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

CGRP and Migraine

The trigeminovascular system plays an integral role in migraine pathogenesis.[11] Within this framework, CGRP and various other neuropeptides are heavily involved in mediating certain aspects of the headache phase of migraine.[12,13] CGRP is expressed in almost 50% of neurons within the trigeminal ganglion (TG)[14] as well as in the C-fibers of trigeminal sensory afferents.[15] Following its release from the latter, CGRP modulates afferent and efferent nociceptive transmission through the activation of its receptors located in the meningeal vasculature, Aδ-fibers of trigeminal sensory afferents, TG neurons, and satellite glial cells.[16–19]

The role of CGRP in migraine pathogenesis is well-established, with an abundance of available clinical and preclinical data.[20] First, intravenous infusion of CGRP triggers migraine-like attacks in individuals with migraine.[21–23] Second, anti-CGRP medications have proven benefits in migraine prevention.[24–26] Last, several effective drugs (eg, triptans, ditans, ergot alkaloids) for migraine inhibit CGRP release from within the trigeminovascular system.[27–29] However, the exact mechanisms by which CGRP induces migraine remain unsettled, although some hypotheses have been proposed. At the meningeal vessels, the peptide contributes to vasodilation and local release of inflammatory mediators, thereby increasing the nociceptive transmission of primary sensory afferents.[30–32] Short- and long-term effects may amplify signals transferred to the TG and second-order neurons at the trigeminal nucleus caudalis (TNC), ultimately producing central sensitization, and the manifestation of hyperalgesia and allodynia.[33–35] Other peripheral effects of CGRP involve both neurons and satellite glial cells in the TG, resulting in an increased production of peptide neurotransmitters and ion channels that amplify pain signals at the brainstem.[36,37] Presence of CGRP in brain areas involved in migraine pathophysiology, such as the TNC,[38] locus coeruleus, ventrolateral periaqueductal gray, thalamus, hypothalamus, hippocampus, amygdala, and cortex[39–43] support the involvement of CGRP in many central nervous system (CNS) mediated symptoms that accompany migraine.