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Objective In the absence of head-to-head comparisons, the objective of this study was to conduct a network meta-analysis (NMA) to indirectly compare the relative efficacy and safety of rimegepant, ubrogepant, and lasmiditan for the acute treatment of migraine. Methods A systematic literature review was conducted to identify randomized controlled trials (RCTs) of rimegepant, ubrogepant, and lasmiditan in adults with acute migraine. Outcomes included sustained pain freedom and -relief 2-48 hours post-dose, and adverse events. No RCTs were identified that directly compared these interventions. Therefore, a fixed-effects Bayesian NMA was conducted by identifying a connected (via comparison to placebo) network of RCTs. Results Five RCTs were identified as follows: rimegepant study 303 (n = 1,466), ubrogepant ACHIEVE I and II (n = 1,672 and n = 1,686, respectively), and lasmiditan SAMURAI and SPARTAN (n = 2,231 and n = 3,005, respectively). Efficacy outcomes (pain freedom and relief at 2, 24, 48 hours) tended to be highest for lasmiditan 200 mg and rimegepant followed lower doses of lasmiditan and all doses of ubrogepant. However, lasmiditan 200 mg was also associated with higher rates of adverse events, particularly somnolence and dizziness. Conclusions Lasmiditan, rimegepant, and ubrogepant all performed significantly better than placebo with respect to pain freedom and pain relief. Efficacy results were similar for rimegepant and lasmiditan with rimegepant having higher rates of pain freedom and relief than lower doses of lasmiditan, while somnolence and dizziness outcomes were lower for rimegepant than higher doses of lasmiditan.

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

Migraine headache treatment is quickly evolving. There have been three new acute migraine treatment options (i.e., lasmiditan, rimegepant, ubrogepant) and four new preventive migraine treatment options (i.e., erenumab, fremanezumab, galcanezumab, eptinezumab) released in the past 3 years. The new migraine treatments are focusing on pathways within the newly, better understood neurovascular hypothesis that further describes the pathophysiology of migraine headaches in more detail than before. The discovery of vasoactive peptides, such as calcitonin gene-related peptide, has led to the development of many of these migraine agents. Rimegepant is one of these newly approved agents for acute migraine treatment in adults with or without aura. Rimegepant has been found to decrease pain and symptoms associated with migraine attacks and is generally well-tolerated.

To evaluate the efficacy of lasmiditan (LTN) in treating migraine attacks of mild vs. moderate or severe pain intensity.Pooled data from two single-attack, placebo-controlled studies (SAMURAI [NCT02439320] and SPARTAN [NCT02605174]), and a prospective, randomized, open-label study (GLADIATOR [NCT02565186]) were assessed. Efficacy measures included the proportion of attacks with 2-h pain freedom (PF), 2-h most bothersome symptom (MBS) freedom, and 24-h sustained pain freedom (SPF). Fisher's exact test was used to compare the proportion of PF, SPF, or MBS freedom outcomes among attacks treated at mild, moderate, or severe pain.In SAMURAI and SPARTAN, most treated attacks were of moderate (Data from two placebo-controlled, single-attack trials, and an open-label study including treatment of multiple attacks, suggested a tendency to relatively better efficacy outcomes when LTN treatment was initiated at mild vs. moderate to severe pain. Further research is needed to better understand the relationship of lasmiditan outcomes to the time of administration in the course of a migraine attack.

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.

Migraine with brainstem aura (MBA) accompanied by disorders of consciousness (DOC) is a rare subtype of migraine. The pathophysiology of MBA with DOC has not been elucidated yet. Some patients have a family history of migraine, and women are more affected than men. The aura symptoms are diverse; however, when MBA is combined with DOC, the clinical manifestations are more complicated. Coma is the most common clinical manifestation. The overall duration of the patient’s DOC is short and can often return to normal within half an hour. Headache often occurs after regaining consciousness and can also occur at the same time as DOC. The most common headache is located at the occipital region. Although DOC is reversible, considering the current small number of cases, we still need to improve our understanding of the disease to avoid misdiagnosis. The MBA patient’s electroencephalogram and cerebral blood flow perfusion may have transient changes and may return to normal in the interictal period or after the DOC. Although triptans have traditionally been contraindicated in MBA under drug instructions, the evidence of basilar artery constriction, as postulated in MBA, is lacking. Lasmiditan is currently the first and only 5-HT 1F receptor agonist approved by the Food and Drug Administration. The calcitonin gene-related peptide receptor antagonists and monoclonal antibody therapies may be the most promising for future consideration. Here, the pathophysiology, clinical manifestations, diagnostic tools, and treatment progress for MBA with DOC are reviewed.

