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Given the relatively large number of controlled studies of tricyclic antidepressants in the treatment of neuropathic pain, it is surprising that few controlled trials of anticonvulsants were conducted following these early studies of carbamazepine and phenytoin (for one exception, see Leijon and Boivie, 1989[32]). This has recently begun to change with the publication of several clinical trials of second-generation anticonvulsants.[33-35] Although lamotrigine had an analgesic effect in a placebo-controlled study of refractory trigeminal neuralgia[33] and in an open-label study of painful diabetic neuropathy,[34] a 1999 report[35] found no benefit compared with placebo in patients enrolled in the study solely on the basis of having 3 or more "neuropathic pain symptoms" (eg, burning pain, shooting pain, allodynia). There is evidence, however, suggesting that lamotrigine may be effective against central pain, the neuropathic pain syndrome that follows damage to the somatosensory regions of the spinal cord, brainstem, thalamus, and cortex.[36]
The 2 largest placebo-controlled clinical trials of anticonvulsants in patients with neuropathic pain were double-blind studies that examined gabapentin in postherpetic neuralgia[37] and in painful diabetic neuropathy.[38] In each study, patients were randomized to receive gabapentin or placebo for 8 weeks. Gabapentin was titrated to a maximum dosage of 3600 mg daily. Treatment with gabapentin was associated with statistically significant reductions in average daily pain ratings and higher ratings of clinical improvement by both patient and clinician, as well as improvements in sleep, mood, and quality of life. The safety and efficacy of gabapentin in postherpetic neuralgia and painful diabetic neuropathy appeared to be at least as favorable as that reported for antidepressant treatment. In both trials, side effects of gabapentin included somnolence and dizziness, but its generally excellent tolerability and high clearance rate distinguish it from other anticonvulsants (Table 3).
One of the first questions addressed about the efficacy of tricyclic antidepressants in neuropathic pain was whether their analgesic effects were independent of their antidepressant effects. This question is especially important, given the large percentage of patients with chronic pain who also suffer from depressive disorders.[39] Various research methods have been used to examine the role of depression in the analgesic efficacy of antidepressants, and the results of several well-designed studies have demonstrated that the relief of neuropathic pain that occurs with tricyclic antidepressants does not result from their antidepressant properties.[31]First generation:
Drug Systemic Effects Neurotoxic Effect Rare Idiosyncratic Reactions Carbamazepine* Nausea, vomiting, diarrhea, hyponatremia, rash, pruritus, fluid retention Drowsiness, dizziness, blurred or double vision, lethargy, headache Agranulocytosis, Stevens-Johnson syndrome, aplastic anemia, hepatic failure, dermatitis or rash, serum sickness, pancreatitis Valproic acid,*
Divalproex, sodiumWeight gain, nausea, vomiting, hair loss, easy bruising Tremor Agranulocytosis, Stevens-Johnson syndrome, aplastic anemia, hepatic failure, dermatitis or rash, serum sickness, pancreatitis
* Due to significant side-effect profile, long-term compliance may become a problem. Liver function studies should be performed at regular intervals.
Second generation:
Drug Systemic Effects Neurotoxic Effect Rare Idiosyncratic Reactions Gabapentin Gastrointestinal upset, edema (non-pitting) Somnolence, fatigue, ataxia, dizziness Lamotrigine* Rash, gastrointestinal upset Dizziness, tremor, ataxia, diplopia, headache Stevens-Johnson syndrome Felbamate* Anorexia, nausea, aplastic anemia, hepatic failure Irritability, insomnia, headache Topiramate Fatigue, gastrointestinal upset, renal calculi Cognitive difficulties, tremor, dizziness, ataxia, headache
* Lamotrigine and felbamate have significant serious side-effect risks similar to those of first-generation drugs. Felbamate is known to cause an unacceptably high probability of fatal aplastic anemia and hepatic failure.
Importantly, anticonvulsants also have beneficial effects in patients with mood disorders.[40-43] These findings raise the question of whether the analgesic effects of anticonvulsants in patients with neuropathic pain may result, at least in part, from their beneficial effects on mood. For example, gabapentin treatment significantly ameliorates depression, anxiety, fatigue, and other mood symptoms and also improves sleep in patients with postherpetic neuralgia and painful diabetic neuropathy.[37,38] Thus, it will be important in future studies to examine the role that such effects on mood and sleep play in the analgesic effects of anticonvulsants.
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