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

Abstract

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.