CGRP Monoclonal Antibodies: How They Work
For decades, migraine prevention relied on drugs borrowed from other conditions — beta blockers from cardiology, anticonvulsants from neurology, antidepressants from psychiatry. They worked, sometimes, with side effects that often outweighed the benefit. The CGRP monoclonal antibodies were the first class of drugs designed from the ground up specifically to prevent migraine, and they have changed what the preventive landscape looks like.
This piece walks through what CGRP is, what the antibodies do, and how to think about this class in practice.
What CGRP is
CGRP — calcitonin gene-related peptide — is a small protein released by trigeminal nerve endings during a migraine attack. Once released, it does several things that drive the migraine forward:
- Dilates blood vessels in the meninges (the membranes surrounding the brain).
- Sensitizes pain pathways in the trigeminal nerve, so that normally innocuous signals start being interpreted as pain.
- Promotes neurogenic inflammation around the meningeal blood vessels.
- Acts on second-order neurons in the trigeminocervical complex, amplifying the pain signal sent toward the brain.
Migraine attacks raise CGRP levels in the blood and in cerebrospinal fluid. Infusing CGRP into people with migraine triggers an attack. Block CGRP, and the migraine cascade is interrupted at one of its most important steps.
That is the basic logic the CGRP-targeting drugs are built on.
The two CGRP drug classes
There are two ways to block CGRP signaling — and the FDA has approved drugs in both classes.
1. CGRP monoclonal antibodies. Large protein drugs that bind either CGRP itself or the CGRP receptor, preventing the peptide from doing its job. Given by injection (subcutaneous or IV) monthly or quarterly. Used for prevention only.
2. Gepants (small-molecule CGRP receptor antagonists). Oral drugs that block the CGRP receptor. Some are approved for acute treatment, some for prevention, and some for both. Examples include rimegepant, ubrogepant, and atogepant.
This piece focuses on the monoclonal antibodies.
The four CGRP monoclonal antibodies
Four CGRP monoclonal antibodies are currently approved for migraine prevention:
| Drug | Brand | Target | Dosing |
|---|---|---|---|
| Erenumab | Aimovig | CGRP receptor | 70 mg or 140 mg subcutaneous monthly |
| Fremanezumab | Ajovy | CGRP ligand | 225 mg monthly or 675 mg quarterly subcutaneous |
| Galcanezumab | Emgality | CGRP ligand | 240 mg loading dose, then 120 mg monthly subcutaneous |
| Eptinezumab | Vyepti | CGRP ligand | 100 mg or 300 mg IV every three months |
Erenumab is the only one that targets the receptor; the other three target the CGRP peptide itself. In practice, head-to-head differences are modest, and the choice often comes down to dosing preference, insurance coverage, and individual response.
How they work in the body
Because they are large protein drugs, the CGRP monoclonal antibodies cannot cross the blood-brain barrier. Their action is on the peripheral end of the trigeminal system — at the meningeal blood vessels and the trigeminal nerve endings outside the central nervous system.
That peripheral action is enough. The trigeminovascular system is the entry point for most migraine attacks, and blocking CGRP signaling at that entry point prevents the cascade from progressing.
Practical implications:
- They take effect within the first month for most responders.
- They wear off slowly between doses (the antibodies have half-lives of about a month).
- They are not effective for an acute attack — they are preventive only.
- They have a more favorable side-effect profile than older preventives because they are not acting on the central nervous system.
What they treat
The CGRP monoclonal antibodies are approved for migraine prevention in adults with:
- Episodic migraine (fewer than 15 headache days per month).
- Chronic migraine (15 or more headache days per month, including at least 8 migraine days).
In practice they are used most often in patients who:
- Have failed two or more older preventive classes (beta blockers, anticonvulsants, antidepressants).
- Cannot tolerate the side effects of older preventives.
- Have medical contraindications to older preventives.
Insurance criteria typically reflect this stepped approach.
What "response" looks like
A successful response is typically defined as a 50% reduction in monthly migraine days at three months. Roughly half of patients meet that threshold; a smaller fraction (about 20–30%) experience a 75% or greater reduction, and a small group become essentially migraine-free.
Non-responders to one CGRP antibody sometimes respond to another, though the cross-trial evidence is mixed. Switching is often worth a try if the first agent fails.
Side-effect profile
Compared to older preventives, the CGRP monoclonal antibodies are remarkably well-tolerated. The most common side effects are:
- Injection-site reactions (redness, mild pain, itching).
- Constipation (most prominent with erenumab).
- Mild flu-like symptoms in the first day or two after injection.
- Hypertension has emerged as a small but real signal with erenumab in particular.
What they do not cause, in general, is the fatigue, weight changes, cognitive blunting, and mood effects that drive many patients off older preventives.
Limitations and unknowns
A few caveats are worth knowing:
- Long-term safety data are still accumulating. The drugs have been on the market since 2018, so we have several years of data but not several decades.
- Pregnancy and breastfeeding. Data are limited; the drugs are generally avoided in pregnancy by default.
- Cost. Without insurance coverage, these drugs are expensive. With coverage, copay programs from the manufacturers fill many of the gaps.
- Cardiovascular questions. Because CGRP is a vasodilator, blocking it could in theory worsen cardiovascular events. Studies so far have not shown a clear signal, but caution is warranted in patients with significant cardiovascular disease.
Where pressure tracking fits
CGRP monoclonal antibodies are preventives — they lower the baseline frequency and severity of attacks but do not eliminate triggers. For weather-sensitive patients on a CGRP antibody, knowing when a pressure-driven attack is most likely still matters for planning acute treatment. Pressure Pal works as a migraine tracker app that logs attack patterns alongside barometric pressure, which helps you and your clinician evaluate whether a CGRP antibody is reducing weather-triggered breakthrough attacks specifically — and whether to switch agents if it is not.