Purpose of review Despite the development of several medications for the acute and preventive treatment of migraine, there are still many patients in whom lack of efficacy, tolerability, interactions or contraindications make other options necessary. CGRP-based drugs have opened the door to a new era of migraine-targeted treatments. Beyond CGRP, there are other promising targets covered here. Recent findings For the acute treatment of migraine, 5-HT1F receptor agonists, ditans, are now available. Unlike triptans, 5-HT1B/1D receptor agonists, cardiovascular disease is not a contraindication for the use of ditans. The first study on a monoclonal antibody targeting PAC1 receptor was negative, although this may not be the end for the pituitary adenylate cyclase-activating polypeptide (PACAP) pathway as a target. Summary Following positive phase-III clinical trials, lasmiditan is the first ditan to be FDA-approved. PACAP has experimental evidence suggesting a role in migraine pathophysiology. As for CGRP, the presence of PACAP in key migraine structures along with positive provocative tests for both PACAP-38 and PACAP-27 indicate this pathway may still be a pharmacological target. Glutamate-based targets have long been considered in migraine. Two clinical trials with memantine, an NMDA-R antagonist, for the preventive treatment of migraine have now been published. The hypothalamus has also been implicated in migraine pathophysiology: the potential role of orexins in migraine is discussed. Acid-sensing ion channels, as well as amylin-blocking drugs, may also become migraine treatments in the future: more research is warranted.

Background We present findings from the multicenter, double-blind Phase 3 study, CENTURION. This study was designed to assess the efficacy of and consistency of response to lasmiditan in the acute treatment of migraine across four attacks. Methods Patients were randomized 1:1:1 to one of three treatment groups – lasmiditan 200 mg; lasmiditan 100 mg; or a control group that received placebo for three attacks and lasmiditan 50 mg for either the third or fourth attack. The primary endpoints were pain freedom at 2 h (first attack) and pain freedom at 2 h in ≥2/3 attacks. Secondary endpoints included pain relief, sustained pain freedom and disability freedom. Statistical testing used a logistic regression model and graphical methodology to control for multiplicity. Results Overall, 1471 patients treated ≥1 migraine attack with the study drug. Both primary endpoints were met for lasmiditan 100 mg and 200 mg ( p Conclusions These results confirm the early and sustained efficacy of lasmiditan 100 mg and 200 mg and demonstrate consistency of response across multiple attacks. Trial Registration Number: NCT03670810

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.

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.

Migraine headache has become global pandemics and is the number one reason of work day loss. The most common drugs for anti-migraine are the triptan class of drugs that are agonists for serotonin receptors 5-HT1B and 5-HT1D. However, these drugs have side effects related to vasoconstriction that could have fatal consequences of ischemic heart disease and myocardial infarction. Lasmiditan is a new generation of anti-migraine drug that selectively binds to the serotonin receptor 5-HT1F due to its advantage over the tripan class of anti-migraine drugs. Here we report the cryo-EM structure of the 5-HT1F in complex with Lasmiditan and the inhibitory G protein heterotrimer. The structure reveals the mechanism of 5-HT1F-selective activation by Lasmiditan and provides a template for rational design of anti-migraine drugs.

INTRODUCTION The efficacy of lasmiditan is used to alleviate migraine. We conduct a systematic review and meta-analysis to explore the influence of lasmiditan versus placebo on pain control in patients with migraine. METHODS We search the PubMed, EMbase, Web of science, EBSCO, and Cochrane library databases through June 2020 for randomized controlled trials (RCTs) assessing the effect of lasmiditan versus placebo on pain control in patients with migraine. This meta-analysis was performed using the random effects model. RESULTS Four randomized controlled trials are included in the meta-analysis. Overall, compared with the control group, in patients with migraine, lasmiditan treatment shows positive impact on pain free at 2 hours [risk ratio (RR), 1.74; 95% confidence interval (CI), 1.47-2.07; P < 0.00001], headache response at 2 hours (RR, 1.38; 95% CI, 1.28-1.49; P < 0.00001), pain free at 24 hours (RR, 1.55; 95% CI, 1.16-2.07; P = 0.003), and no or mild disability level (RR, 1.20; 95% CI, 1.11-1.29; P < 0.00001), but has no obvious influence on nausea (RR, 2.22; 95% CI, 0.92-5.35; P = 0.08). In addition, lasmiditan seems to result in the increase in dizziness (RR, 6.36; 95% CI, 3.00-13.46; P < 0.0001) and paresthesia (RR, 5.10; 95% CI, 2.66-9.78; P < 0.00001). CONCLUSIONS Lasmiditan treatment provides additional benefits for pain control in patients with migraine.

Background Migraine patients want acute treatment to provide complete relief of the migraine attack within 30 minutes. Traditionally, “speed of onset of effect” is evaluated by estimating the time-point for first statistical separation of drug and placebo. The estimated onset of effect can be a few percent difference of patients being pain free in very large randomised, controlled trials. This difference, however, can be clinically irrelevant. Methods Placebo-controlled randomised, controlled trials with pain freedom results from 30 min to 2–4 hours were retrieved from the literature. For each time-point, the therapeutic gain (drug minus placebo) (TG) was calculated. Therapeutic gain for being pain free of 5% was chosen for the definition of “onset of action”, since this is approximately 1/3 of the 16% TG and 1/4 of 21% of TG for sumatriptan 50 mg and 100 mg, respectively. Results A total of 22 time-effect curves based on randomised, controlled trials were analysed. Based on the “onset of action” of 5% pain freedom, the evaluated drugs and administration forms can be classified as follows: i) Early time to onset, ≤30 min (three randomised, controlled trials); ii) medium time to onset, 60 min (nine randomised, controlled trials); iii) delayed time to onset, 90–120 min (10 randomised, controlled trials). Conclusion Only three non-oral administration forms with a triptan (subcutaneous sumatriptan and nasal zolmitriptan) resulted in an “onset of action” at ≥30 min; in the future, early onset of action should be a priority in the development of new drugs or new administration-forms for the treatment of acute migraine attacks.

