Migraines are a common disabling headache disorder. However, due to the high socio-economic and personal impact of this health condition, they are ranked as the third most prevalent disorder in the Global Burden of Disease Study 2010 (GBD2010) and the third-highest cause of disability worldwide for people under the age of 50 (GBD2015). 

There are two main classifications for migraines - migraine without aura and migraine with aura. A migraine without aura, also named common migraine or hemicrania simplex in previous classifications, is characterized by recurrent headache attacks of moderate or severe intensity, lasting 4-72 hours. They are unilateral in location with pulsating qualities and are aggravated by routine physical activity. There is also association with nausea and/or photophobia and phonophobia. 

A migraine with aura, previously known as classical migraine or complicated migraine, affects about one third of people with migraines. It is characterized by recurrent attacks of unilateral location, with completely reversible visual, sensory or other central nervous system symptoms, lasting minutes. They typically develop gradually and are usually followed by a headache and associated migraine symptoms. 

The aura is the complex of neurological symptoms that normally occurs before the headache. However, it can also begin after the headache phase has initiated, or continue into the headache phase. Visual aura is the most common symptom, occurring in over 90% of patients suffering from migraine with aura. This type of aura is followed by sensory disturbances, in the form of pins and needles moving slowly from the point of origin and affecting a greater or smaller part of one side of the body, face and/or tongue. Numbness is also frequent at the onset, and can also be the only symptom. Less frequent aura symptoms are speech disturbances, usually aphasic but often difficult to categorise (The International Classification of Headache Disorders, 3rd edition).

The numerous symptoms that can occur during migraine attacks reflect the complex pathophysiology and diffuse involvement of multiple neural networks and anatomical regions in the brain. The underlying genetic and biological foundation and neural networks involved have been enormously clarified in last years, leading to the development of novel, mechanism based and disease-specific therapeutics.

For instance, the local vasodilation of extracerebral blood vessels and simultaneous stimulation of the surrounding trigeminal pain system is a main pathway that results in headache. The activation of the trigeminovascular system causes the release of various vasodilators, especially calcitonin gene-related peptide (CGRP) that induces pain response. At the same time, decreased levels of the neurotransmitter serotonin have been observed in migraineurs.

Serotonin receptors have been found on the trigeminal nerve and cranial vessels, and their agonists, especially triptans (5-HT1B/D agonists), are able to eliminate pain in 20-30 % of patients within 2 hours. However, they are accompanied by adverse effects such as transient flushing, tightness, or tingling in the upper body in 25% of patients. Importantly, patients with - or at high risk of - cardiovascular disease should avoid triptans because of vasoconstrictive properties. 

Accordingly, a growing body of research in last years focused on newer-generation migraine-specific medications with no vasoactive effects. Particularly, the presence of serotonin 5-HT1F receptors on blood vessels and the cardiovascular liability associated with targeting this receptor has prompted the development of ditans - a class of molecules that selectively bind to the 5-HT1F receptor subtype and show efficacy in the treatment of migraine. 

Lasmiditan, in particular, was the first ditan approved. It is a highly selective 5-HT1F receptor agonist that has been shown to be effective for the acute treatment of migraine in adults, with or without aura. Two Phase III randomized, double-blind, placebo-controlled studies (SAMURAI and SPARTAN) have proved Lasmiditan efficacy in an episodic migraine acute treatment. Key studies endpoints were the proportion of participants who became headache-free at 2 hours post-dose and the proportion of participants who were free from the most bothersome symptom at 2 hours post-dose. Secondary outcomes included headache recurrence, changes in pain-killer use, and freedom from migraine associated symptoms. A statistically significant proportion of participants using Lasmiditan were headache-free and relieved of the most bothersome symptoms, compared to the placebo, at 2 hours post-dose. In particular, 32.2% in the SAMURAI study, and 38.8% of the participants in the SPARTAN study receiving Lasmiditan 200 mg, compared to 15.3% and 21.3% respectively in the placebo group, became headache free, and 40.7% in the SAMURAI and 48.7% in the SPARTAN study were free from the most bothersome symptoms compared to 29.5% and 33.5%, respectively, in the placebo group. The most common adverse events observed in patients were vertigo and dizziness, while no vasoconstrictor activity was observed, making Lasmiditan particularly indicative for patients with cardiovascular risk or contraindications to triptans (Goadsby et al., 2019, Loo et al., 2019). On the basis of efficacy and safety observed in these studies, Lasmiditan was approved by FDA in 2019 for the treatment of acute migraine in adults, with and without aura. The mechanism of action of Lasmiditan is not entirely clear, however, it is believed to act by blocking migraine at the level of the brainstem, which could account for the observed central nervous system effects (Dodick 2018).

Similarly, on the basis of the abundance of evidence for a crucial role of CGRP in the pathophysiology of migraine, six small-molecule CGRP receptor antagonists (gepants) have been developed and have shown to be effective in the acute treatment of migraines. Overall, clinical studies confirm that gepants are effective acute-migraine therapies and, like Lasmiditan, do not have vasoconstrictor activity, thus representing a promising therapeutic target (Wrobel Goldberg et al., 2015). At present two gepants, ubrogepant and rimegepant, have been approved by the FDA and are on the market in America. A third gepant, atogepant, is in late phase trials for migraine prophylaxis. The pharmacology of rimegepant, atogepant and ubrogepant has recently been characterized in human arteries and shown to be classical receptor antagonists, acting by blocking the responses of CGRP in a competitive manner. Ubrogepant, available in tablets on the U.S. market since 2020, is indicated for the acute treatment of migraine. In clinical trials, pain freedom at 2 hours was seen in about 20% of subjects vs a placebo rate of 12%. The absence of the most bothersome migraine symptoms was reported in about 38% of those taking the either the 50 mg or 100 mg dose vs a placebo rate of 27.8%. Pain relief was seen in 61% at 2 hours vs placebo rates of 48%. The most common side effects for ubrogepant were nausea and dizziness (Dodick et al., 2019). Rimegepant has also shown to be effective for the acute treatment of migraine, and is the only gepant seeking indication for both acute and preventive treatment of migraine. 

