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Objective: Japan has resumed its health technology assessment to decide how to reduce high-cost drug prices. While drug price rules in Japan are comprehensive, they do not necessarily capture differences in product characteristics. This study examined the drug price revision strategy in Japan using migraine treatment with triptans as an example. Cost data from fiscal years (FY) 2018, 2020, and 2022 were utilized. Methods: A cost-utility analysis was conducted from the perspective of healthcare payers, focusing on Japanese patients aged over 18 years experiencing migraines. The study employed a base-case model with probabilities derived from a network meta-analysis. Direct costs included medical and drug costs. Effectiveness was assessed using the European Quality of Life 5-dimensions—3-level questionnaire. Deterministic and probabilistic sensitivity analyses were conducted to examine the level of uncertainty. Results: In FY2018, sumatriptan and eletriptan were cost-effective; however, the other triptans were dominated by sumatriptan. In FY2020, sumatriptan and eletriptan were cost-effective, and rizatriptan was extended-dominated; nevertheless, the other triptans were dominated by sumatriptan. In FY2022, naratriptan and eletriptan were cost-effective; however, the other triptans were dominated by naratriptan. The hierarchy of triptan strategies varied in each fiscal year. Conclusions: This study provides valuable insights into the drug price revision strategy in Japan. The variations could be problematic because in Japan, formulary management of triptans, for example, those for migraine, may face revaluation every other year. Discussions regarding this issue will be further explored in the future. [ABSTRACT FROM AUTHOR]

Background: Novel abortive treatments for migraine, ditans and gepants, have promising implications in triptan-insufficient responders with minimal existing comparative data. Our study aims to synthesize evidence through a systematic review and network meta-analysis to assess the comparative efficacy of lasmiditan, rimegepant and ubrogepant in triptan-insufficient responders. Method: We searched PubMed, Embase, CENTRAL, and EBSCO Open Dissertations up to May 2024. We included randomized controlled trials (RCTs) that compared novel abortive treatments, including lasmiditan, rimegepant, and ubrogepant, in migraine patients who self-reported insufficient response to triptans. Outcomes are represented using relative risks with corresponding 95% confidence intervals (CI). The surface under the cumulative ranking curve (SUCRA) was used to rank each medication. Results: A total of five phase 3 RCTs involving 3,004 patients were included in the analysis. All three agents were significantly superior to placebo for two-hour pain freedom (RR = 1.93, 95% CI [1.52, 2.46]), freedom from the most bothersome symptoms at two hours (RR = 1.55, 95% CI [1.37, 1.75]), and pain relief at two hours (RR = 1.46, 95% CI [1.35, 1.58]). No statistically significant differences in efficacy outcomes were observed among the three agents. However, lasmiditan 200 mg had the highest cumulative probability for two-hour pain freedom and relief (SUCRA 0.9, 0.8, respective), while rimegepant led in relieving the most bothersome symptoms (SUCRA 0.7). Conclusion: Lasmiditan, rimegepant, and ubrogepant are effective for acute treatment of migraine in triptan-insufficient responders, with high-dose lasmiditan showing the highest efficacy for pain control. [ABSTRACT FROM AUTHOR]

Background and objectives: About a quarter of migraine cases among women have menstrual migraine (MM), which is usually more severe, longer lasting, and less responsive to treatment than typical migraine. Randomized controlled trials (RCTs) have evaluated the efficacy of several medication in the acute and preventive treatment of MM; this meta-analysis compared the effectiveness of these treatments. Methods: We conducted systematic searches in the Cochrane Central Register of Controlled Trials, MEDLINE, and Embase databases. The primary outcomes of acute treatment trials were pain relief at 2 and 24 h after treatment compared with placebo or another treatment. The three endpoints we checked for studying MM prevention were: no recurrence of headaches each month, a 50% reduction in monthly migraine days from baseline, and a decrease in the mean number of headache days per month. Results: Out of 342 studies, 26 RCTs met the criteria. Triptans, combined with or without other analgesics, were superior to placebo in providing pain relief in the acute treatment and prevention of MM. Among the treatments, sumatriptan and lasmiditan demonstrated superior pain relief at 2 h (OR: 4.62) and 24 h (OR: 4.81). Frovatriptan exhibited effectiveness in preventing headache recurrence, whereas galcanezumab and erenumab displayed significant preventive benefits in reducing headache days per month. Conclusion: Sumatriptan and lasmiditan are effective first-line treatments for acute MM. For prevention, frovatriptan may be the more effective of triptans. Compared with triptans, CGRP monoclonal antibodies, here including erenumab and galcanezumab, are more effective in reducing headache days, and therefore, in preventing MM. [ABSTRACT FROM AUTHOR]

Introduction: Migraine is a debilitating, neurological disorder, characterized by episodes of ipsilateral headache, often associated with symptoms such as nausea, vomiting, vertigo, and other sensory symptoms. The role of commonly used triptans (5 HT1B/1D agonists) – rizatriptan and sumatriptan – is very scarcely explored in Indian population with migraine. Thus, this study was done to assess the efficacy and tolerability of 10 mg oral rizatriptan versus 50 mg oral sumatriptan for the treatment of acute moderate-to-severe migraine. Materials and Methods: A total of 113 migraine patients attending the neurology outpatient department were enrolled in our study. The efficacy parameters included in our study were pain relief, pain free at 2 h, and sustained pain-free response in both the groups. Adverse drug reactions, if any, were recorded as a measure of tolerability. Results: Overall rizatriptan showed superior efficacy in terms of pain relief at 2 h (71.92% vs. 60.71%) with a statistically significant difference at 1.5 h (P = 0.0084) and 2 h (P = 0.0099) and complete abolition of headache (pain free) at all the four time points spaced 30 min apart (43.85% vs. 26.78%). Twenty-four hours sustained pain-free response was also more in the rizatriptan group (63.42% vs. 47.06%) as compared to that in the sumatriptan group. The frequency of adverse effects was seen more in the sumatriptan group (83.89%) than those receiving rizatriptan (49.68%). Conclusions: Rizatriptan 10 mg was found to be more efficacious and tolerable as compared to sumatriptan 50 mg. [ABSTRACT FROM AUTHOR]

Background Purpose Cyclic vomiting syndrome (CVS) is identified as one of the “episodic syndromes that may be associated with migraine,” along with benign paroxysmal torticollis, benign paroxysmal vertigo, and abdominal migraine. It has been proposed that CVS and migraine may share pathophysiologic mechanisms of hypothalamic activation and altered dopaminergic signaling, and impaired sensorimotor intrinsic connectivity. The past decade has brought groundbreaking advances in the treatment of migraine and other headache disorders. While many of these therapies have yet to be studied in episodic syndromes associated with migraine including CVS and abdominal migraine, the potential shared pathophysiology among these conditions suggests that use of migraine‐specific treatments may have a beneficial role even in those for whom headache is not the primary symptom.This manuscript highlights newer therapies in migraine. Calcitonin gene‐related peptide (CGRP) and its relation to migraine pathophysiology and the therapies that target the CGRP pathway, as well as a 5HT1F receptor agonist and neuromodulation devices used to treat migraine are briefly discussed as they may potentially prove to be useful in the future treatment of CVS. [ABSTRACT FROM AUTHOR]

Cannabis Use Disorder (CUD) has no FDA-approved treatment. Serotonin-2c (5HT2c) agonists have preclinical and human laboratory evidence for their potential efficacy for CUD. We assessed the tolerability and effects of lorcaserin (5HT2c agonist) on CUD. In a 10-week, open label, uncontrolled trial, the tolerability of lorcaserin was tested in outpatients with CUD. Adverse events (AE) were assessed weekly. Cannabis use was assessed twice weekly by the Timeline follow-back and quantitative urine metabolites. Seventeen participants enrolled, and 14 received medication. Participants' average age was 35 years; majority were male (N = 12). The medication was well tolerated in males. There were no serious adverse events (SAE). The most common AE's were headache/migraine (N = 4, all females), anorexia (N = 3), and irritability (N = 2). Participants decreased their frequency of cannabis use significantly (p < 0.001), adjusted for baseline use. By the end of the trial, participants decreased by 1.76 (SE = 0.47) cannabis using days/week. Average daily amount of cannabis and urine THC metabolite levels did not change significantly. Lorcaserin was well tolerated in males but not females, suggesting possible sex differences. Future trials of other 5HT2c agonists (lorcaserin was withdrawn at the request of the FDA) should consider longer dose titration phases. [ABSTRACT FROM AUTHOR]

