Evidence-based symptomatic treatment of migraine.

Symptomatic treatment of migraine includes patient education, mainly to avoid medication overuse and known trigger factors, as well as pharmaceutical and nonpharmaceutical interventions. Disease-specific and mechanism-based agents include ergotamine and dihydroergotamine targeting the adrenergic, dopaminergic, and serotoninergic systems followed by triptans, specific agonists for 5-HT1B/1D/1F receptors, the latest being more favorable in terms of safety and documentation of efficacy. Recently, antagonists of calcitonin gene-related peptide (gepants) and selective agonists of the 5-HT1F receptor (ditans) have been added, with promising efficacy and safety. Triptans stay as the first option treatment when attacks are moderate to severe, followed by nonspecific agents, including aspirin and paracetamol/acetaminophen and nonsteroidal antiinflammatory drugs (NSAIDs, ibuprofen and naproxen share the best documentation) for mild-to-moderate migraine attacks. Combinations with caffeine are effective as well, but barbiturates and opioids alone or in combinations should be avoided. Simple analgesics and NSAIDs attenuate cephalic pain via prostaglandin mediated mechanisms and may induce peptic, renal and hepatic adverse effects. Neuromodulation techniques include single-pulse transcranial magnetic stimulation (s-TMS), external trigeminal nerve stimulation (e-TNS), remote electrical neuromodulation (REN) and noninvasive vagus nerve stimulation (nVNS). All share good documentation and safety profile and are worthy of alternative treatment options along with physical therapy when medicines are contradicted or not well tolerated or unwanted by the patients.

Clinical guidance for choosing the right pharmacotherapy for migraine attacks.

INTRODUCTION: Migraine as headache attacks with autonomic symptoms is a serious condition and it is important to treat a single attack effectively in order to improve not only the patient's quality of life at a given moment but also to prevent the migraine from becoming a chronic one. AREA COVERED: The article briefly presents the guidance in selecting the most appropriate pharmacological treatment of migraine attack, indicating a personalized approach to migraine patient. EXPERT OPINION: In this short paper, we show the implementation of new drugs into everyday clinical practice. Good cooperation between the physician and the patient and having the patient's trust is one of the elements of a personalized therapeutic approach and the key to achieving satisfaction of both the patient and the doctor.

Unmet Needs in the Acute Treatment of Migraine.

Migraine represents the most common neurologic disorder, ranking second among the world's causes of disability [expressed as years lived with disability (YLDs)]. Patients often do not receive the best therapy because of safety issues, tolerance, and prescription accessibility. General practitioners are not always educated about the disease, and specialists are few and often difficult to reach. Therapies are limited and have many side effects that can impede the prescription. Prophylactic therapy is recommended in case of four or more headaches a month, eight or more headache days a month, debilitating headaches, and medication-overuse headaches. The available therapeutic options are in constant development. The classic one consists of non-specific drugs: ß-blockers, tricyclics, antiepileptics, and botulinum toxin. Monoclonal antibodies targeting the calcitonin gene receptor (CGRP) peptide or its receptor are the only ones specifically designed to treat migraine. Their efficiency and convenient safety profile have been demonstrated in a number of trials versus both placebo and classic therapies. The treatment of acute migraine attack consists of medications designed to affect the painful symptoms. For over 30 years, the cornerstones of treatment in clinical practice have continued to be represented by triptans and non-steroidal anti-inflammatory drugs (NSAIDs), with the well-know related adverse effects. Opioids are used inappropriately and overprescribed. Polytherapy is strongly not recommended but is still a common practice because treatment is not optimized and thus not efficient. Great promise comes from gepants, also targeting CGRP, and ditans, 5-HT1F receptor agonists. They seem to outweigh the risk of medication overuse headache because of their efficacy and rapid onset and have no cardiovascular contraindications. Nonetheless, these points remain to be confirmed. Although therapies have been implemented in the last years, significant unmet treatment needs remain a reality in patients' lives. This commentary aims to identify the most important unmet needs in the acute treatment of migraine, analyzing the current status of available therapies and their limits. We also analyzed some of the prophylactic therapies available, especially focusing on anti-CGRP monoclonal antibodies, to better understand the importance of setting a therapeutic strategy that includes the two modes, both acute and prophylactic, to reach the best result. We hope that having an overview of the shortcomings will help to provide constructive ideas for improvement.

