By Gabriela De Jesús Ríos ’26
Research for migraine headache prevention and treatment is an ever-growing field. As of 2020, migraine headaches have been burdening 15% of the American population both physically and economically with an estimated $36 billion overall cost (Sy & Baldwin, 2020). These costs include direct costs–medical costs like migraine-specific medications and conditions like anxiety and depression that often are linked with migraines– as well as indirect costs–loss of productivity and any long-term disabilities (Bonafede, et. al, 2018). A migraine can be described as a neurovascular disorder defined by a unilateral, throbbing/pounding headache as well as photophobia (sensitivity to light), phonophobia (sensitivity to sound), nausea, and vomiting (Rashid, 2023). A migraine attack can normally last anywhere from 4 to 72 hours. Recently, researchers have been particularly interested in CGRP-receptor antagonist drugs. CGRP (Calcitonin Gene-Related Peptide) is a neuropeptide and a vasodilator (an aid in opening or dilating blood vessels) discovered about 40 years ago (Rashid, 2023). It is produced by neurons found in the central and peripheral nervous systems (Rashid, 2023). The main target of antagonists (blockers), however, is its G-protein coupled receptor, an integral membrane protein that has an extracellular signal receptor, which means it can recognize many different signals produced by the body via ions, proteins, neurotransmitters and hormones. (Rashid, 2023; Rehman, et. al, 2023). Studies have shown that there is a significant and direct correlation between the amount of CGRP and migraine attacks. These CGRP-receptor antagonist medications interact with the CGRP receptors by modulating or blocking the pain signal that they normally mediate. In 2004, the first anti-CGRP treatment called olcegepant was developed. After several years of further clinical trials, in 2018, the FDA approved the first anti-CGRP receptor drug for prevention of migraines: erenumab (Tepper, 2018). This was followed by a number of other FDA approvals of drugs that are administered orally and in injectable formulations. The most recently (March 2023) approved CGRP-receptor antagonist, zavegepant, is a nasal spray (Chaudhari & Syed, 2023).
Selected therapies that are marketed for migraine (Chaudhari & Syed, 2023)
Researchers observed that levels of CGRP are increased in the saliva and blood of patients with a variation of acute headache disorders not limited to migraines, such as neuralgias and rhinosinusitis (Rashid, 2023). Results showed that, in patients that suffer from chronic migraines, levels of CGRP are further boosted during a migraine attack as well as during the time between migraine attacks. Moreover, it can also contribute to the pathogenesis of migraines, meaning that it can begin a migraine attack as well as contribute to its maintenance (Rashid, 2023). Hence, blocking receptors activated by CGRP as well as blocking the CGRP as a signaling molecule have both been proven to relieve migraines. In fact, clinical trials on erenumab, which targets the receptor as opposed to the signal itself, resulted in a >50% reduction in migraine days in phase III for over 50% of patients who were administered a 300mg dose (Do et al., 2019).
Overview of the therapeutic novelties targeting the calcitonin gene-related peptide (CGRP) and pituitary adenylate cyclase-activating polypeptide/pituitary adenylate cyclase 1 (PACAP/PAC1) pathways developed for migraine (Do et al., 2019)
As more research is done in this field, these CGRP-receptor antagonists continue to improve as acute migraine treatments. For instance, zavagepant proved to be more successful than placebo in removing the worst symptoms of migraines, two hours after the dose was administered. This was in addition to a relief duration of up to 24 hours for some subjects and up to 48 hours in others (Pfizer, 2023). This is remarkable, not just because of its success in treating migraines but because of the reduction in secondary effects and even medication-overuse headaches. Previous acute-acting drugs were not as specifically targeted as CGRP-receptor antagonists; they were mostly drugs that were created for treating other conditions but happened to reduce migraines as well (Deen et al., 2017). This would lead to negative responses to the medication (secondary effects) as well as misuse of the drug by the patient: patients would need to increase their dosage or use a combination of drugs to relieve their symptoms (Reuter et al., 2018). Anti-CGRP-receptor medication would help avoid most of these complications by solely blocking CGRP pathways, thus, targeting migraine headaches specifically.
Further research is still needed in this field, including the possible long-term effects of this type of drug, especially because of the key role it plays in the patients’ dilation of blood vessels. Ultimately, this type of treatment might continue to inspire and open doors for other, non-migraine-related conditions, which could be treated through targeted/acute interventions, especially in human protein pathways. Although there is still much more potential for these interventions to be developed, these recent advancements definitely offer a promising start.
Gabriela De Jesús Ríos ’26 is an executive editor at The Princeton Medical Review intending to study ecology and evolutionary biology. She can be reached at gd9181@princeton.edu.
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