Abstract
Background
Chronic migraine (CM) affects 1.4‐2.2% of the population and is defined by ≥15 headache days/month for ≥3 months, with ≥8 migraine days (IHS, 2018). Its pathophysiology involves cortical spreading depression (CSD), CGRP‐mediated neurogenic inflammation, and vascular changes. Several Phase 3 randomized controlled trials have shown that pharmaceutical interventions are effective and safe in reducing the number of Mean Migraine Days compared to placebo.
Objective
This systematic review aims to compare the efficacy and safety of prophylactic agents versus placebo in the treatment of Chronic Migraine.
Methods
A systematic review and meta‐analysis were conducted using the Nested Knowledge platform, with searches of PubMed, Cochrane Library, and Scopus up to August 2025. Studies were included if they were a phase 3 RCT comparing the effect of an intervention versus placebo in the prevention of Chronic Migraine, as defined by ICHD‐3 criteria. Studies were excluded if they were not phase 3 or did not include a placebo arm. Data were extracted on study characteristics, patient populations, and outcomes including monthly migraine days (MMDs), monthly headache days (MHDs), Migraine Disability Assessment (MIDAS) scores, ≥50% responder rates, safety endpoints; Treatment emergent adverse effects (TEAEs), Serious adverse effects (SAEs) and deaths. Meta‐analyses were performed in RStudio (version 4.4.3) using random‐effects models to account for between‐study heterogeneity.
Results
1066 articles were identified and screened, 1052 were excluded and 14 were included and analyzed in this meta‐analysis. MHDs showed consistent reductions across timepoints: ‐3.68 vs ‐1.70 at 4 weeks (2‐day benefit; p < 0.05), ‐5.97 vs ‐4.16 at 12 weeks (1.81‐day benefit; p < 0.05), and extending to ‐8.40 vs ‐6.55 by 24 weeks (1.85‐day benefit). Disability outcomes, reported as MIDAS score, were significantly reduced in the intervention group compared with placebo (p‐value < 0.05). Analyzing ≥50% MMD reduction outcomes, a higher responder count was observed with intervention. A significant reduction was also observed in mean migraine days with intervention compared with placebo (p < 0.05). At 12 weeks, TEAEs were comparable between groups (158 vs 157), with SAEs infrequent (3.8 vs 3.4) and one death reported in the intervention arm.
Conclusion
This data indicates that intervention is more effective than placebo in reducing migraine burden. However, the placebo arm also showed reductions in migraine outcomes, underscoring the need to carefully account for placebo effects in the treatment of chronic migraine.
Disclosure
No public access funding to disclose.