Aim: Diet, including foods and beverages, affects migraine. Conversely, the influence of migraine therapies on dietary habits is largely unknown. This study aimed at investigating the effects of triptan intake on foods and drinks consumed by adults with migraine with and/or without aura. Methods: An exploratory questionnaire‐based survey took place online between November 2022 and June 2023. Participants were recruited through advertisements shared on social media accounts (e.g., Facebook and Instagram) and seasonal newsletters of three Danish patient associations. In addition, posters and flyers in headache and pain centers at Danish hospitals and private neurological, pain, and physiotherapeutic clinics were utilized. Results: A total of 314 adults with migraine with and/or without aura completed the survey. Among the respondents, 236 individuals (75.2%) regularly used triptans to treat their migraines. Compared with non‐triptan users, individuals using triptans were characterized by significantly more foods and/or drinks triggering migraine (74.2% vs. 56.4%, p = 0.005). Alcoholic beverages and most specifically red wine were overreported as migraine triggers by triptan users (48.3% vs. 21.8%, p < 0.001). In the week preceding the survey, red wine was significantly less consumed by triptan users than non‐triptan users (92.4% vs. 76.9%, p < 0.001). Conclusions: Patients who regularly consume triptans report red wine most frequently as a migraine trigger. Triptan users are characterized by a lower consumption of red wine than non‐triptan users, suggesting that a regular triptan intake may promote an increased sensitivity to red wine‐induced migraine. [ABSTRACT FROM AUTHOR]

Migraine headache is a common and potentially debilitating disorder often treated by physician associates/assistants (PAs) and other providers. With the recent advances in new drugs and device technology for the treatment of migraine, the American Headache Society has released a consensus statement on both preventive and acute strategies for clinical practice. The US FDA has recently approved various types of medications and devices for the treatment and prevention of migraine attacks including several calcitonin gene-related peptide (CGRP) receptor inhibitors, a selective serotonin receptor agonist (SSRA), noninvasive vagus nerve stimulation (nVNS), external trigeminal nerve stimulation (e-TNS), and external concurrent occipital and trigeminal neurostimulation (eCOT-NS), among other pharmacologic and nonpharmacologic options. This article provides a review of migraine prevention and acute treatment protocol, highlighting new approaches to both. [ABSTRACT FROM AUTHOR]

Background: The objective of this analysis was to gain new insights into the patient characteristics and other factors associated with lasmiditan usage and clinical outcomes under conditions resembling the real-world setting. Methods: This was a post hoc analysis of data from the 12-month, open-label extension (OLE) of the phase 3, double-blind, randomized, controlled CENTURION trial, which examined the efficacy and safety of lasmiditan as acute treatment across four migraine attacks. Patients completing the main study who treated ≥ 3 attacks could continue in the OLE. The initial lasmiditan dose was 100 mg, with dose adjustments to 50 mg or 200 mg allowed at the investigator's discretion. Patient and clinical characteristics were summarized by dosing pattern and completion status. Safety was assessed based on adverse event (AE) frequency by number of doses. Results: In total, 445 patients treated ≥ 1 migraine attacks with lasmiditan during the OLE, 321 of whom (72.1%) completed the study. Forty-seven percent of patients remained on the 100-mg initial dose during the OLE whereas 20.2% used both 100 mg and 50 mg, 30.6% used both 100 mg and 200 mg, and 6 (1.3%) used multiple dose levels. All dosing patterns were associated with clinical and patient-reported improvement; however, the 100-mg group had the highest proportion of patients reporting improvement in the Patient Global Impression of Change – Migraine Headache Condition (56.5% vs 33.4%–52.2%). In comparison, all three groups that made dose adjustments had higher rates of completion compared to the 100-mg group (72.1%–83.3% vs 68.9%). The frequency of AEs decreased with continued use of lasmiditan. Concomitant triptans and lasmiditan use did not increase AE frequency. Conclusions: Based on high persistence and patient satisfaction rates, the 100-mg dose appears optimal for most patients. For those who adjusted dose levels, dose adjustments appeared beneficial to improve efficacy or tolerability, retaining patients on treatment. Collectively, the data suggest that patients who experienced efficacy continued to use lasmiditan regardless of the occurrence or frequency of AEs, and continued use appeared associated with fewer AEs. Trial registration: European Union Drug Regulating Authorities Clinical Trials Database (EudraCT): 2018–001661-17; ClinicalTrials.gov: NCT03670810; registration date: September 12, 2018. [ABSTRACT FROM AUTHOR]

Introduction and purpose Migraine is a common disease mostly affecting women. It has a huge influence on patients' life strongly decreasing its quality by cause of repetitive headache episodes and often comes with unpleasant and burdensome symptoms like photophobia, nausea or vomiting. This article focuses on migraine treatment, especially on new drugs. Primary drugs used in migraine attacks are non-steroid anti-inflammatory drugs (NSAI) and triptans. Because of their side effects and impact on internal organs, these substances are often contraindicated or inefficient. The same applies to triptans, which cannot be used by patients with cardiovascular diseases. Due to the need of a new migraine treatment path development, new remedies have been found, bringing hope for patients who could not use prior options. They are divided into two groups: ditans (lasmiditan), which are 5-HT1F serotonin receptor agonists and gepants (ubrogepant, rimegepant, atogepant and zavegepant), which are CGRP receptor antagonists. A summary of the current state of knowledge is intended to increase the awareness of physicians and patients when selecting the appropriate treatment. Material and methods The following review was based on articles obtained from the PubMed and Google Scholar databases. Key search terms included migraine, ditans, gepants, migraine treatment. Conclusions Drugs described in this study clearly show the new pathway of migraine treatment and prevention. They are safer and show more benefits than substances currently used. They can also be used in wider range of patients with conditions marked as contraindications for current schemes. However more research is still needed to fully describe their characteristics. [ABSTRACT FROM AUTHOR]

Background: Conventional, non-specific preventive migraine treatments often demonstrate low rates of treatment persistence due to poor efficacy or tolerability. Effective, well-tolerated preventive treatments are needed to reduce migraine symptoms, improve function, and enhance quality of life. Atogepant is a migraine-specific oral calcitonin gene–related peptide receptor antagonist that is indicated for the preventive treatment of migraine in adults. This analysis evaluated the safety and tolerability profile of atogepant for the preventive treatment of migraine, including adverse events (AEs) of interest, such as constipation, nausea, hepatic safety, weight changes, and cardiac disorders. Methods: This post hoc analysis was performed using data pooled from 2 (12-week) randomized, double-blind, placebo-controlled trials (RCTs) and 2 (40- and 52-week) open-label long-term safety (LTS) trials of oral atogepant for episodic migraine (EM). Results: The safety population included 1550 participants from the pooled RCTs (atogepant, n = 1142; placebo, n = 408) and 1424 participants from the pooled LTS trials (atogepant, n = 1228; standard care [SC], n = 196). In total, 643/1142 (56.3%) atogepant participants and 218/408 (53.4%) placebo participants experienced ≥ 1 treatment-emergent AEs (TEAEs) in the RCTs. In the LTS trials, 792/1228 (64.5%) of atogepant participants and 154/196 (78.6%) of SC participants experienced ≥ 1 TEAEs. The most commonly reported TEAEs (≥ 5%) in participants who received atogepant once daily were upper respiratory tract infection (5.3% in RCTs, 7.7% in LTS trials), constipation (6.1% in RCTs, 5.0% in LTS trials), nausea (6.6% in RCTs, 4.6% in LTS trials), and urinary tract infection (3.4% in RCTs, 5.2% in LTS trials). Additionally, weight loss appeared to be dose- and duration-dependent. Most TEAEs were considered unrelated to study drug and few led to discontinuation. Conclusions: Overall, atogepant is safe and well tolerated in pooled RCTs and LTS trials for the preventive treatment of EM in adults. Trial registration: ClinicalTrials.gov identifiers: NCT02848326 (MD-01), NCT03777059 (ADVANCE), NCT03700320 (study 302), NCT03939312 (study 309). [ABSTRACT FROM AUTHOR]

Lasmiditan is an in vitro inhibitor of P‐glycoprotein (P‐gp) and breast cancer resistance protein (BCRP) efflux transporters. We aimed to confirm predictions from physiologically based pharmacokinetic models of lasmiditan, and assess the safety and tolerability of rosuvastatin and dabigatran co‐administered with lasmiditan. In this open‐label, post‐marketing drug–drug interaction, phase 1 clinical trial, eligible participants were adults aged 21‐70 years with a body mass index of 18.5‐35.0 kg/m2. Part 1 (P‐gp, 150 mg dabigatran etexilate with 200 mg lasmiditan) and part 2 (BCRP, 10 mg rosuvastatin with 200 mg lasmiditan) employed similar designs: a single dose of probe substrate administered on day −2 with pharmacokinetic evaluation; 1‐week washout; lasmiditan administered on days 8 and 9 alone; lasmiditan co‐administered with a single dose of probe substrate on day 10, with pharmacokinetic evaluation of probe substrate and lasmiditan. Sixty‐six participants were included in part 1 and 30 participants were included in part 2. Following dabigatran co‐administration with lasmiditan, versus dabigatran alone, 90% confidence intervals for geometric least‐squares (LS) mean ratios of area under the plasma concentration–time curve from time 0 extrapolated to infinity (AUC0–∞) and maximum observed drug concentration (Cmax) were not contained within the non‐effect boundaries (0.80 to 1.25). Dabigatran AUC0–∞ increased by 25% and Cmax increased by 22%. The median time of maximum observed drug concentration (tmax) for dabigatran was 2.0 to 3.0 hours. Following rosuvastatin co‐administration with lasmiditan, versus rosuvastatin alone, 90%CIs for geometric LS mean ratios of AUC0–∞ and Cmax were contained within non‐effect boundaries (0.80‐1.25). Rosuvastatin AUC0–∞ increased by 15% and Cmax increased by 7%. The median tmax for rosuvastatin was 4.0 hours. Results suggest that lasmiditan has a weak effect on P‐gp substrates and no clinically relevant effect on BCRP substrates. [ABSTRACT FROM AUTHOR]