Lasmiditan is a new oral medication for treatment of acute migraine. It was approved by the U.S. Food and Drug Administration in October 2019 and is marketed under the brand name Reyvow (Eli Lilly and Company, Indianapolis, IN). It is the first of its kind in a new drug class called ditans. Lasmiditan has been studied as monotherapy for acute migraine treatment and as an abortive therapy for adults taking chronic migraine preventive medication. Lasmiditan may be an option for individuals who have had no relief with triptans or other acute migraine treatment agents or who are unable to use other migraine treatments because of contraindications.

The objective of this article is to discuss and compare the latest approved drugs (lasmiditan, ubrogepant, and rimegepant) for the management of acute migraine in a clinically relevant manner, emphasizing on their efficacy, safety, as well as cost benefits. A PubMed, clincialtrials.gov , and USFDA literature search (2013–2019) was conducted using the following keywords: Lasmiditan; Ubrogepant; Rimegepant; Acute Migraine; 5HT1F; CGRP. We included only English language articles which discussed the efficacy, safety, and tolerability of newly approved drugs for acute migraine. Triptans and NSAIDs have constitutively been the go-to drugs for the management of acute attack of migraine. These three latest drugs (lasmiditan, ubrogepant, and rimegepant) approved by USFDA may prove to be a game-changer, especially for those migraineurs who have accompanying cardiovascular diseases or have been dissatisfied with the existing therapeutic options. Migraine is a chronic debilitating disease for which the therapeutic options are already available, but for a proportion of patients, these options get either contraindicated, or prove to be clinically ineffective, or crop-out as ill-suited due to the adverse effects. In such conditions, the recently approved three drugs by USFDA stand a chance to fulfill the unmet needs. But due to the paucity of head-on trials between different groups of drugs, it is still difficult to comment about which group may clinically outpace by providing better therapeutic gain.

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.

OBJECTIVES The efficacy of DFN-15 for pain control of migraine remains controversial. We conduct a systematic review and meta-analysis to explore the influence of DFN-15 versus placebo on pain control in migraine patients. PATIENTS AND METHODS We search PubMed, Embase, Web of Science, EBSCO, and Cochrane Library databases through November 2019 for randomized controlled trials assessing the effect of DFN-15 versus placebo on pain control in migraine patients. This meta-analysis is performed using the random-effects model. RESULTS Three randomized controlled trials are included in the meta-analysis. Overall, compared with the control group in migraine patients, lasmiditan treatment shows a positive impact on pain freedom at 2 hours (risk ratio [RR], 1.96; 95% confidence interval, 1.61-2.40; P < 0.00001), headache response at 2 hours (RR, 1.40; 95% CI, 1.25-1.57; P < 0.00001), and pain freedom at 24 hours (RR, 1.87; 95% CI, 1.33-2.62; P = 0.0003), but has no obvious influence or no substantial impact on no or mild disability level (RR, 1.21; 95% CI, 0.97-1.52; P = 0.09) or nausea (RR, 2.42; 95% CI, 0.53-11.01; P = 0.25). In addition, lasmiditan seems to result in the increase in dizziness (RR, 7.33; 95% CI, 1.83-29.30; P = 0.005) and paresthesia (RR, 5.17; 95% CI, 2.08-12.86; P = 0.0004). CONCLUSIONS DFN-15 treatment may be effective and safe for pain control in migraine patients.

BackgroundMigraine has been recognized as one of common diseases in the world whose current treatment options are not ideal. Lasmiditan, an oral 5-hydroxytryptamine (HT)1Freceptor agonist, appears more promising for the acute treatment of migraine because of considerably better effect profiles with no severe adverse events (AEs). This review aimed to systematically evaluate the efficacy and safety of lasmiditan from the results of randomized controlled trials (RCTs).MethodsPubMed, Cochrane Library, Embase were searched on lasmiditan for the acute treatment of migraine from inception of the databases to Feb 1, 2020. Pain free and pain relief, global impression (very much/much better), and no/mild disability at 2 h in efficacy; total treatment-emergent adverse events (TEAEs), dizziness, nausea, fatigue, paraesthesia and somnolence in safety were extracted from the included studies. A systematic review and meta-analysis was performed using Review Manager Software version 5.3 (RevMan 5.3).ResultsFour RCTs with a total of 4960 subjects met our inclusion criteria. The overall effect estimate showed that lasmiditan was significantly superior to placebo in terms of pain free (RR 1.71, 95% CI 1.55–1.87), pain relief (RR 1.40, 95% CI 1.33–1.47), global impression (very much/much better) (RR 1.55, 95% CI 1.44–1.67), and no/mild disability (RR 1.15, 95% CI 1.10–1.20) at 2 h. For the safety, significant number of patients experienced TEAEs with lasmiditan than with placebo (RR 2.77, 95% CI 2.53–3.03), most TEAEs were central nervous system (CNS)-related and included dizziness (RR 5.81, 95% CI 4.72–7.14), nausea (RR 2.58, 95% CI 1.87–3.57), fatigue (RR 5.38, 95% CI 3.78–7.66), paraesthesia (RR 4.48, 95% CI 3.33–6.02), and somnolence (RR 2.82, 95% CI 2.18–3.66).ConclusionsThis meta-analysis suggests that lasmiditan is effective for the acute treatment of migraine with a higher incidence of CNS-related adverse reactions compared with placebo. Long-term, open-label, multi-dose trials are required to verify the current findings.

