
Amitriptyline or nortriptyline Triptans
Dosing
Adverse Reaction
Drug specific
May increase INR, risk of GI bleed and renal toxicity
Up to 4 grams a day Start 5mg TID titrate to effect up to 80 mg/day Start 4 mg every 6-8 hours increase in 2 mg increments up to 36 mg/day Start 200 mg/day. Increase by 100 mg every 3-7 days to goal 1,200 mg/day (dose TID or QID) Start 150 mg/day. Increase by 150 mg every 3-7 days to goal 1200 mg/day (dose BID) Start 0.5 mg at night. Increase by 0.25 mg every 3rd day to goal 4-8 mg/ day (dose TID) Start 300 mg/day. Increase 300 mg every 3rd day to goal 3600 mg (dose TID or QID) Start 25-50 mg/day. Increase 25 mg every 7th day to goal 300-500 mg/ day (dose BID) Start 250 mg/day. Increase by 250 mg every 3-5th day to goal 1000-2000 mg/day (dose BID) Start at 50 mg TID, Increase by 50 mg every 7th day to goal 300-450 mg/ day (dose TID)
Risk of hepatotoxicity in doses >4 gm a day Possible additive affects with CNS depressants
Start 4 mg/day. Increase 2-4 mg every 3rd day to goal 16-20 mg/day (dose BID to QID) Start 25-50 mg/day. Increase 50 mg every 7th day to goal 300-400 mg/ day (dose BID) Start 250 mg BID. Increase 250 mg every 7th day to goal 1,000-2,500 mg/day (dose BID) Start 100 mg/day. Increase 100 mg every 7th day to goal 200-400 mg/ day (dose BID) Start 10 mg at night. Increase 10 mg every 3-4th night to goal 50-100 mg/day (dose QHS) Drug specific
year, and 70 million prescriptions are written for NSAIDs.8 NSAID effects seem to be mediated by inhibiting prostaglandin synthesis via inhibiting cyclooxygenase (COX). The two isoforms of this enzyme are COX-1 and COX-2.9 Prostaglandins play a central role in the regulation of renal blood flow, gastric mucosa maintenance and smooth muscle activity in bronchioles. Prostaglandins (PG) effect inflammation, pain transmission, and body temperature. The COX-1 isoenzyme produces prostaglandins more commonly required in the
Can cause CNS depression Drowsiness, dizziness, diplopia, nausea, leukopenia, elevated liver enzymes, many drug interactions, aplastic anemia (rare) Drowsiness, dizziness, diplopia, nausea, water retention and hyponatremia, rare anemia Drowsiness, depression, dizziness, ataxia and irritability. Rare pancytopenia and elevated liver enzymes Drowsiness, dizziness, fatigue
Dizziness, somnolence, nausea, rash, ataxia, nausea. Rare Stephens-Johnson Syndrome Drowsiness, fatigue, coordination difficulties, behavioral abnormalities Many drug interactions, nystagmus, ataxia, diplopia, vertigo, somnolence, osteomalacia, megaloblastic anemia, nausea, gingival hyperplasia, rash. Rare Stephens-Johnson syndrome Dizziness, somnolence, tremor
Dizziness, fatigue, ataxia, somnolence, kidney stones, weight loss, metabolic acidosis Thrombocytopenia, alopecia, nausea and elevated liver enzymes Avoid with sulfa allergy, anorexia, dizziness, somnolence, nausea, kidney stones Anticholinergic effects, sedating, reduces seizure threshold, weight gain, sexual dysfunction Vasoconstrictive, paresthesias, dizziness, somnolence, nausea, flushing, neck pain
kidney, gastric mucosa, endothelium, and platelets. The Cox-2 isoenzyme usually produces prostaglandins in an inflammatory reaction; however, there is some heterogeneity of isoenzymes within most systems.10 Celecoxib and valdecoxib are the two COX-2-specific NSAIDs currently available in oral form within the United States since rofecoxib was pulled from the market. Contraindication to using NSAIDS include any history of hypersensitivity to aspirin, or other NSAIDs. Most NSAIDs
W.D. Mauck and M.-F.B. Hurdle
222 interact with aspirin, anticoagulants, or other antiinflammatory agents potentially increasing the risk of bleeding. Other side effects include increased blood pressure, fluid retention, and anemia. Common adverse reactions include bleeding, dyspepsia, renal toxicity, hepatic toxicity, and allergic reactions. Gastrointestinal toxicity is common among nonselective NSAIDs. Approximately 1% of patients taking nonselective NSAIDs for 3-6 months develops symptomatic ulcers. Cox-2-specific NSAIDs have a reduced tendency to cause injury to the gastric lining.11 Reduced renal prostaglandin production resulting in reduced renal blood flow and glomerular filtration rate may occur secondary to NSAID use (COX-nonspecific and COX-2-specific).9 This adverse reaction typically involves patients with compromised renal function secondary to volume depletion, congestive heart failure, or cirrhosis.9,12 COX-nonspecific NSAIDs inhibit platelet aggregation by reversibly binding to the COX-1 enzyme that is found in platelets.13 At therapeutic doses, COX-2-selective NSAIDs do not lead to increased bleeding perioperatively.14 Aspirin binds irreversibly to platelets that have a circulation time of up to 10 days. COX-nonspecific NSAIDs such as ibuprofen used with aspirin may diminish the cardioprotective affect of aspirin.15 Whether certain COX-2-specific NSAIDs are cardioprotective or increase the risk for myocardial infarctions remains controversial.16,17 All NSAIDs may impair bone healing.18 The use of ketorolac after spinal fusion with instrumentation leads to a significantly higher rate of nonunion. Most nonsteroidal medications are category C with regard to pregnancy.
Anticonvulsants Anticonvulsants were used in pain management soon after they were developed to treat epilepsy in the 1960s.19 Basic and clinical research has now firmly established anticonvulsants as first line treatment in certain neuropathic pain states including trigeminal neuralgia, diabetic peripheral neuropathy, and postherpetic neuralgia.20-22 Still other neuropathic pain states are treated with anticonvulsants based on proposed pathophysiology and clinical data that may or may not result from randomized, double-blind, placebo-controlled trials. Antiepileptic drugs (AED) exert their action in quite varied and sometimes unspecified ways. A variety of anticonvulsants work, at least in part, by blocking sodium channels and thus ectopic neuronal activity at nerve injury sites and associated dorsal root ganglion.23 Proposed mechanisms of other anticonvulsants include inhibition of excitatory amino acid release, blockade of neuronal calcium channels, increased gamma aminobutyric acid (GABA) transmission, and augmentation of other central nervous system inhibitory pathways. The AED side effects and adverse reactions are as varied as the mechanisms of actions.
Carbamazepine Carbamazepine is an iminostilbene derivative chemically related to the tricyclic antidepressant imipramine. Its efficacy in
treating neuropathic pain has been established in patients with trigeminal neuralgia and painful diabetic peripheral neuropathy.21,24-26 The recommended starting dose is 200 mg/d, increasing every 3-7 days by 100 mg to a maximum goal of 1200 mg/d (divided TID or QID).27 The dose should be increased until the goal dose is reached, satisfactory relief is obtained or intolerance/toxicity appears. The most common adverse events include dizziness, drowsiness, ataxia, diplopia, blurred vision, nausea, and vomiting. Acute intoxication can result in coma, seizures, hyperirritability, and respiratory depression. At high plasma concentrations there is oliguria, water retention, and hyponatremia. In rare instances, erythema multiforme and Stevens-Johnson syndrome have been reported. A transient elevation in hepatic enzymes occurs in up to 10% of patients taking carbamazepine. Ten percent of patients develop a mild transient leukopenia that usually resolves within the first 4 months of therapy and one-quarter of these patients have persistent leukopenia requiring cessation of the drug. Aplastic anemia is a rare irreversible complication with a prevalence of about 1 in 150,000 exposed individuals.28 For this reason, regular monitoring of hematologic function is strongly recommended despite clear evidence that this can avert the development of aplastic anemia. Hepatic and renal function monitoring has also been advocated.29 Carbamazepine use during pregnancy is associated with increased risk of congenital malformations and teratogenic effects in the human fetus. It is a pregnancy category D medication. Carbamazepine induces the cytochrome P450 system and thus its own metabolism as well as that of other drugs. One of the most common drug interactions results in lower plasma levels of estrogen with women taking oral contraceptives, rendering the oral contraceptives less effective, and often requires women to increase their estrogen dose. It also accelerates the metabolism of several medications including valproic acid, corticosteroids, antipsychotic drugs, and anticoagulants. Other medications including propoxyphene, cimetidine, and fluoxetine inhibit carbamazepine metabolism. Monoamine oxidase (MOA) inhibitors should be discontinued for a minimum of 14 days before carbamazepine is begun. Careful monitoring is required when combining carbamazepine with many other medications including anticonvulsants or selective serotonin-reuptake inhibitors because of the change in blood levels of these drugs have on carbamazepine and vice versa.