Background: Migraine and vestibular migraine are disorders associated with a heightened motion sensitivity that provoke symptoms of motion-induced nausea and motion sickness. VM affects (3% of adults in the USA and affects three-fold more women than men. Triptans (selective serotonin receptor agonists) relieve migraine pain but lack efficacy for vertigo. Murine models of photophobia and allodynia have used injections of calcitonin gene-related peptide (CGRP) or other migraine triggers, such as sodium nitroprusside (SNP), to induce migraine sensitivities in mice to touch and light. Yet, there is limited research on whether these triggers affect motion-induced nausea in mice, and whether migraine blockers can reduce these migraine symptoms. We hypothesized that systemic delivery of CGRP or SNP will increase motion sickness susceptibility and motion-induced nausea in mouse models, and that migraine blockers can block these changes induced by systemically delivered CGRP or SNP. Methods: We investigated two measures of motion sickness assessment [motion sickness index (MSI) scoring and motion-induced thermoregulation] after intraperitoneal injections of either CGRP or SNP in C57BL/6J mice. The drugs olcegepant, sumatriptan and rizatriptan were used to assess the efficacy of migraine blockers. Results: MSI measures were confounded by CGRP’s effect on gastric distress. However, analysis of tail vasodilatations as a surrogate for motion-induced nausea was robust for both migraine triggers. Only olcegepant treatment rescued tail vasodilatations. Conclusions: These preclinical findings support the use of small molecule CGRP receptor antagonists for the treatment of motion-induced nausea of migraine, and show that triptan therapeutics are ineffective against motion-induced nausea of migraine [ABSTRACT FROM AUTHOR]

Migraine is a leading cause of disability in more than one billion people worldwide, yet it remains universally underappreciated, even by individuals with the condition. Among other shortcomings, current treatments (often repurposed agents) have limited efficacy and potential adverse effects, leading to low treatment adherence. After the introduction of agents that target the calcitonin gene-related peptide pathway, another new drug class, the ditans — a group of selective serotonin 5-HT1F receptor agonists — has just reached the international market. Here, we review preclinical studies from the late 1990s and more recent clinical research that contributed to the development of the ditans and led to their approval for acute migraine treatment by the US Food and Drug Administration and the European Medicines Agency. Ditans are a recently developed drug class for the treatment of acute migraine. In this Review, the authors provide an overview of ditan development, from the initial rationale to the clinical studies that led to the recent FDA approval of the first ditan. Key points: Various animal studies have shown that selective agonists for the serotonin 5-HT1F receptor can reduce signals from an activated trigeminovascular system, thereby highlighting the receptor as an attractive target for symptomatic treatment of migraine. Long-term clinical studies involving two ditans — a group of 5-HT1F agonists — have provided class I evidence that lasmiditan, the first ditan, is both effective and safe in the symptomatic treatment of migraine. The 5-HT1F receptor is expressed by cells within the brain parenchyma, as well as by the trigeminal neurons, but not in vascular smooth muscle, suggesting that ditans act through neuropeptide release leading to acute headache relief, rather than via potential vasoactive properties, such as vasodilatation. Dizziness is the most common adverse event of lasmiditan; thus people should not drive for 8 h after taking lasmiditan. Development of novel ditans that do not cross the blood–brain barrier is expected to result in better tolerability and improved clinical use. [ABSTRACT FROM AUTHOR]

Migraine is an extremely disabling, common neurological disorder characterized by a complex neurobiology, involving a series of central and peripheral nervous system areas and networks. A growing increase in the understanding of migraine pathophysiology in recent years has facilitated translation of that knowledge into novel treatments, which are currently becoming available to patients in many parts of the world and are substantially changing the clinical approach to the disease. In the first part of this review, we will provide an up to date overview of migraine pathophysiology by analyzing the anatomy and function of the main regions involved in the disease, focusing on how these give rise to the plethora of symptoms characterizing the attacks and overall disease. The second part of the paper will discuss the novel therapeutic agents that have emerged for the treatment of migraine, including molecules targeting calcitonin gene-related peptide (gepants and monoclonal antibodies), serotonin 5-HT1F receptor agonists (ditans) and non-invasive neuromodulation, as well as providing a brief overview of new evidence for classic migraine treatments. [ABSTRACT FROM AUTHOR]

A migraine is a specific kind of headache disorder that primarily affects the head. It can range in severity from mild to severe and is often accompanied by other symptoms like vomiting, nausea, illness, dizziness that gets worse with movement, photophobia, sonophobia, severe disability, or other types of nature. Triptans that are administered intravenously can be used to treat migraines and irritated injection sites. Transdermal delivery means that the medications will be administered through the skin in a precise, regulated manner. Our study aims to identify all possible transdermal patch combination and application for the treatment of migraines. The drug rizatriptan belongs to a group of drugs known as selective serotonin receptor agonists. It functions by constricting blood vessels in the brain, preventing the transmission of pain signals to the brain, and preventing the production of several naturally occurring compounds that produce pain, nausea, and other migraine symptoms. Verapamil belongs to the group of drugs known as calcium-channel blockers. It works by relaxing the blood vessels in order to reduce the workload of the heart. The Lambda max Rizatriptan and Verapamil is 278.9nm and 228nm respectively. They are soluble in most of the solvents. When used with verapamil, rizatriptan's transdermal patch improves patient compliance in those with hypertension. P2 patch shows the optimized results. [ABSTRACT FROM AUTHOR]

Aims: To present a review of the mechanisms of action, available clinical data, and safety profiles of novel migraine therapeutics to inform practice. Methods: PubMed, Medline, and Google Scholar were searched for randomized controlled trials (24 publications), review articles (15 publications), and other pertinent literature (16 publications) discussing the novel migraine therapeutics available between the years 2010 and 2021. All publications were reviewed to assess the mechanism of action, relevant clinical data, and side effect profile for each novel treatment. Therapeutic gain was also recorded in studies that included a placebo arm. Results: A total of 55 studies were included in the final analysis. In the preventive treatment of migraine, novel medications target calcitonin generelated peptide (CGRP) and fall into either the monoclonal anti-CGRP or gepant class. For the acute treatment of migraine, novel medications fall into either the ditan or gepant class. Several medical devices have been developed for the acute and preventive treatment of migraine. Conclusion: Novel therapeutics are available for both the prevention and acute treatment of migraine headaches. These new medications and neuromodulatory devices appear overall to be safe and effective in the management of migraine headaches. [ABSTRACT FROM AUTHOR]

Introduction: This MONONOFU trial subgroup analysis evaluates the efficacy of lasmiditan across patient and migraine characteristics in Japanese patients with migraine.Methods: MONONOFU trial was a multicenter, randomized, double-blind, placebo-controlled study. The patients were randomly assigned in a 3:7:6:7 ratio to receive lasmiditan 50 mg, 100 mg, 200 mg, or placebo for a single migraine attack within 4 h of pain onset. Efficacy of lasmiditan vs placebo was evaluated at 2 h post dose for proportion of patients with headache pain freedom. Efficacy was assessed across patient characteristics (age, sex, body weight, cardiovascular risk factors (CVRF), and comorbidity of tension-type headache), migraine disease characteristics (history of migraine with aura, migraine prevention therapy, triptan response, and triptan use or nonuse), and migraine attack characteristics (headache severity, aggressive headache, attack during perimenstrual period, time to dosing, time of dosing, experienced treatment-emergent adverse event (TEAE) of dizziness, and experienced TEAE of somnolence). Logistic regression was used; all subgroup analyses were not analyzed with multiplicity-adjusted statistical tests.Results: Treatment-by-subgroup interactions (by each arm) were not significant (p ≥ 0.05) for pain freedom at 2 h post dose across all patient subgroups and lasmiditan doses, except for CVRF (100 mg and 200 mg), migraine with aura (50 mg), triptan response (50 mg), and time to dosing (200 mg). Treatment-by-subgroup interactions (by overall) were not significant (p ≥ 0.05) for pain freedom at 2 h post dose across all patient subgroups, except for CVRFs. Higher proportions of patients were pain free at 2 h post dose when treated with lasmiditan (50 mg, 100 mg, and 200 mg) versus placebo, irrespective of most patient characteristics, migraine disease characteristics, and migraine attack characteristics.Conclusion: Although few interactions were observed, lasmiditan could be a promising acute treatment option in a wide range of Japanese patients with migraine, as efficacy is not generally influenced by patient and migraine characteristics. [ABSTRACT FROM AUTHOR]

