Combining Migraine Prevention Treatments: What Works When One Drug Isn't Enough | Research

The takeaway

Combining CGRP-targeting therapies (monoclonal antibodies and gepants) with each other or with botulinum toxin shows promise for treatment-resistant migraine, but large-scale clinical trials are still needed.

4 treatment classes
Oral preventives, onabotulinumtoxin A, CGRP monoclonal antibodies, and gepants — all reviewed as combination partners for migraine prophylaxis

What the researchers found

Dual CGRP inhibition — combining monoclonal antibodies targeting CGRP or its receptor with oral gepant antagonists — may enhance efficacy by blocking the CGRP pain pathway at multiple points. Combining onabotulinumtoxin A with CGRP-targeted treatments offers potentially synergistic pain relief through complementary mechanisms.

Traditional oral preventives (non-CGRP treatments) remain a practical and affordable combination partner, especially for patients with comorbid conditions. Despite these promising strategies, the review found insufficient evidence to support their routine inclusion in clinical guidelines, and the high cost of biological combination regimens poses feasibility challenges.

Why it matters

Many migraine patients do not achieve adequate relief from a single preventive treatment. As the toolkit of migraine-specific therapies expands — particularly CGRP-targeted biologics and gepants — clinicians need evidence-based guidance on which combinations are safe, effective, and cost-justified. This review maps the current landscape and highlights where the biggest evidence gaps remain.

How the study worked

This is a state-of-the-art narrative review synthesizing available evidence on combination migraine prophylaxis strategies, including oral conventional preventives, onabotulinumtoxin A, CGRP-targeting monoclonal antibodies, and gepants. The review was authored by an international panel of headache specialists.

What this study cannot tell us

This is a narrative review, not a systematic review or meta-analysis. Most evidence for combination strategies comes from small studies, retrospective analyses, or case series rather than large randomized controlled trials. The review acknowledges that high costs of biologic combinations may limit real-world adoption regardless of efficacy. Long-term safety data for many combinations is lacking.

How to read the evidence

This is a narrative review by an expert international panel. While it provides a comprehensive overview, it acknowledges that most combination strategies lack support from large randomized controlled trials, limiting the strength of the conclusions.

When this study was published

Published in 2024, this is a very current review that captures the latest state of combination migraine prophylaxis, including the newest gepant and CGRP antibody combinations.

The bigger picture

The migraine treatment landscape has been transformed by CGRP-targeting therapies over the past decade. As these drugs become more established, the natural next question is whether combining them — with each other or with older treatments — can help the substantial number of patients who don't fully respond to monotherapy. This review reflects a field moving from single-agent optimization toward rational polytherapy.

Questions still open

Does dual CGRP blockade (mAb + gepant) provide meaningfully better outcomes than either agent alone in randomized trials?
What is the long-term safety profile of combining onabotulinumtoxin A with CGRP-targeting biologics?
Can combination strategies be made cost-effective enough for routine clinical use, particularly in resource-limited settings?

Common questions

What is dual CGRP blockade and why might it work better than a single CGRP treatment?

Dual CGRP blockade means using two different types of drugs that both target the CGRP pain pathway — typically a monoclonal antibody (which blocks the CGRP molecule or its receptor for weeks) combined with a gepant pill (which blocks the CGRP receptor on demand). The idea is that hitting the same pathway at two different points may provide more complete relief than either drug alone.

Why aren't combination migraine treatments already standard practice?

While combinations show promise, there haven't been enough large, well-designed clinical trials to prove they're consistently better than single treatments. Additionally, combining biologic drugs like CGRP antibodies with botulinum toxin is expensive, and insurers often won't cover multiple high-cost therapies simultaneously. Doctors need more evidence before they can confidently recommend these combinations as routine.

Read the original research

Combining treatments for migraine prophylaxis: the state-of-the-art.

The journal of headache and pain, 25(1), 214

View on PubMed ↗Publisher’s paper ↗

Citation

Pellesi, Lanfranco; Garcia-Azorin, David; Rubio-Beltrán, Eloisa; Ha, Wook-Seok; Messina, Roberta; Ornello, Raffaele; Petrusic, Igor; Raffaelli, Bianca; Labastida-Ramirez, Alejandro; Ruscheweyh, Ruth; Tana, Claudio; Vuralli, Doga; Waliszewska-Prosół, Marta; Wang, Wei; Wells-Gatnik, William. (2024). Combining treatments for migraine prophylaxis: the state-of-the-art.. The journal of headache and pain, 25(1), 214. https://doi.org/10.1186/s10194-024-01925-w