Oxcarbazepine Oxcarbazepine, an analog of carbamazepine, was designed to have fewer side effects and similar efficacy due to its lack of formation of the toxic metabolite carbamazepine 10,11 epoxide.30 Like carbamazepine, its principal mechanism is sodium channel blockade, but it shows some advantages over carbamazepine in that it does not undergo autoinduction of its own metabolism and is not metabolized by the cytochrome P450 system. It does, however, induce certain cytochrome P450 isoforms that can reduce the efficacy of oral contraceptives. There is
Complications of nonopiate pharmacotherapy no evidence of interaction with warfarin, cimetidine, or propoxyphene. Common dose-related side effects include dizziness, somnolence, headache, ataxia, nausea, and diplopia. Like carbamazepine, the antidiuretic effects of water retention and hyponatremia persist (3-23%), especially in the elderly.31 Allergic skin reactions (4%), leukopenia (⬍1%), and aplastic anemia occurs less frequently than with carbamazepine. Caution should be exercised in those sensitive to carbamazepine due to a 30% cross-sensitivity with oxcarbazepine. Oxcarbazepine crosses the human placenta, is structurally similar carbamazepine (teratogenic in humans) and has been observed to cause teratogenic effects in animal studies. For these reasons it is classified as a pregnancy category C medication.
Clonazepam Clonazepam is certainly not a first line medication for neuropathic pain, but a few limited studies show some benefit for facial neuralgias, cluster headaches, and trigeminal neuralgia.32,33 Unlike the rest of the AEDs discussed here, clonazepam is pharmacologically related to the benzodiazepine family and thus has a similar side effect profile. The primary complaint of drowsiness and lethargy occur initially in 50% of patients, but these symptoms tend to subside with chronic administration. Other side effects occurring from 3 to 13% include depression, dizziness, ataxia, and irritability.34 Depression can be particularly pronounced in the elderly. Much less common complications include transiently elevated serum transaminases and alkaline phosphatase, leukopenia, anemia, thrombocytopenia, and eosinophilia. Periodic blood counts and liver function tests have been advocated. Like most of the AEDs, a rapid discontinuation of clonazepam can precipitate seizures. Because of experience with other members of the benzodiazepine family, clonazepam is assumed to be capable of causing congenital abnormalities when administered to women in the first trimester of pregnancy. It is a pregnancy class D medication.
Gabapentin Gabapentin is structurally similar to ␥-aminobutyric acid (GABA), although its precise mechanism is unknown. It has gained wide-spread popularity for the treatment of neuropathic pain states in part due to its perceived efficacy as well as its relatively low incidence of severe side effects. Two large, randomized clinical trials demonstrated that gabapentin reduced pain in patients with painful diabetic neuropathy and those suffering from postherpetic neuralgia.20,22 For adults, a starting dose of 300 mg/d is recommended with a 300 mg increase every day to a total goal of 1800-3600 mg/d (divided TID or QID). Some patients may require a slower titration due its common side of effect of somnolence. Gabapentin possesses two desirable pharmacokinetic properties; it is not hepatically metabolized and it is excreted unchanged in the urine. Reduced dosing is required in those with impaired renal function due to its renal excretion. It does not affect the plasma level of other anticonvulsants or oral contraceptives. No serious side effects have been re-
223 ported, and acute overdoses up to 48.9 g have been reported without fatality. Somnolence, dizziness, ataxia, fatigue, nystagmus, headache, tremor, and diplopia have an occurrence greater than 10%.35 Other common side effects include nausea and/or vomiting, nystagmus, blurred vision, and rhinitis. Most of these were observed early in therapy, transient in duration, and disappeared with prolonged therapy. It is a pregnancy category C medication.
Lamotrigine Lamotrigine blocks voltage-dependent sodium channels and inhibits glutamate release. Hepatically metabolized, it does not induce or inhibit hepatic enzymes and thus does not effect the metabolism of most other medications. However, concurrent use of lamotrigine with carbamazepine may increase the epoxide metabolite of carbamazepine resulting in toxicity. Enzyme inducing medications including phenytoin and carbamazepine can reduce the plasma level of lamotrigine, whereas valproic acid coadministration can increase lamotrigine plasma levels while lowering valproic acid levels.29 Consider dose reduction in hepatic impairment. Lamotrigine is generally started at 25-50 mg/d. The dose is increased by 25-50 mg every 7-14 days to a maximum dose of 300-500 mg/d (divided BID). A rash occurs in up to 10% of patients and rarely (0.1-0.3%) can develop into StevensJohnson syndrome. This risk is increased by concurrent valproic acid use and rapid dose escalation.27 Discontinue lamotrigine at the first sign of rash unless the rash is clearly not drug related. The more common adverse effects are headache, dizziness, somnolence, ataxia, nausea/vomiting, diplopia, blurred vision, and rhinitis. Lamotrigine is a pregnancy category C medication.
Levetiracetam Levetiracetam was approved in 1999 for treatment of partialonset seizures in adults and has only anecdotal support for treatment of neuropathic pain. Its exact mechanism is unknown but it does not appear to have activity against traditional drug targets implicated in the modulation of inhibitory and excitatory neurotransmission.36 It is renally eliminated, therefore the dosing must be reduced in patients with renal impairment. Levetiracetam can be started at 250-500 mg/d increasing 250 mg every third day to a goal of 1000-2000 mg/d (divided BID). Overall, the drug has a high safety margin and is well tolerated. It is a pregnancy category C medication.
Phenytoin Phenytoin has been available since 1938 and was the first anticonvulsant used in pain management. Despite its long historical use, there is limited and conflicting evidence for its treatment of neuropathic pain. Phenytoin limits the repetitive firing of neuron action potentials by slowing the rate of recovery of voltageactivated sodium channels from the inactive state. The pharmacokinetics of phenytoin are complex and even small dosage increases can result in toxicity. In addition, the drug interactions with phenytoin are many and varied. The majority of phenytoin is metabolized by the cytochrome P450 system. Other drugs
W.D. Mauck and M.-F.B. Hurdle
224 metabolized by these enzymes can saturate the pathways, limit metabolism, and increase plasma levels of phenytoin as well as other drugs including warfarin. Warfarin levels will initially rise and later fall due to phenytoin’s induction of the cytochrome P450 system. This ultimately increases the metabolism of many other medications (carbamazepine, valproic acid, warfarin, oral contraceptives). The potential for teratogenic effects during pregnancy include a pattern of malformations called “fetal hydantoin syndrome” (wide-set eyes, broad mandible, finger deformities). This is a pregnancy category D medication. The toxic effects of phenytoin depend on the route of administration, duration of use, and dosage. Focusing on side effects associated with the oral route include cerebellarvestibular dysfunction (nystagmus, ataxia, diplopia, vertigo), which is the primary adverse reaction, but other side effects include slurred speech, somnolence, gastrointestinal intolerance (GI), osteomalacia, megaloblastic anemia, and behavioral changes. Gingival hyperplasia occurs in 20% of chronically treated patients. Other cosmetic sided effects include acne, hirsutism, and coarsening of facial features. Hyperglycemia appears to be due to inhibition of insulin secretion. Allergic reactions include morbilliform rash (2-5%) and rarely Steven-Johnson syndrome. Plasma phenytoin level, liver function tests, and complete blood counts should be followed.
Tiagabine Tiagabine has a novel mechanism of action, blocking the reuptake of GABA into presynaptic neurons. A starting dose of 4 mg/d is recommended with a 2-mg increase every third day to a total goal of 16-20 mg/d (divided BID to QID). Because it is metabolized primarily in the liver by the cytochrome P450 system, its half-life and plasma levels are reduced when it is coadministered with hepatic enzyme-inducing drugs such as phenytoin and carbamazepine. It has a negligible effect on other anticonvulsants, warfarin, oral contraceptives, and digoxin. Dosage reduction may be necessary in patients with liver impairment. Tiagabine is well tolerated. The principal adverse effects include mild to moderate dizziness, asthenia, somnolence, and tremor. It also has the potential to exacerbate absence seizures. It is a pregnancy category C medication.