Introduction: Lasmiditan is the first 5-HT1F receptor agonist with potential to address the huge unmet medical needs for the treatment of migraine in China. The CENTURION study was the first phase 3 study of lasmiditan in Caucasian and Chinese patients with migraine. This post hoc analysis further demonstrates the safety profile of lasmiditan in the Chinese population and was urgently needed.Methods: Patients were randomized 1:1:1 to lasmiditan 200 mg lasmiditan 100 mg, or a control group. The incidence of treatment-emergent adverse events (TEAEs), their severity, and incidence by treated attacks for frequently reported TEAEs (≥ 5%) were evaluated. The duration, onset, and relationship of efficacy with very common TEAEs (≥ 10%) was analyzed.Results: A total of 281 Chinese patients were included in this post hoc analysis. No deaths and no study drug-related treatment emergent serious adverse events (TESAEs) were reported. The incidence of at least one TEAE was higher in patients receiving lasmiditan 200 mg (73.9%) and 100 mg (66.3%) versus placebo (26.6%). TEAEs were generally mild or moderate in severity, and the incidence of frequently reported TEAEs was generally highest during the first attack. Very common TEAEs with lasmiditan included dizziness, asthenia, somnolence, muscular weakness, fatigue, and nausea. The duration of dizziness was longest during the first attack. There were no cardio-cerebrovascular ischemic events and serotonin syndrome. The presence of very common TEAEs (except nausea), and severe dizziness, did not appear to have a negative influence on the efficacy.Conclusion: In the Chinese population of the CENTURION study, most of the TEAEs were neurologic, of mild or moderate severity, and self-limiting. The distribution of frequently reported TEAEs at the first attack differed from the primary cohort, while the overall safety profile of lasmiditan in the Chinese population was generally consistent with the CENTURION primary cohort. No new safety concerns were observed in the Chinese population.Trial Registration: NCT03670810. [ABSTRACT FROM AUTHOR]

Introduction: Over the last two decades, there has been no novel acute treatment for migraine to address the large unmet medical need in Chinese patients. Lasmiditan, a novel selective serotonin 1F receptor agonist (ditan), is anticipated to bring clinical benefit in Chinese patients with migraine. The CENTURION study is a multi-country, placebo-controlled phase 3 study designed to assess the first attack efficacy and the consistency of response of lasmiditan in acute treatment of migraine. This subpopulation analysis pooled Chinese patients' data from the primary cohort and additional extended enrollment cohort which was not published previously. This is the first analysis focusing on lasmiditan's efficacy and safety in Chinese patients with migraine and aims to provide relevant evidence for Chinese physicians. Methods: Patients were randomized 1:1:1 to one of the three treatment groups for four attacks: (a) lasmiditan 100 mg; (b) lasmiditan 200 mg; or (c) control group. Primary endpoints were pain freedom at 2 h (first attack) and pain freedom at 2 h in at least two out of three attacks. Secondary endpoints included pain relief, sustained pain freedom, and disability freedom. Results: In total, 281 Chinese patients (lasmiditan 100 mg, 95; lasmiditan 200 mg, 92; control, 94) were treated for at least one migraine attack. Both doses of lasmiditan showed improvement versus placebo for pain freedom at 2 h after first attack, with lasmiditan 200 mg showing nominal significance. An early onset of effect was observed with lasmiditan versus placebo. Both doses of lasmiditan showed better results for all key secondary endpoints versus placebo. The most commonly reported treatment-emergent adverse event across all groups was dizziness. Conclusion: In the Chinese population, lasmiditan was better than placebo for both primary endpoints and key secondary endpoints with an acceptable safety profile. No new safety signals were detected in the Chinese population. These findings are generally consistent with those observed in the CENTURION study published data and the established product profile. Trial Registration Number: NCT03670810. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Objective: Calcitonin gene-related peptide (CGRP) receptor antagonists have been suggested as novel treatments for acute migraine. This study aimed to use meta-analysis to compare the safety and tolerability of five existing oral CGRP receptor antagonists (BI44370TA, MK-3207, rimegepant, telcagepant, and ubrogepant) with that of a placebo or triptans against acute migraine. Methods: Five prominent databases were searched to identify randomized controlled trials on this topic. The primary safety outcomes of interest were any adverse events (AEs) and treatment-related adverse events (TRAEs), and secondary outcomes were individual events, namely diarrhea, dizziness, dry mouth, fatigue, nausea, paresthesia, somnolence, upper abdominal pain, and vomiting. Results: Fifteen studies met the eligibility criteria and were examined in detail. Although, compared to placebo, oral CGRP receptor antagonists significantly increased the incidence of any AEs (risk ratio [RR] = 1.15; 95% confidence interval [CI] = 1.07–1.23), there was no difference in the incidence of TRAEs (RR = 1.18; 95% CI = 1.00–1.38). Moreover, CGRP receptor antagonists were safer than triptans with respect to primary safety outcomes, such as any AEs (RR = 0.78; 95% CI = 0.63–0.98) and TRAEs (RR = 0.68; 95% CI = 0.58–0.79). Conclusion: Despite oral CGRP receptor antagonists posing a significantly higher risk of AEs when compared to placebo, CGRP receptor antagonists have a favorable safety profile compared to triptans. Our findings inform strategies to enhance safety and tolerability in the treatment of acute migraine. [ABSTRACT FROM AUTHOR]

Background: In the absence of head-to-head trials, comprehensive evidence comparing onset of efficacy of novel agents for acute treatment of migraine is lacking. This study aimed to explore the relative efficacy of lasmiditan (serotonin [5-hydroxytryptamine] 1F receptor agonist) versus rimegepant and ubrogepant (calcitonin gene-related peptide antagonists) for the acute oral treatment of migraine through network meta-analysis (NMA). Methods: Data included in the NMA were identified through a systematic literature search (conducted April 2018, updated May/December 2020) of phase II–IV, randomised controlled trials (RCTs) in adults with chronic/episodic migraine with/without aura. Treatments included: lasmiditan 50, 100, 200 mg; rimegepant 75 mg; ubrogepant 25, 50, 100 mg. Pairwise treatment comparisons from Bayesian fixed-effect/random-effects NMA, adjusted by baseline risk where appropriate, were conducted. Comparisons were reported as odds ratios with 95% credible intervals. Early-onset efficacy endpoints included: pain freedom at 2 hours and pain relief at 1 and 2 hours. Adverse drug reaction (ADR) profiles were summarised. Heterogeneity and inconsistency in the network were explored; sensitivity analyses investigated robustness of findings. Results: Across 12 RCTs included in the base case, females represented >80% of included patients (mean age 37.9–45.7 years). Odds of achieving both pain freedom and pain relief at 2 hours were higher with lasmiditan 100 and 200 mg versus rimegepant 75 mg and ubrogepant 25 and 50 mg. Results for pain relief at 1 hour were consistent with those at 2 hours, but fewer comparisons were available. There were no statistically significant differences between lasmiditan 50 mg and ubrogepant or rimegepant for any outcome. Sensitivity analyses were in the same direction as base case analyses. Most commonly reported ADRs (incidence ≥2%) were: dizziness, fatigue, paraesthesia, sedation, nausea/vomiting and muscle weakness with lasmiditan; nausea with rimegepant; and nausea, somnolence and dry mouth with ubrogepant. Conclusions: The efficacy findings of this indirect comparison indicate that lasmiditan 100 mg or 200 mg might be an appropriate acute treatment option for patients with migraine seeking a fast onset of action. Differently from rimegepant and ubrogepant, lasmiditan use is associated with mainly neurological events, which are mostly mild or moderate in severity and self-limiting. 350/350 words [ABSTRACT FROM AUTHOR]

Background: Migraine may be an important factor for paresthesia in the limbs, especially in the upper limbs. In several patients, paresthesia is responsible for a low quality of life. Treatment with the serotonin agonist may be a triggering factor for paresthesia in certain patients. Various serotonin receptor agonists are available for migraine treatment. We performed a meta-analysis of updated clinical trials of the serotonin agonist to figure out the risk of paresthesia. Methods: PubMed, Embase, and Cochrane Library databases were searched for clinical trials that evaluated the serotonin agonist for migraine treatment versus placebo. The main outcomes were to perform dose-response model-based network meta-analysis of different serotonin agonists and to compute the relative risk for paresthesia. In addition, probability of paresthesia among various treatments was estimated by the Surface Under the Cumulative Ranking (SUCRA) method. The R 4.30 and Rev Man 5.3 softwares were used to perform meta-analysis. Results: A total of 30 placebo-controlled clinical trials (29,154 subjects) were included in the study to perform dose-response model-based network meta-analysis to explore the risk of paresthesia with different serotonin agonists versus placebo. The drugs Topiramate 200 mg, Lasmiditan 400 mg, and Zolmitriptan 10 mg showed higher relative risks for paraesthesia as 2.71, 2.2, and 2.42, respectively. However, the SUCRA probabilities of paresthesia for each treatment in the network were higher for Lasmiditan. Conclusions: This meta-analysis of reported placebo-controlled clinical trials suggests that the SUCRA probabilities for the manifestation of paresthesia are higher with Lasmiditan. The relative risk of paresthesia is higher with the use of Topiramate 200 mg, Lasmiditan 400 mg, and Zolmitriptan 10 mg. In addition, Lasmiditan exhibited a gradual dose-response of relative risk for the manifestation of paresthesia. [ABSTRACT FROM AUTHOR]