Lasmiditan (LY573144/COL‐144) is a high‐affinity, centrally penetrant, selective 5‐HT1F receptor agonist currently under investigation for acute treatment of migraine. Although lasmiditan is not known to induce vasoconstriction, it remains important to understand its effect on cardiovascular parameters because it is likely to be coadministered with β‐adrenergic receptor antagonists used for migraine prophylaxis, such as propranolol. This phase 1, single‐center, open‐label, fixed‐sequence study evaluated the cardiovascular and pharmacokinetic effects of 200 mg lasmiditan in 44 healthy subjects receiving repeated oral doses of twice‐daily 80 mg propranolol under fasting conditions. Coadministration caused statistically significant decreases in mean hourly heart rate relative to propranolol alone, but the maximum magnitude of this effect was –6.5 bpm and recovered to predose levels by 3 to 4 hours before stabilizing. Additionally, short‐lived (≤2.5 hours) statistically significant increases in systolic blood pressure (8.3 mm Hg) and diastolic blood pressure (6.4 mm Hg) were observed following coadministration. Consistent with the largely nonoverlapping metabolic pathways of lasmiditan and propranolol, exposure to either drug was not affected by coadministration. Overall, compared with administration of either drug alone, coadministration was generally well tolerated.

Purpose In four large controlled trials with lasmiditan and ubrogepant placebo was administered in the first step to demonstrate an effect on migraine attack. In the same trials the investigators also asked the question: is a second dose of the drug effective in non-responders to the first dose? In this phase patients who received placebo in the first phase of the trial again after 2 hours received another dose of placebo. Conclusion To be ethical, clinical research requires balancing rigorous science with the protection of human subjects; and it is, in our view, questionable whether placebo was used with “scientific rigor” in the second step of these trials, and this design is not recommended.

Objective To incorporate recent research findings, expert consensus, and patient perspectives into updated guidance on the use of new acute and preventive treatments for migraine in adults. Background The American Headache Society previously published a Consensus Statement on the use of newly introduced treatments for adults with migraine. This update, which is based on the expanded evidence base and emerging expert consensus concerning postapproval usage, provides practical recommendations in the absence of a formal guideline. Methods This update involved four steps: (1) review of data about the efficacy, safety, and clinical use of migraine treatments introduced since the previous Statement was published; (2) incorporation of these data into a proposed update; (3) review and commentary by the Board of Directors of the American Headache Society and patients and advocates associated with the American Migraine Foundation; (4) consideration of these collective insights and integration into an updated Consensus Statement. Results Since the last Consensus Statement, no evidence has emerged to alter the established principles of either acute or preventive treatment. Newly introduced acute treatments include two small-molecule calcitonin gene-related peptide (CGRP) receptor antagonists (ubrogepant, rimegepant); a serotonin (5-HT1F ) agonist (lasmiditan); a nonsteroidal anti-inflammatory drug (celecoxib oral solution); and a neuromodulatory device (remote electrical neuromodulation). New preventive treatments include an intravenous anti-CGRP ligand monoclonal antibody (eptinezumab). Several modalities, including neuromodulation (electrical trigeminal nerve stimulation, noninvasive vagus nerve stimulation, single-pulse transcranial magnetic stimulation) and biobehavioral therapy (cognitive behavioral therapy, biofeedback, relaxation therapies, mindfulness-based therapies, acceptance and commitment therapy) may be appropriate for either acute and/or preventive treatment; a neuromodulation device may be appropriate for acute migraine treatment only (remote electrical neuromodulation). Conclusions The integration of new treatments into clinical practice should be informed by the potential for benefit relative to established therapies, as well as by the characteristics and preferences of individual patients.

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

Background A significant proportion of triptan users exhibit an insufficient response or inadequate tolerability to a triptan, and some may develop a contraindication. Lasmiditan, a selective 5-HT1F receptor agonist, may be an option for these individuals. We assessed lasmiditan efficacy in a subgroup of patients in CENTURION (Phase 3 migraine consistency study) who exhibited an insufficient response to triptans, including a subgroup with insufficient response due to efficacy only. Methods Patients were randomized to lasmiditan 200 mg for four attacks, lasmiditan 100 mg for four attacks, or placebo for three and lasmiditan 50 mg for one attack. Triptan insufficient responders were pre-defined as patients with insufficient efficacy or tolerability, or who developed a contraindication. Results In triptan insufficient responders, lasmiditan was superior to placebo ( p Conclusions Lasmiditan was efficacious across multiple clinically relevant endpoints in the acute treatment of migraine independent of prior response to triptans. Trial Registration: CENTURION (NCT03670810); SAMURAI (NCT02439320); SPARTAN (NCT02605174)

