CGRP antagonists and dietary changes show promise for migraine treatment

By Hugo Francisco de SouzaReviewed by Susha Cheriyedath, M.Sc.Jan 17 2024

In a recent article published in the journal Medicina, researchers review advancements in migraine therapy, specifically the classification of the disease and the clinical and diet intervention advancements aimed at significantly reducing the frequency, pain, and severity of attacks. They highlight progress in calcitonin gene-related peptide (CGRP) research and the role of CGRP antagonists in treating the disease. They further reveal the role of diets such as ketogenic- and low-glycemic diets in disease management. Their findings indicate that CGRP receptor antagonists, in combination with dietary and physical activity modifications, can substantially increase the number of migraine-free monthly days for patients of the disease.

Review: CGRP Antagonism and Ketogenic Diet in the Treatment of Migraine. Image Credit: Krakenimages.com / Shutterstock

Migraine – A Brief Overview

'Migraine' refers to a group of chronic neurological conditions characterized by recurrent attacks of moderate to severe throbbing and pulsating pain on one side of the head. It is often accompanied by nausea and increased sensitivity to light and sound. It most commonly affects adolescents, though it has been reported in some children. People older than 50 are at a lower risk for migraines.

Migraine is more prevalent in women, affecting 12-14% of the sex in comparison to 6-8% of men. Furthermore, women generally suffer from more pronounced symptoms and longer attack durations than their male counterparts. The condition is usually preceded by blurred vision, loss of motor control, and difficulty speaking, which, when paired with its direct symptoms, has led the World Health Organization (WHO) to rate it as the seventh most disabling disease globally or third if just including women.

Hitherto, no cures for the condition have been discovered, with clinical interventions primarily aimed at managing the disease's frequency and severity. Recent research has additionally explored the factors (triggers) contributing to the disease and has identified five macro-groups – 1. Hormonal factors (especially in women), 2. Dietary factors, 3. Environmental triggers, 4. Psychological factors (stress), and 5. Others. Understanding the interplay between these factors and developing patient-personalized interventions aimed at managing them may drastically reduce the losses in quality of life currently experienced by patients.

Migraine classification and diagnoses

Migraines were initially classified by the International Headache Society (IHS) in 1988, representing a breakthrough in disease management as it allowed, for the first time, the use of common terminologies in medical and scientific research. The latest edition, titled "International Classification of Headache Disorders (ICHD-3rd edition beta version, called ICHD-3)," has formed a part of the WHO's International Classification of Diseases (ICD-11) since its publication in 2018.

Conventional migraine classification recognizes more than 300 unique types of headaches, which are classified in a hierarchical fashion into 14 groups, with each group having higher diagnostic accuracy than the previous one. Groups one through four are used for diagnosing primary headaches, usually having a genetic basis. Groups 5 through 12 are used to diagnose migraines that arise as comorbidities in other diseases. Finally, groups 13 and 14 are used to identify secondary headaches that occur due to non-genetic factors, such as head trauma, psychiatric disorders, hormonal imbalances, and substance abuse.

Surprisingly, despite decades of research in the field, there remains a lack of clinical diagnostic tests for migraine, with diagnosis restricted to screening of symptoms associated with the disease.

Therapeutic interventions against migraines

Traditionally, clinical migraine interventions (drugs) have been aimed at reducing attack frequency via the treatment of migraine-associated pathologies and have hence focused on groups 5 through 12 of the classification mentioned above. For example, in the case of migraines as a side-effect of preexisting heart conditions, beta-blockers are used to treat these heart problems on the assumption that cardiovascular improvements would cascade to beneficial migraine outcomes.

Interventions focused on managing attacks once they occur are treated on a case-by-case basis based on the severity of the attack – mild attacks are treated with painkillers (such as ibuprofen), while most severe ones involve the use of combinations of antiemetic and triptan drugs alongside intravenous fluids to compensate for those lost through vomiting. Notably, none of the medications conventionally used were developed against migraines, resulting in their low efficacy (best-case scenario – a 50% reduction in attack frequency and severity).

Encouragingly, recent research has identified the role of the calcitonin gene-related peptide (CGRP) receptor in migraine pathology. CGRP belongs to a family (B) of G-protein-coupled receptors (GPCRs) and is predominantly expressed in trigeminal neural ganglions. The discovery of these receptors and elucidation of their association with migraines has allowed for the rapid development of CGRP antagonists and, more recently, anti-CGRP monoclonal antibodies, novel drugs usually injected subcutaneously that block CGRP receptors, substantially improving migraine outcomes.

