Calcitonin Gene-Related Peptide (CGRP) inhibitors are a class of medications that target certain headache disorders. They interfere with CGRP, a small protein. These inhibitors are available as injections, intravenous infusions, and oral pills.
Understanding CGRP’s Role
Calcitonin Gene-Related Peptide (CGRP) is a naturally occurring neuropeptide, a protein released by nerve cells throughout both the central and peripheral nervous systems. It is involved in several bodily processes, including regulating blood pressure, tissue repair, and inflammation. CGRP is a potent vasodilator, widening blood vessels.
In headache disorders, CGRP plays a significant role in pain pathways and neuroinflammation, particularly in migraine. During a migraine attack, CGRP levels increase, especially in the trigeminal nerve system, which senses the head and face. This increase can worsen pain signals, prolong headache duration, and contribute to inflammation in the meninges, the membranes surrounding the brain. Infusing CGRP has been shown to induce migraine-like attacks in individuals prone to migraines, supporting its involvement.
How CGRP Inhibitors Work
CGRP inhibitors target the CGRP pathway to prevent or alleviate pain signaling. They either bind directly to the CGRP molecule or block its receptor, preventing CGRP from attaching and initiating pain. This interferes with the events that lead to migraine pain, including vasodilation and neurogenic inflammation.
The CGRP receptor is a complex structure composed of several subunits, including the calcitonin receptor-like receptor (CLR), receptor activity-modifying protein 1 (RAMP1), and receptor component protein (RCP). Some CGRP inhibitors, such as erenumab, block CGRP from activating its receptor by binding to it. Other inhibitors, including eptinezumab, fremanezumab, and galcanezumab, bind directly to the CGRP molecule, preventing interaction with its receptor. This targeted action reduces pain signals and inflammation associated with migraine.
Types of CGRP Inhibitors and Their Applications
CGRP inhibitors are broadly categorized into two main types: monoclonal antibodies (mAbs) and gepants.
Monoclonal antibodies are large protein molecules administered via injection (subcutaneously or intravenously). They are generally used for the prevention of migraine attacks, typically monthly or every three months. Examples of approved CGRP monoclonal antibodies include:
Erenumab (Aimovig)
Fremanezumab (Ajovy)
Galcanezumab (Emgality)
Eptinezumab (Vyepti)
Gepants, on the other hand, are small-molecule CGRP receptor antagonists, typically taken orally as pills or nasal sprays. Unlike monoclonal antibodies, gepants can penetrate the brain more rapidly and are used for both acute treatment of migraine attacks and, in some cases, for prevention. Approved gepants include:
Ubrogepant (Ubrelvy)
Rimegepant (Nurtec ODT)
Atogepant (Qulipta)
Zavegepant (Zavzpret)
CGRP inhibitors are primarily approved and used for the prevention of episodic and chronic migraine, as well as for the acute treatment of migraine attacks. Some are also being investigated for cluster headaches.
Potential Side Effects and Important Considerations
While CGRP inhibitors have generally shown a favorable safety profile, some potential side effects can occur. Common side effects associated with CGRP inhibitors include reactions at the injection site, such as pain, redness, or itching, especially with subcutaneous injections. Other frequently reported side effects include constipation, muscle pain, fatigue, and upper respiratory symptoms like nasal congestion or a sore throat.
Patients should discuss their medical history with a healthcare provider, especially if they have pre-existing cardiovascular conditions, as CGRP also plays a role in regulating blood pressure and protecting heart health. While initial concerns existed, clinical trials have not shown an increased risk of cardiovascular issues. Most side effects are mild to moderate and may lessen over time. It is important to consult a doctor promptly if any side effects are severe or persistent. These medications are prescribed by headache specialists and may be considered when other preventive treatments have not been effective.