CGRP antagonists and dietary changes show promise for migraine treatment

In a recent article published in the journal Medicine, Researchers examine developments in migraine treatment, specifically the classification of the disease and advances in clinical and nutritional intervention 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 disease treatment. They further reveal the role of diets such as the ketogenic and low glycemic index diets in disease management. Their findings suggest that CGRP receptor antagonists, combined with dietary and physical activity modifications, can significantly increase the number of monthly migraine-free days for migraineurs.

Review: CGRP antagonism and ketogenic diet in the treatment of migrainem. 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 throbbing pain on one side of the head. It is often accompanied by nausea and increased sensitivity to light and sound. It most commonly affects teenagers, although it has been reported in some children. People over the age of 50 are at a lower risk for migraines.

Migraine is more prevalent in women, affecting 12-14% of the sex compared to 6-8% of men. In addition, women generally suffer more severe symptoms and longer duration of attacks than men. The condition is usually preceded by blurred vision, loss of motor control and difficulty speaking, which, when combined with its immediate symptoms, have led the World Health Organization (WHO) to rank it as the seventh most disabling disease worldwide, or third, if just including women.

So far, no cures have been discovered for the condition, with clinical interventions mainly aimed at managing the incidence and severity of the disease. Recent research has further explored the factors (triggers) that contribute to the disease and identified five macro-groups – 1. Hormonal factors (especially in women), 2. Dietary factors, 3. Environmental factors, 4. Psychological factors (stress), and 5 . But. Understanding the interplay between these factors and developing patient-tailored interventions aimed at managing them can drastically reduce the quality of life losses currently experienced by patients.

Classification and diagnoses of migraine

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

Conventional migraine classification recognizes more than 300 unique headache types, which are classified hierarchically into 14 groups, with each group having greater diagnostic accuracy than the last. Groups 1 to 4 are used to diagnose primary headaches, which usually have a genetic basis. Groups 5 to 12 are used to diagnose migraines occurring as comorbidities in other diseases. Finally, clusters 13 and 14 are used to identify secondary headaches that occur due to nongenetic factors, such as head trauma, psychiatric disorders, hormonal imbalances, and substance abuse.

Surprisingly, despite decades of research in the field, there is still a lack of clinical diagnostic tests for migraine, with diagnosis being limited to checking the symptoms associated with the disease.

Therapeutic interventions against migraine

Traditionally, clinical migraine interventions (drugs) have aimed to reduce the frequency of attacks by treating migraine-related pathologies and have therefore focused on groups 5 to 12 of the classification mentioned above. For example, in the case of migraines as a side effect of pre-existing heart conditions, β-blockers are used to treat these heart problems under the assumption that cardiovascular improvements would lead to beneficial migraine effects.

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

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

Olcegepant was the first CGRP antagonist developed specifically against migraines, but due to 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 have allowed the development of anti-CGRP monoclonal antibodies, which have been shown to be safe and without side effects even with prolonged use, while being superior to CGRP antagonists in treatment efficacy.

“These antibodies have a rapid onset of action. They can quickly provide the intended therapeutic benefits, even in patients who have not responded to previous prophylactic therapies or are using concurrent oral prophylactic therapies. Their administration is monthly or in some cases quarterly, by subcutaneous or intramuscular intravenous injection.”

Research has shown that treatment with monoclonal antibodies can lead to a 50% reduction in migraine frequency, significantly reduced attack severity and overall improvements in patients’ quality of life. More recently, bioprospecting is exploring the utility of venoms derived from arthropods and snakes as future antimigraine interventions, given the vasoconstrictor and anti-inflammatory properties of their peptides.

Can diet play a role?

Research has revealed a strong link between food and different types of migraine, with some foods and diets increasing the risk of migraine while others prevent or manage the condition. Coffee is a prime example of the rule of “everything in moderation” – excessive use has been found to trigger migraines, while moderate use is one of the most well-known natural anti-attack management practices.

Foods rich in complex carbohydrates, fiber and minerals (especially calcium and magnesium) have been shown to be useful in treating the condition, with recent reports highlighting the effectiveness of Zingiber officinale (ginger) and Cannabis sativa (cannabis) as natural, side-effect-free alternatives to migraine medications.

“In 1983, researchers from the Hospital for Sick Children in London reported the results of their observations of 88 children with severe and frequent migraine attacks who had begun 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 had seizures. The researchers then began reintroducing various foods into the diet and found that these caused migraine attacks to resume in all but 8 of the children. In subsequent trials using disguised foods, most children became asymptomatic again when the foods that caused the attacks were avoided.”

While trigger foods vary from patient to patient, the most common culprits are dairy, chocolate, eggs, meat, wheat, nuts, and certain 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 from Dietary Approaches to Stop Hypertension (DASH) revealed that adult migraines can be managed through sodium restriction (< 2400 mg/day) and increased calcium and magnesium intake. Based on this work, clinical trials have shown that diets such as the Mediterranean diet, rich in plant foods and healthy fats, can significantly reduce the frequency and duration of attacks through their association with the gut microbiome.

The ketogenic (keto) diet is a low-carb, high-fat diet that was originally developed in the 1920s to treat childhood epilepsy, but has been found surprisingly beneficial against other conditions, 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 since 1928, only in recent years has this strategy returned to foreground, first with individual case studies and then with clinical studies’.

Notably, the ketogenic diet resulted in the complete disappearance of migraines in some clinically tested patients, underscoring its utility as a safe anti-disease behavior modification. Unfortunately, research has yet to reveal the mechanism by which this dietary pattern alters migraine pathology.

conclusions

This review presents an overview of conventional and recent advances in migraine research. It explores the classification of the disease, therapeutic interventions aimed at managing the chronic condition, and the effect of food as either a migraine trigger or treatment. The paper highlights the benefits of anti-CGRP monoclonal antibodies and diets such as the Mediterranean and ketogenic diets as safe and effective interventions that can improve a patient’s quality of life and, in some cases, stop migraines altogether.