Effectiveness and tolerability of pharmacological prophylaxis for migraine headaches: a systematic review and network meta-analysis of randomised controlled trials

OBJECTIVES: Migraine headaches are common and potentially disabling disorders, with several interventions available for prevention and symptom reduction. We explored the comparative effectiveness and tolerability of pharmacological prophylaxis for migraine through a network meta-analysis of randomised trials (RCTs). DESIGN: Our study design was a systematic review and network meta-analysis (PROSPERO registration CRD42023456915). ELIGIBILITY CRITERIA: We included randomised controlled trials of prophylactic pharmacological interventions that enrolled adults diagnosed with chronic and/or episodic migraine headaches. DATA SOURCES: Medline, Embase, Cochrane Central, PsycINFO, Web of Science and Scopus from inception to 15 January 2026. RISK OF BIAS AND CERTAINTY EVIDENCE: Risk of bias was assessed using the modified Cochrane risk-of-bias tool 2.0 and the certainty evidence was evaluated by using the Grading of Recommendations Assessment, Development and Evaluation approach. SYNTHESIS OF RESULTS: We performed a frequentist network meta-analysis using a random-effects model to compare the efficacy of interventions. RESULTS: We included 199 RCTs (47 420 participants). Overall, 29 trials (14.6%) were at low risk of bias; an adequate random allocation sequence generation was reported in 92 trials (46.2%), and missing outcome data was the most common limitation (110 trials, 55.3%). Compared with placebo, calcium channel blockers (mean difference (MD) -1.78 (95% CI -2.96 to -0.60), moderate certainty), calcitonin gene-related peptide (CGRP)-targeted therapies (MD -1.69 (95% CI -2.16 to -1.23), high certainty) and beta-blockers (MD -1.50 (95% CI -2.54 to -0.47), moderate certainty) were the most effective in reducing monthly migraine days. Moderate certainty evidence suggests beta-blockers (MD -1.31 (95% CI -1.76 to -0.85)), calcium channel blockers (MD -1.11 (95% CI -1.65 to -0.57)), anticonvulsants (MD -1.12 (95% CI -1.66 to -0.58)) and CGRP-targeted therapies (MD -0.76 (95% CI -1.49 to -0.02)) probably reduce monthly migraine attacks. However, moderate to high certainty evidence found that patients were more likely to discontinue calcium channel blockers (relative risk (RR) 1.40, 95% CI 1.04 to 1.88) and anticonvulsants (RR 1.14, 95% CI 1.01 to 1.29), compared with placebo. CONCLUSIONS: When restricted to moderate or high certainty evidence, beta-blockers and CGRP-targeted therapies probably reduce migraine frequency and may be well-tolerated prophylactic options for migraine. Calcium channel blockers and anticonvulsants may also be effective for reducing migraine frequency but are less well tolerated by some patients. PROSPERO REGISTRATION NUMBER: CRD42023456915.