Objective: To determine the impact of the 2018 Japan Floods, one of the largest water disasters in Japan, on the number of prescriptions for triptans and ergotamine (acute treatment). Background: Natural disasters frequently occur worldwide and may cause psychological stress–related diseases. Acute migraine attacks can be triggered by psychological stress. Disaster victims are likely to experience tremendous psychological stress; however, the relationship between natural disasters and migraine attacks is not well investigated. Methods: A retrospective longitudinal cohort study was conducted using the National Database of Health Insurance Claims in the hardest‐hit areas of the disaster 1 year before and after the disaster. We included people between the ages of 15 and 64 years. Those who had a victim code that was certificated by a local government were assigned to the victim group, and others to the nonvictim group. For those who were not prescribed acute treatment before the disaster (i.e., group without previous acute treatment), the cumulative incidence of new prescriptions for acute treatment at 12 months of follow‐up was calculated and compared between victims and nonvictims with survival analysis. Results: Of 3,475,515 people aged 15 to 64 years enrolled in the study, 16,103 (0.46%) were assigned to the victim group. In the group without previous acute treatment, 111 (0.70%) of 15,933 victims and 14,626 (0.43%) of 3,431,423 nonvictims were newly prescribed acute treatment after the disaster, and new prescriptions for acute treatment were significantly more likely to occur in victims than in nonvictims (adjusted hazard ratio, 1.68; 95% CI, 1.39–2.02). Conclusions: The 2018 Japan Floods increased the number of prescriptions for acute migraine medications among victims, suggesting that acute migraine attacks occurred more frequently after a natural disaster. [ABSTRACT FROM AUTHOR]

Migraine is a neurological disorder characterized by severe headaches, visual aversions, auditory, and olfactory disorders, accompanied by nausea and vomiting. Zolmitriptan (ZMT®) is a potent 5HT1B/1D serotonin receptor agonist frequently used for the treatment of migraine. It has erratic absorption from the gastrointestinal tract (GIT), but its oral bioavailability is low (40–45%) due to the hepatic metabolism. This makes it an ideal candidate for oral fast dissolving formulations. Hence, the current study was undertaken to design and develop oral fast-dissolving films (OFDFs) containing ZMT for migraine treatment. The OFDFs were formulated by the solvent casting method (SCM) using Pullulan (PU) and maltodextrin (MDX) as film-forming agents and propylene glycol (PG) as a plasticizer. The strategy was designed using Box–Behnken experimental design considering the proportion of PU:MDX and percentage of PG as independent variables. The effectiveness of the OFDF's was measured based on the following responses: drug release at five min, disintegration time (D-time), and tensile strength (TS). The influence of formulation factors, including percent elongation (%E), thickness, water content, moisture absorption, and folding endurance on ZMT-OFDFs, were also studied. The results showed a successful fabrication of stable ZMT-OFDFs, with surface uniformity and amorphous shape of ZMT in fabricated films. The optimized formulation showed a remarkable rapid dissolution, over 90% within the first 5 min, a fast D-time of 18 s, and excellent mechanical characteristics. Improved maximum plasma concentration (C max) and area under the curve (AUC 0–t) in animals (rats) treated with ZMT-OFDFs compared to those treated with an intra-gastric (i-g) suspension of ZMT were also observed. Copolymer OFDFs with ZMT is an exciting proposition with great potential for the treatment of migraine headache. This study offers a promising strategy for developing ZMT-OFDFs using SCM. ZMT-OFDFs showed remarkable rapid dissolution and fast D-time, which might endeavor ZMT-OFDFs as an auspicious alternative approach to improve patient compliance and shorten the onset time of ZMT in migraine treatment. [ABSTRACT FROM AUTHOR]

The treatment of migraine has taken a significant leap forward since 2018 with seven new agents. The place in therapy of all these agents is still to be determined; however, for especially hard to treat patients, they can be life changing. [ABSTRACT FROM AUTHOR]

Introduction: Migraine is a neurological disease with a considerable economic and societal burden that negatively impacts quality of life and productivity. Triptans are potent serotonin receptor agonists widely used to treat migraine attacks. Little is known about German patients with migraine diagnosed with triptan contraindications or those who discontinue triptans. Methods: This retrospective observational study identifies adults with migraine from a German sickness fund database (2010–2018). Migraine prevalence was calculated for the database population and extrapolated to the German Statutory Health Insurance (SHI) population. Medication use, proportion and demographics of patients with triptan contraindications, prevalence of triptan discontinuation and use of triptans by patients with contraindications were analysed. Results: In total 120,170 patients with migraine were identified in the database population, of whom 77.7% were female; migraine prevalence was 2.0% (male) and 7.3% (female), leading to an extrapolated 2,923,979 patients with migraine in the entire German SHI population (2019); of these, 14.5% had ≥ 1 triptan contraindication. The most frequent contraindication was a history of stroke/transient ischaemic attack. However, an extrapolated 25.9% of patients who had a triptan contraindication received a triptan prescription following diagnosis. We calculated that 975,698 patients in the entire German SHI population had ever received a triptan, of whom 596,364 did not receive a triptan prescription in the follow-up year. Of these 596,364 individuals, 96.6% continued to receive a migraine diagnosis after their last triptan prescription. These 'triptan discontinuers' were predominantly female (82.6%). Most patients utilized only one specific triptan, with a large majority of ongoing triptan users who had used this specific triptan receiving > 4 prescriptions. Conclusion: We confirm the existence of German patients with migraine and unmet therapeutic needs. These are patients diagnosed with triptan contraindications or patients who have discontinued triptan use despite continued migraine attacks. More research is needed to ascertain reasons for triptan discontinuation and the risk of triptan use by patients with contraindications. [ABSTRACT FROM AUTHOR]

Migraine is a common and often disabling neurologic disease, its high prevalence and disability significantly impact on patients and relatives, contributing to heavy social and economic burden. However, currently available migraine treatment options are limited and are often associated with many intolerable sideeffects. Therefore, it is necessary to explore new therapeutic options for migraine. This review discusses the most recent and evidencebased advances in pharmacological and nonpharmacological treatment approaches for migraine. [ABSTRACT FROM AUTHOR]

Monotherapy with triptans in acute migraine is ineffective in many patients and contraindicated in certain cardiovascular diseases where alternative therapeutic options are necessary to explore. This meta‐analysis has evaluated the efficacy and safety of lasmiditan for the treatment of acute migraine in adults. After performing a literature search on MEDLINE/PubMed, Scopus, Cochrane databases, and International Clinical Trial Registry Platform, reviewers assessed eligibility and extracted data from 4 relevant articles. Preferred Reporting Items for Systematic Reviews and Meta‐Analysis guidelines were followed in the selection, analysis, and reporting of findings. A random‐effects model was used to estimate effect size. Quality assessment was done using the risk of bias assessment tool and meta‐regression for probable variables affecting effect size. Subgroup analysis was done depending on the dose of lasmiditan. Lasmiditan use was associated with a significantly higher percentage of patients with pain freedom (odds ratio [OR], 2.02; 95% confidence interval [CI], 1.72‐2.39; P <.00001), sustained pain freedom (OR, 1.93; 95%CI, 1.55‐2.39; P <.00001), headache response (OR, 2.05; 95%CI, 1.77‐2.36; P <.00001), clinical disability level (OR, 1.36; 95%CI, 1.20‐1.55; P <.00001), patients' global impression (OR, 1.88; 95%CI, 1.69‐2.10; P <.00001), and significantly lower use of rescue medication (OR, 0.49; 95%CI, 0.38‐0.63; P <.00001) compared to placebo. Lasmiditan use was also associated with a higher likelihood of adverse effects like dizziness (OR, 6.54; 95%CI, 4.24‐10.07; P <.00001), paresthesia (OR, 4.28; 95%CI, 2.97‐6.17; P <.00001), and fatigue (OR, 5.67; 95%CI, 3.78‐8.52; P <.00001) compared to placebo. Subgroup analysis showed a dose‐dependent effect of lasmiditan on pain freedom, sustained pain freedom, patient's global impression, and occurrence of adverse drug reactions. Prediction probability for effect estimate favoring placebo was calculated to be 0.0017%. Lasmiditan has shown a favorable effect in terms of efficacy and safety in the treatment of an acute attack of migraine in comparison to placebo. Further studies are needed to evaluate long‐term safety, efficacy, and use in specific subgroups of patients. PROSPERO Registration Number: CRD42020177838 [ABSTRACT FROM AUTHOR]

