The World Health Organisation (WHO) rates migraine as the most common, debilitating, long-term neurological condition(1). Globally, migraines affect more than 10% of people, primarily those between the ages of 20 and 50. Migraines are also three times more common in women than men. About one-third of migraineurs are able to anticipate when an episode is about to begin as it is preceded by an ‘aura’ or visual abnormalities like flashing lights, zigzag lines, or a temporary loss of vision(2).
A severe pulsing or throbbing pain in one area of the head is a common way to describe the discomfort of a migraine headache. The International Headache Society defines a migraine as pain with at least five attacks, lasting four to 72 hours if left untreated, as well as other symptoms including nausea, vomiting, or sensitivity to light and sound(3). Depending on the number of days a month a person has headaches, a migraine can be classified as either episodic (EM) or chronic (CM). When a migraine sufferer has fewer than 15 headache days per month, they are said to have episodic migraine, according to the International Classification of Headache Disorders (ICHD-2) criteria. 15 or more headache days per month match the requirements for chronic migraines, according to general definitions. Some sufferers of chronic migraine endure daily headaches, while others constantly feel discomfort(4).
Is migraine a serious disease?
Migraine headaches rarely cause death or brain damage. However, there may be an elevated risk of cardiovascular events and a stroke in those who experience migraines with aura(5).
According to the American Migraine Foundation, stroke can occur independently of a migraine headache and is more common in people who currently have or have had migraines.Sufferers of migraine are more likely to get hemorrhagic strokes than ischemic strokes. Compared to women without migraines, women with auras had a 2 to 3 times higher risk of having a stroke. Young individuals less than 45 years old are more likely to develop strokes associated with migraine(6). A web-based survey revealed that people suffering from migraines had considerably greater rates of insomnia, depression, anxiety, gastric ulcers, gastrointestinal bleeding, angina, and epilepsy(7).
Researchers have found a connection between migraine and heart disease all over the world. Recent research from the Nurses’ Health Study, which enrolled participants between the ages of 25 and 42, demonstrated a 50% increased risk of stroke, coronary events, and related death in migraineurs. The likelihood of developing ischemic heart disease was also doubled in numerous study populations. Although the exact causes are unknown, they most likely involve coagulation, inflammation, and malfunction of the arteries of the endothelial lining(8).
The negative impact of migraine
Every element of a person’s life, including their relationships with friends, family, and partners, can be impacted by migraines. People with migraines frequently experience loneliness and isolation. When asked what the most discouraging aspect of having migraines was, 48% said that it was being misunderstood by others(9).
According to a cross-sectional study carried out in several headache clinics in Austria, about 34% of respondents, the majority of whom had episodic (56.4%) or chronic (38.3%) headaches, said their headaches had a negative impact on their careers, and 21.5% said they had a negative impact on their earnings. Only approximately 50% of respondents thought that their coworkers understood their headaches, which highlights the stigma connected with headaches that migraine sufferers face. According to this study, the negative effects on one’s job and financial situation grew as headache frequency increased9. It is only because of a lack of education that migraine is viewed as a minor issue; in reality, it is a highly serious illness that can drastically reduce your quality of life.
How was migraine treated traditionally?
Initially, non-migraine-specific medications like antiemetics, analgesics, and opium were used to treat migraines. Analgesics were regarded as the first-line medication therapy for treating migraines, while antiemetics were used to lessen the vomiting and nausea brought on by migraine attacks(10). In the 1990s, triptans—selective 5-HT1B/1D receptor agonists were authorised for the treatment of acute migraines and were the first migraine-specific drugs to be introduced.
Acetaminophen, aspirin, and NSAIDs were suggested treatments for mild episodes. Tablets of diclofenac and effervescent aspirin start working more quickly than the powdered versions. Moderate to severe migraines were treated with triptans or dihydroergotamine (DHE). Triptans typically outperform DHE because they are more tolerable, have a lower risk of side effects, and are more effective. For a subsequent attack, a different triptan should be attempted if the patient does not respond well to the first one. Nasal, injectable intranasal, and intranasal work better for migraines that are most painful when they first start and for migraines that cause nausea and vomiting(11).
Even though numerous migraine treatment options were available at that time, migraine sufferers still faced difficulties because attacks can come on suddenly and without warning. The biggest loss was that these drug formulations were never convenient for them to use while travelling or in an emergency because they always required assistance for administration.
Introduction of novel therapy options
Until the development of monoclonal antibodies in 2018, there had been no new migraine drug since triptans were developed. The CGRP monoclonal antibody treatment truly advanced the field of migraine because it was the first approved preventive medication treatment that targeted the CGRP molecule, the root cause of migraine(12).
In 2019, a group of drugs called ditans was introduced. Lasmiditan was the first among them, making ditans the first novel class of acute migraine medications to be approved by the FDA in more than 20 years. They block the spread of nerve inflammation and stop pain signals from reaching the brain(12).
This period also saw the development of CGRP ‘gepants’, a class of CGRP receptor antagonists that prevent the CGPR molecule from correctly attaching to receptor sites in the body. By doing this, they can prevent the series of reactions that leads to a migraine episode.
