cGRP inhibitors

By Marcello Cherchi, MD PhD

For patients

The cGRP inhibitors are a new group of medications used for helping people with migraine.  These medications are easy to use and do not cause many symptoms.  They may help people whose migraines cause disequilibrium.

For clinicians

Overview

The activity of calcitonin gene-related peptide (cGRP) at nerve terminals of meningeal and trigeminal nociceptors promotes vasodilation. The cGRP inhibitor medications interfere with this pathway (thereby diminishing vasodilation), and appear to interrupt the development of migraine.

Introduction

The pathophysiology of migraine is incompletely understood. The pioneering work of Peter Goadsby and colleagues (Goadsby and Edvinsson 1993; Goadsby et al. 1990; Ho et al. 2010) implicated calcitonin gene-related peptide (cGRP) as a contributory mechanism of disease.

Pharmacology

Research from human and animal studies suggests that cGRP activity at nerve terminals of meningeal and trigeminal nociceptors promotes vasodilation (Burstein et al. 2020), and interference with this pathway (thereby reducing vasodilation) appears to bring about improvement in migraine.

The cGRP inhibitors are broadly divided into small molecule antagonists (whose names end in “‑gepant”) and monoclonal antibodies (whose names end in “‑mab”).

Some cGRP inhibitors function as receptor antagonists, while others interfere with the cGRP molecule itself.

Drug	Type	Formulation and notes	FDA-approved indications
Atogepant (Qulipta®)	Small molecule	Oral	Prophylaxis against episodic and chronic migraine
Rimagepant (Nurtec ODT®)	Small molecule	Oral	Prophylaxis against episodic and chronic migraine
Ubrogepant (Ubrelvy®)	Small molecule	Oral, may take a second dose after 2 hours	Acute migraine abortive
Zavegepant (Zavzpret®)	Small molecule	Nasal	Acute migraine abortive
Eptinezumab (Vyepti®)	Monoclonal antibody	Injected	Migraine prophylaxis
Erenumab (Aimovig®)	Monoclonal antibody	Injected	Migraine prophylaxis
Fremanezumab (Ajovy®)	Monoclonal antibody	Injected	Migraine prophylaxis
Galcanezumab (Emgality®)	Monoclonal antibody	Injected	Migraine prophylaxis

Relevance in otoneurology

The overall efficacy and tolerability of cGRP inhibitors has firmly established their use in the management of migraine, to the point that the American Headache Society recommends they be considered among first-line therapies (Charles et al. 2024).

Insofar as cGRP inhibitors can manage migraine, they may have some role in otoneurology, such as in the management of migraine associated vertigo, though the literature about this is nascent, consisting of a retrospective chart review (Hoskin and Fife 2021) and a prospective observational study (Russo et al. 2023). Animal studies suggest that cGRP may specifically sensitize vestibular nuclei (Zhang et al. 2020); if similar data are found in humans, then this would offer a specific rationale for the use of cGRP inhibitors in migraine associated vertigo.

Cautions and contraindications

Generally the cGRP inhibitors are reported to be well-tolerated. “The most commonly reported adverse events are constipation in 1.6% – 3.4% of the cohort, nausea, local injection site reaction (5%) and fatigue in 3% – 6% of patients. Emerging real-world data, however, shows constipation occurs at a rate of 10% – 20%, with local site reactions, pruritis, bloating, or coryzal symptoms occurring in 1% – 2% of patients” (Ray et al. 2021).

References

Burstein R, Blumenfeld AM, Silberstein SD, Manack Adams A, Brin MF (2020) Mechanism of Action of OnabotulinumtoxinA in Chronic Migraine: A Narrative Review. Headache 60: 1259-1272. doi: 10.1111/head.13849

Goadsby PJ, Edvinsson L (1993) The trigeminovascular system and migraine: studies characterizing cerebrovascular and neuropeptide changes seen in humans and cats. Ann Neurol 33: 48-56. doi: 10.1002/ana.410330109

Goadsby PJ, Edvinsson L, Ekman R (1990) Vasoactive peptide release in the extracerebral circulation of humans during migraine headache. Ann Neurol 28: 183-7. doi: 10.1002/ana.410280213

Ho TW, Edvinsson L, Goadsby PJ (2010) CGRP and its receptors provide new insights into migraine pathophysiology. Nature Reviews Neurology 6: 573-582. doi: 10.1038/nrneurol.2010.127

Hoskin JL, Fife TD (2021) New Anti-CGRP Medications in the Treatment of Vestibular Migraine. Front Neurol 12: 799002. doi: 10.3389/fneur.2021.799002

Ray JC, Kapoor M, Stark RJ, Wang SJ, Bendtsen L, Matharu M, Hutton EJ (2021) Calcitonin gene related peptide in migraine: current therapeutics, future implications and potential off-target effects. J Neurol Neurosurg Psychiatry 92: 1325-1334. doi: 10.1136/jnnp-2020-324674

Russo CV, Sacca F, Braca S, Sansone M, Miele A, Stornaiuolo A, De Simone R (2023) Anti-calcitonin gene-related peptide monoclonal antibodies for the treatment of vestibular migraine: A prospective observational cohort study. Cephalalgia 43: 3331024231161809. doi: 10.1177/03331024231161809

Zhang Y, Zhang Y, Tian K, Wang Y, Fan X, Pan Q, Qin G, Zhang D, Chen L, Zhou J (2020) Calcitonin gene-related peptide facilitates sensitization of the vestibular nucleus in a rat model of chronic migraine. J Headache Pain 21: 72. doi: 10.1186/s10194-020-01145-y