Calcitonin Gene-Related Peptide (CGRP) is a protein naturally found in the body, synthesized and released by nerve cells. It functions as a signaling molecule within the nervous system. CGRP is produced in both peripheral neurons, which extend throughout the body, and central neurons located in the brain and spinal cord.
This neuropeptide has various effects depending on its location. One of its primary functions is vasodilation, the widening of blood vessels, which can help regulate blood pressure and increase blood flow. CGRP also participates in modulating the immune system, bone formation, and gastrointestinal motility.
The Connection Between CGRP and Migraines
During a migraine attack, the trigeminal nerve, a large nerve responsible for sensation in the face and head, becomes activated. This activation leads to the release of several inflammatory substances, including substantial amounts of CGRP, from nerve endings in the meninges, the protective layers covering the brain.
The surge of CGRP contributes directly to the pain and inflammation characteristic of a migraine episode. It binds to receptors on blood vessels in the meninges, causing them to dilate, and it helps transmit pain signals along nerve pathways. Think of the trigeminal nerve as a communication highway for facial sensation; when a migraine starts, CGRP floods this highway, amplifying pain signals and contributing to the throbbing sensation many people experience.
This process creates a cycle of inflammation and pain. The initial release of CGRP sensitizes the nerve pathways, making them more responsive to pain stimuli. This heightened sensitivity, known as allodynia, is why many individuals experiencing a migraine find normal stimuli, like light or touch, to be painful. The elevated levels of CGRP sustain the vasodilation and inflammation, prolonging the migraine attack.
Medications Targeting CGRP
A newer class of medications specifically designed to interfere with the activity of CGRP has provided new options for managing migraines. They are designed to either prevent migraine attacks from starting or to stop an attack that is already in progress.
One category is monoclonal antibodies. These are laboratory-produced proteins designed to function like immune system antibodies. They are used as preventive treatments to reduce the frequency and severity of migraine attacks. These medications are administered as injections that patients can typically give to themselves at home. Depending on the specific drug, the injections are given on a monthly or quarterly schedule. Examples include:
- Erenumab
- Galcanezumab
- Fremanezumab
- Eptinezumab
Another category of CGRP-targeting medications is known as gepants. These are small-molecule CGRP receptor antagonists, meaning they are not proteins like the monoclonal antibodies. Gepants offer more flexibility in their use; some are taken orally as needed to treat an acute migraine attack once it has begun. Other formulations are designed for prevention and are taken as a daily pill. This class of drugs includes ubrogepant and rimegepant for acute treatment, with atogepant used for prevention.
How CGRP Medications Work
The two classes of CGRP medications interrupt the migraine process through different mechanisms, though they ultimately achieve a similar outcome. Monoclonal antibodies are large proteins that circulate in the bloodstream for an extended period. They function by either binding directly to the CGRP protein itself or by attaching to the CGRP receptor on cells.
When a monoclonal antibody binds to the CGRP protein, it effectively neutralizes it, preventing it from attaching to its receptor. Alternatively, some monoclonal antibodies are designed to block the receptor, preventing CGRP from docking and activating the nerve cell. Both methods stop CGRP from initiating the cascade of events that lead to pain and vasodilation.
Gepants, being much smaller molecules, work in a slightly different way. They are designed to fit precisely into the CGRP receptor on the surface of nerve cells. By occupying this docking station, they physically block CGRP from binding. This competitive inhibition prevents CGRP from delivering its pain-transmitting signal. Because they are small molecules, they are cleared from the body more quickly, which is why they can be used for acute treatment.
Side Effects and Patient Considerations
Treatments that target CGRP come with potential side effects that can differ between the two classes. For monoclonal antibodies, the most commonly reported side effects are related to the injection itself, such as pain, redness, or swelling at the injection site. Some individuals may also experience constipation. These effects are generally considered mild to moderate for most patients.
Gepants, which are taken orally, are associated with different side effects. The most common among these are nausea and fatigue or sleepiness. Because gepants are processed through the liver, their interaction with other medications is a consideration for healthcare providers.
Since CGRP is involved in various bodily functions, including the dilation of blood vessels, there has been consideration of the long-term effects of blocking its activity. Current studies have not shown significant cardiovascular concerns, but research is ongoing, particularly for patients with pre-existing cardiovascular conditions.
These medications represent a significant cost, and insurance coverage can be a hurdle. Payers often require patients to have tried and failed multiple other types of preventive medications before approving a CGRP-targeted therapy. This step-therapy approach means these treatments are often reserved for those with frequent or debilitating migraines who have not found relief with other options.