Seguridad cardiovascular de los nuevos fármacos para el tratamiento agudo y preventivo de la migraña: gepantes y ditanes / Cardiovascular safety of new drugs for the acute and preventive treatment of migraine: gepants and ditans

Introducción: La migraña es una patología neurológica prevalente caracterizada por ataques de cefalea incapacitantes. En las últimas décadas se han desarrollado nuevos fármacos específicos para el tratamiento agudo y preventivo de la migraña basados en su fisiopatología. Entre éstos se encuentran los antagonistas del péptido relacionado con el gen de la calcitonina (CGRP) (gepantes) y los agonistas selectivos del receptor serotoninérgico 5-HT1F (ditanes). El CGRP es un neuropéptido liberado por los terminales trigeminales que actúa como vasodilatador, provoca inflamación neurógena y, con ello, generación del dolor y sensibilización en la migraña. Posee, además, una potente acción vasodilatadora y participa en la regulación cardiovascular, razón por la cual se están llevando a cabo numerosos estudios que evalúan la seguridad vascular de actuar contra el CGRP. La alta selectividad de los ditanes para el receptor serotoninérgico 5-HT1F con una baja afinidad para otros receptores serotoninérgicos parece traducirse en un bajo o nulo efecto vasoconstrictor, que es mediado por la activación de los receptores 5-HT1B. Desarrollo: Nuestro objetivo es revisar la seguridad cardiovascular demostrada por estos nuevos fármacos para el tratamiento de la migraña analizando la evidencia publicada. Realizamos una búsqueda bibliográfica en la base de datos PubMed y una revisión de los ensayos clínicos publicados en clinicaltrial.gov. Incluimos revisiones bibliográficas, metaanálisis y ensayos clínicos en español e inglés. Analizamos los efectos adversos cardiovasculares informados. Conclusiones: Basándonos en los resultados hasta ahora publicados, podemos concluir que el perfil de seguridad cardiovascular de estos nuevos tratamientos es favorable. Para confirmar estos resultados son necesarios estudios de seguridad a más largo plazo.(AU)

Introduction: Migraine is a prevalent neurological condition characterised by disabling headache attacks. In recent decades, new drugs have been developed specifically for the acute and preventive treatment of migraine based on its pathophysiology. These include calcitonin gene-related peptide (CGRP) antagonists (CGRP) (gepants) and selective serotoninergic 5-HT1F receptor agonists (ditans). CGRP is a neuropeptide released by trigeminal terminals that acts as a vasodilator, causes neurogenic inflammation and thus generates pain and sensitisation in migraine. It also has a powerful vasodilatory action and is involved in cardiovascular regulation, which is why numerous studies are under way to assess the vascular safety of acting against CGRP. The high selectivity of ditans for the serotoninergic 5-HT1F receptor with a low affinity for other serotoninergic receptors seems to translate into little or no vasoconstrictor effect, which is mediated by the activation of 5-HT1B receptors. Development: The aim of our study is to review the cardiovascular safety demonstrated by these new drugs for the treatment of migraine by analysing the evidence published to date. We conducted a literature search in the PubMed database and a review of clinical trials published at clinicaltrial.gov. We included literature reviews, meta-analyses and clinical trials in English and Spanish. We analysed reported cardiovascular adverse effects. Conclusions: Based on the results published to date, we can conclude that the cardiovascular safety profile of these new treatments is favourable. Longer-term safety studies are needed to confirm these results.(AU)

Efficacy, safety and indirect comparisons of lasmiditan, rimegepant, and ubrogepant for the acute treatment of migraine: A systematic review and network meta-analysis of the literature.

BACKGROUND: We performed a random-effects network meta-analysis to study the efficacy and safety of newly developed drugs for the acute treatment of migraine attacks. METHODS: MEDLINE via PubMed, Embase and The Cochrane Register of Controlled Trials were searched from inception to 11 February 2022. Phase 3 randomized controlled trials examining all formulations of lasmiditan, rimegepant and ubrogepant for the acute treatment of adults with migraine, were included. Data were extracted following the PRISMA guidelines. RESULTS: Seven studies (SAMURAI, SPARTAN, CENTURION, Study 302, Study 303, ACHIEVE I and II) involving n = 12,859 patients were included. All treatments were superior in efficacy to placebo. Lasmiditan 200 mg showed the highest two-hour pain freedom, while two-hour freedom from most bothersome symptom was equally achieved by the higher doses of lasmiditan (100 and 200 mg), rimegepant and the higher doses of ubrogepant (50 and 100 mg). The odds of treatment-emergent adverse events were greatest with all doses of lasmiditan. CONCLUSION: Lasmiditan 200 mg was the most effective intervention in the treatment of migraine attacks, although it was associated with high degrees of dizziness, nausea and somnolence. Rimegepant showed slightly lower, but similar efficacy rates to lasmiditan. Ubrogepant had overall the best tolerability profile. These conclusions are limited by the absence of head-to-head comparisons, limitations of individual trials and of the meta-analysis methodology itself.PROSPERO trial registration: CRD42022308224.