Topiramate Topiramate reduces neuronal activity by slowing recovery of voltage-dependent sodium channels in a manner similar to phenytoin, enhances GABAA receptors, and antagonizes the kainate subtype of the glutamate receptors. It is also a weak carbonic anhydrase inhibitor. The initial dose is 25-50 mg/d followed by weekly increases of 50 mg to a maximum goal of 300-400 mg/d (divided BID). Patients with renal impairment (creatine clearance ⬍70 mL/min) should reduce their maximum dose by 50% and titrate doses slowly. Hepatic impairment may also slow drug clearance to a lesser degree. Plasma topiramate levels are decreased when coadministered with phenytoin, carbamazepine, and valproic acid. Topiramate decreases valproic acid levels (11%), while increasing phe-
nytoin levels by 25%. Administering topiramate to patients receiving digoxin requires careful monitoring of digoxin levels because topiramate reduces serum digoxin levels by 12%. In addition, the efficacy of oral contraceptives may be reduced in patients also taking topiramate. Fatigue, dizziness, ataxia, somnolence, nervousness, and decreased concentration are common adverse effects. Other clinically relevant adverse events include a 1.5% incidence of nephrolithiasis and mild weight loss averaging 1-6 kg.37 The carbonic anhydrase inhibitory effect not only increases the risk of nephrolithiasis but also metabolic acidosis due to increased renal bicarbonate loss. Patients with a predisposing condition (renal, respiratory, and/or hepatic impairment), ketogenic diet, or concurrent treatment with other drugs that may cause acidosis are at a higher risk of developing metabolic acidosis. Baseline and periodical serum bicarbonate levels should be monitored during treatment. There is animal model evidence of teratogenicity, but there are no studies in humans. Topiramate is a pregnancy class C medication.
Valproic Acid Valproic acid is approved for migraine prophylaxis by the FDA, but little evidence of therapeutic efficacy in neuropathic pain exists. Thrombocytopenia, alopecia, and elevated liver enzymes in up to 40% of patients limit its therapeutic efficacy. This drug is a teratogenic agent causing neural tube defects and is a pregnancy category D medication.
Zonisamide Zonisamide is a sulfonamide derivative that was approved as an anticonvulsant in the year 2000. It inhibits the T-type calcium currents as well as blocking sodium channels in a manner similar to actions of phenytoin and carbamazepine. The majority of the oral dose is renally excreted in the unmetabolized and glucuronide of sulfamoylacetyl phenol form, which is cytochrome P450 metabolite.29 Slower titration and frequent monitoring are indicated in those with renal and hepatic impairment. Patients with hypersensitivity to sulfonamides should avoid zonisamide. Medications that induce the cytochrome P450 system (carbamazepine, phenytoin, valproic acid) could decrease the levels and effect of zonisamide, while those that inhibit the same system could increase the levels. It does not inhibit the cytochrome P450 system and has no appreciable effect on steady-state concentrations of other anticonvulsants studied. Overall, zonisamide is well tolerated. Anorexia (13%), dizziness (13%), and somnolence (17%) are the most common adverse events. Other less common side effects include ataxia, fatigue, headache, nausea, irritability, and nervousness. Approximately 4% of individuals develop calcium or urate kidney stones during treatment with zonisamide. Zonisamide is teratogenic in laboratory animals and is a pregnancy class C medication.
Antidepressants Antidepressants are one of the most commonly prescribed classes of drugs for the treatment of chronic pain. Tricyclic
Complications of nonopiate pharmacotherapy antidepressants (TCA) block both norepinephrine (NE) and serotonin (5-HT) reuptake in varying degrees at spinal dorsal horn synapses. Studies using TCAs in diabetic neuropathy, postherpetic neuralgia, and tension headaches offer the most compelling evidence for pain relief.38,39 The cardiovascular system is the most vulnerable to the toxic side effects of tricyclic antidepressants. Hypotension, heart block, and arrhythmias are the most serious complications. Severe postural hypotension associated with falls and injuries40 is the principal cardiovascular event and is likely related to the drugs anti-␣1-adrenergic actions. Imipramine and amitriptyline have the greatest orthostatic effect, whereas nortriptyline has the least. TCAs have direct cardiac depressing actions similar to class 1 antiarrhythmics that can result in heart block and potentially dangerous complex arrhythmias. The elderly, those taking other cardiac depressants, and those with a history of ischemic heart disease or cardiac conduction defects are at higher risk. A baseline electrocardiogram before starting TCAs is recommended by some.41 Anticholinergic effects following tricyclic antidepressant therapy may be pronounced. Amitriptyline, imipramine, and doxepin cause the highest incidence of anticholinergic effects including dry mouth, constipation, blurred vision, tachycardia, and urinary retention. Nortriptyline and desipramine are only mildly anticholinergic. Central nervous system depression in the form of sedation can either be quite limiting or advantageous depending on previous insomnia symptoms. Sedation is likely mediated by blockade of histamine (H1) receptors and is most marked with amitriptyline, imipramine, and doxepin, whereas nortriptyline and desipramine are less sedating. The sedating effects usually wane after several weeks of use. TCAs may also reduce the seizure threshold thus limiting their use in patients with seizure disorders or those taking medications that may also produce seizures. Weight gain, sexual dysfunction, and psychiatric complications may also limit treatment with TCAs. Use of tricyclic antidepressants, and amitriptyline in particular, have been implicated in increased appetite and weight gain. Delayed or even inability to orgasm can also limit TCA use in both sexes.42 The primary psychiatric concern is suicide. The cardiovascular effects and lowered seizure threshold can quickly lead to a lethal outcome when overdosed.41 Tricyclic antidepressants are oxidized by hepatic microsomal enzymes and then conjugated with glucuronic acid. The usual starting dose of amitriptyline or nortriptyline is 10-25 mg at bedtime and increasing the dose by the same increment every 3-4 nights to satisfactory pain relief or a goal of 100 mg/d in single day dosing.41 Individual variance in TCA plasma levels to a given dose is as high as 10- to 30-fold and is largely due to genetic variance and control of hepatic microsomal enzymes.43 Consider reducing the dose of TCA or monitoring plasma levels in patients with hepatic impairment. Abrupt discontinuation of TCAs should be avoided to prevent withdrawal symptoms of malaise, chills, coryza, muscle aches, and sleep disturbances. A gradual taper over a week is advisable. Tricyclic antidepressants are involved in several clinically important drug reactions. The catecholamine uptake-blocking properties, central nervous system, and anticholinergic
225 effects are most likely to be responsible for drug interactions. Combination therapy with monoamine oxidase inhibitors can precipitate serotonin syndrome characterized by myoclonus, hyperreflexia, tremor, increased muscle tone, fever, shivering, sweating, diarrhea, delirium, and coma. Clonidine cessation rebound hypertension may be accentuated during TCA therapy. Beta-agonists when combined with TCAs may predispose patients to cardiac dysrhythmias. Coadministration of medications that prolong the electrocardiogram QT interval (type 1 and 3 antiarrhythmics, selected quinolones, and other agents) may increase the risk of fatal arrhythmias. The pregnancy categories for TCAs range from B to D.
Muscle Relaxants Baclofen Baclofen, a central acting muscle relaxant, is FDA approved for the treatment of spasticity. Baclofen exerts its effects as an agonist at presynaptic GABA-B receptors. Baclofen may be helpful in the treatment of trigeminal neuralgia.44,45 Intrathecal baclofen has been shown to produce analgesia in patients with chronic pain in case reports and smaller studies.46,47 Typically, oral dosing is started with 5 mg TID titrating up to a maximum of 80 mg/d based on patient tolerance. Common side effects include drowsiness, dizziness, confusion, and muscle weakness. Treatments for overdose include supportive care as well as physostigmine to improve respiratory depression and sedation. It is a pregnancy category C medication.
Tizanidine Tizanidine (Zanaflex) is a central acting alpha-adrenergic agonist approved in the United States for the treatment of spasticity related to spinal cord injuries and multiple sclerosis.48 Chronic headaches may be treated with tizanidine.49-51 It is metabolized in the liver and excreted both via the renal (60%) and fecal (20%) route. Some of the more serious possible adverse reactions include hepatotoxicity, arrhythmias, blood dyscrasias, hallucinations, and seizures. Tizanidine potentiates the central nervous system (CNS) effects of alcohol. Avoid concomitant use of alpha-adrenergic agonist. An overdose could lead to respiratory depression that is then treated with furosemide or mannitol in conjunction with supportive care. It is a pregnancy category C medication.
Triptans Triptans are selective serotonin agonists (5-hydroxytryptophan [5-HT]1B/1D agonists) used effectively in the treatment of acute migraine attacks. These drugs activate serotonin receptors 5-HT1B and 5-HT1D on cerebral vessels, thus causing selective constriction of blood vessels, inhibiting the release of vasoactive neuropeptides by trigeminal terminals innervating the intracranial vessels and inhibiting nociceptive neurotransmission within the trigeminocervical complex.52 The 5-HT1B receptors is also found on coronary arteries and can be activated by triptans.53 The various triptans (sumatriptan, rizatriptan, zolmitriptan, naratriptan, almotriptan, frovatriptan, eletriptan) dif-
W.D. Mauck and M.-F.B. Hurdle
226 fer very little in terms of safety. The most frequent adverse effects are tingling, paresthesias, and sensations of warmth involving the head, neck, chest, and limbs. Other common symptoms include dizziness, somnolence, flushing, nausea, and neck pain or stiffness. Triptans can constrict coronary arteries and cause chest symptoms that mimic angina pectoris; however, chest pain associated with oral triptan use is generally not associated with electrocardiographic changes and is unlikely due to cardiac ischemia.54 Triptans are contraindicated in patients with histories of cerebral vascular disease, ischemic heart disease, Prinzmetal’s angina, peripheral vascular syndromes, and uncontrolled hypertension. Triptans should not be used in the management of hemiplegic or basilar migraine due to an increased risk of migraineassociated stroke. The use of triptans in combination with ergotamine derivatives must be avoided based on both drugs’ ability to stimulate serotonergic receptors on cerebral and coronary vessels. Monoamine oxidase (MOA) inhibitors can delay the metabolism of sumatriptan, rizatriptan, and zolmitriptan, thus increasing plasma levels. MAO inhibitors should be discontinued 2 weeks before administering these triptans. Propranolol increases plasma levels of rizatriptan and frovatriptan. All triptans have a low risk of causing serotonin syndrome when given in combination with other serotomimetic agents. The neurologic symptoms are usually transient but can be lifethreatening. The triptans are a pregnancy class C medication.
