CGRP-Targeting Medications Revolutionize Migraine Prevention and Treatment

What Is CGRP and Why Does It Matter in Migraine?

Calcitonin gene-related peptide (CGRP) is a 37-amino acid neuropeptide found abundantly in the trigeminal nervous system, which is the primary pain pathway involved in migraine. During a migraine attack, CGRP is released from trigeminal sensory nerve fibers, causing potent vasodilation of cerebral and dural blood vessels, promoting neurogenic inflammation, and facilitating pain signal transmission. Elevated CGRP levels have been consistently measured in the jugular venous blood of patients during migraine attacks.

The discovery of CGRP's role in migraine took decades of research. In 1985, CGRP was identified as the most potent vasodilator known. By the 1990s, researchers demonstrated that intravenous CGRP infusion could trigger migraine attacks in susceptible individuals, confirming its causal role. This understanding led to the development of two distinct drug classes targeting the CGRP pathway: monoclonal antibodies that bind CGRP itself or its receptor, and small-molecule CGRP receptor antagonists called gepants.

The CGRP pathway represents the first migraine-specific drug target since triptans were developed in the 1990s. Unlike triptans, which work through serotonin receptors and carry cardiovascular contraindications, CGRP-targeting therapies do not cause vasoconstriction, making them suitable for patients with cardiovascular disease, a population previously underserved by migraine treatments.

How Do CGRP Monoclonal Antibodies Prevent Migraines?

Three CGRP-targeting monoclonal antibodies are FDA-approved for migraine prevention: erenumab (Aimovig), fremanezumab (Ajovy), and galcanezumab (Emgality), all approved between 2018 and 2019. A fourth, eptinezumab (Vyepti), is administered as a quarterly intravenous infusion. Erenumab uniquely targets the CGRP receptor, while the other three bind circulating CGRP ligand directly. Despite these mechanistic differences, all four demonstrate similar clinical efficacy.

Clinical trials have consistently shown that CGRP monoclonal antibodies reduce monthly migraine days by 50% or more in a significant proportion of patients. In the pivotal STRIVE trial, erenumab 140 mg reduced monthly migraine days by 3.7 compared to 1.8 with placebo in episodic migraine patients. For chronic migraine (15 or more headache days per month), the REGAIN trial demonstrated galcanezumab reduced monthly migraine days by 4.8 compared to 2.7 with placebo. Response rates of 50% or greater reduction were achieved by approximately 40-50% of treated patients.

These antibodies are administered as subcutaneous injections, either monthly (erenumab, galcanezumab) or monthly/quarterly (fremanezumab), with eptinezumab given as a quarterly IV infusion. Their long half-lives allow for sustained CGRP pathway blockade. Importantly, they carry minimal side effects, with injection site reactions being the most common. They have no hepatotoxicity concerns, no drug interactions, and no central nervous system side effects, making them well-tolerated for long-term use.

What Are Gepants and How Do They Treat Acute Migraine Attacks?

Gepants represent a second class of CGRP-targeting medications: small-molecule antagonists that block the CGRP receptor. Unlike monoclonal antibodies, gepants are oral medications suitable for acute migraine treatment. Ubrogepant (Ubrelvy) was the first gepant approved by the FDA in December 2019 for acute migraine treatment, followed by rimegepant (Nurtec ODT) in February 2020. Rimegepant subsequently received a dual indication for both acute treatment and preventive use (taken every other day) in 2021.

In the ACHIEVE I trial, ubrogepant 50 mg demonstrated superior pain freedom at 2 hours (19.2%) compared to placebo (11.8%), and freedom from the most bothersome symptom at 2 hours (38.6% vs 27.8%). Rimegepant showed similar results, with the Study 301 trial demonstrating 21% pain freedom at 2 hours compared to 11% with placebo. A key advantage of gepants is the absence of medication overuse headache risk, a significant concern with triptans and NSAIDs used frequently.

Atogepant (Qulipta) is a gepant specifically developed and FDA-approved for preventive migraine treatment (not acute use), available in daily oral dosing. The ADVANCE trial demonstrated that atogepant 60 mg daily reduced monthly migraine days by 4.2 compared to 2.5 for placebo in episodic migraine. Together, these gepants provide flexible treatment options across the migraine spectrum, from acute relief to daily or every-other-day prevention.