Effectiveness and Tolerability of Pharmacologic Prophylaxis for Chronic Migraine : A Systematic Review of Randomized Controlled Trials.

Abstract

Migraine headaches are considered chronic when they occur on 15 or more days per month. Newer medications are available for prevention. To explore the effectiveness and tolerability of pharmacologic prophylaxis for chronic migraine. Medline, Embase, Cochrane Central Register of Controlled Trials, PsycINFO, Web of Science, and Scopus to October 2025. Independent paired reviewers identified randomized controlled trials (RCTs) of prophylactic pharmacologic interventions for adults with chronic migraine. Paired reviewers independently extracted data and assessed risk of bias using the Cochrane Risk of Bias 2 tool. Random-effects meta-analysis and assessment of certainty of evidence were performed using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach. The review included 43 RCTs (14 725 participants). High- and moderate-certainty evidence suggests that eptinezumab (mean difference [MD], -2.34 [95% CI, -2.76 to -1.92]), erenumab (MD, -2.08 [CI, -2.82 to -1.33]), fremanezumab (MD, -1.77 [CI, -2.45 to -1.09]), galcanezumab (MD, -2.00 [CI, -2.96 to -1.04]), and atogepant (MD, -2.10 [CI, -3.06 to -1.14]) reduce monthly migraine headache days by 2 versus placebo. Botulinum toxin may slightly reduce monthly migraine days (MD, -1.34 [CI, -2.27 to -0.41]; low certainty), whereas rimegepant probably has no effect (MD, -1.20 [CI, -2.59 to 0.19]; moderate certainty). Galcanezumab probably reduces dropout due to any cause versus placebo (relative risk [RR], 0.52 [CI, 0.33 to 0.83]; moderate certainty). Botulinum toxin probably increases discontinuation due to adverse events (RR, 3.36 [CI, 1.75 to 6.45]; moderate certainty). Studies on topiramate, valproate, and propranolol were sparse and had high risk of bias. Most trials had high risk of bias, with few available comparisons. Most calcitonin gene-related peptide-targeted therapies are probably effective for chronic migraine prophylaxis. Evidence for botulinum toxin, propranolol, topiramate, and valproate mostly had high risk of bias. None. (PROSPERO: CRD42023456915).