Importance New therapeutic classes of migraine-specific treatment have been developed, including 5-hydroxytryptamine1Freceptor agonists (lasmiditan) and calcitonin gene-related peptide antagonists (rimegepant and ubrogepant). Objective To compare outcomes associated with the use of lasmiditan, rimegepant, and ubrogepant vs triptans for acute management of migraine headaches. Data Sources The Cochrane Register of Controlled Trials, Embase, and PubMed were searched from inception to March 5, 2020. Study Selection Double-blind randomized clinical trials examining current available migraine-specific acute treatments were included. Data Extraction and Synthesis The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline was applied to extract the data according to a predetermined list of variables of interest, and all network meta-analyses were conducted using a random-effects model. Main Outcomes and Measures The primary outcome was the odds ratio (OR) for freedom from pain (hereafter referred to aspain freedom) at 2 hours after the dose, and the secondary outcomes were ORs for pain relief at 2 hours after the dose and any adverse events. Results A total of 64 randomized clinical trials were included (46 442 participants; 74%-87% women; age range, 36-43 years). Most of the included treatments were associated with reduced pain at 2 hours compared with placebo. Most triptans were associated with higher ORs for pain freedom at 2 hours compared with lasmiditan (range: OR, 1.72 [95% CI, 1.06-2.80] to OR, 3.40 [95% CI, 2.12-5.44]), rimegepant (range: OR, 1.58 [95% CI, 1.07-2.33] to OR, 3.13 [95% CI, 2.16-4.52]), and ubrogepant (range: OR, 1.54 [95% CI, 1.00-2.37] to OR, 3.05 [95% CI, 2.02-4.60]). Most triptans were associated with higher ORs for pain relief at 2 hours compared with lasmiditan (range: OR, 1.46 [95% CI, 1.09-1.96] to OR, 3.31 [95% CI, 2.41-4.55]), rimegepant (range: OR, 1.33 [95% CI, 1.01-1.76] to OR, 3.01 [95% CI, 2.33-3.88]), and ubrogepant (range: OR, 1.38 [95% CI, 1.02-1.88] to OR, 3.13 [95% CI, 2.35-4.15]). The comparisons between lasmiditan, rimegepant, and ubrogepant were not statistically significant for both pain freedom and pain relief at 2 hours. Lasmiditan was associated with the highest risk of any adverse events, and certain triptans (rizatriptan, sumatriptan, and zolmitriptan) were also associated with a higher risk of any adverse events than the calcitonin gene-related peptide antagonists. Conclusions and Relevance For pain freedom or pain relief at 2 hours after the dose, lasmiditan, rimegepant, and ubrogepant were associated with higher ORs compared with placebo but lower ORs compared with most triptans. However, the lack of cardiovascular risks for these new classes of migraine-specific treatments may offer an alternative to triptans.

Background While pain freedom at 2 h is a key primary outcome for current trials for acute treatment of migraine, the relationship between the degree of head pain and other efficacy measures at 2 h has rarely been explored. Following lasmiditan treatment of a migraine attack with moderate or severe head pain, we contrast those who achieve pain freedom with those who achieve mild pain but not pain freedom 2 h post dosing. Methods Patient-level data were pooled across studies and treatment arms from two Phase 3 trials comparing lasmiditan and placebo, SAMURAI and SPARTAN. This post hoc analysis assessed freedom from the most bothersome symptom (MBS), freedom from migraine-related functional disability (disability), and improved patient global impression of change (PGIC) in patients who achieved 2 h pain freedom compared to those who experienced 2 h mild pain. Mild pain differs from pain relief which is defined as either mild pain or pain freedom. Results Patients who achieved 2 h pain freedom (N = 913), in comparison with those with 2 h mild pain (N = 864), were significantly more likely to experience MBS freedom (91.9% vs. 44.9%), disability freedom (87.1% and 13.4%), and improved PGIC (86.5% and 31.5%) (p p Conclusions This study demonstrated that, at 2 h post treatment, patients who were pain free were more likely to achieve other outcomes including freedom from their MBS, freedom from migraine-related functional disability, and improved PGIC compared to those with mild pain, confirming that 2 h pain freedom is more robustly associated with other clinical outcomes than the 2 h mild pain endpoint. Trial Registration SAMURAI (NCT02439320); SPARTAN (NCT02605174).

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

Objective: To review the efficacy and safety of the newly Food and Drug Administration approved drug lasmiditan, and its place in therapy in the treatment of acute migraine attacks. Data Sources: A literature search of Web of Science, PubMed, and Google Scholar was preformed (September 1999 to May 2021) using the following search terms: acute migraine treatment, triptans, lasmiditan, Reyvow, Rimegepant, Nurtec, Ubrogepant, Ubrelvy, migraine, vasoconstriction, and cardiovascular risk. Product labeling, https://www.clinicaltriasl.gov , and product monographs were also reviewed. Study Selection and Data Extraction: Relevant English-language studies were considered. Data Synthesis: Lasmiditan is the first in its class approved for acute migraine treatment. Lasmiditan exerts its therapeutic effect through agonism at the 5-HT1F receptor, which has been shown to produce no vasoconstriction in preclinical models. Relevance to Patient Care and Clinical Practice: It is both scientifically and clinically relevant to review lasmiditan and determine the value of an acute migraine drug that does not induce vasoconstriction. Patients with preexisting cardiovascular conditions for which current migraine therapy is contraindicated may benefit from therapeutic use of lasmiditan. However, the potential cardiovascular benefit needs to be weighed against the increased central nervous system risks observed with lasmiditan. Conclusions: Lasmiditan is an oral tablet drug that is used for acute migraine abortive treatment and data suggest that it does not induce vasoconstriction, a common side effect often observed with the current first-line abortive migraine treatment drug class, triptans. This is especially important in acute migraine patients with cardiovascular risk factors in which triptan use is contraindicated.

