Migraine-Associated Nausea: The Therapeutic Role of CGRP Receptor Antagonists

Migraine is primarily characterized by intense headache, but patients often experience additional debilitating symptoms such as photophobia, phonophobia, nausea, and vomiting. Among these, nausea is reported in approximately 60–95% of migraine sufferers, while 50–62% experience vomiting during an attack. These associated symptoms can be as distressing, if not more so, than the headache itself, significantly impacting daily functioning and quality of life.

Evolution of Clinical Trial Endpoints in Migraine Treatment

Historically, clinical trials evaluating acute migraine therapies have focused on pain relief and the reduction of associated symptoms like nausea and photophobia. These symptoms have often been included as co-primary endpoints. In February 2018, the U.S. Food and Drug Administration (FDA) released a draft guidance for the development of acute migraine treatments, recommending a dual primary endpoint approach: pain freedom and freedom from the most bothersome symptom (typically nausea, photophobia, or phonophobia) two hours post-dosing.

Understanding the Pathophysiology of Migraine-Related Nausea

The underlying mechanisms of migraine-related nausea are complex and involve dysregulation of both the gastrointestinal (GI) tract and central nervous system (CNS). Several key neurotransmitters are implicated, including serotonin, dopamine, substance P, neurokinin, acetylcholine, and calcitonin gene-related peptide (CGRP). Among these, CGRP has emerged as a crucial mediator in migraine pathophysiology.

CGRP and Its Role in Migraine and Nausea

CGRP is a neuropeptide released by sensory neurons and plays a significant role in vasodilation and inflammatory responses. It is also involved in modulating pain perception and gastrointestinal motility. Dysregulation of CGRP signaling has been linked to both migraine attacks and functional GI disorders such as dyspepsia.

Gepants: A New Class of CGRP Receptor Antagonists

Gepants, a class of CGRP receptor antagonists, have shown promising results in the acute treatment of migraine. A meta-analysis encompassing 65 clinical trials and 23,008 participants (10,770 in gepant groups and 12,238 in placebo or non-gepant groups across 14 published studies) provided strong evidence supporting the efficacy of gepants in alleviating migraine-related nausea.

Potential Mechanisms Behind Gepant Anti-Nausea Effects

While the exact mechanism remains under investigation, it is believed that gepants exert their anti-nausea effects by blocking CGRP receptors in the gastrointestinal tract. Despite limited blood-brain barrier penetration, these drugs may also act on brainstem regions such as the area postrema and dorsal vagal complex, which lack a complete blood-brain barrier. Additionally, CGRP is found in the vestibular system, including the cochlea, vestibular end organs, and vestibular nuclei. Vestibular dysfunction, such as vertigo, is frequently associated with migraines and may contribute to nausea. This suggests that gepants could potentially benefit other conditions involving nausea and vomiting, such as cyclic vomiting syndrome, irritable bowel syndrome, and gastroparesis.