Background: Lasmiditan (LTN) is a selective 5-HT1F receptor agonist for the acute treatment of migraine in adults. We present detailed safety findings from the placebo-controlled, double-blind Phase 3 study, of LTN treatment across 4 attacks (CENTURION). Methods: Patients were randomized 1:1:1 to LTN 200 mg (LTN200), LTN100, or a control group that received placebo for 3 attacks and LTN50 for either the 3rd or 4th attack (1:1). Safety analyses were conducted for patients who took ≥1 dose of study drug and, in some cases, those who took all 4 doses. Results: Overall, 1471 patients treated 4494 attacks. The incidences of treatment-emergent serious adverse events (SAEs) were - placebo, n=2 (0.4 %); LTN100, n=1 (0.2 %); LTN200, n=2 (0.4 %); no specific treatment-emergent SAE was reported in more than one patient. The most common treatment emergent adverse events (TEAEs) with lasmiditan were dizziness, paresthesia, fatigue, nausea, vertigo, and somnolence; the vast majority were mild or moderate in severity. The incidences of these TEAEs were highest during the first attack and decreased during subsequent attacks. For patients who experienced a common TEAE with the first attack, less than 45 % experienced the same event in subsequent attacks. Patients who did not experience an event in the 1st attack infrequently experienced the same event in subsequent attacks. The time of onset of the common TEAE ranged from ~40 min to 1 h (dependent upon TEAE) and, for individual TEAE, the onset was similar across attacks. Duration was dependent upon TEAE and attack. It was shortest for paresthesia (< 2 h for all attacks); it ranged from 1.8 to 5.5 h for other common TEAEs and was generally similar across attacks. Serotonin syndrome was reported for 2 patients post LTN dosing; there were no meaningful differences across treatment groups in suicidality; there was no evidence of an increase in motor vehicle accidents. Conclusion: In this blinded, controlled, multiple-attack study, LTN was associated with generally mild or moderate CNS-related TEAEs of short duration. TEAEs tended to decrease in frequency across the 4 attacks. Trial registration: NCT03670810 [ABSTRACT FROM AUTHOR]

The treatment of migraine is often complicated by insufficient headache relief, a miscellany of side effects and the risk of developing Medication Overuse Headache (MOH). Novel acute therapies have been recently developed and are now in the early post-marketing phase. Lasmiditan is a highly selective serotonin receptor agonist that binds to the 5-HT1F receptor, while ubrogepant and rimegepant antagonize the calcitonin gene-related peptide receptor. All three medications are now prescribed in a real-world setting, and an adequate level of knowledge is the starting point for rational use. In this rapid systematic review, we have established what is known about lasmiditan, ubrogepant and rimegepant, highlighting the most relevant safety aspects available from published studies and speculating about their risk of MOH. [ABSTRACT FROM AUTHOR]

Background. Migraine has a great impact on public health. Current acute therapies do not satisfy all migraineurs. The novel serotonin 5-HT1F receptor agonist appears more promising for aborting migraine attacks. Objective. To evaluate the clinical efficacy and safety of lasmiditan in treating acute migraine attacks. Methods. The literature search was performed in PubMed, Embase, and the Cochrane Central Register of Controlled Trials for randomized controlled trials (RCTs) which assessed the effect and safety of lasmiditan on migraine. The risk of bias was assessed using the Cochrane Collaboration's risk of bias tool. Results were extracted and pooled as risk ratios (RRs) with a fixed or random-effects model. Results. Based on the four included RCTs, pooled estimates showed that lasmiditan with the 50 mg, 100 mg, and 200 mg doses was superior to placebo at 2 h after the first dose in terms of pain freedom, absence of migraine-associated symptoms, headache relief, no/mild disability, and global impression of change (very much/much better) (RRs ranged from 1.13 to 1.96), except for nausea-free and vomiting-free. Both lasmiditan 100 mg and 200 mg resulted in significantly fewer patients using rescue medication (100 mg: RR = 0.75 , 95% CI (0.61, 0.92), P = 0.007 ; 200 mg: RR = 0.81 , 95% CI (0.66, 0.99), P = 0.04) at 2-24 h postdose, compared with placebo. Safety data showed that the proportion of patients reporting at least one treatment-emergent adverse event (TEAE) and the incidence of most common TEAEs such as dizziness, paresthesia, fatigue, somnolence, and nausea was higher in the lasmiditan groups (50 mg, 100 mg, and 200 mg), compared with placebo. There was no significant difference between lasmiditan and placebo in terms of cardiovascular-related TEAEs (RR = 2.75 , 95% CI (0.81, 9.37), P = 0.11). Compared with lasmiditan 100 mg, lasmiditan 200 mg was more effective in pain freedom at 2 h after the first dose (RR = 0.83 , 95% CI (0.74, 0.94), P = 0.004) but associated with a higher risk of reporting at least one TEAE (RR = 0.88 , 95% CI (0.81, 0.96), P = 0.006). Conclusions. Lasmiditan with the 50 mg, 100 mg, and 200 mg doses are effective and safe in acute migraine treatment. Lasmiditan 200 mg is more effective than lasmiditan 100 mg in pain freedom, while lasmiditan 100 mg is better tolerated in the short-term follow-up. Further larger sample-size RCTs are required to verify the applicability and tolerability in the long term. [ABSTRACT FROM AUTHOR]

Importance: Migraine is common and can be associated with significant morbidity, and several treatment options exist for acute therapy.Objective: To evaluate the benefits and harms associated with acute treatments for episodic migraine in adults.Data Sources: Multiple databases from database inception to February 24, 2021.Study Selection: Randomized clinical trials and systematic reviews that assessed effectiveness or harms of acute therapy for migraine attacks.Data Extraction and Synthesis: Independent reviewers selected studies and extracted data. Meta-analysis was performed with the DerSimonian-Laird random-effects model with Hartung-Knapp-Sidik-Jonkman variance correction or by using a fixed-effect model based on the Mantel-Haenszel method if the number of studies was small.Main Outcomes and Measures: The main outcomes included pain freedom, pain relief, sustained pain freedom, sustained pain relief, and adverse events. The strength of evidence (SOE) was graded with the Agency for Healthcare Research and Quality Methods Guide for Effectiveness and Comparative Effectiveness Reviews.Findings: Evidence on triptans and nonsteroidal anti-inflammatory drugs was summarized from 15 systematic reviews. For other interventions, 115 randomized clinical trials with 28 803 patients were included. Compared with placebo, triptans and nonsteroidal anti-inflammatory drugs used individually were significantly associated with reduced pain at 2 hours and 1 day (moderate to high SOE) and increased risk of mild and transient adverse events. Compared with placebo, calcitonin gene-related peptide receptor antagonists (low to high SOE), lasmiditan (5-HT1F receptor agonist; high SOE), dihydroergotamine (moderate to high SOE), ergotamine plus caffeine (moderate SOE), acetaminophen (moderate SOE), antiemetics (low SOE), butorphanol (low SOE), and tramadol in combination with acetaminophen (low SOE) were significantly associated with pain reduction and increase in mild adverse events. The findings for opioids were based on low or insufficient SOE. Several nonpharmacologic treatments were significantly associated with improved pain, including remote electrical neuromodulation (moderate SOE), transcranial magnetic stimulation (low SOE), external trigeminal nerve stimulation (low SOE), and noninvasive vagus nerve stimulation (moderate SOE). No significant difference in adverse events was found between nonpharmacologic treatments and sham.Conclusions and Relevance: There are several acute treatments for migraine, with varying strength of supporting evidence. Use of triptans, nonsteroidal anti-inflammatory drugs, acetaminophen, dihydroergotamine, calcitonin gene-related peptide antagonists, lasmiditan, and some nonpharmacologic treatments was associated with improved pain and function. The evidence for many other interventions, including opioids, was limited. [ABSTRACT FROM AUTHOR]