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-HT1Freceptor 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.

Lasmiditan (REYVOW™; Eli Lilly and Company) is an orally available serotonin (5-HT)1F receptor agonist. In October 2019, the US FDA approved lasmiditan 50 mg and 100 mg tablets for the acute treatment of migraine with or without aura in adults. Approval was based on positive results from two pivotal phase III trials, in which lasmiditan significantly improved the proportions of patients achieving freedom from headache pain and freedom from the most bothersome symptom (photophobia, phonophobia or nausea), relative to placebo, when used to treat a migraine with moderate to severe pain. Lasmiditan is not for use in the preventive treatment of migraine. This article summarizes the milestones in the development of lasmiditan leading to its first approval for the acute treatment of migraine in adults.

Lasmiditan is a centrally penetrant, highly selective 5‐hydroxytryptamine (serotonin) receptor 1F (5HT1F) agonist under development as a novel therapy for acute treatment of migraine. A phase 1 randomized, placebo‐ and positive‐controlled crossover study assessed the abuse potential of lasmiditan in adult recreational polydrug users. Following a qualification phase, subjects were randomized into treatment sequences, each consisting of 5 study treatments: placebo, alprazolam 2 mg, lasmiditan 100, 200 (lasmiditan 100 and 200 mg are proposed therapeutic doses), and 400 mg (supratherapeutic). The abuse potential of lasmiditan was investigated and compared with alprazolam and with placebo using the maximal effect score (Emax) of the Drug‐Liking Visual Analog Scale as the primary end point. Lasmiditan was not similar to placebo in drug‐liking scores at all doses tested, with a maximum difference observed with the lasmiditan 400‐mg dose (upper 90% confidence limit on difference in least‐squares [LS] means > 14 for all lasmiditan doses). Drug‐liking scores for lasmiditan 400 mg were not significantly different from alprazolam (lower 90% confidence limit on difference in LS means < 5), but drug‐liking scores at lower doses (100 and 200 mg) were significantly different from alprazolam. During the treatment phase, the incidence of treatment‐emergent adverse events (TEAEs) increased with increasing dose of lasmiditan; all TEAEs reported with lasmiditan treatment were mild. Subjective drug‐liking effects for lasmiditan versus placebo and versus alprazolam, and the safety and tolerability profile of lasmiditan suggest that lasmiditan has a low potential for abuse.

Objectives To address the need for long-term lasmiditan data, the GLADIATOR study evaluated the safety (primary) and efficacy (secondary) of lasmiditan for the intermittent, acute treatment of migraine attacks for up to 1 year. Methods In this prospective, randomized, open-label, Phase 3 study, patients who had completed either of two single-attack studies were offered the opportunity to be randomized 1:1 to lasmiditan 100 mg or 200 mg. Patients were asked to use lasmiditan as the first treatment for each new migraine attack of at least moderate severity. Assessments occurred at baseline and at prespecified time increments up to 48 hours after each dose of study drug using an electronic diary, and safety was assessed throughout the study. Migraine Disability Assessment (MIDAS) was assessed at each visit. Results As of the cut-off date for this interim analysis (6 March 2018), 1978 patients had received ≥ 1 lasmiditan dose and treated 19,058 migraine attacks. Overall, treatment-emergent adverse events (TEAEs) were similar to those in the single-attack studies and included dizziness (18.6%), somnolence (8.5%), and paresthesia (6.8%). The frequency of TEAEs generally decreased with subsequent attacks. No treatment-related serious adverse events and no cardiovascular TEAEs potentially due to vasoconstriction were observed. For both lasmiditan doses, efficacy measures were generally consistent over study quarters and treated attacks. Overall, across all treated attacks at 2 hours post-dose, pain freedom was observed in 26.9% of the attacks treated with lasmiditan 100 mg and 32.4% of the attacks treated with lasmiditan 200 mg. MIDAS total scores decreased over time. Conclusions The interim results of this long-term study showed intermittent lasmiditan (100 mg and 200 mg) to be generally well tolerated and efficacious for the acute treatment of migraine over a 1-year period. Trial registration number: NCT02565186; https://clinicaltrials.gov/ct2/show/NCT02565186

