CGRP inhibitors are a class of migraine medications that block a protein called calcitonin gene-related peptide, one of the key drivers of migraine attacks. There are currently eight FDA-approved CGRP inhibitors, split between injectable antibodies used for prevention and oral or nasal medications that can treat attacks as they happen or prevent them from occurring.
How CGRP Drives Migraine Pain
CGRP is the most potent peptide known for dilating blood vessels in the brain and surrounding tissues. During a migraine, sensory nerve fibers in and around the brain become activated and release CGRP along with other signaling molecules. This flood of CGRP widens blood vessels, triggers inflammation, causes blood vessels to leak, and activates immune cells called mast cells. The combined effect amplifies pain signals traveling from blood vessels in the skull to the brainstem and then to higher brain centers where pain is processed.
People with migraine have elevated levels of CGRP in their blood during attacks, and those with chronic migraine often have higher baseline levels even between attacks. CGRP inhibitors work by interrupting this cycle, either by binding to the CGRP molecule itself (preventing it from reaching its receptor) or by blocking the receptor so CGRP can’t activate it.
Two Types: Antibodies and Gepants
CGRP inhibitors fall into two categories that work differently and serve different purposes.
Monoclonal antibodies are large, lab-engineered proteins that stay in the body for weeks. Three of them (fremanezumab, galcanezumab, and eptinezumab) latch onto the CGRP molecule itself, neutralizing it before it can do anything. The fourth, erenumab, takes the opposite approach: it binds to the CGRP receptor on cells, blocking CGRP from docking there. All four antibodies are used exclusively for migraine prevention.
Gepants are small-molecule drugs taken as pills or nasal sprays. They block the CGRP receptor, similar to erenumab, but they’re much smaller molecules that clear the body within hours rather than weeks. This makes them flexible enough for both acute treatment (stopping an attack in progress) and daily prevention.
All Eight Approved Medications
Monoclonal Antibodies (Prevention Only)
- Erenumab (Aimovig): Self-injected under the skin once a month at 70 mg or 140 mg. The only antibody that targets the CGRP receptor rather than the molecule.
- Fremanezumab (Ajovy): Self-injected under the skin, either 225 mg monthly or 675 mg (three injections) every three months.
- Galcanezumab (Emgality): Self-injected under the skin. Starts with a loading dose of 240 mg (two injections), then 120 mg monthly.
- Eptinezumab (Vyepti): The only antibody given by IV infusion, administered over about 30 minutes at a doctor’s office every three months.
Gepants (Acute, Preventive, or Both)
- Ubrogepant (Ubrelvy): Oral tablet for acute treatment only. Taken at 50 or 100 mg when a migraine starts, with a possible second dose after two hours.
- Rimegepant (Nurtec ODT): Dissolves on the tongue. Approved for both acute treatment (75 mg as needed) and prevention (75 mg every other day).
- Atogepant (Qulipta): Oral tablet for prevention only, taken daily at 10, 30, or 60 mg.
- Zavegepant (Zavzpret): Nasal spray for acute treatment, one 10 mg spray per attack.
How Well They Work
In real-world use, the antibodies reduce migraine days substantially. A cohort study of patients starting with an average of 16 migraine days per month found that number dropped to about 6 days by month three and 5 days by month twelve. That translates to a roughly 69% reduction in monthly migraine days over the first year. Some patients respond even more dramatically, while others see more modest improvement.
Gepants work faster for acute attacks, typically providing relief within two hours. Their preventive effects are more modest than the antibodies in head-to-head comparisons, but they offer the advantage of being pills or sprays rather than injections.
Common Side Effects
CGRP inhibitors are generally well tolerated compared to older migraine preventives like blood pressure medications or antidepressants, which often cause fatigue, weight gain, or cognitive dulling.
The most notable side effect of the antibodies is constipation, particularly with erenumab. In FDA adverse event data, constipation accounted for about 18% of reported side effects with erenumab, a significantly stronger signal than with the other three antibodies. Injection site reactions are common across all three self-injected antibodies: pain, redness, itching, and occasionally bruising or swelling at the injection spot. Galcanezumab had the highest rate of injection site issues in post-market reporting.
Gepants can cause nausea in some people, and rimegepant occasionally causes allergic reactions. Because they clear the body quickly, side effects from gepants tend to be short-lived.
Cardiovascular Safety
CGRP naturally helps regulate blood vessel tone throughout the body, so blocking it raised early concerns about heart and blood pressure risks. The evidence so far has been reassuring. A multicenter study that specifically included patients with conditions excluded from the original clinical trials (obesity, diabetes, prior stroke, coronary artery disease) found no vascular events after starting treatment. Among patients with a history of heart attacks or angina, there were no recurrences, and heart function remained stable.
Blood pressure increases were uncommon. Out of 487 patients with various comorbidities, only 4 (less than 1%) needed a blood pressure medication adjustment after starting a CGRP antibody. Seven patients with Raynaud’s phenomenon, a condition involving restricted blood flow to the fingers and toes, did experience worsening symptoms, which improved when the medication was stopped. For patients with existing vascular conditions, monitoring makes sense, but population-level data has not shown the cardiovascular risks that were initially feared.
Getting Access and Insurance Coverage
The American Headache Society updated its guidelines in March 2024, recommending CGRP-targeted medications as first-line treatments for migraine prevention. Previously, guidelines suggested trying two older, less targeted oral medications for at least eight weeks each before moving to CGRP inhibitors.
Insurance coverage hasn’t fully caught up. While 95% of plans cover at least one CGRP medication, individual drug coverage varies widely. Galcanezumab has the broadest coverage at about 85% of plans, while atogepant is covered by only 62%. Most insurers still require step therapy, meaning you’ll likely need to document that older preventive medications didn’t work or caused intolerable side effects before a CGRP inhibitor gets approved. This process can take months, and your doctor’s office will typically handle the prior authorization paperwork.
Choosing Between Options
The choice between a CGRP antibody and a gepant often comes down to your migraine pattern and preferences. If you have frequent or chronic migraines and want set-it-and-forget-it prevention, a monthly or quarterly injection removes the need to remember daily pills. If you prefer oral medication, atogepant offers daily prevention without injections, and rimegepant pulls double duty as both a preventive and an acute treatment.
For people who only get occasional migraines and mainly need something to stop attacks, ubrogepant or zavegepant work as acute-only options without the cardiovascular concerns that come with older migraine medications like triptans. Unlike triptans, gepants don’t constrict blood vessels, making them a safer choice for people with heart disease or uncontrolled blood pressure.