Malahat Khalili, Faraidoon Haghdoost, Amin Liaghatdar, Kian Torabiardakani, Fatemeh Mahdian, Tal Levit, Sara Moradi, Ehsan Hedayati, Farzaneh Ahmadi, Sahar Khademioore, Tariq Atkin-Jones, Ahmad Sofi- Mahmudi, Vivek Patil, Fatemeh Mirzayeh Fashami, Soheil Mehmandoost, Harjind S. Kahlon, Rachel Couban, Kameshwar Prasad, Seyed‐Mohammad Fereshtehnejad, Norman Buckley, Jason W. Busse, Behnam Sadeghirad
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. PRIMARY FUNDING SOURCE: None. (PROSPERO: CRD42023456915).