Objective: To review the efficacy, safety, and cost of 3 newly approved agents-ubrogepant, lasmiditan, and rimegepant-representing 2 therapeutic classes, calcitonin gene-related peptide (CGRP) receptor antagonist and serotonin 1F (5-HT1F) agonists, for the acute treatment of migraine with or without aura.Data Sources: The Institute of Health US National Library of Medicine Clinical Trials, PubMed, and Cochrane databases were queried. Abstracts, journal articles, and other relevant sources published or present were reviewed. Search terms included the following: ubrogepant, MK-1602, Ubrelvy®, rimegepant, Nurtec®, BHV-3000, BMS-927711, lasmiditan, Reyvow®, LY573144.Study Selection and Data Extraction: Relevant English-language articles from June 30, 2010, to August 31, 2020, were evaluated and included in the narrative.Data Synthesis: CGRP receptor antagonists, ubrogepant and rimegepant, achieved 2-hour pain freedom and freedom from the most bothersome migraine symptom (MBS) at 2 hours. Both agents were well tolerated, with adverse effects similar to placebo. Lasmiditan, a 5-HT1F receptor antagonist, also improved 2-hour pain freedom and freedom from the MBS at 2 hours. Lasmiditan is associated with dizziness, paresthesia, somnolence, nausea, fatigue, and lethargy.Relevance To Patient Care and Clinical Practice: Ubrogepant, rimegepant, and lasmiditan represent a new and exciting chapter in acute migraine therapy. To date, no head-to-head studies have compared these agents with the triptans. Ubrogepant and lasmiditan are effective in triptan nonresponders. None of the 3 agents is contraindicated in cardiovascular disease, unlike the triptans.Conclusions: Based on available data, ubrogepant, rimegepant, and lasmiditan should be reserved as second-line therapy and may be safe in patients with cardiovascular risk. Lasmiditan's adverse effect profile may limit its use. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the efficacy and safety of lasmiditan in Japanese adults with migraine. Background: Global clinical studies have demonstrated the efficacy and safety of lasmiditan in the acute treatment of migraine. Methods: This was a multicenter, randomized, double‐blind, placebo‐controlled, phase 2 study in Japan (NCT03962738), which enrolled adults with migraine with or without aura. Participants were randomized 7:3:7:6 to placebo, lasmiditan 50 mg, 100 mg, or 200 mg to be self‐administered orally within 4 h of onset of a single moderate‐to‐severe migraine attack. Participants recorded their response to treatment prior to dosing and for 48 h postdose. The primary endpoint was headache pain freedom at 2 h postdose. Results: Participants (N = 846) were randomized and treated (N = 691, safety; N = 682, modified intent‐to‐treat). At 2 h postdose, a significantly higher proportion of participants were headache pain‐free in the lasmiditan 200 mg (40.8%, 73/179; odds ratio 3.46 [95% confidence interval 2.17 to 5.54]; p < 0.001; primary objective) and 100 mg groups (32.4%, 67/207; odds ratio 2.41 [1.51 to 3.83]; p < 0.001) compared with the placebo group (16.6%, 35/211), whereas the lasmiditan 50 mg group had a numerically higher proportion of participants headache pain‐free (23.5%, 20/85; odds ratio 1.55 [0.83 to 2.87]; p = 0.167) compared with placebo. A statistically significant linear dose–response relationship for pain freedom was achieved at 2 h by a Cochran–Armitage trend test (p < 0.001). Lasmiditan treatment was also associated with headache pain relief, most bothersome symptom freedom, and improvement on disability and Patient Global Impression of Change outcomes. The majority of treatment‐emergent adverse events were mild and of short duration, the most common of which were dizziness (39.4%; 188/477), somnolence (19.3%; 92/477), and malaise (10.5%; 50/477) in all lasmiditan groups, with no serious adverse events reported. Conclusions: Lasmiditan was well tolerated and effective for the acute treatment of Japanese patients with migraine, consistent with global phase 3 studies. [ABSTRACT FROM AUTHOR]

Background: Lasmiditan is a selective serotonin (1F) receptor agonist approved for acute treatment of migraine with 3 doses: 50, 100, and 200 mg.Objective: To help provide dosing insights, we assessed the efficacy and safety of lasmiditan in patients who treated two migraine attacks with the same or different lasmiditan doses.Methods: Integrated analyses used data from the migraine attack treated in either of two controlled, Phase 3, single attack studies (SAMURAI/SPARTAN), and after the first attack treated in the open-label GLADIATOR extension study. Eight patient groups were created based on the initial dose received in SAMURAI or SPARTAN and the subsequent dose in GLADIATOR: placebo-100, placebo-200, 50-100, 50-200, 100-100, 100-200, 200-100, 200-200. Migraine pain freedom, migraine-related functional disability freedom, most bothersome symptom (MBS) freedom, and pain relief were evaluated at 2-h post-dose. The occurrence of most common treatment-emergent adverse events (MC-TEAE) was evaluated. Shift analyses were performed for pain freedom and ≥1 MC-TEAE. The incidence of patients with a specific outcome from the first and subsequent doses were compared within each dose change group using McNemar's test.Results: Small, but consistent, increases in incidences of pain freedom, migraine-related functional disability freedom, MBS freedom, and pain relief occurred when the second lasmiditan dose was higher than the initial dose. For patients starting on 50 mg, increasing to 100 or 200 mg provided a positive efficacy-TEAE balance, despite an increase in incidence of ≥1 MC-TEAE. For patients starting on 100 mg, increasing to 200 mg provided a positive efficacy-TEAE balance. If the initial dose was 100 or 200 mg, the incidence of patients experiencing ≥1 MC-TEAE decreased or stayed the same with their subsequent dose, regardless of dose. Decreasing from 200 to 100 mg led to a decrease in patients with pain freedom and ≥1 MC-TEAE, resulting in a neutral efficacy-TEAE balance. Shift analyses supported these findings.Conclusion: A positive efficacy-TEAE balance exists for patients increasing their lasmiditan dose for treatment of a subsequent migraine attack. These results could be important for optimizing dosing for individual patients.Clinicaltrials.gov: SAMURAI (NCT02439320); SPARTAN (NCT02605174); GLADIATOR (NCT02565186). [ABSTRACT FROM AUTHOR]

Background: The current target of migraine treatment is focused on Triptans. Lasmiditan, a non-vasoconstrictive and highly selective 5HT1F receptor agonist is a novel therapeutic discovery for migraine for patients with cardiovascular (CV) risk factors or stable cardiovascular diseases and who fail to respond to the existing treatment. Objective: To identify an optimal dosing of Lasmiditan 100 mg versus 200 mg for the treatment of acute migraine attacks in adult patients with cardiovascular risk factors. Methods: Systematic searches were run in databases such as Cochrane Central Register of Controlled Trials (CENTRAL), Scopus, Google scholar, and PUBMED. Out of 83 study records identified, two studies were included for quantitative analysis. Results: There was a significant headache pain freedom at 2 h [Odds Ratio (OR): 0.77; 95% Confidence interval (CI): 0.64--0.92] and sustained pain freedom at 24 h (OR): 0.75; 95% CI: 0.61--0.93] in patients taking Lasmiditan 200 mg compared to those taking Lasmiditan 100 mg. The results were statistically insignificant for parameters like most bothersome symptoms (MBS) free at 2 h, headache relief at 2 h, disability level at 2 h, and global impression of change at 2 h. A combined analysis of these parameters showed a remarkable difference between both the groups favoring Lasmiditan 200 mg [OR: 0.88; 95% CI: 0.81--0.95]. Conclusion: An oral dosing of Lasmiditan 200 mg is ideal for the treatment of acute migraine in adult patients with CV risk factors for attaining headache pain freedom at 2 h and sustained pain freedom at 24 compared to Lasmiditan 100 mg. [ABSTRACT FROM AUTHOR]

This article reviews seven drugs recently approved by the FDA, including indications, precautions, adverse reactions, and nursing considerations. [ABSTRACT FROM AUTHOR]

Objective: The goal of this study is to determine the strength of association between treatment with triptans and acute myocardial infarction, heart failure, and death. Background: Case reports in the literature have raised concerns over an association between treatment of migraine headaches with triptans and cardiovascular events. This study aims to systematically evaluate this association in a contemporary population‐based cohort. We hypothesized that triptan exposure is not associated with increased cardiovascular events. Methods: A retrospective cohort study was conducted within an integrated healthcare delivery system in Southern California. From January 2009 to December 2018, 189,684 patients age ≥18 years had a diagnosis of migraine. In this group, 130,656 were exposed to triptans. Patients treated with triptans were matched 1:1 to those not exposed to triptans by using a propensity score. The primary outcome was acute myocardial infarction; secondary outcomes were heart failure, all‐cause death, and combined acute myocardial infarction, heart failure, and death. Results: The incidence rate of acute myocardial infarction was 0.67 per 1000 person‐year in triptan‐exposed vs 1.44 per 1000 person‐year in not exposed patients. In propensity‐matched analyses, the adjusted hazard ratio for triptan exposure was 0.95 (95% confidence interval [CI] 0.84‐1.08) for acute myocardial infarction; 1.00 (95% CI 0.93‐1.08) for all‐cause death; 0.93 (95% CI 0.81‐1.08) for heart failure; and 0.99 (95% CI 0.93‐1.06) for a composite of acute myocardial infarction, heart failure, or death. Sensitivity analyses focusing on stratified subgroups based on age, gender, ethnicity, and several cardiac risk factors also revealed no significant association between triptan exposure and cardiovascular events. Conclusions: No association was found between exposure to triptans and an increased risk of cardiovascular events. These data provide reassurance regarding the cardiovascular safety of utilizing triptans for the medical management of migraine headaches. [ABSTRACT FROM AUTHOR]

Supplemental digital content is available in the text. [ABSTRACT FROM AUTHOR]

The article focuses on the Institute for Clinical and Economic Review final evidence report on the clinical and economic value of novel acute treatments for migraine, rimegepant, and lasmiditan. Topics include the randomized trials of acute therapies for migraine has designed to assess the primary outcomes, and the U.S. Food and Drug Administration guidance and the guidelines for clinical trials of drugs has issued by the International Headache Society Clinical Trial Standing Committee.

