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

BTX-A and the CGRP Pathway

BTX-A is internalized into local afferent nerve terminals, where it cleaves soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins.[58] This prevents the adhesion of synaptic vesicles to the cell surface membrane,[59–63] which results in an inhibition of neuropeptide release and insertion of new receptors. This includes the blocking of pain-modulating neurotransmitters, such as CGRP, glutamate, and substance P.[64–66] These peptides can lead to a cascade of local events, including plasma extravasation and release of cytokines, that ultimately sensitize peripheral afferent terminals.[67,68] BTX-A predominantly blocks CGRP-release from meningeal and extracranial C-fibers[69–71] through a direct mechanism and, in addition, also indirectly by modulating ion channels.[72,73] In humans, the peripheral antinociceptive mechanisms of the toxin have been studied along with the intradermal injection of capsaicin.[74,75] Capsaicin activates the transient receptor potential cation channel subfamily V member 1 (TRPV1) located on C-fibers and excites primary sensory afferents, causing intense pain following the release of pain mediators, such as CGRP and substance P. In both studies,[74,75] pre-treatment with BTX-A reduced pain, flare, and hyperalgesia, appearing to preferentially target C-fibers and blocking neurotransmitter release. An effect on unmyelinated C-fibers has been reported for extracranial and intracranial meningeal nociceptors as well.[69] When BTX-A is administered into extracranial sutures, it selectively inhibited C- but not Aδ-meningeal nociceptors,[69,70] reverting and preventing their sensitization. The selective inhibition of the unmyelinated C-fibers appears to block the ability of these nociceptors to respond to the stimulation of TRPV1 and transient receptor potential ankyrin 1 (TRPA1),[71] likely due to their reduced expression in the synaptic membrane following the BTX-A administration. Accordingly, reduced sensitivity to molecules that activate C-meningeal nociceptors through TRPV1 and TRPA1 and reduce the CGRP release might contribute to the clinical efficacy of BTX-A in migraine. In people with CM, an effective treatment was correlated with higher serum CGRP levels,[76,77] that decrease in the interictal phase.[73] These results assume that the effectiveness of BTX-A depends on the inhibition of CGRP release from peripheral sensory afferents and the consequent reduction of its serum level. However, current data are not strong enough to validate the assumption.[78]