Calcitonin gene–related peptide–targeted therapies reduced monthly migraine headache days by about 2 days vs placebo among patients with chronic migraine, according to a systematic review of randomized controlled trials published in Annals of Internal Medicine.
The review included 43 randomized controlled trials involving 14,725 adult patients with chronic migraine, defined as headache occurring on at least 15 days per month, including at least 8 days with migraine features. Researchers searched Medline, Embase, Cochrane Central Register of Controlled Trials, PsycINFO, Web of Science, and Scopus from inception through October 1, 2025, without language restrictions.
Using random-effects pairwise meta-analysis and GRADE certainty assessments, the researchers found high-certainty evidence that eptinezumab, erenumab, fremanezumab, galcanezumab, and atogepant reduced monthly migraine headache days by approximately 2 days compared with placebo.
The therapies also generally improved the likelihood of achieving at least a 50% reduction in monthly migraine headache days or attacks, although certainty differed across agents. Fremanezumab and erenumab demonstrated high-certainty evidence for the 50% response outcome, whereas evidence for eptinezumab was rated low certainty because of unexplained heterogeneity across trials.
Rimegepant, evaluated in 2 trials that included mixed chronic and episodic migraine populations, probably had little or no effect on monthly migraine headache days.
The review identified few clinically meaningful tolerability differences across CGRP-targeted therapies. However, galcanezumab probably reduced dropout due to any cause compared with placebo, making it the only CGRP-targeted therapy to show that signal. Erenumab and atogepant probably increased constipation risk, and atogepant probably also increased nausea risk, based on moderate-certainty evidence.
Among older preventive therapies, botulinum toxin may have slightly reduced monthly migraine headache days compared with placebo, although evidence certainty was low and treatment effects varied according to study risk of bias. The larger treatment effect was observed in the lone low-risk-of-bias trial, whereas higher-risk trials showed smaller reductions. Botulinum toxin also probably increased discontinuation because of adverse events.
Evidence for propranolol, topiramate, valproate, fluoxetine, and several other preventive agents was based largely on small trials with high risk of bias, limiting confidence in the findings.
One notable head-to-head comparison favored erenumab over topiramate. In a phase 4 randomized trial included in the review, high-certainty evidence showed erenumab reduced monthly migraine headache days more than topiramate, while moderate-certainty evidence showed fewer discontinuations because of adverse events.
The researchers noted that most trials evaluating CGRP-targeted therapies were industry funded and that median follow-up across studies was only 12 weeks, limiting conclusions regarding long-term safety and durability of benefit. Planned network meta-analysis was not performed because of sparse comparative data.
“Most calcitonin gene–related peptide–targeted therapies are probably effective for chronic migraine prophylaxis,” wrote lead study researcher Malahat Khalili, PhD, of McMaster University, and colleagues.
The researchers called for larger independent head-to-head trials comparing CGRP-targeted therapies with established preventive agents, along with longer-term studies evaluating safety, adherence, quality of life, and cost-effectiveness.
Disclosures: The study received no direct funding. Most included trials evaluating CGRP-targeted therapies were industry funded. Disclosure forms were available with the article online.
Source: Annals of Internal Medicine
