Effectiveness and tolerability of pharmacological prophylaxis in migraine patients with prior preventive treatment failure: A systematic review and network meta-analysis of randomized controlled trials

Abstract

Background Despite advances in migraine management, some patients fail to respond to preventive treatments for migraine. We aimed to assess the comparative effects of available pharmacological prophylaxis in adults with a treatment failure history.Methods We searched Medline, Embase, Cochrane Central, PsycINFO, Web of Science, and Scopus up to July 2025. Pairs of reviewers independently screened titles, abstracts, and full-text articles to identify randomized controlled trials of prophylactic pharmacological interventions that enrolled adults diagnosed with chronic or episodic migraine and a prior preventive treatment failure. We performed a frequentist random-effects network meta-analysis and used the GRADE approach to assess the certainty of evidence.Results We included 18 randomized trials (7281 participants). Compared to placebo, low certainty evidence suggest fremanezumab mean difference (MD) -3.30 (95% CI: -4.11 to -2.49), eptinezumab MD -3.35 (95% CI: -4.38 to -2.32), galcanezumab MD -2.73 (95% CI: -3.43 to -2.03), atogepant MD -2.30 (95% CI: -3.47 to -1.13), and erenumab MD -2.20 (95% CI: -2.72 to -1.68) may be among the most effective in reducing the monthly migraine headache days. Low to moderate certainty evidence suggests that, compared with placebo, galcanezumab relative risk (RR) 1.94 (95% CI: 1.52 to 2.48), fremanezumab RR 3.98 (95% CI: 2.40 to 6.59), atogepant RR 2.80 (95% CI: 1.73 to 4.54), erenumab RR 2.56 (95% CI: 2.01 to 3.26), and eptinezumab RR 2.35 (95% CI: 1.61 to 3.42) may increase the likelihood of achieving a 50% response rate.Conclusion Evidence for migraine patients with prior preventive treatment failure is limited. Low- to moderate-certainty data suggest that CGRP-targeted therapies may provide some benefit and are generally tolerable, but the available evidence is driven by a few industry-sponsored trials. Additional independent, well-powered studies with longer follow-up are needed to strengthen the evidence base.Registration number PROSPERO (CRD42024547860).