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Migraine: unknown causes, little funding and innovative therapies

Migraine is one of the most common types of headache, which usually occurs in the front or side of the head and can last for a few hours, up to a few days. It has a frequency that varies from a few episodes per year, to 2-3 attacks per week in severe cases. It is a neurovascular disorder that is often underestimated, although it is more common than you might think: 8% of men and 18% of women suffer from it. Of these, 13% have at least one attack per week. According to some studies, just over 40% of people with chronic migraine receive treatment; of these, only one fourth are correctly diagnosed and less than half of the latter receive appropriate care (therefore less than 5% of the total). Of this 5%, not everyone follows the indicated therapy, because sometimes it is ineffective or causes side effects. In fact, most of the treatments proposed have not been studied for migraines, but for example developed to treat mood disorders, depression, anxiety or other psychological conditions.

Little funding

The question is logical: why don’t we study specific drugs for migraine? Because migraine has never been a priority for research, neither for funding. It is reasonable to believe that financing of the study of a disease is proportional to its impact on the population, and it usually works this way. As for migraine, however, the situation is different. Its impact is similar to that of cirrhosis of the liver and schizophrenia, but while the latter receive funding for over $ 200 million a year, the migraine receives only 20. A possible explanation lies in the stigma of the disease. Those who do not suffer from it think “it is only a headache, it is because of the stress. You can do some yoga”. It is surprisingly difficult to convince people that it is a widespread and serious pathological condition.

How migraine develops

The causes of migraine are still unknown, while the mechanism of action is understood and mainly involves CGRP. It is a variant of calcitonin, known as the “calcitonine gene-related peptide” (hence the acronym). CGRP plays an important role in vasodilatation and for this reason it is relevant in the cardiovascular system and in the treatment of wounds. Since it is released by the sensory nerves (those responsible for the perception of various stimuli), CGRP is also involved in the perception of pain. Its role in migraine is consolidated and measurable by the elevation of its level in the blood and saliva of patients with this condition. Pain sensitivity comes from the sensory fibers of the trigeminal nerve, which provide dense innervation to the meningeal blood vessels within the skull. Activation of the trigeminal ganglion causes the release of various molecules into the blood, including CGRP, which leads to vasodilation and neurogenic inflammation.

Therapies and treatments

The first drugs tested against migraine were triptans, which however have heavy side effects due to the generalized vasoconstrictive effect. In 2000, it was tested the first of many drugs that act as CGRP antagonists, that aim to prevent its mechanism of action, trying to limit side effects. Despite this, several clinical trials have been aborted due to unwanted physiological consequences, such as liver toxicity. A marked improvement was achieved with the introduction of monoclonal antibodies specific for CGRP. A monoclonal antibody recognizes one and only one target against which it was designed, specifically blocking its mechanism of action. This way, the side effects are minimized. Currently, four companies develop monoclonal antibody drugs: Amgen, Teva Pharmaceuticals, Eli Lilly & Company and Alder Pharmaceuticals. In addition, there are four drugs in phase 3 clinical trials, which show encouraging results on both episodic and chronic migraines. In April 2020, the U.S. Food and Drug Administration (FDA) approved Vyepti, the newest migraine drug. It is a GPRD antagonist and is administered intravenously. Only 2% of the tests were stopped due to the side effects. The great advantage of this treatment is that, compared to the others, it has an almost immediate effect (less than a day in half of the patients treated), while for the other drugs it is necessary to wait days, weeks, or even months before they have a concrete effect.

There are also some non-pharmacological treatments, which have the advantage of not presenting side effects. Currently, two devices (portable, therefore usable directly by the patient) are approved by the FDA and available for the treatment of migraine: the single pulse transcranial magnetic stimulation device (sTMS) (eNeura) and the Cefaly device (Cefaly-Technology). The former is a neuromodulation device that generates a magnetic field of specific intensity and duration by passing electric current through specially shaped coils adapted to the posterior region of the skull. These magnetic fields can pass through the bones and tissues painlessly, stimulating complementary electrical activity within the brain, thus counteracting the perception of pain. Instead Cefaly is an external trigeminal nerve stimulation device. The device is magnetically connected to a self-adhesive electrode, which is placed on the forehead. Precise micro-pulses are sent through the electrode to the upper branch of the trigeminal nerve to relieve headaches during a migraine attack or to prevent future attacks.

Sources

https://www.healio.com/news/primary-care/20170714/new-targeted-approaches-offer-renewed-hope-for-migraine-treatment

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4187032/

https://jamanetwork.com/journals/jama/article-abstract/197628

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