In addition to the increased risk for cardiovascular (CV) disease and CV events associated with migraine, patients with migraine can also present with a number of CV risk factors (CVRFs). Existing treatment options can be limited due to contraindications, increased burden associated with monitoring, or patient avoidance of side effects. Safe and effective migraine treatment options are needed for patients with migraine and a history of CV or cerebrovascular disease or with increased risk for CV events. This analysis was designed to evaluate the safety and efficacy of oral lasmiditan, a selective serotonin 5-hydroxytryptamine 1F receptor agonist, in acute treatment of migraine attacks in patients with CVRFs. SAMURAI and SPARTAN were similarly designed, Phase 3, randomized, double-blind, placebo-controlled trials in adults treating a single migraine attack with lasmiditan 50, 100, or 200 mg. Both studies included patients with CVRFs, and SPARTAN allowed patients with coronary artery disease, clinically significant arrhythmia, or uncontrolled hypertension. Efficacy and safety of lasmiditan in subgroups of patients with differing levels of CVRFs are reported. For efficacy analyses, logistic regression was used to assess treatment-by-subgroup interactions. For safety analyses, Cochran-Mantel-Haenszel test of general association evaluated treatment comparisons; Mantel-Haenszel odds ratio assessed significant treatment effects. In this pooled analysis, a total of 4439 patients received ≥1 dose of study drug. A total of 3500 patients (78.8%) had ≥1 CVRF, and 1833 patients (41.3%) had ≥2 CVRFs at baseline. Both trials met the primary endpoints of headache pain freedom and most bothersome symptom freedom at 2 h. The presence of CVRFs did not affect efficacy results. There was a low frequency of likely CV treatment-emergent adverse events (TEAEs) overall (lasmiditan, 30 [0.9%]; placebo, 5 [0.4%]). There was no statistical difference in the frequency of likely CV TEAEs in either the absence or presence of any CVRFs. The only likely CV TEAE seen across patients with ≥1, ≥ 2, ≥ 3, or ≥ 4 CVRFs was palpitations. When analyzed by the presence of CVRFs, there was no statistical difference in lasmiditan efficacy or the frequency of likely CV TEAEs. Despite the analysis being limited by a single-migraine-attack design, the lack of differences in efficacy and safety with increasing numbers of CVRFs indicates that lasmiditan might be considered in the treatment algorithm for patients with CVRFs. Future studies are needed to assess long-term efficacy and safety. ClinicalTrials.gov NCT02439320 (SAMURAI), registered 18 March 2015 and ClinicalTrials.gov NCT02605174 (SPARTAN), registered 11 November 2015.

We studied the efficacy and safety of a second dose of lasmiditan for acute treatment of migraine. SAMURAI and SPARTAN were double-blind, placebo-controlled Phase 3 studies in which individuals with migraine were randomized to oral lasmiditan 50 mg (SPARTAN only), 100 mg, 200 mg, or placebo. Study drug was to be taken within 4 h (h) of onset of a migraine attack (moderate or severe pain). A second dose of study drug was provided for rescue (patient not pain-free at 2 h and took a second dose 2-24 h post-first dose) or recurrence (patient pain-free at 2 h, but experienced recurrence of mild, moderate, or severe migraine pain and took a second dose 2-24 h after first dose). Randomization to second dose occurred at baseline; patients originally assigned lasmiditan were randomized to the same lasmiditan dose or placebo (2:1 ratio), and those originally assigned placebo received placebo. Data from SAMURAI and SPARTAN were pooled for efficacy and safety assessment of a second dose of lasmiditan. The proportion of patients taking a second dose was lower with lasmiditan versus placebo, and decreased with increasing lasmiditan dose; the majority who took a second dose did so for rescue. In patients taking lasmiditan as first dose, outcomes (pain free, most bothersome symptom [MBS] free) at 2 h after a second dose for rescue were similar whether the second dose was lasmiditan or placebo (p > 0.05 in all cases). In patients taking lasmiditan for first dose, outcomes at 2 h after a second dose for recurrence were as follows: lasmiditan pooled versus placebo - pain free, 50% vs 32% (p > 0.05); MBS free, 71% vs 41% (p = 0.02); pain relief, 77% vs 52% (p = 0.03). In patients whose first dose was lasmiditan, the incidence of treatment emergent adverse events (TEAEs) reported after the second dose was similar whether second dose was lasmiditan or placebo. A second dose of lasmiditan showed some evidence of efficacy when taken for headache recurrence. There was no clear benefit of a second dose of lasmiditan for rescue treatment. The incidences of TEAEs were similar whether the second dose was lasmiditan or placebo. SAMURAI ( NCT02439320 ) [April 2015]. SPARTAN ( NCT02605174 ) [May 2016].

Background Sustained pain freedom is an important attribute of acute migraine therapies for patients and physicians. Here we report efficacy of the centrally penetrant, highly selective, 5-HT1F agonist lasmiditan on sustained pain freedom and other outcomes at 24 and 48 hours post-dose. Study design and methods Data from the similarly designed, Phase 3, double-blind studies SAMURAI (NCT02439320) and SPARTAN (NCT02605174) were pooled to more precisely estimate efficacy effects in these post-hoc analyses. In both studies, inclusion criteria were 3–8 migraine attacks per month and Migraine Disability Assessment Score of ≥ 11 (at least moderate disability). Patients were randomized equally to lasmiditan 200 mg, 100 mg, 50 mg (50 mg only in SPARTAN), or to placebo. The study drug was to be taken within 4 hours of onset of pain for non-improving headache of at least moderate severity. Sustained pain freedom was defined as being pain free at 2 hours and at the given time point (24 or 48 hours) post-dose without use of additional study drug or migraine medications. Sustained responses were assessed similarly for most bothersome symptom-free, total migraine-free, and disability-free outcomes. For comparisons with previously published data on other acute medications, an additional endpoint of modified sustained pain freedom at 24 hours was defined as being pain free at 2 hours and no moderate-to-severe headache at 24 hours post-dose without use of additional study drug or migraine medications. Results Significantly higher proportions of patients treated with lasmiditan versus placebo achieved headache pain freedom at 2 hours post-dose: 200 mg: 35.6%; 100 mg: 29.9%; 50 mg: 28.6%; placebo: 18.3% (all p Conclusion Sustained responses at 24 and 48 hours were noted in significantly more patients treated with lasmiditan versus placebo for several efficacy outcomes including pain freedom, most bothersome symptom-free, total migraine-free and disability-free responses. Clinicaltrials.gov identifier numbers SAMURAI: NCT02439320; SPARTAN: NCT02605174.