Reaching the Nadir of Medication Overuse in Chronic Migraine.

The introduction of new drug classes for chronic migraine, such as monoclonal antibodies for calcitonin-gene-related peptide or its receptor (CGRPr), or antagonists of the same CGRP, have opened a new scenario in a selected population of individuals with migraine, and those presenting with chronic form of migraine in association with medication overuse. Medication overuse is now considered a complication of chronic migraine and, in fact, the treatment with CGRP(r)-MAbs of chronic migraine with medication overuse results in a clinical improvement of chronic migraine itself, accompanied by a parallel and obvious reduction in the intake of specific and non-specific acute migraine drugs. Education on the correct use of these drugs will be an essential tool to reduce the disability and costs of people suffering from CM complicated by MO, considering the long-term safety of the new therapies targeting the CGRP pathways. Only in this way can medication overuse risk can be reduced at its nadir in the scenario of chronicity of migraines.

Ditans: a new prospective for the therapy of migraine attack?

INTRODUCTION: Migraine attack is characterized by disabling pain and associated symptoms. Triptans represent the "gold standard" therapy, but cardiac subjects have significant limitations for this approach. New drug families are under consideration to expand therapeutic offerings, especially in the presence of contraindications or for non-responsive patients. This review aimed to analyze studies related to the category of "ditans," with a focus on lasmiditan, which is available for human use. MATERIALS AND METHODS: We consulted PubMed/MEDLINE, Web of Science, and www. CLINICALTRIALS: gov to find both original and review articles on the mechanism of action of 5-HT1F agonists in migraine, and for randomized, double-blind, placebo-controlled trials (RCTs) on the family of drugs called "ditans," with a focus on "lasmiditan," published in the time frame of 01-Jan-2010 to 31-Mar-2022. Only studies conducted in human subjects and published in English were included in this review. RESULTS: We retrieved four RCTs (named SAMURAI, SPARTAN, GLADIATOR, and CENTURION) and several studies that analyzed the efficacy and safety of lasmiditan. Lasmiditan at increasing doses showed significant improvement in pain and most other troublesome symptoms at 2 h. Adverse events were mild and mainly represented by dizziness, vertigo, drowsiness, and fatigue. No vasoconstrictive effects were described, suggesting the use of ditans as a safe option in chronic cardio- and cerebro-vascular disease. DISCUSSION: Lasmiditan could be a viable alternative to triptans, although further RCT studies and real-world evidence are needed to better understand its potential and possible adverse events in a larger population.

Recently approved and emerging drug options for migraine prophylaxis.

INTRODUCTION: Migraine occupies the first position regarding the disability caused in female working population (15-49 years). Research in the field of prophylaxis in this pathology has made enormous strides in recent years. AREAS COVERED: In this narrative review, we retrace the most important scientific evidence regarding recently approved and emerging drugs for the prophylactic treatment of migraine. The purpose of this article is in fact to evaluate currently approved or emerging pharmacological agents for migraine prophylaxis. This review is based on the literature published in the peer review journal obtained through PubMed, Cochrane library, Clinicaltrials.gov, and US FDA. EXPERT OPINION: Monoclonal antibodies (mAbs) that target the calcitonin gene-related peptide signaling pathway (CGRP) have marked an innovation in prophylactic migraine therapy. The combination of Onabotulinumtoxin-A (OBTA) and mAbs appears to be an effective, but costly, therapeutic option for resistant cases. New classes of molecules like gepants and ditans seem to give exceptional results. In addition, new prophylactic drugs are emerging with several targets: the pituitary adenylate cyclase-activating polypeptide (PACAP), ion channels, several receptors coupled to G proteins, orexin, and glutamate. All these therapies will implement and improve migraine management, as well as personalized medicine for each patient.

Drug Safety in Episodic Migraine Management in Adults Part 1: Acute Treatments.