Gepants, in contrast to triptan medicines, do not cause blood vessels to constrict, making them safe for people who have heart or vascular disease, stroke survivors, or both. Ubrogepant was the first in this category to be approved by the FDA in 2019 (13).
FDA approval of Rimegepant (Nurtec ODT)
Monoclonal antibodies are administered using injections, which can be a deal breaker for some patients, although they have a favourable safety record and have significantly benefitted many patients. With the advent of gepants, a major advancement was made. Gepants function similarly to monoclonal antibodies and inhibit CGRP; however, they are not administered through injections(14). As a breakthrough in migraine medicine, Nurtec (rimegepant) is an orally dissolving tablet that provides benefits for individuals experiencing nausea.
The U.S. Food and Drug Administration approved Nurtec ODT, the first and only calcitonin gene-related peptide (CGRP) receptor antagonist available in a quick-dissolve ODT formulation, for the acute treatment of migraine with or without aura and the preventive treatment of episodic migraine in adults. It is believed that the pathophysiology of migraines is caused in part by the neuropeptide CGRP’s activation. The CGRP receptor antagonist Nurtec ODT inhibits the biological function of the CGRP neuropeptide by reversibly blocking CGRP receptors(15). The effectiveness of rimegepant was evaluated for individuals having a 1-year history of migraine (with or without aura) and 2–8 moderate or severe migraine headaches per month in two double-blind clinical studies. Patients were administered either a single dose of rimegepant 75 mg or a placebo following the onset of a moderate or severe migraine headache. According to the findings, rimegepant patients experienced a considerable reduction in pain after two hours(16).
One dose of Nurtec ODT can give sustained efficacy that lasts up to 48 hours for many patients instant pain relief, and a return to normal function within one hour. This provides migraine sufferers with a simple, convenient way to take their medication whenever and wherever they need it. It dissolves instantaneously in the mouth without the need for water(17). This innovative method of treating the complete range of migraine disorders, from acute therapy to prevention, can significantly improve the quality of life for patients by assisting in the reduction of treatment plan complexity and difficulties with adherence and polypharmacy(15). This approval marks a noteworthy improvement in treatment for hundreds of millions of migraine sufferers worldwide. With Nurtec ODT, a single drug can now both treat and prevent migraine attacks for the very first time.
Acquisition by Pfizer
The acquisition of Biohaven Pharmaceuticals, the manufacturer of Nurtec ODT, by Pfizer, was announced on October 3, 2022. With this acquisition, Pfizer now has access to a portfolio of calcitonin gene-related peptides (CGRP), including rimegepant, zavegepant, and a variety of pre-clinical CGRP assets. Pfizer paid USD 149.50 per share, or about USD 11.6 billion, to purchase all of Biohaven’s outstanding shares(18).
In the months before the acquisition closed, Biohaven spun off a new Biohaven company, retaining the company’s preclinical product candidates, Kv7 ion channel activators, glutamate modulation, myostatin inhibition platforms, non-CGRP development stage pipeline compounds, and some corporate infrastructure assets that were not included in the Pfizer acquisition. Pfizer currently owns 3% of the new Biohaven company(19).
The future of migraine treatment
With the development of novel targeted acute and preventive migraine treatments, we are currently in an exciting era in migraine therapeutics. We must develop emergency treatments for the future that are both safe and effective over the long term and don’t cause pharmaceutical overuse or vasoconstriction. The ability to safely combine various medications, such as a triptan and a gepant, or a gepant and a monoclonal antibody, will broaden the range of therapeutic options available to patients. More treatments will be required in the near future, especially for patient populations like the elderly, young children, and pregnant women. Future research on oral lasmiditan and rimegepant in children may provide our younger patients with a good therapeutic option.
The ongoing research in the field includes Amylin, a neuropeptide that is speculated to work like that of the calcitonin gene-related peptide (CGRP). A better understanding of amylin may lead to new migraine medications, including neuronal nitric oxide synthase inhibition, which may reduce CRGP and neuronal vasodilation. Orexins, metabotropic glutamate receptor 5, non-μ-opioid receptors, and cannabinoids are some of the emerging drugs that hold the potential for managing migraines in the future(20).
Conclusion
Chronic migraine is a very disabling condition that imposes severe social and personal restrictions on sufferers(20). With the arrival of CGRP antibodies, well-tolerated and targeted medicines with strong long-term safety profiles have emerged as an appealing treatment approach. Ditans and gepants can be clinically tested to determine whether they follow suit and alter the acute treatment landscape for many patients by offering an even more logistically straightforward way of delivering such treatments. The once-daily dosage of gepants is appealing to people in terms of feasibility and compliance.
The future studies are required to determine the extent to which successful migraine treatments may prevent or reverse the anatomical and functional changes seen in chronic migraine. The development of neuroimaging methods and the strengthening of preclinical models may make it easier to identify novel, customised therapy targets and increase our understanding of this complicated, multifaceted disease(21). There is currently research being done to develop ODTs for new medications used to treat migraines. ODTs can therefore pave the way for successful and effective migraine treatment.
References
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