Olcegepant was the first CGRP antagonist developed specifically against migraines, but given its large volume, it required frequent intravenous administration. Telcagepant was subsequently developed as an oral alternative to Olcegepant. Unfortunately, like all CGRP antagonists that followed, these drugs had the notable side effect of causing milder migraine-like headaches in patients. In contrast, breakthroughs in monoclonal antibody research allowed for the development of anti-CGRP monoclonal antibodies, which have been demonstrated to be safe and side-effect-free even on prolonged use while outperforming CGRP antagonists in treatment efficacy.

"These antibodies exhibit a rapid onset of effect. They can quickly provide the intended treatment benefits, even in patients who have not responded to previous preventive treatments or are concurrently using oral preventive treatments. Their administration is monthly, or in some cases quarterly, through subcutaneous or intramuscular intravenous injection."

Research has presented that monoclonal antibody therapy can result in a 50% reduction in migraine frequency, substantially reduced attack severity, and overall improvements in patients' quality of life. Most recently, bioprospecting is exploring the utility of arthropod- and snake-derived venoms as future anti-migraine interventions, given the vasoconstrictory and anti-inflammatory properties of their peptides.

Can diet play a role?

Research has revealed a strong association between food and various types of migraine, with some foods and diets increasing migraine risk while others prevent or manage the condition. Coffee forms a prime example of the "everything in moderation" rule – its excessive use has been found to have a migraine-inducing effect, while its controlled use is one of the best-known natural management practices against attacks.

Foods rich in complex carbohydrates, fibers, and minerals (specifically calcium and magnesium) have proven helpful in treating the condition, with recent reports highlighting the efficacy of Zingiber officinale (ginger) and Cannabis sativa (cannabis) as side-effect-free natural alternatives to anti-migraine drugs.

"In 1983, researchers from the Hospital for Sick Children in London reported the results of their observations on 88 children with severe and frequent migraine crises who had started an elimination diet. Of these 88 children, 78 recovered completely and 4 improved significantly. In the same study, some children who also had seizures noticed that they no longer experienced seizure episodes. Researchers then began reintroducing various foods into the diet and found that these triggered the resumption of migraine attacks in all but 8 of the children. In subsequent trials using disguised foods, most of the children became asymptomatic again when the foods that triggered the seizures were avoided."

While trigger foods vary from patient to patient, the most common culprits are dairy products, chocolate, eggs, meat, wheat, nuts, and specific fruits and vegetables (tomatoes, onions, corn, bananas, and apples). The worst and almost ubiquitous triggers, however, are alcoholic beverages, especially red wine. In contrast, research by the Dietary Approaches to Stop Hypertension (DASH) has revealed that adult migraines can be managed via sodium abstinence (< 2400 mg/day) and increased calcium and magnesium intake. Building on this work, clinical trials have depicted that diets such as the Mediterranean diet, rich in plant-based foods and healthy fats, can significantly reduce attack frequency and duration through their association with the gut microbiome.

The ketogenic diet (keto) is a low-carb, high-fat diet initially developed in the 1920s to treat childhood epilepsy but has been found surprisingly beneficial against other pathologies, including migraine.

"This diet is safe when performed under the supervision of a trained professional and has negligible side effects in the short to medium term. Although the ketogenic diet has been used to successfully treat migraine sufferers as early as 1928, only in recent years has this strategy returned to the forefront, first with individual case studies, then with clinical studies."

Remarkably, the ketogenic diet has resulted in the complete loss of migraines in some clinically tested patients, highlighting its utility as a safe behavioral modification against the disease. Unfortunately, research has not yet unraveled the mechanism by which this dietary pattern alters migraine pathology.

Conclusions

The present review paints an overview of conventional and recent advances in anti-migraine research. It explores the classification of the disease, therapeutic interventions aimed at managing the chronic condition, and the influence of food as either trigger or cure against migraines. The work highlights the benefits of anti-CGRP monoclonal antibodies and diets such as the Mediterranean and ketogenic diets as safe and efficient interventions that can improve patient's quality of life and, in some cases, halt migraine altogether.