New CGRP Migraine Treatments: How They Work

For most of the history of migraine medicine, preventive treatments were medications developed for other conditions that happened to reduce migraine frequency as a secondary effect. Beta blockers developed for heart disease. Anticonvulsants developed for epilepsy. Antidepressants developed for mood disorders. They worked for some people with migraine, not because they were designed for migraine, but because they influenced neurological systems that migraine also involves.

That changed with the development of CGRP-targeted treatments. For the first time, medications were designed from the ground up specifically for migraine, targeting a molecule that plays a central and well-established role in the migraine cascade. The result is a class of treatments with a specificity and tolerability profile that older preventive medications cannot match.

What CGRP Is

Calcitonin gene-related peptide (CGRP) is a neuropeptide, a small protein produced by nerve cells, that plays multiple roles in the nervous system and peripheral tissues. In the context of migraine, it is released from trigeminal nerve terminals during an attack and drives several of the processes that produce and sustain migraine pain.

CGRP causes blood vessels to dilate, including the meningeal blood vessels whose dilation contributes to the throbbing quality of migraine pain. It activates pain signaling pathways in the trigeminal system. It promotes neurogenic inflammation, the release of inflammatory substances from nerve terminals that sensitizes surrounding tissues.

Research has consistently shown that CGRP levels in the bloodstream rise significantly during migraine attacks and return to baseline when attacks resolve. Intravenous infusion of CGRP in people with migraine reliably triggers migraine-like attacks, demonstrating that CGRP is not merely a correlate of migraine but a direct contributor to the process.

Two Classes of CGRP-Targeted Medication

CGRP-targeted migraine treatments fall into two distinct classes that work through related but distinct mechanisms.

The first class is anti-CGRP monoclonal antibodies. These are large protein molecules, administered by injection or infusion, that either bind to CGRP itself and prevent it from interacting with its receptor, or bind to the CGRP receptor and block CGRP from activating it. The four approved medications in this class are erenumab, which targets the receptor, and fremanezumab, galcanezumab, and eptinezumab, which target CGRP itself.

Because these are large protein molecules, they cannot be taken orally and must be administered by injection or intravenous infusion. Erenumab, fremanezumab, and galcanezumab are self-administered by monthly or quarterly subcutaneous injection. Eptinezumab is administered by intravenous infusion every three months in a clinical setting.

The second class is CGRP receptor antagonists, known as gepants. These are small molecule drugs that can be taken orally. Rimegepant and ubrogepant are approved for acute migraine treatment. Atogepant and the preventive formulation of rimegepant are approved for migraine prevention and are taken as daily or every-other-day oral medications.

Clinical Evidence

The clinical trial evidence for CGRP-targeted treatments is extensive and consistently positive. Large randomized controlled trials have demonstrated that anti-CGRP monoclonal antibodies reduce monthly migraine days by fifty percent or more in approximately half of patients, with meaningful reductions in a larger proportion.

A key feature of the clinical evidence is that CGRP-targeted treatments have been shown to work in people who have previously failed two or more preventive medications, a population historically difficult to treat effectively.

Tolerability and Safety

One of the most notable features of CGRP-targeted treatments is their tolerability profile. Because they target a specific molecule involved in migraine pathophysiology rather than broadly affecting neurological systems, they produce fewer of the systemic side effects associated with older preventive medications.

The most common side effects of the injectable monoclonal antibodies are injection site reactions, constipation with erenumab in some patients, and occasional hypersensitivity reactions. Long-term safety data continues to accumulate as these medications have been in use since 2018. The medications are generally not recommended in pregnancy due to limited safety data.

Who Is Most Likely to Benefit

CGRP-targeted treatments are approved for both episodic and chronic migraine prevention and are indicated for people who have not achieved adequate control with lifestyle modification and behavioral interventions, who have failed or cannot tolerate older preventive medications, or who prefer a migraine-specific treatment with a favorable tolerability profile.

The decision about which specific medication to use involves considering attack frequency, preferred administration route, insurance coverage, and individual patient factors in a conversation with a treating neurologist or headache specialist.

The development of CGRP-targeted treatments has meaningfully expanded what is possible for people with difficult-to-treat migraine. For a condition that has historically been undertreated, that expansion matters.