Calcitonin gene-related peptide therapies effective for chronic migraine

1. In this systematic review and meta-analysis, prophylaxis with calcitonin gene-related peptide-targeting therapies (eptinezumab, erenumab, fremanezumab, galcanezumab, and atogepant) consistently reduced monthly migraine headache days compared with placebo.

2. Only a small proportion of included studies were at low risk of bias, and head-to-head comparisons between therapies were limited.

Evidence Rating Level: 1 (Excellent)

Study Rundown: Migraine affects approximately 1 billion people worldwide and is the second leading cause of years lived with disability. Chronic migraine, defined as headache occurring on ≥15 days per month, with migraine on at least 8 of those days, affects about 10% of individuals with migraine. Management includes both acute and preventive therapies, but existing systematic reviews of pharmacologic prophylaxis do not fully capture all drug classes or clinically important outcomes. This study evaluated the effectiveness and tolerability of pharmacologic prophylaxis for chronic migraine. High- and moderate-certainty evidence showed that calcitonin gene-related peptide (CGRP)-targeting therapies (eptinezumab, erenumab, fremanezumab, galcanezumab, and the receptor antagonist atogepant) reduce monthly migraine days by approximately two compared with placebo. In contrast, moderate-certainty evidence indicated that rimegepant likely has no meaningful effect. Low-certainty evidence suggested that botulinum toxin may provide a small reduction in migraine days but likely increases discontinuation due to adverse events. Galcanezumab also probably reduced all-cause discontinuation compared with placebo. Evidence for traditional therapies (e.g., topiramate, valproate, propranolol) was limited and of low certainty. Generalizability is constrained by the high risk of bias and short follow-up in many included trials. Overall, CGRP-targeted therapies appear promising for migraine prophylaxis, but large, independent head-to-head trials evaluating efficacy, safety, and cost-effectiveness are needed to better inform clinical recommendations.

Click to read this study in AIM

Relevant Reading: The comparative effectiveness of migraine preventive drugs: a systematic review and network meta-analysis

In-Depth [systematic review and meta-analysis]: This systematic review and meta-analysis evaluated pharmacologic prophylaxis for chronic migraine. MEDLINE, Embase, Cochrane CENTRAL, PsycINFO, Web of Science, and Scopus were searched from inception to October 1, 2025, along with reference lists of relevant studies. Eligible randomized controlled trials enrolled adults (≥18 years) with chronic migraine assigned to pharmacologic prevention versus placebo, usual care, or another active comparator, and reported at least one effectiveness outcome. Trials with ≥80% medication overuse headache or prior preventive failure, dose-comparison studies, and non-pharmacologic interventions were excluded. Outcomes included monthly migraine headache days, ≥50% and 100% response rates, pain relief, analgesic use, and discontinuation. From 61,217 records, 43 randomized controlled trials (n=14,725) were included. Mean age was 40.9 years (interquartile range [IQR] 37.3-42.2), and 85% were female. Trial sizes ranged from 29 to 1,130 participants, and 56% were industry-funded. Baseline migraine frequency ranged from 10 to 24 days/month. Eleven trials (26%) were at low risk of bias. CGRP-targeted therapies showed consistent benefit. Erenumab (3 trials, n=1,326) reduced monthly migraine days by ~2 (mean difference [MD], −2.08; 95% confidence interval [CI], −2.82 to −1.33; high certainty) and increased ≥50% response (relative risk [RR], 1.47). Fremanezumab (3 trials, n=1,948) reduced migraine days (MD, −1.77; 95% CI, −2.45 to −1.09) and improved ≥50% response (RR, 2.05). Eptinezumab (3 trials, n=616) reduced migraine days (MD, −2.34; 95% CI, −2.76 to −1.92) and may improve ≥50% (RR, 1.44) and 100% response (RR, 2.07). Galcanezumab (1 trial, n=1,113) reduced migraine days (MD, −2.00) and improved ≥50% response (RR, 1.79). Atogepant (1 trial, n=778) reduced migraine days (MD, −2.10; high certainty) and improved ≥50% response (RR, 1.61). Rimegepant showed little or no effect. Botulinum toxin (5 trials, n=2,477) slightly reduced migraine days (MD, −1.34) but increased discontinuation due to adverse events (RR, 3.36). Evidence for traditional agents (e.g., topiramate, valproate) and head-to-head comparisons was low or very low certainty. Overall, CGRP-targeted therapies (except rimegepant) may be effective pharmaceuticals for chronic migraine prophylaxis.

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