The acute treatment indication was approved in February 2020 by the Food and Drug Administration (FDA), while its use in migraine prevention is still being studied. As with ubrogepant, rimegepant relieved the most bothersome migraine symptoms by 2 hours better than placebo. There were no serious side effects observed in these studies, and the only side effects observed by patients were nausea and urinary tract infection (1% above the placebo pill). In the rimegepant preventive study, the 75 mg tablet was found to be effective for the prevention of migraine on alternate days dosing. In patients taking rimegepant with a baseline of ≥14 migraine days per month, there was a 6.4 day reduction in monthly migraine days. In those with <14 migraine days per month, there was a 4 day reduction in headache days in the rimegepant group. Once this data is officially sanctioned, rimegepant will be the first medication approved for both acute and preventive use in migraine, representing a novel approach to migraine management. (Chiang and Schwedt , 2020). 

The critical role of CGRP in the pathogenesis of migraine prompted the development of monoclonal antibodies targeting either GCRP or its receptor. Fremanezumab and galcanezumab are anti-CGRP monoclonal antibodies targeting the peptide, while erenumab specifically targets the CGRP receptor. Apart from Lasmiditan and the gepants, monoclonal antibodies are not effective in the acute treatment of migraine, but were shown to be successful in preventing both episodic and chronic migraine. Also, protein antibodies should not have off-target toxic effects since they are catabolised into their own constitutive aminoacids (Detke et al., 2017, Sun et al., 2016). The long half-life of these monoclonal antibodies (3-6 weeks) allows for the monthly administration of erenumab, galcanezumab and fremanezumab. Since the mechanism of monoclonal antibodies is to sequester or block the receptor of a potent vasodilator, CGRP, safety concerns were largely investigated in clinical studies, particularly for patients with acute vascular stress, such as stroke, myocardial infarction or hypertension, and results are encouraging. Erenumab, for instance, was shown to be effective and safe also in long term studies (Depre et al., 2017, Goadsby et al., 2021). Long term open-label extension studies and post-marketing data will provide additional safety data on all these new biologics. 

The development of ditans, gepants and anti-calcitonin gene-related peptide monoclonal antibodies for the treatment of migraine, is one of the greatest advances in headache medicine, providing a new perspective for those patients who do not benefit from traditional therapies or for those with contraindication to triptans.

Aside from these newer biological drugs, at the forefront of migraine treatment are neuromodulation devices. Neuromodulation devices are advanced medical tools that can increase or decrease the activity of the nervous system. Research has found this technology may be effective in reducing migraine attacks and cluster headaches. Neuromodulation is conducted with a device that uses electrical currents or magnets to adjust or change activity in the brain. Some of these devices can stop attacks that are already ongoing, while others are used preventatively. At present, three neuromodulation devices received approval by FDA in the USA for the treatment of migraine, and several others have shown promise in early clinical trials (Najib et al., 2019).

The Single Pulse Transcranial Magnetic Stimulator (sTMS) is a handheld device that works by generating a magnetic impulse that affects electrical signaling in the brain. The mechanism of action of sTMS for headache is thought to be disruption of cortical spreading depression and modulation of thalamic nociceptive circuit activity, via downregulation of thalamocortical neurons (Lipton et al., 2010). It was first approved for the acute treatment of migraine with aura, and has recently been approved for the preventive treatment of migraine. In a survey of people with migraines who used sTMS over 3 months, there was efficacy for participants with migraines with and without aura, with a reduction in attacks frequency and medication use (Bhola et al., 2015). 

The Transcutaneous Vagus Nerve Stimulator (nVNS) is a noninvasive handheld device that uses electrical stimulation to target the vagus nerve in the neck. It has been approved by FDA for the acute treatment of attacks in patients with episodic cluster headache as well as for the acute treatment of migraine pain. In clinical studies on nVNS use for acute self-treatment of migraine attacks, 64.6% of people with chronic migraine or high-frequency episodic migraine had pain relief within 2 hours., and 39.6% of responders had freedom from pain (Barbanti et al., 2015). Benefits of treatment with nVNS for cluster headache were seen as early as 2 weeks after first stimulation, and continued for several weeks in extension studies (Gaul et al., 2017).

Another promising technology, the Transcutaneous External Trigeminal Nerve Stimulation (eTNS), uses non-invasive electrical stimulation to stimulate the bilateral supratrochlear and supraorbital nerves. The device may be helpful in reducing migraine frequency, and it is currently FDA-approved for both preventive and acute treatment of migraine. For migraine preventive treatment, 20 minutes of active stimulation daily for 3 months resulted in significant reduction of the mean number of headache days (Schoenen et al., 2013). For acute migraine treatment, 1 hour of eTNS given in an outpatient clinic within 3 hours of onset resulted in almost 60% reduction of pain after 1-2 hours, also enormously reduces the use of rescue medication in most patients in the longer period (Chou et al., 2017).

Overall, clinical data endorse the potential of biologicals and non-invasive neuromodulation devices, possibly representing a paradigm shift in headache medicine. Nonetheless, a deeper understanding of several key mechanisms is still necessary for a further step in migraine medicine. Primarily, the molecular switch that stops a migraine attack is still unknown. Similarly, concerning the disease course and prognosis, establishing the factors that influence remission and progression to persistent symptoms over time will be crucial in the development of disease-modification strategies.