Topical Medications Capsaicin is a medication composed of chili pepper extract. It induces the release of substance P from nociceptive primary afferents and after repeated application depletes the neuron of substance P and prevents reaccumulation. On application, it produces mild to severe burning that usually diminishes with continued use. It should not be applied to mucous membranes or broken/irritated skin. Gloves should be worn during and hands washed following application to avoid unwanted application to other parts of the body. It is a pregnancy category C medication. Local anesthetics in the form of a gel, patch, and cream have proven effective in various pain states. In chronic pain states, the lidocaine patch is frequently chosen over the gel and cream due to ease of application and documented low plasma lidocaine levels that are well below the expected toxic levels. The most common adverse reaction involves mild skin irritation at the site of application. Patients with severe hepatic disease are at greater risk of developing toxic blood concentrations because of their inability to metabolize lidocaine. Care must be taken with those taking other class 1 antiarrhythmics and local anesthetics as the toxic effects are additive and possibly synergistic. Application to broken/inflamed skin or mucous membranes may lead to higher blood concentrations of lidocaine. It is a pregnancy category B medication.
Summary Nonopioid analgesics and adjuvants are being used increasingly for neuropathic pain syndromes, myofascial pain, head-
aches, and other pain states. They are the first line treatment for mild to moderate pain and are often continued even if opioids are eventually added. Knowledge of their potential complications is necessary to safely choose these medications and treat those suffering with pain.
References 1. Ostapowicz G, Fontana RJ, Schiodt FV, et al: Results of a prospective study of acute liver failure at 17 tertiary care centers in the United States. Ann Intern Med 137:947-954, 2002 2. Schmidt LE, Dalhoff K, Poulsen HE: Acute versus chronic alcohol consumption in acetaminophen-induced hepatotoxicity. Hepatology 35: 876-882, 2002 3. Whitcomb DC, Block GD: Association of acetaminophen hepatotoxicity with fasting and ethanol use. J Am Med Assoc 272:1845-1850, 1994 4. Garcia Rodriguez LA, Hernandez-Diaz S: Relative risk of upper gastrointestinal complications among users of acetaminophen and nonsteroidal anti-inflammatory drugs. Epidemiology 12:570-576, 2001 5. Kurth T, Glynn RJ, Walker AM, et al: Analgesic use and change in kidney function in apparently healthy men. Am J Kidney Dis 42:234244, 2003 6. Blantz RC: Acetaminophen: Acute and chronic effects on renal function. Am J Kidney Dis 28:S3-S6, 1996 7. Duggin GG: Combination analgesic-induced kidney disease: The Australian experience. Am J Kidney Dis 28:S39-S47, 1996 8. Lichtenstein DR, Syngal S, Wolfe MM: Nonsteroidal antiinflammatory drugs and the gastrointestinal tract. The double-edged sword. Arthritis Rheum 38:5-18, 1995 9. Gambaro G, Perazella MA: Adverse renal effects of anti-inflammatory agents: Evaluation of selective and nonselective cyclooxygenase inhibitors. J Intern Med 253:643-652, 2003 10. Pairet M, Engelhardt G: Distinct isoforms (COX-1 and COX-2) of cyclooxygenase: Possible physiological and therapeutic implications. Fund Clin Pharmacol 10:1-17, 1996 11. Bjarnason I, Macpherson A, Rotman H, et al: A randomized, doubleblind, crossover comparative endoscopy study on the gastroduodenal tolerability of a highly specific cyclooxygenase-2 inhibitor, flosulide, and naproxen. Scand J Gastroenterol 32:126-130, 1997 12. Perazella MA: Drug-induced renal failure: Update on new medications and unique mechanisms of nephrotoxicity. Am J Med Sci 325:349-362, 2003 13. Schafer AI: Effects of nonsteroidal antiinflammatory drugs on platelet function and systemic hemostasis. J Clin Pharmacol 35:209-219, 1995 14. Reuben SS, Fingeroth R, Krushell R, et al: Evaluation of the safety and efficacy of the perioperative administration of rofecoxib for total knee arthroplasty. J Arthroplasty 17:26-31, 2002 15. Catella-Lawson F, Reilly MP, Kapoor SC, et al: Cyclooxygenase inhibitors and the antiplatelet effects of aspirin. N Engl J Med 345:18091817, 2001 16. Mamdani M, Rochon P, Juurlink DN, et al: Effect of selective cyclooxygenase 2 inhibitors and naproxen on short-term risk of acute myocardial infarction in the elderly. Arch Intern Med 163:481-486, 2003 17. Mukherjee D, Nissen SE, Topol EJ: Risk of cardiovascular events associated with selective COX-2 inhibitors. J Am Med Assoc 286:954-959, 2001 18. Simon AM, Manigrasso MB, O’Connor JP: Cyclo-oxygenase 2 function is essential for bone fracture healing. J Bone Miner Res 17:963-976, 2002 19. McQuay H, Carroll D, Jadad AR, et al: Anticonvulsant drugs for management of pain: A systematic review. Br Med J 311:1047-1052, 1995 20. Backonja M, Beydoun A, Edwards KR, et al: Gabapentin for the symptomatic treatment of painful neuropathy in patients with diabetes mellitus: A randomized controlled trial. J Am Med Assoc 280:1831-1836, 1998 21. Nicol CF: A four year double-blind study of tegretol in facial pain. Headache 9:54-57, 1969 22. Rowbotham M, Harden N, Stacey B, et al: Gabapentin for the treatment
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of postherpetic neuralgia: A randomized controlled trial. J Am Med Assoc 280:1837-1842, 1998 Catterall WA: Common modes of drug action on Na⫹ channels: Local anesthetics, antiarrhythmics and anticonvulsants. Trends Pharm Sci 8:57-65, 1987 Campbell FG, Graham JG, Zilkha KJ: Clinical trial of carbazepine (tegretol) in trigeminal neuralgia. J Neurol Neurosurg Psychiatry 29:265267, 1966 Rull JA, Quibrera R, Gonzalez-Millan H, et al: Symptomatic treatment of peripheral diabetic neuropathy with carbamazepine (Tegretol): Double blind crossover trial. Diabetologia 5:215-218, 1969 Rockliff BW, Davis EH: Controlled sequential trials of carbamazepine in trigeminal neuralgia. Arch Neurol 15:129-136, 1966 Rowbotham M, Peterson K: Anticonvulsants and local anesthetic drugs, in Loesser J, Butler S, Chapman C (eds): Bonica’s Management of Pain (ed 3). Philadelphia, PA, Lippincott Williams and Wilkins, 2001, pp 1727-1735 Pellock JM: Carbamazepine side effects in children and adults. Epilepsia 28:S64-S70, 1987 McNamara JO: Drugs effective in the therapy of the epilepsies, in Hardman J, Limbird L, Gilman A (eds): Goodman and Gilman’s: The Pharmacological Basis of Therapeutics (ed 10). New York, NY, McGrawHill, 2001, pp 521-548 Pellock JM, Watemberg N: New antiepileptic drugs in children: Present and future. Semin Pediatr Neurol 4:9-18, 1997 Friis ML, Kristensen O, Boas J, et al: Therapeutic experiences with 947 epileptic out-patients in oxcarbazepine treatment. Acta Neurol Scand 87:224-227, 1993 Caccia MR: Clonazepam in facial neuralgia and cluster headache: clinical and electrophysiological study. Eur Neurol 13:560-563, 1975 Court JE, Kase CS: Treatment of tic douloureux with a new anticonvulsant (clonazepam). J Neurol Neurosurg Psychiatry 39:297-299, 1976 Rosenbaum JF, Moroz G, Bowden CL: Clonazepam in the treatment of panic disorder with or without agoraphobia: a dose-response study of efficacy, safety, and discontinuance. Clonazepam Panic Disorder DoseResponse Study Group. J Clin Psychopharmacol 17:390-400, 1997 The US Gabapentin Study Group No. 5. Gabapentin as add-on therapy in refractory partial epilepsy: a double-blind, placebo-controlled, parallel-group study. Neurology 43:2292-2298, 1993 Klitgaard H: Levetiracetam: The preclinical profile of a new class of antiepileptic drugs? Epilepsia 42:S13-S18, 2001 Shorvon SD: Safety of topiramate: Adverse events and relationships to dosing. Epilepsia 37:S18-S22, 1996
