Antiepileptic medications have been used in pain management for decades, with some showing efficacy in treating various neuropathic pain conditions. Zonisamide is a sulfonamide indicated as adjunct in partial onset seizures in patients ages ≥16; the exact mechanism of action is unknown, although it is reported to reduce sodium-dependent high firing action potentials in nerves, inhibit some calcium currents that may prevent the spread of seizure discharges between cells, alter dopamine, 5-hydroxytryptamine (5-HT), and acetylcholine metabolism, weakly inhibit carbonic anhydrase, and affect amino butyric acid (GABA)-mediated neuronal inhibition and glutamate release.

A new review in the Cochrane Library sought to assess the analgesic efficacy and associated adverse events of zonisamide for chronic neuropathic pain in adults by examining published results from randomized controlled trials (RCTs) with double-blind assessment of participant outcomes following two weeks of treatment or longer in adults ages ≥18. Only one study was eligible for inclusion in the review – a 12-week, double-blind parallel-group comparison of zonisamide, titrated over six weeks to a target dose of 300–600mg daily or placebo in 25 patients with painful diabetic neuropathy. Eight of 13 patients in the zonisamide group withdrew before the end of the study (mostly due to adverse events); only one patient in the placebo group withdrew from the study.

The small sample size and insufficient data led the review authors to conclude that there is no evidence to suggest that zonisamide provides pain relief for any neuropathic pain condition. More studies are needed to determine if there are any positive benefits associated with zonisamide for neuropathic pain.