MEMANTINE IN THE TREATMENT OF DIABETICS WITH PAINFUL PERIPHERAL NEUROPATHY: A PLACEBO‐CONTROLLED PHASE IIB TRIAL

Louis C. Kirby, MD: Peoria, AZ; The Memantine Study Group Injured peripheral nerves induce the release of excitatory amino acids in the dorsal horn of the spinal cord, causing excitation of N‐methyl‐D‐aspartate (NMDA) receptors. Continuous stimulation of NMDA receptors by C‐fiber input leads to central facilitation. The critical role of NMDA receptors in the wind‐up process suggests that they are a final common pathway for the induction of neuropathic pain. Memantine, a moderate‐affinity, uncompetitive NMDA receptor antagonist, has been shown to reduce pain responses in rodent and primate chronic pain models. The objective of this 8‐week multicenter, randomized, dose‐ranging, double‐blind, placebo‐controlled trial was to determine the analgesic efficacy and safety of memantine in diabetic patients with painful peripheral neuropathy (PPN). A total of 421 PPN patients participated in the study (placebo n=86, 20 mg/day memantine n=171, 40 mg/day memantine n=164). Participants had a pain visual analog score (VAS) of ≥30 mm, were on stable analgesics at least one month prior to enrollment, and were stratified by narcotic use. Memantine treatment was initiated at 10 mg/day and titrated to 20 or 40 mg/day. The primary outcome measure was the week 8 nocturnal peak pain intensity score, rated by VAS. Secondary measures included categorical pain intensity, sleep interference, patient pain relief and global assessments. Paired group comparisons revealed a significant difference in mean nocturnal VAS score at week 8 between the 40 mg/day memantine and placebo groups (p=0.018). Patients in the 40 mg/day memantine group also had significant improvement in nocturnal categorical pain intensity (p=0.018) and sleep interference ratings (p=0.037) compared to placebo at week 8. Concomitant narcotic use did not differentially influence the efficacy of memantine. Adverse events in memantine‐treated patients were generally mild, and only dizziness and nausea occurred more frequently compared with placebo. Discontinuation rates due to adverse events were similar across the treatment groups. In conclusion, 40 mg/day memantine was effective and well tolerated for the treatment of diabetic PPN.