227 38. McQuay HJ, Tramer M, Nye BA, et al: A systematic review of antidepressants in neuropathic pain. Pain 68:217-227, 1996 39. Bendtsen L, Jensen R, Olesen J: A non-selective (amitriptyline), but not a selective (citalopram), serotonin reuptake inhibitor is effective in the prophylactic treatment of chronic tension-type headache. J Neurol Neurosurg Psychiatry 61:285-290, 1996 40. Ray WA, Griffin MR, Schaffner W, et al: Psychotropic drug use and the risk of hip fracture. N Engl J Med 316:363-369, 1987 41. Max MB, Gilron IH: Antidepressants, muscle relaxants, and N-methylD-aspartate receptor antagonists, in Loesser J, Butler S, Chapman C (eds): Bonica’s Management of Pain (ed 3). Philadelphia, PA, Lippincott Williams and Wilkins, 2001, pp 1710-1726 42. Segraves RT: Antidepressant-induced sexual dysfunction. J Clin Psychiatry 59:S48-S54, 1998 43. DeVane CL, Nemeroff CB: Psychotropic drug interactions. Econ Neurosci 2:55-75, 2000 44. Das B, Saha SP: Trigeminal neuralgia: current concepts and management. J Indian Med Assoc 99:704-709, 2001 45. Sindrup SH, Jensen TS: Pharmacotherapy of trigeminal neuralgia. Clin J Pain 18:22-27, 2002 46. Zuniga RE, Schlicht CR, Abram SE: Intrathecal baclofen is analgesic in patients with chronic pain. Anesthesiology 92:876-880, 2000 47. Herman RM, D’Luzansky SC, Ippolito R: Intrathecal baclofen suppresses central pain in patients with spinal lesions. A pilot study. Clin J Pain 8:338-345, 1992 48. Stien R, Nordal HJ, Oftedal SI, et al: The treatment of spasticity in multiple sclerosis: A double-blind clinical trial of a new anti-spastic drug tizanidine compared with baclofen. Acta Neurol Scand 75:190194, 1987 49. Lake AE 3rd, Saper JR: Chronic headache: New advances in treatment strategies. Neurology 59:S8-S13, 2002 50. D’Alessandro R: Tizanidine for chronic cluster headache. Arch Neurol 53:1093, 1996 51. Nakashima K, Tumura R, Wang Y, et al: Effects of tizanidine administration on exteroceptive suppression of the temporalis muscle in patients with chronic tension-type headache. Headache 34:455-457, 1994 52. Goadsby PJ: Serotonin receptors and the acute attack of migraine. Clin Neurosci 5:18-23, 1998 53. Longmore J, Shaw D, Smith D, et al: Differential distribution of 5HT1Dand 5HT1B-immunoreactivity within the human trigemino-cerebrovascular system: Implications for the discovery of new antimigraine drugs. Cephalalgia 17:833-842, 1997 54. Jamieson DG: The safety of triptans in the treatment of patients with migraine. Am J Med 112:135-140, 2002
A
ccording to the World Health Organization (WHO), analgesic nonopioid analgesics are recommended as first line agents in the treatment of mild to moderate pain. Traditionally these analgesics have consisted of acetaminophen, acetylsalicylic acid, and nonsteroidal antiinflammatory drugs (NSAIDs) alone and in conjunction with anticonvulsants, antidepressants, local anesthetics, and other adjuvants. The algorithm indicates that these nonopioid pharmacotherapies can be titrated for increasing pain intensity as stronger opioids are added. While the WHO analgesic ladder was developed for cancer pain management, the principles and use of nonopioid medications as a first-line approach to pain control apply to many pain states. The reluctance of health care providers in prescribing opioids to cancer patients due to fear of addiction and tolerance lead to the WHOs analgesic recommendations. However, nonopioid medications can have equal or worse deleterious effects. Nonopioid medications used in the treatment and alleviation of pain are diverse and varied in their mechanism of action and efficacy. The risks associated with these medications are also diverse and must be carefully weighed against the potential benefits. This is a review of complications associated with the more commonly used nonopioid medications prescribed for pain control. Table 1 contains the common dosages and adverse reactions of the medications discussed. Many of the medications are not approved by the Food and Drug Administration (FDA) for the treatment of pain. The medications discussed are limited to those commonly prescribed in the outpatient setting with limited discussion on the intravenous, intramus-
Division of Pain Medicine, Mayo Clinic College of Medicine, Rochester MN. Address reprint requests to W. David Mauck, MD, Division of Pain Medicine, Mayo Clinic College of Medicine, 200 First Street SW, Rochester MN 55905. E-mail: [email protected]
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1537-5897/04/$-see front matter © 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.spmd.2004.09.009
cular, injectable, epidural, or intrathecal route. Emphasis is placed on common reactions, life-threatening reactions, drug interactions, and safety in pregnancy. Data cited are based on adult studies, usage, and doses. Complications not discussed are certainly possible, and we refer the reader to a pharmacology reference book or database for a complete drug monograph.
Acetaminophen Acetaminophen is indicated for pain and fever but possesses no antiinflammatory activity. Its mechanism of action remains poorly defined. The maximum daily dose of 4 g per day is recommended for patients with normal liver function. Hepatotoxicity is a serious complication of monotherapy. Acetaminophen overdose is the most common cause of acute liver failure in the United States.1 It usually occurs after a large, single, short-term dose or after chronic exposure of a low dose (less than 4 g). Age, malnutrition, and alcohol abuse are all independent risk factors for hepatotoxicity with acetaminophen.2,3 According to one study, a daily dose of greater than 2 g of acetaminophen is associated with an increased risk of an upper gastrointestinal bleed.4 Occasional to moderate intake of acetaminophen does not appear to increase the risk for nephrotoxicity in healthy individuals.5,6 However, concomitant use of aspirin has lead to nephrotoxicity.7 It is a pregnancy category B medication.
NSAIDs (Nonsteroidal Antiinflammatory Drugs) Nonsteroidal antiinflammatory drugs (NSAIDs) are one of the most prescribed classes of drugs in the United States. More than 30 billion over-the-counter tablets are sold each
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Table 1 Nonopioid Oral Pain Medication Dosing and Side-Effects Drug Nonsteroidal antiinflammatory drugs (NSAID) Acetaminophen Baclofen Tizanidine Carbamazepine
Oxcarbazepine
Clonazepam
Gabapentin
Lamotrigine
Levetiracetam
Phenytoin
Tiagabine
Topiramate
Valproic acid
Zonisamide
Amitriptyline or nortriptyline Triptans
Dosing
Adverse Reaction
Drug specific
May increase INR, risk of GI bleed and renal toxicity
Up to 4 grams a day Start 5mg TID titrate to effect up to 80 mg/day Start 4 mg every 6-8 hours increase in 2 mg increments up to 36 mg/day Start 200 mg/day. Increase by 100 mg every 3-7 days to goal 1,200 mg/day (dose TID or QID) Start 150 mg/day. Increase by 150 mg every 3-7 days to goal 1200 mg/day (dose BID) Start 0.5 mg at night. Increase by 0.25 mg every 3rd day to goal 4-8 mg/ day (dose TID) Start 300 mg/day. Increase 300 mg every 3rd day to goal 3600 mg (dose TID or QID) Start 25-50 mg/day. Increase 25 mg every 7th day to goal 300-500 mg/ day (dose BID) Start 250 mg/day. Increase by 250 mg every 3-5th day to goal 1000-2000 mg/day (dose BID) Start at 50 mg TID, Increase by 50 mg every 7th day to goal 300-450 mg/ day (dose TID)
Risk of hepatotoxicity in doses >4 gm a day Possible additive affects with CNS depressants
Start 4 mg/day. Increase 2-4 mg every 3rd day to goal 16-20 mg/day (dose BID to QID) Start 25-50 mg/day. Increase 50 mg every 7th day to goal 300-400 mg/ day (dose BID) Start 250 mg BID. Increase 250 mg every 7th day to goal 1,000-2,500 mg/day (dose BID) Start 100 mg/day. Increase 100 mg every 7th day to goal 200-400 mg/ day (dose BID) Start 10 mg at night. Increase 10 mg every 3-4th night to goal 50-100 mg/day (dose QHS) Drug specific
year, and 70 million prescriptions are written for NSAIDs.8 NSAID effects seem to be mediated by inhibiting prostaglandin synthesis via inhibiting cyclooxygenase (COX). The two isoforms of this enzyme are COX-1 and COX-2.9 Prostaglandins play a central role in the regulation of renal blood flow, gastric mucosa maintenance and smooth muscle activity in bronchioles. Prostaglandins (PG) effect inflammation, pain transmission, and body temperature. The COX-1 isoenzyme produces prostaglandins more commonly required in the
Can cause CNS depression Drowsiness, dizziness, diplopia, nausea, leukopenia, elevated liver enzymes, many drug interactions, aplastic anemia (rare) Drowsiness, dizziness, diplopia, nausea, water retention and hyponatremia, rare anemia Drowsiness, depression, dizziness, ataxia and irritability. Rare pancytopenia and elevated liver enzymes Drowsiness, dizziness, fatigue
Dizziness, somnolence, nausea, rash, ataxia, nausea. Rare Stephens-Johnson Syndrome Drowsiness, fatigue, coordination difficulties, behavioral abnormalities Many drug interactions, nystagmus, ataxia, diplopia, vertigo, somnolence, osteomalacia, megaloblastic anemia, nausea, gingival hyperplasia, rash. Rare Stephens-Johnson syndrome Dizziness, somnolence, tremor
Dizziness, fatigue, ataxia, somnolence, kidney stones, weight loss, metabolic acidosis Thrombocytopenia, alopecia, nausea and elevated liver enzymes Avoid with sulfa allergy, anorexia, dizziness, somnolence, nausea, kidney stones Anticholinergic effects, sedating, reduces seizure threshold, weight gain, sexual dysfunction Vasoconstrictive, paresthesias, dizziness, somnolence, nausea, flushing, neck pain
