Dual Therapy With Anti-CGRP Monoclonal Antibodies and Botulinum Toxin for Migraine Prevention

Is There a Rationale?

Lanfranco Pellesi, MD; Thien P. Do, MD; Håkan Ashina, MD; Messoud Ashina, MD, PhD, DMSc; Rami Burstein, PhD

Disclosures

Headache. 2020;60(6):1056-1065. 

In This Article

Abstract and Introduction

Abstract

Objective: To narratively review the pathophysiological rationale of dual therapy with anti-calcitonin gene-related peptide monoclonal antibodies and botulinum toxin type A in treatment-resistant chronic migraine prevention.

Background: For the prevention of chronic migraine, several pharmacological therapies are available, including oral medications, botulinum toxin type A, and the newly approved monoclonal antibodies targeting calcitonin gene-related peptide or its receptor. However, monotherapy does not yield benefits in some affected individuals, which raises the question of whether dual therapy with monoclonal antibodies and botulinum toxin type A hold promise in patients with treatment-resistant chronic migraine.

Method: We searched MEDLINE for articles published from database inception to December 31st, 2019. Publications were largely selected from the past 10 years but commonly referenced and highly regarded older publications were not excluded.

Results: Preclinical data suggest that anti-calcitonin gene-related peptide monoclonal antibodies and botulinum toxin type A have synergistic effects within the trigeminovascular system. Of note, findings indicate that fremanezumab – an antibody targeting the calcitonin gene-related peptide – mainly prevents the activation of Aδ-fibers, whereas botulinum toxin type A prevents the activation of C-fibers.

Conclusion: There is currently only indirect preclinical evidence to support a rationale for dual therapy with anti-calcitonin gene-related peptide monoclonal antibodies and botulinum toxin type A for chronic migraine prevention. Rigorous studies evaluating clinical efficacy, safety, and cost-effectiveness are needed.

Introduction

Preventive treatment should always be provided to individuals with chronic migraine (CM).[1] The aim is to relieve pain, reduce disability, and obtain a disease-modifying effect. Headache guidelines recommend several pharmacological therapies, including oral medications, botulinum toxin type A (BTX-A), and the newly approved monoclonal antibodies (mAbs) targeting the calcitonin gene-related peptide (CGRP) or its receptor.[2] As first-line preventive measure, monotherapy is widely preferred by neurologists and headache specialists.[3] Monotherapy is of immediate advantage, resulting in simpler patient management, lower costs, and minimization of potential adverse events. However, a significant proportion of patients does not benefit from monotherapy, that is, experiencing no clinical meaningful relief of headaches.[4]

If meaningful effectiveness is not obtained, further measures can be considered, such as increasing dose, switching medication, or adding a second medication. Thus, the combination of more than 1 preventive drug is potentially attractive.[5–7] Indeed, some headache specialists have argued in favor of dual therapy as a strategy to combat treatment-resistant migraine.[8] With respect to a substituted monotherapy, a dual therapy may promote a synergic effect through different pharmacological mechanisms, resulting in an advantage for those patients with a history of repetitive failures of individual monotherapies. In addition, the use of lower dosages ensures greater tolerability and a lower risk of adverse events.[7]

The recent development and introduction to the market of mAbs neutralizing CGRP or its receptor has sparked a debate on the possibility of adding the latter to current migraine preventive medications. Some results have been obtained with oral medications, as part of a post hoc analysis.[9] Considering that the majority of headache experts also prescribe BTX-A,[10] they would definitely take a look whether it makes sense to combine BTX-A with anti-CGRP antibodies. As such, we find it timely to provide a Narrative Review, in which we discuss the pathophysiological rationale for dual therapy with anti-CGRP mAbs and BTX-A in the prevention of migraine.

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