PURPOSE OF REVIEW: The aim of this review is to aid in choosing safe options when assessing potential risks of acute migraine treatments based on known mechanisms of action and anticipated safety concerns. RECENT FINDINGS: Part 1 highlights safety issues associated with commonly used medications to treat acute migraine attacks. Strategies to mitigate cardiovascular and gastrointestinal risks of nonsteroidal anti-inflammatory drugs, evaluation of cardiovascular risks of triptan and ergot alkaloids, and precautions with use of antiemetics and the novel drugs gepants and ditans are discussed to help practitioners in clinical decision-making. When available, we included recommendations from professional societies and data from pharmacovigilance systems. While guidelines on efficacy are available, one must also consider the possible risks and adverse effects of a drug when creating treatment plans.

5-hydroxytryptamine in migraine: The puzzling role of ionotropic 5-HT3 receptor in the context of established therapeutic effect of metabotropic 5-HT1 subtypes.

5-hydroxytryptamine (5-HT; serotonin) is traditionally considered as a key mediator implicated in migraine. Multiple 5-HT receptor subtypes contribute to a variety of region-specific functional effects. The raphé nuclei control nociceptive inputs by releasing 5-HT in the brainstem, whereas dural mast cells provide the humoral source of 5-HT in the meninges. Triptans (5-HT1B/D agonists) and ditans (5-HT1F agonists) are the best established 5-HT anti-migraine agents. However, activation of meningeal afferents via ionotropic 5-HT3 receptors results in long-lasting excitatory drive suggesting a pro-nociceptive role for these receptors in migraine. Nevertheless, clinical data do not clearly support the applicability of currently available 5-HT3 antagonists to migraine treatment. The reasons for this might be the presence of 5-HT3 receptors on inhibitory interneurons dampening the excitatory drive, a lack of 5-HT3 A-E subunit-selective antagonists and gender/age-dependent effects. This review is focusing on the controversial role of 5-HT3 receptors in migraine pathology and related pharmacological perspectives of 5-HT ligands. LINKED ARTICLES: This article is part of a themed issue on Advances in Migraine and Headache Therapy (BJP 75th Anniversary). To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.3/issuetoc.

Progress in the Treatment of Migraine Attacks: From Traditional Approaches to Eptinezumab.

Migraine is the second cause of disability and of lost years of healthy life worldwide. Migraine is characterized by recurrent headache attacks and accompanying disabling symptoms lasting 4-48 h. In episodic migraine, attacks occur in less than 15 days per month and in chronic migraine, in more than 15 monthly days. Whilst successful translation of pharmacological discoveries into efficacious therapeutics has been achieved in the preventative therapy of chronic migraine, treatment of acute migraine suffers the lack of effective advancements. An effective treatment affords complete freedom from pain two hours after therapy and provides the absence of the most bothersome symptom (MBS) associated with migraine after 2 h. However, available anti-migraine abortive treatments for acute attacks do not represent an effective and safe treatment for all the populations treated. In particular, the most used specific treatment is represented by triptans that offer 2-h sustained freedom from pain achieved in 18-50% of patients but they are contraindicated in coronary artery disease, stroke and peripheral vascular disease due to the vasoconstriction at the basis of their pharmacologic action. The most novel therapies, i.e., gepants and ditans, are without sufficient post-marketing data for secure use. Here, an attempt is proposed to analyse the rational basis and evidence in favour of investigating the efficacy and safety in acute migraine attacks of eptinezumab, i.e., monoclonal antibody (mAb) directed towards calcitonin gene-related peptide (CGRP) unique for intravenous infusion administration.

CGRP Receptor Antagonists and 5-HT1F Receptor Agonist in the Treatment of Migraine.

Discovering that calcitonin-related peptide (CGRP) plays a key role in the complex pathophysiology of migraine has allowed us to make great strides in the development of new approaches for acute and preventive treatment. This evidence has led to the development of small molecules antagonist molecules of the CGRP receptor ("gepants") and of a new class of medications called "Ditans". This review presents the data from clinical trials reporting the efficacy, safety, and tolerability of the new drugs used in the treatment of migraines. Evidences show that therapeutic approaches targeted to CGRP have the potential to transform the clinical management of migraine, even though its appropriate place has yet to be determined with accuracy.

Lasmiditan: an additional therapeutic option for the acute treatment of migraine.

