Author: Lanfranco Pellesi

As the range of treatment options for migraine prevention continues to grow, Dr Lanfranco Pellesi, from the Department of Public Health at the University of Southern Denmark, Odense, Denmark, considers the evidence supporting the use of combination treatment with onabotulinumtoxinA and anti-CGRP therapies.

The preventive treatment of migraine has undergone a major transformation over the past decade with the introduction of therapies targeting the CGRP pathway.¹ Monoclonal antibodies against CGRP or its receptor, CGRP receptor antagonists and onabotulinumtoxinA have substantially improved outcomes for many patients, particularly those with chronic migraine. As these treatments have become established in clinical practice, interest has grown in combining them in patients with an insufficient response to monotherapy.² However, despite increasing use, the clinical evidence supporting this approach remains limited and deserves careful consideration.

From a mechanistic perspective, combining onabotulinumtoxinA with anti-CGRP therapies appears biologically plausible. OnabotulinumtoxinA inhibits the release of CGRP and other neurotransmitters from peripheral trigeminal afferents, particularly C-fibres, while CGRP-targeting therapies block the CGRP ligand or receptor, mainly affecting Aδ-fibre signalling. By targeting different components of the trigeminovascular system, the combination could theoretically provide broader modulation of migraine pathophysiology than either treatment alone.³

Clinical data supporting this strategy are primarily derived from real world and retrospective studies conducted in patients with chronic migraine, often after failure of multiple preventive treatments. Most of these studies report additional reductions in monthly migraine or headache days when a CGRP-targeting therapy is added to ongoing onabotulinumtoxinA, or vice versa.⁴ Overall, safety signals have been reassuring, with adverse events largely consistent with those observed for each therapy used alone. Nevertheless, it is important to acknowledge that there are no randomised, placebo-controlled clinical trials demonstrating that the combination of onabotulinumtoxinA and anti-CGRP therapies is superior to either treatment alone. The Phase 3 Nordic Chronic Migraine (NorMig) trial of CGRP mAb and onabotulinumtoxinA dual therapy compared to CGRP mAb monotherapy may help to address this lack of clinical trial evidence.⁵ It is currently recruiting, with plans to enrol 450 patients and report initial results in 2029.

Real world studies are subject to selection bias and the absence of appropriate control groups. Patients selected for combination therapy are often highly treatment-resistant, which complicates interpretation of outcomes and limits generalisability. As a result, the current evidence base does not support routine or widespread use of this combination in all patients with migraine. Rather, it suggests a potential role in carefully selected individuals, particularly those with chronic migraine who have derived partial but insufficient benefit from monotherapy. In these cases, combination therapy should be viewed as an individualised strategy.

An often underemphasised but critical aspect of this discussion is cost. Both onabotulinumtoxinA and CGRP-targeting therapies are associated with high direct costs, and combining them substantially increases the economic burden of treatment.⁶ These costs may be borne by patients themselves, private insurance systems or public healthcare providers, depending on the healthcare setting. Regardless of the payer, economic sustainability is a legitimate component of clinical decision-making and should be explicitly addressed.

In practical terms, clinicians considering this combination should engage in shared decision-making with patients. This process should include a transparent discussion of the current level of evidence, the uncertainty regarding added efficacy compared with monotherapy, and the potential financial implications. Patients who express a clear interest in trying the combination and who can realistically sustain the associated costs may be appropriate candidates, particularly when migraine-related disability remains high despite optimised monotherapy. Close monitoring is advisable.

Given the lack of controlled data, clinicians should define clear treatment goals and timeframes for reassessment, discontinuing one component if meaningful additional benefit is not observed. This pragmatic approach may help balance potential clinical gains against economic and therapeutic burden. Future well-designed clinical studies are needed to clarify which patients are most likely to benefit and to establish the true added value of this combination in routine clinical practice. Until then, its use should remain individualised, evidence-aware and grounded in shared decision-making.

 

References

 

1. Zobdeh F, Ben Kraiem A, Attwood MM et al. Pharmacological treatment of migraine: Drug classes, mechanisms of action, clinical trials and new treatments. Br J Pharmacol. 2021;178(23):4588-4607.
2. Pellesi L, Garcia-Azorin D, Rubio-Beltrán E et al. Combining treatments for migraine prophylaxis: the state-of-the-art. J Headache Pain. 2024;25(1):214.
3. Pellesi L, Do TP, Ashina H et al. Dual therapy with anti-CGRP monoclonal antibodies and botulinum toxin for migraine prevention: is there a rationale? 2020;60(6):1056-1065.
4. Pellesi L. Combining onabotulinumtoxin A with a CGRP antagonist for chronic migraine prophylaxis: where do we stand? Front Pain Res (Lausanne). 2023;4:1292994.
5. National Institutes of Health. The Nordic chronic migraine trial of CGRP monoclonal antibody and Onabotulinumtoxin A dual therapy compared to CGRP mAbs monotherapy (NorMig).
6. Schwedt TJ, Lee J, Knievel K et al. Real-world persistence and costs among patients with chronic migraine treated with onabotulinumtoxinA or calcitonin gene-related peptide monoclonal antibodies. J Manag Care Spec Pharm. 2023;29(10):1119-1128.