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


Headache. 2020;60(6):1056-1065. 

In This Article

Rationale for Combination Therapy With Anti-CGRP MABS and Botulinum Toxin

Although combination therapy has not been systematically studied, clinical practice suggests that a rational approach to CM treatment, using more than 1 preventative medication, might be beneficial if monotherapy is inadequate.[79,80] Anti-CGRP mAbs are currently considered a comparable alternative to BTX-A in migraine prevention.[81,82] Both medications are the only parenteral treatments, among migraine preventive medicines. Erenumab and galcanezumab are administered by monthly subcutaneous injection, fremanezumab is administered by quarterly or monthly injection, while eptinezumab is delivered by quarterly infusion.[83] BTX-A is injected in 31 to 39 fixed-site, fixed-dose injections across head and neck muscle areas. There are no direct comparative studies to inform the choice between mAbs or BTX-A. Current clinical practice is that therapies should not be administered together, and, in some cases, it is required to suspend BTX-A before starting an anti-CGRP therapy.[82] However, such claims are purely speculative, because this has not yet been systematically investigated. New animal studies have further explored their pharmacological impact on the trigeminovascular system, with renewed implications on the pathophysiological understanding of migraine prevention. Most significant data show that fremanezumab, an antibody targeting the CGRP peptide, prevents the activation of Aδ- but not C-fibers whereas BTX-A prevents the activation of C- but not Aδ-fibers (Figure 1). Predominant distribution of CGRP in C-fibers and CGRP receptors in Aδ-fibers[18,84] further supports the findings above. Fremanezumab is likely effective in migraine patients with pain signals from meningeal Aδ-fibers and HT neurons. In contrast, non-responders may involve other pathways, mediated by C-fibers and/or different central trigeminovascular neurons. Thus, concomitant use of medications blocking the activation of meningeal C-fibres may provide a synergistic effect on the trigeminal nociceptive pathway. However, dual-therapy with anti-CGRP mAbs and BTX-A in migraine prevention requires verification in the clinical setting.

Figure 1.

Proposed mechanisms for the synergic activity of anti-calcitonin gene-related peptide (CGRP) monoclonal antibodies (mAbs) and botulinum toxin A (BTX-A) in the prevention of migraine with a focus on the CGRP signaling pathway. BTX-A acts by inhibiting the release of CGRP from thin unmyelinated C fiber meningeal nociceptors in the dura, thus preventing a CGRP-dependent activation of meningeal vessels and thick myelinated Aδ nociceptors. At the same time, anti-CGRP mAbs prevent the interaction between the CGRP and its receptor within the meningeal vessel walls, as well as in the extremities and along the fibers in at the nodes of Ranvier of the Aδ nociceptors. [Color figure can be viewed at wileyonlinelibrary.com]