LAUSR

Migraine is a complex disorder affecting mostly young individuals, and it is considered one of the most common disabling neurological conditions. Thus, all migraineurs require an effective acute treatment to relieve headache attacks and prevent the risk of progression from episodic to chronic migraine that is associated with noneffective acute treatments. Nowadays, although a wide range of acute medications are available, there are several limiting factors, as follows: (i) potential ineffectiveness, (ii) side effects, (iii) contraindications, and (iv) risk to develop medication overuse headache (MOH). Accordingly, almost half of migraineurs are not satisfied with their current therapy that, at present, includes analgesics, NSAIDs, triptans, and ergots [1]. Driven from this unmet need, the increasing understanding of molecular mechanisms underlying migraine pathophysiology has led to development of different new drugs targeting CGRP and 5-HT, finally broadening the therapeutic armamentarium. Ditans and gepants are promising new classes for acute migraine medications in development. Several selective 5-HT1F agonists (ditans) have been developed in recent years in clinical trials. Among them, lasmiditan was approved in the USA for the acute treatment of migraine with or without aura in adults. RCTs have demonstrated that oral doses of lasmiditan (50–200 mg) is efficacious, safe, and generally well tolerated for the acute treatment of migraine [2, 3]. The percentage of patients with 2-h pain freedom in trials ranges from 28.2 to 38.8%. The most reported adverse events were dizziness, paresthesia, somnolence, fatigue, nausea, lethargy, and vertigo. Interestingly, lasmiditan does not cause vasoconstriction, and its safety has been extensively investigated, with no increase in frequency of cardiovascular treatmentemergent adverse events. These findings make lasmiditan an attractive option for individuals who cannot use triptans for cardiovascular reasons (e.g., uncontrolled hypertension or coronary artery disease) [2, 3]. The second new class of acute migraine medications is gepants that are small molecule CGRP receptor antagonists. Among these, ubrogepant and rimegepant are still in development. Ubrogepant is administrated orally with 25–100 mg doses. The percentage of patients with 2-h pain freedom in trials ranges from 19.2 to 19.6%. The most commonly reported adverse events (in less than 5% of patients) were nausea, somnolence, and dry mouth [2, 3]. The other CGRP receptor antagonist on development is rimegepant. The percentage of patients with 2-h pain freedom with orally administered rimegepant 75 mg is approximately 20%. The most common adverse events (in less than 2% of patients) were nausea and urinary tract infection. Overall, adverse event rate is reported to be similar to placebo [2, 3]. Collectively, RCTs demonstrated efficacy (defined as superiority over placebo) of lasmiditan and gepants for the acute treatment of migraine. However, the therapeutic gain for gepants (rimegepant, 5–7.6%; ubrogepant, 6.4–9.4%) seems to be low, especially compared with lasmiditan (7.3–17.5%) and sumatriptan (16–21%). Unfortunately, other ditans’ or gepants’ development failedmainly due to liver toxicity [2, 3]. Another area of therapeutic research consists in developing new formulations of existing medications. Migraine attacks are associated with nausea/vomiting and gastric motility dysfunction resulting in delayed absorption of orally administered drugs, affecting the time to reach maximum plasma concentration (Tmax) and, consequently, clinical efficacy. Patients may take adjunctive antidopaminergic drugs, such as metoclopramide, which act both as antiemetic and as prokinetic. However, these medications are limited by potential concerning side effects, such as extrapyramidal features [1]. Nasal spray formulations only partially resolve the issue since it has been shown that most of the intranasally administered triptans or ergot are still absorbed through * Sabina Cevoli [email protected]