Introduction: Migraine is currently listed as the second cause of 'years lived with disability' and the sixth cause of global disability. Despite the burden associated to the disease, availability of specific drugs is still limited.Areas covered: The authors have evaluated lasmiditan, the first 'ditan' approved by the Food and Drugs Administration in 2019, from a global perspective: basic chemistry, pharmacodynamic and pharmacokinetic profiles, efficacy in migraine as a 5-HT1F receptor selective agonist, tolerability and clinical safety, and impact on migraine-related disability. Our evaluation considered original papers and review articles published from 2010 to 2020.Expert opinion: Available data point to the efficacy of lasmiditan in reducing migraine pain and the most bothersome symptoms within 2 hours from oral administration. Moreover, lasmiditan has a positive effect on migraine-related disability. Its side effects mostly reflect an involvement of the central nervous system or the vestibular system, while cardiovascular side effects are rare and mild.Lasmiditan can be safely prescribed in patients who have failed non-steroid anti-inflammatory drugs or triptans or with cardiovascular risk factors. Caution is advised in frequent users, due to lack of reliable data on its abuse potential. Further data are necessary to determine the usability of lasmiditan in particular populations, e.g. children and adolescents, pregnancy.

Lasmiditan for acute treatment of migraine.

Lasmiditan, a selective 5-HT1F receptor agonist, is a harbinger for the novel ditan class of medications for acute migraine treatment. Lasmiditan activates 5-HT1F receptors on presynaptic trigeminal nerve terminals, which impedes the release of calcitonin gene-related peptide (CGRP) from trigeminal nerve endings and thereby suppresses activation of the trigeminovascular system. Notably, lasmiditan does not result in vasoconstriction, making lasmiditan a migraine-specific acute treatment option for those with cardiovascular risk factors. However, lasmiditan does have centrally mediated side effects. This review will discuss the background of lasmiditan development, its preclinical pharmacology, safety, drug interactions and indications for use.

Rational Use of Lasmiditan for Acute Migraine Treatment in Adults: A Narrative Review.

PURPOSE: This narrative review provides an update on the research that led to the development of ditans and lasmiditan for the acute treatment of migraine in adults and discusses the potential advantages and disadvantages of lasmiditan in clinical use. METHODS: The electronic databases PubMed, Scopus, and ClinicalTrials.gov were searched from database inception through January 9, 2021, to identify relevant studies. Search results were assessed for their overall relevance to this review. FINDINGS: Because part of the effect of the triptans is mediated by the serotonin 1F receptors, which are not present in the smooth muscle, a pure agonist of these receptors, lasmiditan, was developed. Lasmiditan is hypothesized to act on antinociceptive pathways and inhibit the calcitonin gene-related peptide release. Lasmiditan was approved by the US Food and Drug Administration in 2019 based on the results of 2 pivotal trials that found a significant difference from placebo in the percentage of patients who achieved freedom from pain and most bothersome symptom at 2 h. The main concern of lasmiditan derives from its central nervous system-related adverse effects, mainly dizziness and paraesthesia, probably attributable to its high blood brain barrier penetration. These central nervous system adverse effects impair driving performance for hours and might be suboptimal for individuals with migraine who want to quickly stop the migraine attack to resume their activities as soon as possible. IMPLICATIONS: Despite the advantage of being beneficial in the acute treatment of migraine without vasocostrictive action, lasmiditan also presents limitations, in particular the central nervous system adverse effects. Moreover, head-to-head trials against triptans and gepants are indispensable to determine the better option for patients.

Novel synthetic treatment options for migraine.

Introduction: Migraine is one of the most common neurological disorders. Nowadays, the 5-HT1B/1D receptor agonists, namely triptans, are considered as the standard of care for migraine acute treatment. However, triptans have limitations in some patients, such as incomplete pain relief, headache recurrence, and cardiovascular contraindications. New 5-HT1F receptor agonists, namely ditans, and calcitonin gene-related peptide receptor antagonists, namely gepants, have been developed as migraine-specific treatments.Areas covered: This paper reviews the available data from RCTs to assess the clinical efficacy, safety, and tolerability profile of lasmiditan, rimegepant, and ubrogepant for the acute treatment of migraine and atogepant for the prevention of migraine.Expert opinion: Available data suggest that lasmiditan, rimegepant, and ubrogepant might not have a clinical efficacy similar to triptans. Lasmiditan did not cause the typical triptan side effects but was associated with central nervous system side effects, causing temporary driving impairment. On the contrary, the new generation of gepants showed a placebo-like tolerability profile and the absence of a specific pattern of side effects. Future studies on lasmiditan and gepants with respect to established effective comparators are mandatory to support phase III results and to help clinicians to balance the benefit/risk profiles of the various acute and preventive medications.