Gepants (CGRP receptor antagonists) for acute migraine

The trigeminovascular system is now known to have a significant role in the initiation of migraines, including the release of pain mediators such as calcitonin gene-related peptide (CGRP) and substance P (1)

• when administered, calcitonin gene-related peptide (CGRP) has been shown to cause mast cell degranulation and cerebral vasculature vasodilation leading directly to the development of migraine
• CGRP is a neuropeptide involved in pain transmission and neurogenic inflammation, and it has a central role in the pathophysiology of migraine attacks (2)
• two main classes of CGRP modulators have been developed:
  • CGRP receptor antagonists (gepants)
  • CGRP monoclonal antibodies
  • both gepants and CGRP monoclonal antibodies are believed to target peripheral CGRP receptors
• rimegepant is a second-generation gepant that was first introduced in 2012
  • is a CGRP receptor antagonist approved for the acute treatment of migraine with or without aura in adults, and for the preventive treatment of episodic migraine in adults (2)
  • based on the currently existing evidence, rimegepant appears to be an effective and safe acute migraine treatment with few adverse effects (1)
    • the most common and promising effects include freedom from pain and freedom of most bothersome migraine-related symptoms when used as an acute treatment
    • the orally dissolving tablet rimegepant has been approved by both the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) for acute treatment, while at the time of writing (September 2025) oral ubrogepant and zavegepant nasal spray have been approved by the FDA only (2)

Gepants were well tolerated in clinical trials. Use should be avoided in pregnancy due to lack of safety data (2)

• gepants have not shown any signal of cardiac adverse events and are therefore considered safe in patients with cardiovascular risk factor

A review states (2):

• gepants (CGRP receptor antagonists) are an option for treatment of acute migraines in patients who do not respond to triptans or in whom triptans are contraindicated
• gepants are likely slightly less effective than triptans but have fewer side effects
• gepants may be used in patients with cardiovascular contraindications to triptan use

Reference:

1. Berger AA et al. Rimegepant for the treatment of migraine. Health Psychol Res. 2022 Oct 12;10(5):38534. doi: 10.52965/001c.38534. PMID: 36262478; PMCID: PMC9560892.
2. Burch R, Rittenberg E. New treatments for migraine: CGRP monoclonal antibodies, gepants, and ditansBMJ 2025; 390 :e085564