Efficacy and Safety of Ion Channel Modulators in Painful Diabetic Neuropathy

ABSTRACT Aims To systematically evaluate the efficacy and safety of ion channel modulators for the treatment of painful diabetic neuropathy (PDN). Materials and Methods We searched PubMed, Web of Science, Embase, and the Cochrane Library for randomized controlled trials (RCTs) in PDN patients treated with ion channel modulators. The primary outcome was the pain score. Secondary outcomes included the visual analog scale (VAS) score, 30% and 50% pain reduction, patient global impression of change (PGIC), sleep interference score, adverse events, and treatment discontinuation. Independent authors extracted the data and assessed the quality. Heterogeneity among studies was quantified using the I 2 statistic. The analyses were in accordance with the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) reporting guidelines. Results A total of 36 RCTs comprising 6611 participants with PDN were included in the analyses, of which 21 were evaluated with calcium channel blockers, 12 with sodium channel blockers, 2 with TRPA1 antagonists, and 1 with P2X3 antagonists. Compared with placebo, ion channel modulators, particularly calcium channel blockers (mirogabalin, pregabalin, gabapentin, crisugabalin) and sodium channel antagonists (oxcarbazepine, lacosamide, lamotrigine, sodium valproate), can significantly reduce pain, VAS, and sleep interference scores, improve PGIC, and increase the proportion of patients achieving 30% and 50% pain reduction. The therapeutic effects of the TRPA1 antagonists and P2X3 antagonists did not differ significantly from those of the control. The adverse events of ion channel modulators were mild to moderate and well tolerated, but the risk of discontinuation due to adverse events was higher with mirogabalin and oxcarbazepine than with the other modulators. Conclusion Ion channel modulators, especially calcium channel blockers and sodium channel antagonists, have favourable safety profiles and beneficial effects on reducing pain and improving the quality of life of patients with PDN.