Which Drugs for Migraine Prophylaxis Are Most Efficacious and Tolerated?

Calcitonin gene-related peptide or its receptor (CGRP[r]mAbs) are superior to other drugs for migraine prophylaxis in safety and efficacy.

A systematic review and network meta-analysis identified monoclonal antibodies (mAbs) targeting CGRP receptor component (CGRP) or its receptor (CGRP(r)) as the migraine prophylaxis drug with the best safety and efficacy profiles compared with other active medications. These findings were published in The Journal of Headache and Pain.

Many classes of medications are used for migraine prophylaxis. Although there is much evidence about the safety and efficacy of drugs, few head-to-head comparisons have been published.

This analysis was performed to try and compare active migraine prophylaxis medications. To that end, publication databases were searched through August 2022 for randomized trials of pharmacologic treatments for migraine. A total of 73 publications comprising 32,990 participants were included in the analysis.

Commonly used older classes of drugs appear to not only be less effective than CGRP(r)mAbs and gepants, but they are also associated with substantially higher risk of adverse events.

Most trials were funded by industry (73%), and the interventions included amitriptyline, beta-blockers, calcium channel blockers, carismabate, eptinezumab, erenumab, fremanezumab, gabapentin, galcanezumab, gepants, oxcarbazepine, pregabalin, topiramate, and valproate.

The study population comprised 16% men, they had a mean age of 41 years, 45% had migraine with aura, 49% had prior migraine prophylaxis use, and the mean migraine days (MMDs) per month was 11.

For the change in monthly migraine days, 7 interventions were found to be more beneficial than placebo. These best-performing interventions were fremanezumab (mean difference [MD], -2.22 days), galcanezumab (MD, -1.97 days), eptinezumab (MD, -1.85 days), erenumab (MD, -1.6 days), gepants (MD, -1.12 days), topiramate (MD, -0.73 days), and beta-blockers (MD, -0.69 days).

A total of 6 therapeutics were favored over placebo for the outcome of a 50% reduction in MMDs, specifically, fremanezumab (risk difference [RD], 341.1 per 1000 people), galcanezumab (RD, 223.9 per 1000 people), erenumab (RD, 206 per 1000 people), eptinezumab (RD, 173 per 1000 people), gepants (RD, 146.8 per 1000 people), and topiramate (RD, 123.5 per 1000 people).

Only one medication, erenumab, was found to have a similar safety profile as placebo with regard to adverse events, leading to discontinuation (RD, 0.3 per 1000 people). In addition, 5 medications were probability no different than placebo, specifically gepants (RD, 2.6 per 1000 people), carismabate (RD, 2.6 per 1000 people), fremanezumab (RD, 3.9 per 1000 people), eptinezumab (RD, 9.4 per 1000 people), and galcanezumab (RD, 9.5 per 1000 people). The medications associated with the greatest discontinuation rate due to adverse events were valproate (RD, 67.1 per 1000 people) and amitriptyline (RD, 64 per 1000 people.

In secondary analyses, all indicated that CGRP(r)mAbs and gepants were most effective at increasing the proportion of patients who achieved a 50% or better reduction in MMDs.

This analysis was limited by not evaluating function, disability, or quality of life outcomes.

The study authors concluded, “CGRP(r)mAbs are the most effective and tolerated treatment for migraine prophylaxis, followed closely by gepants. Commonly used older classes of drugs appear to not only be less effective than CGRP(r)mAbs and gepants, but they are also associated with substantially higher risk of adverse events.”

Disclosure: Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.


Lampl C, MaassenVanDenBrink A, Deligianni CI, et al. The comparative effectiveness of migraine preventive drugs: a systematic review and network meta‑analysis. J Headache Pain. 2023;24(1):56. doi:10.1186/s10194-023-01594-1