kidney, gastric mucosa, endothelium, and platelets. The Cox-2 isoenzyme usually produces prostaglandins in an inflammatory reaction; however, there is some heterogeneity of isoenzymes within most systems.10 Celecoxib and valdecoxib are the two COX-2-specific NSAIDs currently available in oral form within the United States since rofecoxib was pulled from the market. Contraindication to using NSAIDS include any history of hypersensitivity to aspirin, or other NSAIDs. Most NSAIDs
W.D. Mauck and M.-F.B. Hurdle
222 interact with aspirin, anticoagulants, or other antiinflammatory agents potentially increasing the risk of bleeding. Other side effects include increased blood pressure, fluid retention, and anemia. Common adverse reactions include bleeding, dyspepsia, renal toxicity, hepatic toxicity, and allergic reactions. Gastrointestinal toxicity is common among nonselective NSAIDs. Approximately 1% of patients taking nonselective NSAIDs for 3-6 months develops symptomatic ulcers. Cox-2-specific NSAIDs have a reduced tendency to cause injury to the gastric lining.11 Reduced renal prostaglandin production resulting in reduced renal blood flow and glomerular filtration rate may occur secondary to NSAID use (COX-nonspecific and COX-2-specific).9 This adverse reaction typically involves patients with compromised renal function secondary to volume depletion, congestive heart failure, or cirrhosis.9,12 COX-nonspecific NSAIDs inhibit platelet aggregation by reversibly binding to the COX-1 enzyme that is found in platelets.13 At therapeutic doses, COX-2-selective NSAIDs do not lead to increased bleeding perioperatively.14 Aspirin binds irreversibly to platelets that have a circulation time of up to 10 days. COX-nonspecific NSAIDs such as ibuprofen used with aspirin may diminish the cardioprotective affect of aspirin.15 Whether certain COX-2-specific NSAIDs are cardioprotective or increase the risk for myocardial infarctions remains controversial.16,17 All NSAIDs may impair bone healing.18 The use of ketorolac after spinal fusion with instrumentation leads to a significantly higher rate of nonunion. Most nonsteroidal medications are category C with regard to pregnancy.
Anticonvulsants Anticonvulsants were used in pain management soon after they were developed to treat epilepsy in the 1960s.19 Basic and clinical research has now firmly established anticonvulsants as first line treatment in certain neuropathic pain states including trigeminal neuralgia, diabetic peripheral neuropathy, and postherpetic neuralgia.20-22 Still other neuropathic pain states are treated with anticonvulsants based on proposed pathophysiology and clinical data that may or may not result from randomized, double-blind, placebo-controlled trials. Antiepileptic drugs (AED) exert their action in quite varied and sometimes unspecified ways. A variety of anticonvulsants work, at least in part, by blocking sodium channels and thus ectopic neuronal activity at nerve injury sites and associated dorsal root ganglion.23 Proposed mechanisms of other anticonvulsants include inhibition of excitatory amino acid release, blockade of neuronal calcium channels, increased gamma aminobutyric acid (GABA) transmission, and augmentation of other central nervous system inhibitory pathways. The AED side effects and adverse reactions are as varied as the mechanisms of actions.
Carbamazepine Carbamazepine is an iminostilbene derivative chemically related to the tricyclic antidepressant imipramine. Its efficacy in
treating neuropathic pain has been established in patients with trigeminal neuralgia and painful diabetic peripheral neuropathy.21,24-26 The recommended starting dose is 200 mg/d, increasing every 3-7 days by 100 mg to a maximum goal of 1200 mg/d (divided TID or QID).27 The dose should be increased until the goal dose is reached, satisfactory relief is obtained or intolerance/toxicity appears. The most common adverse events include dizziness, drowsiness, ataxia, diplopia, blurred vision, nausea, and vomiting. Acute intoxication can result in coma, seizures, hyperirritability, and respiratory depression. At high plasma concentrations there is oliguria, water retention, and hyponatremia. In rare instances, erythema multiforme and Stevens-Johnson syndrome have been reported. A transient elevation in hepatic enzymes occurs in up to 10% of patients taking carbamazepine. Ten percent of patients develop a mild transient leukopenia that usually resolves within the first 4 months of therapy and one-quarter of these patients have persistent leukopenia requiring cessation of the drug. Aplastic anemia is a rare irreversible complication with a prevalence of about 1 in 150,000 exposed individuals.28 For this reason, regular monitoring of hematologic function is strongly recommended despite clear evidence that this can avert the development of aplastic anemia. Hepatic and renal function monitoring has also been advocated.29 Carbamazepine use during pregnancy is associated with increased risk of congenital malformations and teratogenic effects in the human fetus. It is a pregnancy category D medication. Carbamazepine induces the cytochrome P450 system and thus its own metabolism as well as that of other drugs. One of the most common drug interactions results in lower plasma levels of estrogen with women taking oral contraceptives, rendering the oral contraceptives less effective, and often requires women to increase their estrogen dose. It also accelerates the metabolism of several medications including valproic acid, corticosteroids, antipsychotic drugs, and anticoagulants. Other medications including propoxyphene, cimetidine, and fluoxetine inhibit carbamazepine metabolism. Monoamine oxidase (MOA) inhibitors should be discontinued for a minimum of 14 days before carbamazepine is begun. Careful monitoring is required when combining carbamazepine with many other medications including anticonvulsants or selective serotonin-reuptake inhibitors because of the change in blood levels of these drugs have on carbamazepine and vice versa.
Oxcarbazepine Oxcarbazepine, an analog of carbamazepine, was designed to have fewer side effects and similar efficacy due to its lack of formation of the toxic metabolite carbamazepine 10,11 epoxide.30 Like carbamazepine, its principal mechanism is sodium channel blockade, but it shows some advantages over carbamazepine in that it does not undergo autoinduction of its own metabolism and is not metabolized by the cytochrome P450 system. It does, however, induce certain cytochrome P450 isoforms that can reduce the efficacy of oral contraceptives. There is
Complications of nonopiate pharmacotherapy no evidence of interaction with warfarin, cimetidine, or propoxyphene. Common dose-related side effects include dizziness, somnolence, headache, ataxia, nausea, and diplopia. Like carbamazepine, the antidiuretic effects of water retention and hyponatremia persist (3-23%), especially in the elderly.31 Allergic skin reactions (4%), leukopenia (⬍1%), and aplastic anemia occurs less frequently than with carbamazepine. Caution should be exercised in those sensitive to carbamazepine due to a 30% cross-sensitivity with oxcarbazepine. Oxcarbazepine crosses the human placenta, is structurally similar carbamazepine (teratogenic in humans) and has been observed to cause teratogenic effects in animal studies. For these reasons it is classified as a pregnancy category C medication.
Clonazepam Clonazepam is certainly not a first line medication for neuropathic pain, but a few limited studies show some benefit for facial neuralgias, cluster headaches, and trigeminal neuralgia.32,33 Unlike the rest of the AEDs discussed here, clonazepam is pharmacologically related to the benzodiazepine family and thus has a similar side effect profile. The primary complaint of drowsiness and lethargy occur initially in 50% of patients, but these symptoms tend to subside with chronic administration. Other side effects occurring from 3 to 13% include depression, dizziness, ataxia, and irritability.34 Depression can be particularly pronounced in the elderly. Much less common complications include transiently elevated serum transaminases and alkaline phosphatase, leukopenia, anemia, thrombocytopenia, and eosinophilia. Periodic blood counts and liver function tests have been advocated. Like most of the AEDs, a rapid discontinuation of clonazepam can precipitate seizures. Because of experience with other members of the benzodiazepine family, clonazepam is assumed to be capable of causing congenital abnormalities when administered to women in the first trimester of pregnancy. It is a pregnancy class D medication.
