Anticonvulsants are believed to be particularly useful in lancinating, electrical, or tic-like pain. These medications may be also beneficial in patients with neuropathic pain who do not respond to tricyclics.
The older generation of anticonvulsants includes carbamazepine, valproic acid, clonazepam, and phenytoin.
Carbamazepine was perhaps the most popular agent used for neuropathic pain, especially for trigeminal neuralgia. However, carbamazepine may cause serious side effects such as sedation, nausea, vomiting, bone marrow suppression, hyponatremia, hepatic dysfunction and serious drug-drug interaction. Carbamazepine should be started at 100 mg at night and titrate up slowly, especially for the elderly.
About Valproic Acid
Valproic acid has been proven to be effective in reducing the frequency of migraine attacks. Recent randomized double-blind placebo-controlled trials found that valproates may provide significant pain relief in patients of post-herpetic neuralgia and diabetic neuropathy. However, negative results have also been reported. Common side effects include tremor, ankle swelling, sedation, and gastrointestinal discomfort. Weight gain and hair loss may be a major cosmetic concern especially for younger patients. Valproates should not be used for children less than 2 years of age because of hepatotoxicity. Generally, valproates are not the first line choice for neuropathic pain.
In the last two decades, gabapentin has gained popularity for the treatment of neuropathic pain. The analgesic efficacy of gabapentin has been demonstrated in several types of nonmalignant neuropathic pain. It is now used to treat a wide variety of pain conditions. Due to the high safety profile, few drug-drug interactions, and the proven analgesic effect in several types of neuropathic pain, gabapentin is now recommended as a first-line co-analgesic for the treatment of a variety of neuropathic pains, especially in the medically ill and elderly patients. The most common adverse effects are drowsiness, dizziness, and unsteadiness. Gabapentin should be started at a dose of 100–300 mg at bedtime. If titrated carefully, gabapentin is usually well tolerated up to 3600mg daily. However, gabapentin has a nonlinear pharmacokinetic profile. The rate of bioavailability decreases, as the dose increases.
Pregabalin is a GABA analog with similar structure and actions to gabapentin. It has antiepileptic, analgesic and anxiolytic activity. Pregabalin is indicated for the management of neuropathic pain associated with diabetic neuropathy, post-herpetic neuralgia and fibromyalgia. Food does not significantly affect the extent of absorption. Pregabalin is not protein-bound and exhibits a plasma half-life of about 6 hours. Hepatic metabolism is negligible, and most of the oral dose (95%) appears unchanged in the urine. At a dose of 300mg/day, about 45% of diabetic neuropathy patients had 50% pain relief. This means that pregabalin has a NNT of 2.2 for diabetic neuropathy. Pregabalin seems to be more effective than gabapentin and other anticonvulsants for neuropathic pain. Common side effects of pregabalin include dizziness, sedation, dry mouth and peripheral edema.
Oxcarbazepine is a keto-derivative of carbamazepine with better tolerability. It can block sodium-dependent action potentials. The medication does not induce hepatic enzymes and has less drug-drug interaction than carbamazepine. Recent studies have reported oxcarbazepine to be promising for refractory diabetic neuropathic pain with a NNT of 6.0. Another randomized trial in diabetic neuropathy has shown that patients taking oxcarbazepine 1,200 and 1,800 mg/day had improvements in pain compared with the placebo. However, the results were not statistically significant.
Lamotrigine is an antiepileptic drug that stabilizes neural membranes by blocking the activation of voltage-sensitive sodium channels and inhibiting the presynaptic release of glutamate. Lamotrigine has also been reported to relieve nonmalignant neuropathic pain in several randomized trials. A recent controlled three year prospective open study also found lamotrigine to be highly effective in reducing migraine aura and migraine attacks. For adults, lamotrigine has to be started in a low dose such as 25 mg twice a day and slowly increased in 6-8 weeks to the target dose. The most serious adverse effect of lamotrigine is skin rash, which is dose-dependent and more common in combination with valproate. Other adverse effects include headaches, tremors, nausea, drowsiness, dizziness, and an unsteady gait.
Topiramate has been reported to be effective in reducing migraine frequency. However, double-blind clinical controlled studies do not find topiramate to be significantly more effective than the placebo in reducing pain scores in patients with painful diabetic polyneuropathy. Topiramate treatment may reduce chronic sciatica in some patients but causes frequent side effects that cause patients to cease taking the drug. The mechanisms of action include blockade of sodium channels, enhancement of GABA inhibition, and attenuation of kainate-induced responses at glutamate receptors. The starting dose is usually small, e.g., 25 mg twice a day for an adult. It may be increased weekly by 50 mg with an increment to 200 mg per day. Topiramate may induce memory loss, word-finding difficulties, disorientation, and sedation. The other common adverse affects are renal calculi, tremors, dizziness, ataxia, headaches, fatigue, and gastrointestinal upset. Topiramate may also induce significant weight loss. This medication may be more helpful in obese pain patients.
Tiagabine is a selective gamma-aminobutyric acid reuptake inhibitor. A recent open label study indicates that tiagabine might reduce pain intensity and improve sleep in patients with neuropathic pain. Zonisamide also has been used to treat neuropathic pain. However, a recent randomized, controlled pilot trial on zonisamide for diabetic neuropathic pain failed to yield statistical significance between the zonisamide and the placebo group. Levetiracetam has the advantage of not interacting with food or other drugs. Some anecdotal evidence suggests that levetiracetam could be effective in the treatment of neuropathic pain. More studies are needed to evaluate the clinical efficacy and safety of these antiepileptics for the treatment of pain.