Objective: To identify factors predicting response (2‐hour headache pain freedom or most bothersome symptom freedom) to lasmiditan based on individual patient characteristics, migraine disease characteristics, and migraine attack characteristics. Further, efficacy specifically in difficult‐to‐treat patient/migraine disease characteristics or attack characteristics (ie, historically considered less responsive to certain acute therapies) subgroups was analyzed. Background: Knowledge of factors associated with a positive or negative response to acute treatment would be useful to practitioners prescribing acute treatments for migraine. Additionally, practitioners and patients would benefit from understanding the efficacy of lasmiditan specifically in subgroups of patients with migraine disease characteristics and migraine attack characteristics historically associated with decreased pain threshold, reduced efficacy of acute treatment, or increased burden of migraine. Methods: Pooled analyses were completed from 2 Phase 3 double‐blind clinical trials, SPARTAN and SAMURAI. Data from baseline to 2 hours after taking lasmiditan (50, 100, or 200 mg) or placebo were analyzed to assess efficacy based on patient characteristics, migraine disease characteristics, and migraine attack characteristics. A total of 3981 patients comprising the intent‐to‐treat population were treated with placebo (N = 1130), lasmiditan 50 mg (N = 598), lasmiditan 100 mg (N = 1133), or lasmiditan 200 mg (N = 1120). Data were analyzed for the following efficacy measures at 2 hours: headache pain freedom and most bothersome symptom freedom. Results: None of the analyzed subgroups based on individual patient characteristics, migraine disease characteristics, or migraine attack characteristics predicted headache pain freedom or most bothersome symptom freedom response at 2 hours following lasmiditan treatment (interaction P ≥.1). For the difficult‐to‐treat patient/migraine disease characteristics subgroups (defined as those with ≥24 headache days in the past 3 months, duration of migraine history ≥20 years, severe disability [Migraine Disability Assessment score ≥21], obesity [≥30 kg/m2], and history of psychiatric disorder), single doses of lasmiditan (100 or 200 mg) were significantly more effective than placebo (P ≤.002) in achieving both endpoints. Headache pain freedom response rates for higher doses of lasmiditan were numerically greater than for lower doses of lasmiditan. For the difficult‐to‐treat migraine attack subgroups, patients with severe headache, co‐existent nausea at the time of treatment, or who delayed treatment for ≥2 hours from the time of headache onset, both endpoint response rates after lasmiditan 100 or 200 mg were significantly greater than after placebo. Among those who delayed treatment for ≥4 hours from the time of headache onset, headache pain freedom response rates for the 200 mg dose of lasmiditan met statistical significance vs placebo (32.4% vs 15.9%; odds ratio = 2.7 [1.17, 6.07]; P =.018). While the predictors of response interaction test showed similar efficacy of lasmiditan vs placebo across subgroups defined by baseline functional disability (mild, moderate, or needs complete bed rest) at the time of treatment, analyses of lasmiditan efficacy within the subgroup "needs complete bed rest" appeared to show less efficacy (eg, in the 200 mg vs placebo group, 25.9% vs 18.5%; odds ratio = 1.56 [0.96, 2.53]; P =.070). Conclusions: Efficacy of lasmiditan 200 and 100 mg for headache pain freedom and most bothersome symptom freedom at 2 hours post‐treatment was generally not influenced by the individual patient characteristics, migraine disease history, or migraine attack characteristics that were analyzed. In the analyses of difficult‐to‐treat subgroups, patients receiving lasmiditan achieved greater responses (2‐hour headache pain freedom and most bothersome symptom freedom) vs placebo recipients. [ABSTRACT FROM AUTHOR]

Introduction: Migraine has been known for many years, but its mechanism remains unclear. Different cerebral hemodynamic changes have been observed at different stages of a migraine attack. Published results on cerebral hemodynamics are contradictory. For this reason, we aimed to investigate cerebral hemodynamic changes during attacks as well as the effects of frovatriptan and rizatriptan. Methods: Forty migraine patients with aura using rizatriptan (n=20) and frovatriptan (n=20) and 20 healthy individuals were included in our study. Cerebral blood flow velocities and breath-holding indices were recorded bilaterally from middle and posterior cerebral arteries. All procedures were repeated one hour after treatments and one week after attacks. Results: We observed similar values of cerebral blood flow velocities and breath holding indices in all patients with migraine during the attack-free period compared to the control group. All cerebral vascular structures in migraine patients had significantly lower cerebral blood flow velocities and higher values in breath-holding indices during attacks. After taking rizatriptan and frovatriptan for an attack, the changes in hemodynamics disappeared. Conclusion: During attacks of migraineurs with aura, vasodilatation develops. In addition, higher vasomotor reactivity during attacks supports hypersensitivity in migraine pathophysiology. Triptans, acting as vasoconstrictor agents, were able to stop over-vasodilatation during attacks. In other words, it is possible that triptans show their effects by eliminating vascular hypersensitivity during acute attacks. [ABSTRACT FROM AUTHOR]

Background: Medication overuse is a significant issue that complicates the treatment of headache disorders. The most effective medications for the acute treatment of migraine all have the capacity to induce medication overuse headache (MOH). Novel acute migraine-specific treatments are being developed. However, because the mechanism(s) underlying medication overuse headache are not well understood, it is difficult to predict whether any particular acute medication will induce MOH in susceptible individuals. LY573144 (lasmiditan), a 5-HT1F receptor agonist, has recently been shown to be effective in the acute treatment of migraine in phase 3 trials. The aim of this study is to determine whether frequent administration of lasmiditan induces behaviors consistent with MOH in a pre-clinical rat model.Methods: Sprague Dawley rats were administered six doses of lasmiditan (10 mg/kg), sumatriptan (10 mg/kg), or sterile water orally over 2 weeks and cutaneous allodynia was evaluated regularly in the periorbital and hindpaw regions using von Frey filaments. Testing continued until mechanosensitivity returned to baseline levels. Rats were then submitted to bright light stress (BLS) or nitric oxide (NO) donor administration and were again evaluated for cutaneous allodynia in the periorbital and hindpaw regions hourly for 5 hours.Results: Both lasmiditan and sumatriptan exhibited comparable levels of drug-induced cutaneous allodynia in both the periorbital and hindpaw regions, which resolved after cessation of drug administration. Both lasmiditan and sumatriptan pre-treatment resulted in cutaneous allodynia that was evoked by either BLS or NO donor.Conclusions: In a pre-clinical rat model of MOH, oral lasmiditan, like sumatriptan, induced acute transient cutaneous allodynia in the periorbital and hindpaw regions that after resolution could be re-evoked by putative migraine triggers. These results suggest that lasmiditan has the capacity to induce MOH through persistent latent peripheral and central sensitization mechanisms. [ABSTRACT FROM AUTHOR]

Migraine is a leading cause of disability worldwide, but it is still underdiagnosed and undertreated. Research on the pathophysiology of this neurological disease led to the discovery that calcitonin gene-related peptide (CGRP) is a key neuropeptide involved in pain signaling during a migraine attack. CGRP-mediated neuronal sensitization and glutamate-based second- and third-order neuronal signaling may be an important component involved in migraine pain. The activation of several serotonergic receptor subtypes can block the release of CGRP, other neuropeptides, and neurotransmitters, and can relieve the symptoms of migraine. Triptans were the first therapeutics developed for the treatment of migraine, working through serotonin 5-HT1B/1D receptors. The discovery that the serotonin 1F (5-HT1F) receptor was expressed in the human trigeminal ganglion suggested that this receptor subtype may have a role in the treatment of migraine. The 5-HT1F receptor is found on terminals and cell bodies of trigeminal ganglion neurons and can modulate the release of CGRP from these nerves. Unlike 5-HT1B receptors, the activation of 5-HT1F receptors does not cause vasoconstriction. The potency of different serotonergic agonists towards 5-HT1F was correlated in an animal model of migraine (dural plasma protein extravasation model) leading to the development of lasmiditan. Lasmiditan is a newly approved acute treatment for migraine in the United States and is a lipophilic, highly selective 5-HT1F agonist that can cross the blood-brain barrier and act at peripheral nervous system (PNS) and central nervous system (CNS) sites. Lasmiditan activation of CNS-located 5-HT1F receptors (e.g., in the trigeminal nucleus caudalis) could potentially block the release of CGRP and the neurotransmitter glutamate, thus preventing and possibly reversing the development of central sensitization. Activation of 5-HT1F receptors in the thalamus can block secondary central sensitization of this region, which is associated with progression of migraine and extracephalic cutaneous allodynia. The 5-HT1F receptors are also elements of descending pain modulation, presenting another site where lasmiditan may alleviate migraine. There is emerging evidence that mitochondrial dysfunction might be implicated in the pathophysiology of migraine, and that 5-HT1F receptors can promote mitochondrial biogenesis. While the exact mechanism is unknown, evidence suggests that lasmiditan can alleviate migraine through 5-HT1F agonist activity that leads to inhibition of neuropeptide and neurotransmitter release and inhibition of PNS trigeminovascular and CNS pain signaling pathways. [ABSTRACT FROM AUTHOR]