Objective To review and highlight current literature on emerging acute migraine treatments, focusing on CGRP receptor antagonists, gepants, and 5-HT1F receptor agonists (ditans). Background Current acute migraine therapy consists of nonspecific analgesia and triptans. Limitations to these medicines, including lack of efficacy in many patients, side effects and the contraindication of triptans in patients with cardiovascular disease, suggest that there is an unmet need for new treatments. Studies of serotonin pharmacology led to the development of triptans, 5-HT1B/1D receptor agonists, some of which have actions at the 5-HT1F receptor. Exploration of the role of calcitonin gene-related peptide (CGRP) has resulted in the development of CGRP receptor antagonists. Method The authors performed a literature search of Pubmed and Cochrane databases as well as reviewed abstracts presented at meetings: American Headache Society, American Academy of Neurology, European Headache Federation and the Migraine Trust International Symposium, as well as on-line sources. The authors briefly detail the relevant migraine pathophysiology pertaining to 5-HT1F receptor and the CGRP pathway relevant to acute therapies. Recent clinical trials of acute therapies in which 5-HT1F receptor agonists or CGRP receptor antagonists were studied are summarized. Results Two 5-HT1F receptor agonists have reached phase II clinical trials. One, lasmiditan, has completed 2 phase III clinical trials, demonstrating a significant effect for pain freedom and most bothersome symptom at 2 hours. Among the 6 gepants tested for the acute treatment of migraine to date, after issues for some of hepatic safety or efficacy, 2 CGRP receptor antagonists, rimegepant and ubrogepant, have completed phase III trials showing efficacy and safety. Conclusion Current available therapies have either been nonspecific or had important limitations, including in patients with cardiovascular risk factors. Phase III clinical trials of lasmiditan, rimegepant and ubrogepant all met their primary endpoints, so the options for migraine-targeted acute therapy will likely soon increase.

Objective To study the efficacy and safety of lasmiditan for acute treatment of migraine in patients using migraine preventive medications. Background While lasmiditan has been proven to be an effective acute treatment for migraine, its effectiveness has not been examined when used concurrently with migraine preventives. Methods SAMURAI and SPARTAN were similarly designed, double-blind, phase 3, placebo-controlled studies of patients 18 years or older with 3 to 8 migraine attacks per month. Patients were randomized to treat a migraine attack with oral lasmiditan 50 mg (SPARTAN only), 100 mg, 200 mg, or placebo. Migraine preventives were allowed as long as doses were stable for 3 months prior to screening and were unchanged during the study. Preventive medications with established or probable efficacy, as recommended by the American Academy of Neurology, the American Headache Society, and the European Headache Federation, plus botulinum toxin type A and candesartan, were included. Within the subgroups of patients using and not using preventive therapies, lasmiditan and placebo groups were analyzed for the outcome of pain-free at 2 h and other efficacy outcomes. The subgroups of patients using and not using preventive therapies were compared and interaction p-values were calculated for safety and efficacy outcomes. Results In these trials, 698 of 3981 patients (17.5%) used migraine preventive treatments. Among patients using preventives, all lasmiditan doses resulted in significantly more patients being pain-free at 2 h, compared to placebo (p

Background We assessed the safety profile of lasmiditan, a selective 5-HT1F receptor agonist without vasoconstrictive activity being developed as an acute therapy for migraine. Methods SAMURAI and SPARTAN were Phase 3 double-blind studies of patients with migraine, randomized to oral lasmiditan 50 mg (SPARTAN only), 100 mg, 200 mg, or placebo to be taken within 4 hours of onset of migraine pain. Safety data from the studies were integrated. Treatment-emergent adverse events (occurring within 48 hours of first dose) were considered in the analyses. Results The safety population comprised 1262 patients assigned placebo, and 654, 1265, and 1258 assigned lasmiditan 50 mg, 100 mg, and 200 mg, respectively. There were no deaths; serious adverse events were reported for seven patients (placebo, n = 2 [0.2%]; lasmiditan 50 mg, n = 1 [0.2%]; lasmiditan 100 mg, n = 1 [0.2%]; lasmiditan 200 mg, n = 3 [0.2%]). Patients reporting ≥ 1 treatment-emergent adverse events were: Placebo, n = 174 (13.5%); lasmiditan 50 mg, n = 166 (25.4%); lasmiditan 100 mg, n = 458 (36.2%); and lasmiditan 200 mg, n = 510 (40.6%). Treatment-emergent adverse events were generally mild or moderate in severity. The most common treatment-emergent adverse events with lasmiditan were dizziness, paresthesia, somnolence, fatigue, nausea, muscular weakness and hypoesthesia. There were no ischemic events. Conclusions As a centrally-penetrant drug, lasmiditan use was associated with neurologic treatment-emergent adverse events; most were mild or moderate in severity and self-limiting. Trial registration at clinicaltrials.gov SAMURAI (NCT02439320) and SPARTAN (NCT02605174).