Anticonvulsant Drugs

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Anticonvulsant drugs (ACDs) have efficacy in mitigating neuropathic pain, including trigeminal neuralgia and phantom limb pain (McQuay et al. 1995), as well as migraine (Pappagallo 2003, Snow et al. 2002). As with the antidepressants, analgesic differences exist among the ACDs with regard to utility across types of pain conditions. Carbamazepine is Food and Drug Administration (FDA)-approved for the treatment of trigeminal neuralgia; gabapentin, for treatment of postherpetic neuralgia; pregabalin, for postherpetic neuralgia, diabetic neuropathy, and fibromyalgia (Crofford et al. 2005); and divalproex sodium and topiramate have both been indicated for migraine prophylaxis.

Although the neuromodulator^ mechanisms underlying analgesia produced by ACDs are varied, the mechanisms of action are thought to influence several of the physiologic processes contributing to neural hyperexcitability predisposing patients to central sensitization and chronic pain. The precise mechanisms of action of ACDs remain uncertain. The principal proposed mechanism of action for both pregabalin and gabapentin is the interaction with the alpha 2-delta subunit of L-type voltage-regulated calcium channels thought to influence central pro-neuropathic processes, i.e., glutamate release (Frampton and Scott 2004, Guay 2003, Vinik 2005). Other mechanisms of action are presumed to involve enhanced gamma-aminobutyric acid inhibition (valproate, topiramate) or a stabilizing effect on neuronal cell membranes via inhibition of voltage-gated sodium channels (carbamazepine). The net effects ofthese presumed mechanisms are believed to mediate inhibition ofpain pathways within the CNS, e.g., reducing the ability of neurons to fire at high frequency (Chong and Smith 2000).

Evidence has been limited with regard to the relative effectiveness of ACDs. For example, one systematic review demonstrated that although gabapentin was effective in treating pos-therpetic and diabetic neuropathy, it did not appear to be superior to carbamazepine. There were, however, no direct comparisons between these two drugs (Wiffen et al. 2009).

Table 12.5 Major antidepressant classes used in pain management.

Tricyclic antidepressants

General uses: neuropathic pain, headache, poststroke pain, thalamic pain, fibromyalgia, irritable bowel (diarrhea type), and chronic pelvic pain with or without comorbid depression/anxiety Pain-related FDA approvals: none available for any of the TCAs

Standard dosage: initiate with 10 mg daily at bedtime. Increase the dosage gradually (e.g., by 10 mg weekly), to achieve desired pain-mitigating and antidepressant effects until side effects supervene. Analgesic doses are often considerably lower than those required for antidepressant efficacy, e.g., 75-150 mg/d for amitriptyline; 25-350 mg/d for imipramine; and 10-75 mg/d for nortriptyline

Main side effects: anticholinergic side effects, drowsiness, insomnia, agitation, and cardiac arrhythmia

Drug interactions: TCAs should not be used with monoamine oxidase inhibitors; can accentuate CNS sedative effects when combined with alcohol, benzodiazepines, and barbiturates

Serotonin-norepinephrine re-uptake inhibitors (SNRIs)

General uses: neuropathic pain and fibromyalgia

Pain-related FDA approvals: duloxetine has received FDA approval for treatment of diabetic neuropathy and fibromyalgia. Milnacipran has received FDA approval for treatment of patients with fibromyalgia

Standard dosage: milnacipran: 100-200 mg/d; duloxetine: 60-120 mg/d; venlafaxine: 15-225 mg/d

Main side effects: nausea, dry mouth, nervousness, constipation, somnolence, and elevations in diastolic blood pressure

Drug interactions: SNRIs should not be used with monoamine oxidase inhibitors or thioridazine

Serotonin selective re-uptake inhibitors (SSRIs)

General uses: data are limited; paroxetine and citalopram may be effective in alleviating symptoms of diabetic neuropathy and fluoxetine may be useful in fibromyalgia Pain-related FDA approvals: none available for any of the SSRIs

Standard dosage: citalopram: 20-40 mg/d; fluoxetine: 20-80 mg/d; paroxetine: 20-40 mg/d Main side effects: nausea, diarrhea, insomnia or sedation, tremors, and sexual dysfunction Drug interactions: SSRIs should not be used in conjunction with monoamine oxidase inhibitors, triptans, tramadol, dextromethorphan, or other highly serotonergic agents because of the potential for serotonin syndrome

FDA = Food and Drug Administration; CNS = central nervous system. (Adapted from Leo 2007; Tomkins et al. 2001; Arnold et al.

2000; Lynch 2001;Ansari 2000.)

Emerging evidence suggests the potential analgesic roles of newer ACDs, e.g., lamotrigine, oxcarbazepine, and tiagabine (Pappagallo 2003, Galer 1995, Khoromi et al. 2005, Novak et al. 2001). Although these agents demonstrate some promise with regard to mitigating neuropathic states (Remillard 1994, Solaro et al. 2001, Zakrzewska et al. 1997), the utility and safety of several of these agents among chronic pain patients has not been systematically investigated. A recent review indicated that for lamotrigine, some evidence existed for efficacy in central poststroke pain and in a subgroup of HIV-related neuropathy. However, no benefit was demonstrated with lamotrigine for diabetic neuropathy, spinal cord injury, or trigeminal neuralgia (Wiffen and Rees 2009).

Adverse effects common to ACDs include sedation, fatigue, gastrointestinal, and motor side effects (tremor, ataxia, and nystagmus). Rash and Stevens-Johnson syndrome are possible with carbamazepine and lamotrigine (Pappagallo 2003). Patients taking gabapentin or pregabalin do not require serum drug, hematologic, electrolyte, or hepatic enzyme monitoring as is often required with other ACDs, e.g., carbamazepine or divalproex sodium. Both gabapentin and pregabalin are eliminated through renal excretion; dose reductions are required in patients with impaired renal function. ACDs can accentuate sedative effects when combined with alcohol, benzodiazepines, or barbiturates. Carbamazepine, oxcarbazepine, phenytoin, and topiramate can reduce the efficacy of oral contraceptives, increasing the risk of pregnancy. Fetal malformations are associated with carbamazepine, valproate, and phenytoin use during pregnancy (Yerby 2000).

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