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

Background: Migraine headaches are considered chronic when they occur on 15 or more days per month. Newer medications are available for prevention. Purpose: To explore the effectiveness and tolerability of pharmacologic prophylaxis for chronic migraine. Data Sources: Medline, Embase, Cochrane Central Register of Controlled Trials, PsycINFO, Web of Science, and Scopus to October 2025. Study Selection: Independent paired reviewers identified randomized controlled trials (RCTs) of prophylactic pharmacologic interventions for adults with chronic migraine. Data Extraction: 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. Data Synthesis: 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. Limitation: Most trials had high risk of bias, with few available comparisons. Conclusion: 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.