Gabapentin Gabapentin is structurally similar to ␥-aminobutyric acid (GABA), although its precise mechanism is unknown. It has gained wide-spread popularity for the treatment of neuropathic pain states in part due to its perceived efficacy as well as its relatively low incidence of severe side effects. Two large, randomized clinical trials demonstrated that gabapentin reduced pain in patients with painful diabetic neuropathy and those suffering from postherpetic neuralgia.20,22 For adults, a starting dose of 300 mg/d is recommended with a 300 mg increase every day to a total goal of 1800-3600 mg/d (divided TID or QID). Some patients may require a slower titration due its common side of effect of somnolence. Gabapentin possesses two desirable pharmacokinetic properties; it is not hepatically metabolized and it is excreted unchanged in the urine. Reduced dosing is required in those with impaired renal function due to its renal excretion. It does not affect the plasma level of other anticonvulsants or oral contraceptives. No serious side effects have been re-
223 ported, and acute overdoses up to 48.9 g have been reported without fatality. Somnolence, dizziness, ataxia, fatigue, nystagmus, headache, tremor, and diplopia have an occurrence greater than 10%.35 Other common side effects include nausea and/or vomiting, nystagmus, blurred vision, and rhinitis. Most of these were observed early in therapy, transient in duration, and disappeared with prolonged therapy. It is a pregnancy category C medication.
Lamotrigine Lamotrigine blocks voltage-dependent sodium channels and inhibits glutamate release. Hepatically metabolized, it does not induce or inhibit hepatic enzymes and thus does not effect the metabolism of most other medications. However, concurrent use of lamotrigine with carbamazepine may increase the epoxide metabolite of carbamazepine resulting in toxicity. Enzyme inducing medications including phenytoin and carbamazepine can reduce the plasma level of lamotrigine, whereas valproic acid coadministration can increase lamotrigine plasma levels while lowering valproic acid levels.29 Consider dose reduction in hepatic impairment. Lamotrigine is generally started at 25-50 mg/d. The dose is increased by 25-50 mg every 7-14 days to a maximum dose of 300-500 mg/d (divided BID). A rash occurs in up to 10% of patients and rarely (0.1-0.3%) can develop into StevensJohnson syndrome. This risk is increased by concurrent valproic acid use and rapid dose escalation.27 Discontinue lamotrigine at the first sign of rash unless the rash is clearly not drug related. The more common adverse effects are headache, dizziness, somnolence, ataxia, nausea/vomiting, diplopia, blurred vision, and rhinitis. Lamotrigine is a pregnancy category C medication.
Levetiracetam Levetiracetam was approved in 1999 for treatment of partialonset seizures in adults and has only anecdotal support for treatment of neuropathic pain. Its exact mechanism is unknown but it does not appear to have activity against traditional drug targets implicated in the modulation of inhibitory and excitatory neurotransmission.36 It is renally eliminated, therefore the dosing must be reduced in patients with renal impairment. Levetiracetam can be started at 250-500 mg/d increasing 250 mg every third day to a goal of 1000-2000 mg/d (divided BID). Overall, the drug has a high safety margin and is well tolerated. It is a pregnancy category C medication.
Phenytoin Phenytoin has been available since 1938 and was the first anticonvulsant used in pain management. Despite its long historical use, there is limited and conflicting evidence for its treatment of neuropathic pain. Phenytoin limits the repetitive firing of neuron action potentials by slowing the rate of recovery of voltageactivated sodium channels from the inactive state. The pharmacokinetics of phenytoin are complex and even small dosage increases can result in toxicity. In addition, the drug interactions with phenytoin are many and varied. The majority of phenytoin is metabolized by the cytochrome P450 system. Other drugs
W.D. Mauck and M.-F.B. Hurdle
224 metabolized by these enzymes can saturate the pathways, limit metabolism, and increase plasma levels of phenytoin as well as other drugs including warfarin. Warfarin levels will initially rise and later fall due to phenytoin’s induction of the cytochrome P450 system. This ultimately increases the metabolism of many other medications (carbamazepine, valproic acid, warfarin, oral contraceptives). The potential for teratogenic effects during pregnancy include a pattern of malformations called “fetal hydantoin syndrome” (wide-set eyes, broad mandible, finger deformities). This is a pregnancy category D medication. The toxic effects of phenytoin depend on the route of administration, duration of use, and dosage. Focusing on side effects associated with the oral route include cerebellarvestibular dysfunction (nystagmus, ataxia, diplopia, vertigo), which is the primary adverse reaction, but other side effects include slurred speech, somnolence, gastrointestinal intolerance (GI), osteomalacia, megaloblastic anemia, and behavioral changes. Gingival hyperplasia occurs in 20% of chronically treated patients. Other cosmetic sided effects include acne, hirsutism, and coarsening of facial features. Hyperglycemia appears to be due to inhibition of insulin secretion. Allergic reactions include morbilliform rash (2-5%) and rarely Steven-Johnson syndrome. Plasma phenytoin level, liver function tests, and complete blood counts should be followed.
Tiagabine Tiagabine has a novel mechanism of action, blocking the reuptake of GABA into presynaptic neurons. A starting dose of 4 mg/d is recommended with a 2-mg increase every third day to a total goal of 16-20 mg/d (divided BID to QID). Because it is metabolized primarily in the liver by the cytochrome P450 system, its half-life and plasma levels are reduced when it is coadministered with hepatic enzyme-inducing drugs such as phenytoin and carbamazepine. It has a negligible effect on other anticonvulsants, warfarin, oral contraceptives, and digoxin. Dosage reduction may be necessary in patients with liver impairment. Tiagabine is well tolerated. The principal adverse effects include mild to moderate dizziness, asthenia, somnolence, and tremor. It also has the potential to exacerbate absence seizures. It is a pregnancy category C medication.
Topiramate Topiramate reduces neuronal activity by slowing recovery of voltage-dependent sodium channels in a manner similar to phenytoin, enhances GABAA receptors, and antagonizes the kainate subtype of the glutamate receptors. It is also a weak carbonic anhydrase inhibitor. The initial dose is 25-50 mg/d followed by weekly increases of 50 mg to a maximum goal of 300-400 mg/d (divided BID). Patients with renal impairment (creatine clearance ⬍70 mL/min) should reduce their maximum dose by 50% and titrate doses slowly. Hepatic impairment may also slow drug clearance to a lesser degree. Plasma topiramate levels are decreased when coadministered with phenytoin, carbamazepine, and valproic acid. Topiramate decreases valproic acid levels (11%), while increasing phe-
nytoin levels by 25%. Administering topiramate to patients receiving digoxin requires careful monitoring of digoxin levels because topiramate reduces serum digoxin levels by 12%. In addition, the efficacy of oral contraceptives may be reduced in patients also taking topiramate. Fatigue, dizziness, ataxia, somnolence, nervousness, and decreased concentration are common adverse effects. Other clinically relevant adverse events include a 1.5% incidence of nephrolithiasis and mild weight loss averaging 1-6 kg.37 The carbonic anhydrase inhibitory effect not only increases the risk of nephrolithiasis but also metabolic acidosis due to increased renal bicarbonate loss. Patients with a predisposing condition (renal, respiratory, and/or hepatic impairment), ketogenic diet, or concurrent treatment with other drugs that may cause acidosis are at a higher risk of developing metabolic acidosis. Baseline and periodical serum bicarbonate levels should be monitored during treatment. There is animal model evidence of teratogenicity, but there are no studies in humans. Topiramate is a pregnancy class C medication.
Valproic Acid Valproic acid is approved for migraine prophylaxis by the FDA, but little evidence of therapeutic efficacy in neuropathic pain exists. Thrombocytopenia, alopecia, and elevated liver enzymes in up to 40% of patients limit its therapeutic efficacy. This drug is a teratogenic agent causing neural tube defects and is a pregnancy category D medication.
Zonisamide Zonisamide is a sulfonamide derivative that was approved as an anticonvulsant in the year 2000. It inhibits the T-type calcium currents as well as blocking sodium channels in a manner similar to actions of phenytoin and carbamazepine. The majority of the oral dose is renally excreted in the unmetabolized and glucuronide of sulfamoylacetyl phenol form, which is cytochrome P450 metabolite.29 Slower titration and frequent monitoring are indicated in those with renal and hepatic impairment. Patients with hypersensitivity to sulfonamides should avoid zonisamide. Medications that induce the cytochrome P450 system (carbamazepine, phenytoin, valproic acid) could decrease the levels and effect of zonisamide, while those that inhibit the same system could increase the levels. It does not inhibit the cytochrome P450 system and has no appreciable effect on steady-state concentrations of other anticonvulsants studied. Overall, zonisamide is well tolerated. Anorexia (13%), dizziness (13%), and somnolence (17%) are the most common adverse events. Other less common side effects include ataxia, fatigue, headache, nausea, irritability, and nervousness. Approximately 4% of individuals develop calcium or urate kidney stones during treatment with zonisamide. Zonisamide is teratogenic in laboratory animals and is a pregnancy class C medication.
