Migraine-Associated Nausea: The Role of CGRP Receptor Antagonists in Treatment
Migraine is a complex neurological condition characterized primarily by intense headaches. However, accompanying symptoms such as photophobia, phonophobia, nausea, and vomiting can often be more distressing to patients than the headache itself. According to various studies, approximately 60–95% of migraine sufferers experience nausea during an attack, while 50–62% report vomiting. Historically, clinical trials evaluating acute migraine treatments have focused on pain relief, with secondary endpoints including reduction in nausea, sensitivity to light, and sound. In February 2018, the U.S. Food and Drug Administration (FDA) released a draft guidance for developing acute migraine therapies, recommending that trials adopt two co-primary endpoints: pain freedom and freedom from the most bothersome symptom, both assessed two hours post-dosing.
Understanding the Physiology of Migraine-Related Nausea
Nausea associated with migraine involves a complex interplay between the gastrointestinal and central nervous systems. This process is mediated by six key neurotransmitters: serotonin, dopamine, substance P, neurokinin, acetylcholine, and calcitonin gene-related peptide (CGRP). Among these, CGRP has emerged as a critical player in migraine pathophysiology. It is a neuropeptide released by sensory neurons and plays a key role in vasodilation and inflammatory responses. Notably, dysfunction in CGRP signaling has been linked to gastrointestinal disturbances, including symptoms similar to functional dyspepsia.
What Are CGRP Receptor Antagonists?
CGRP receptor antagonists, also known as gepants, are a class of medications specifically developed to target CGRP activity. These drugs work by blocking the CGRP receptor, thereby inhibiting the peptide's effects. A comprehensive review of 65 clinical trials involving 23,008 participants across 14 published articles showed strong evidence supporting the efficacy of gepants in treating nausea associated with episodic migraine. These findings suggest that targeting CGRP pathways can significantly reduce migraine-related nausea.
How Gepants May Alleviate Nausea
One theory suggests that the anti-nausea effects of gepants may stem from their ability to block CGRP receptors in the gastrointestinal tract. Although these drugs have limited ability to cross the blood-brain barrier, their effectiveness in reducing nausea implies that they may act on areas of the brainstem that lack this barrier, such as the area postrema and the dorsal vagal complex. These regions are known to play a central role in the vomiting reflex and autonomic regulation.
Potential Applications Beyond Migraine
Interestingly, CGRP has also been identified in the vestibular system, including the cochlea, vestibular end organs, and the vestibular nuclei in the medulla. Vestibular disturbances, such as vertigo, are commonly reported in migraine patients and are closely associated with nausea. Given this connection, researchers hypothesize that gepants may offer therapeutic benefits for other conditions involving nausea and gastrointestinal dysfunction, such as cyclic vomiting syndrome, irritable bowel syndrome (IBS), and gastroparesis.
As research into CGRP and its role in migraine and nausea continues to evolve, gepants represent a promising treatment option that addresses both the primary and secondary symptoms of migraine. Their unique mechanism of action, combined with clinical evidence of efficacy, makes them a valuable addition to the current therapeutic landscape for migraine management.