Benefit-risk comparison of gabapentin enacarbil versus pregabalin for restless legs syndrome: A dose-response model-based network meta-analysis.

PURPOSE: Gabapentin enacarbil (GEn) and pregabalin are considered amongst the first-line drugs for restless legs syndrome (RLS). However, concerns remain about their dose-limiting side effects. This study aimed to elucidate the differences in their benefit-risk profiles through a dose-response model-based network meta-analysis (MBNMA). METHODS: A systematic review and dose-response MBNMA was conducted to evaluate the effects of GEn and pregabalin on International RLS Study Group Rating Scale (IRLS) scores, rates of responders on investigator-initiated Clinical Global Impression-Improvement (CGI-I) scales, and on prevalence of treatment-emergent adverse effects (TEAE). Dose-response curves (DRC), model-derived median effective and toxic doses (ED50, TD50) and therapeutic indices (TI = TD50/ED50) were calculated. RESULTS: Fifteen studies involving 2,885 were analyzed. DRCs showed dose-response relationship for IRLS scores only for pregabalin and dose-response relationships for both GEn and pregabalin for CGI-I responder rates, somnolence and dizziness TEAEs. Based on CGI-I responder rates, the model-derived ED50 for GEn and pregabalin was 93.80 mg/d and 123.55 mg/d, respectively. The model-derived TD50 for somnolence and dizziness for GEn and pregabalin were 112.85 mg/d and 101.59 mg/d, and 106.08 mg/d and 104.83 mg/d, respectively. At their model-derived ED50 and TD50, there were no significant differences between GEn and pregabalin rankings. The TIs for GEn and pregabalin ranged from 1.08 to 1.20, and 0.84—1.19, respectively. CONCLUSIONS: GEn and pregabalin have narrow TIs based on model-derived ED50 and TD50.Estimates from this MBNMA could inform future trials for studying optimal dosing that would maximize benefits and minimize risks.