Antidepressants Antidepressants are one of the most commonly prescribed classes of drugs for the treatment of chronic pain. Tricyclic
Complications of nonopiate pharmacotherapy antidepressants (TCA) block both norepinephrine (NE) and serotonin (5-HT) reuptake in varying degrees at spinal dorsal horn synapses. Studies using TCAs in diabetic neuropathy, postherpetic neuralgia, and tension headaches offer the most compelling evidence for pain relief.38,39 The cardiovascular system is the most vulnerable to the toxic side effects of tricyclic antidepressants. Hypotension, heart block, and arrhythmias are the most serious complications. Severe postural hypotension associated with falls and injuries40 is the principal cardiovascular event and is likely related to the drugs anti-␣1-adrenergic actions. Imipramine and amitriptyline have the greatest orthostatic effect, whereas nortriptyline has the least. TCAs have direct cardiac depressing actions similar to class 1 antiarrhythmics that can result in heart block and potentially dangerous complex arrhythmias. The elderly, those taking other cardiac depressants, and those with a history of ischemic heart disease or cardiac conduction defects are at higher risk. A baseline electrocardiogram before starting TCAs is recommended by some.41 Anticholinergic effects following tricyclic antidepressant therapy may be pronounced. Amitriptyline, imipramine, and doxepin cause the highest incidence of anticholinergic effects including dry mouth, constipation, blurred vision, tachycardia, and urinary retention. Nortriptyline and desipramine are only mildly anticholinergic. Central nervous system depression in the form of sedation can either be quite limiting or advantageous depending on previous insomnia symptoms. Sedation is likely mediated by blockade of histamine (H1) receptors and is most marked with amitriptyline, imipramine, and doxepin, whereas nortriptyline and desipramine are less sedating. The sedating effects usually wane after several weeks of use. TCAs may also reduce the seizure threshold thus limiting their use in patients with seizure disorders or those taking medications that may also produce seizures. Weight gain, sexual dysfunction, and psychiatric complications may also limit treatment with TCAs. Use of tricyclic antidepressants, and amitriptyline in particular, have been implicated in increased appetite and weight gain. Delayed or even inability to orgasm can also limit TCA use in both sexes.42 The primary psychiatric concern is suicide. The cardiovascular effects and lowered seizure threshold can quickly lead to a lethal outcome when overdosed.41 Tricyclic antidepressants are oxidized by hepatic microsomal enzymes and then conjugated with glucuronic acid. The usual starting dose of amitriptyline or nortriptyline is 10-25 mg at bedtime and increasing the dose by the same increment every 3-4 nights to satisfactory pain relief or a goal of 100 mg/d in single day dosing.41 Individual variance in TCA plasma levels to a given dose is as high as 10- to 30-fold and is largely due to genetic variance and control of hepatic microsomal enzymes.43 Consider reducing the dose of TCA or monitoring plasma levels in patients with hepatic impairment. Abrupt discontinuation of TCAs should be avoided to prevent withdrawal symptoms of malaise, chills, coryza, muscle aches, and sleep disturbances. A gradual taper over a week is advisable. Tricyclic antidepressants are involved in several clinically important drug reactions. The catecholamine uptake-blocking properties, central nervous system, and anticholinergic
225 effects are most likely to be responsible for drug interactions. Combination therapy with monoamine oxidase inhibitors can precipitate serotonin syndrome characterized by myoclonus, hyperreflexia, tremor, increased muscle tone, fever, shivering, sweating, diarrhea, delirium, and coma. Clonidine cessation rebound hypertension may be accentuated during TCA therapy. Beta-agonists when combined with TCAs may predispose patients to cardiac dysrhythmias. Coadministration of medications that prolong the electrocardiogram QT interval (type 1 and 3 antiarrhythmics, selected quinolones, and other agents) may increase the risk of fatal arrhythmias. The pregnancy categories for TCAs range from B to D.
Muscle Relaxants Baclofen Baclofen, a central acting muscle relaxant, is FDA approved for the treatment of spasticity. Baclofen exerts its effects as an agonist at presynaptic GABA-B receptors. Baclofen may be helpful in the treatment of trigeminal neuralgia.44,45 Intrathecal baclofen has been shown to produce analgesia in patients with chronic pain in case reports and smaller studies.46,47 Typically, oral dosing is started with 5 mg TID titrating up to a maximum of 80 mg/d based on patient tolerance. Common side effects include drowsiness, dizziness, confusion, and muscle weakness. Treatments for overdose include supportive care as well as physostigmine to improve respiratory depression and sedation. It is a pregnancy category C medication.
Tizanidine Tizanidine (Zanaflex) is a central acting alpha-adrenergic agonist approved in the United States for the treatment of spasticity related to spinal cord injuries and multiple sclerosis.48 Chronic headaches may be treated with tizanidine.49-51 It is metabolized in the liver and excreted both via the renal (60%) and fecal (20%) route. Some of the more serious possible adverse reactions include hepatotoxicity, arrhythmias, blood dyscrasias, hallucinations, and seizures. Tizanidine potentiates the central nervous system (CNS) effects of alcohol. Avoid concomitant use of alpha-adrenergic agonist. An overdose could lead to respiratory depression that is then treated with furosemide or mannitol in conjunction with supportive care. It is a pregnancy category C medication.
Triptans Triptans are selective serotonin agonists (5-hydroxytryptophan [5-HT]1B/1D agonists) used effectively in the treatment of acute migraine attacks. These drugs activate serotonin receptors 5-HT1B and 5-HT1D on cerebral vessels, thus causing selective constriction of blood vessels, inhibiting the release of vasoactive neuropeptides by trigeminal terminals innervating the intracranial vessels and inhibiting nociceptive neurotransmission within the trigeminocervical complex.52 The 5-HT1B receptors is also found on coronary arteries and can be activated by triptans.53 The various triptans (sumatriptan, rizatriptan, zolmitriptan, naratriptan, almotriptan, frovatriptan, eletriptan) dif-
W.D. Mauck and M.-F.B. Hurdle
226 fer very little in terms of safety. The most frequent adverse effects are tingling, paresthesias, and sensations of warmth involving the head, neck, chest, and limbs. Other common symptoms include dizziness, somnolence, flushing, nausea, and neck pain or stiffness. Triptans can constrict coronary arteries and cause chest symptoms that mimic angina pectoris; however, chest pain associated with oral triptan use is generally not associated with electrocardiographic changes and is unlikely due to cardiac ischemia.54 Triptans are contraindicated in patients with histories of cerebral vascular disease, ischemic heart disease, Prinzmetal’s angina, peripheral vascular syndromes, and uncontrolled hypertension. Triptans should not be used in the management of hemiplegic or basilar migraine due to an increased risk of migraineassociated stroke. The use of triptans in combination with ergotamine derivatives must be avoided based on both drugs’ ability to stimulate serotonergic receptors on cerebral and coronary vessels. Monoamine oxidase (MOA) inhibitors can delay the metabolism of sumatriptan, rizatriptan, and zolmitriptan, thus increasing plasma levels. MAO inhibitors should be discontinued 2 weeks before administering these triptans. Propranolol increases plasma levels of rizatriptan and frovatriptan. All triptans have a low risk of causing serotonin syndrome when given in combination with other serotomimetic agents. The neurologic symptoms are usually transient but can be lifethreatening. The triptans are a pregnancy class C medication.
Topical Medications Capsaicin is a medication composed of chili pepper extract. It induces the release of substance P from nociceptive primary afferents and after repeated application depletes the neuron of substance P and prevents reaccumulation. On application, it produces mild to severe burning that usually diminishes with continued use. It should not be applied to mucous membranes or broken/irritated skin. Gloves should be worn during and hands washed following application to avoid unwanted application to other parts of the body. It is a pregnancy category C medication. Local anesthetics in the form of a gel, patch, and cream have proven effective in various pain states. In chronic pain states, the lidocaine patch is frequently chosen over the gel and cream due to ease of application and documented low plasma lidocaine levels that are well below the expected toxic levels. The most common adverse reaction involves mild skin irritation at the site of application. Patients with severe hepatic disease are at greater risk of developing toxic blood concentrations because of their inability to metabolize lidocaine. Care must be taken with those taking other class 1 antiarrhythmics and local anesthetics as the toxic effects are additive and possibly synergistic. Application to broken/inflamed skin or mucous membranes may lead to higher blood concentrations of lidocaine. It is a pregnancy category B medication.
Summary Nonopioid analgesics and adjuvants are being used increasingly for neuropathic pain syndromes, myofascial pain, head-
aches, and other pain states. They are the first line treatment for mild to moderate pain and are often continued even if opioids are eventually added. Knowledge of their potential complications is necessary to safely choose these medications and treat those suffering with pain.
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