Neuropathic Pain

Amanda Macone, MD; James A. D. Otis, MD, FAAN, DABPM


Semin Neurol. 2018;38(6):644-653. 

In This Article

Antiseizure Drugs

Phenytoin, gabapentin, carbamazepine, and several other AEDs have efficacy in neuropathic pain.[25] Mechanisms of action vary, but generally relate to GABAergic action, sodium channel blockade, or modulation of calcium channels. AEDs can reduce pain by reducing neuronal excitability and local neuronal discharges and are most helpful in pain syndromes characterized by paroxysmal pain, lancinating pain, burning pain, and allodynia.[26] The first AED used for pain management was phenytoin, which was found to be effective in trigeminal neuralgia in 1942. It has been utilized in a variety of neuropathic pain syndromes, including trigeminal neuralgia and postherpetic neuralgia.[27] Phenytoin use has decreased, as it has been replaced by newer medications with fewer drug interactions, lower toxicity, and more approved indications. For instance, carbamazepine remains first-line therapy for trigeminal neuralgia.[27] The average dose of phenytoin for pain management is 300 mg/day. A loading dose of 1 g can be considered for acute pain management. Phenytoin use can further be limited due to its effects on protein-bound medications, including rifampin, methadone, and several antifungal agents. Both phenytoin and carbamazepine induce cytochrome P450 and glucuronyl transferase enzymes and can thus reduce the serum concentration of drugs that are substrates of these enzymes, including other AEDs, steroids, cyclosporin A, warfarin, and cardiovascular, antineoplastic, and psychotropic drugs.[28] Adverse events with phenytoin include dizziness, somnolence, serious skin reactions such as Stevens–Johnson syndrome, leukopenia, and elevation of liver enzymes. Carbamazepine has been well studied and used successfully in a variety of neuropathic pain states;[26,29] however, it is unproven in the treatment of postherpetic neuralgia.[10] Important side effects include dizziness, somnolence, significant leukopenia, as well as Stevens–Johnson syndrome. Hyponatremia also can occur as an idiosyncratic reaction. To minimize dizziness, one can start at a dose of 100 mg, gradually escalating in 100-mg increments every 3 to 7 days. Close monitoring of the white blood count is necessary and limits the utility of this drug in HIV patients. Carbamazepine has significant autoinduction of metabolism and may require escalating doses over time to achieve the same plasma levels and clinical effect. Oxcarbazepine has similar issues clinically, with conflicting evidence regarding its effectiveness in the management of neuropathy. Some studies suggest its effectiveness in spinal cord injury (SCI), radiculopathy, and diabetic neuropathy, as well as in carbamazepine nonresponsive trigeminal neuralgia.[30,31] Other randomized control trials have found no statistically significant difference between oxcarbazepine and placebo in the management of diabetic neuropathy.[13,32,33] Oxcarbazepine tends to be better tolerated than carbamazepine, with fewer drug interactions. Hyponatremia is a frequent problem, particularly when combined with several psychotropic drugs. Valproic acid has been used for the management of lancinating pain, with mixed results, and for pain of diabetic neuropathy.[34] There are currently no large studies of high-quality evidence demonstrating long-term effectiveness to definitively support its use in the management of neuropathic pain.[13,35] In addition, the large number of drug interactions and significant hepatic dysfunction that can occur make valproic acid a second-line choice.

Several newer AEDs, released in the last 15 to 20 years, have been found to be useful in treating neuropathic pain, and the gabapentinoids have become first-line agents for several of them. Gabapentin is well established, and multiple studies have demonstrated efficacy in both lancinating and continuous dysesthetic pain.[36–40] A randomized controlled trial compared gabapentin with nortriptyline in 56 people with neuropathic pain. It found that the combination of these two medications resulted in a significantly greater pain reduction (52.8%) than did gabapentin alone (31.1%) or nortriptyline alone (38.8%).[41] Gabapentin tends to be well tolerated with few drug interactions. Treatment is typically started at 100 mg three times per day and then escalated in increments of 100 to 300 mg every 3 to 5 days. Most patients start to respond at 300 mg three times per day but may require dosing up to 3,600 mg/day.[40] There is some evidence that doses higher than 3,600 to 4,800 mg are not well absorbed; so, doses above this range are of questionable utility.[42] The most frequently reported side effect is somnolence, which typically diminishes after the first 2 weeks of therapy. Lamotrigine has been shown to have reduced efficacy compared with gabapentin and pregabalin in the treatment of neuropathic pain, and additionally requires slow titration to avoid dermatologic side effects, making it a poor choice for neuropathic pain therapy.[13,43] Similarly, topiramate has been shown to have little to no efficacy in the management of neuropathic pain.

The newest AED with well-documented efficacy in neuropathic pain is pregabalin, with a similar profile to gabapentin. Like gabapentin, it binds the α-2-delta subunit of calcium channels, reducing neurotransmitter release. In multiple large-scale trials, 150 to 600 mg/day of pregabalin had good efficacy in controlling neuropathic pain in both postherpetic neuralgia and diabetic peripheral neuropathy.[38,44–47] Overall, patients were found to have greater than 50% benefit (quantified with the McGill pain questionnaire), lower average daily pain scores, improved global impression of change, sensory/affective pain scores, and other efficacy measures. Scores were similar to gabapentin trials. Sleep interference scores were also improved across multiple studies. However, at least one study suggests that pregabalin may not be effective in the treatment of HIV neuropathy.[48] A typical starting dose for pregabalin is 50 mg three times per day, which can be increased to 100 mg three times per day over a week. Best pain control usually occurs after 1 week of dosing, and twice daily dosing is also possible. Effective management of neuropathic pain may require up to 600 mg/day. Commonly reported side effects are dizziness and somnolence, which are typically tolerated and resolve with drug habituation. Weight gain is also common. Absolute platelet number can be decreased with pregabalin; thus, it should be used with caution in patients prone to thrombocytopenia (Table 3).