|ORIGINAL RESEARCH ARTICLE
|Year : 2022 | Volume
| Issue : 6 | Page : 397-406
Lasmiditan abortive therapy for episodic migraine in Phase II/III randomized clinical trials: A meta-analysis
Marya Ahsan1, Ayaz Khurram Mallick2
1 Department of Pharmacology, College of Medicine, Imam Mohammad Ibn Saud Islamic University, Riyadh, Saudi Arabia
2 Department of Clinical Biochemistry, College of Medicine, King Khalid University, Abha, Saudi Arabia
|Date of Submission||27-Nov-2021|
|Date of Decision||08-Dec-2022|
|Date of Acceptance||10-Dec-2022|
|Date of Web Publication||31-Jan-2023|
Department of Pharmacology, College of Medicine, Imam Mohammad Ibn Saud Islamic University, Riyadh 13317
Source of Support: None, Conflict of Interest: None
OBJECTIVE: Although migraine is common, there are very few treatment options. Recently, lasmiditan, a specific 5-HT1F agonist, has gained approval as abortive therapy for migraine. This meta-analysis and trial sequential analysis (TSA) was performed to analyze efficacy and tolerability of lasmiditan therapy for episodic migraine.
MATERIALS AND METHODS: Phase II and Phase III double-blinded placebo-controlled randomized controlled trials (RCTs) evaluating lasmiditan for episodic migraine were searched for from electronic databases. The risk of bias was estimated, data were extracted, and relative risk (RR) were calculated for efficacy and safety outcomes with a fixed/random effect model. Forest plots and funnel plots were created. TSA graph was plotted. Therapeutic gain with lasmiditan was calculated.
RESULTS: Six high-quality RCTs were included with 7122 patients. Compared to placebo, lasmiditan demonstrated a significant proportion of migraineurs reporting freedom from headache, most bothersome symptom, headache response, no disability, global impression “very much/much better” 2 h posttreatment and sustained pain freedom at 24 and 48 h with 50, 100, 200, and 400 mg doses (RR range = 1.26–2.50). 39.3% of patients in the lasmiditan group (RR = 2.43) reported one or more treatment-emergent adverse event (TEAE). Dizziness, somnolence, paresthesia, fatigue, nausea, vertigo, hypoesthesia, asthenia, muscular weakness, lethargy, and malaise had a high incidence (RR range = 3.16–12.77). Most TEAEs were mild to moderate. No vasoconstriction-related TEAE was reported.
CONCLUSION: Lasmiditan demonstrated efficacy as abortive therapy for episodic migraine with central nervous system-related side effects.
Keywords: Episodic migraine, lasmiditan, meta-analysis, migraineurs, trial sequential analysis
|How to cite this article:|
Ahsan M, Mallick AK. Lasmiditan abortive therapy for episodic migraine in Phase II/III randomized clinical trials: A meta-analysis. Indian J Pharmacol 2022;54:397-406
|How to cite this URL:|
Ahsan M, Mallick AK. Lasmiditan abortive therapy for episodic migraine in Phase II/III randomized clinical trials: A meta-analysis. Indian J Pharmacol [serial online] 2022 [cited 2023 Mar 23];54:397-406. Available from: https://www.ijp-online.com/text.asp?2022/54/6/397/368846
| » Introduction|| |
The Global Burden of Disease Study of 2019 ranked headache disorders third in the years lived with disability, of which 88.2% were attributed to migraine alone. Patients of migraine suffer from recurrent, unilateral, pulsatile headache, often debilitating in nature and associated with nausea, vomiting, phonophobia, or photophobia., In almost a quarter of cases, migraine headaches can be preceded by an aura. Auras are commonly described as visual symptoms but can also be auditory, olfactory, or somatosensory in nature. The standard treatment of acute migraine has been nonsteroidal anti-inflammatory drugs (NSAIDs) or specific anti-migraine drugs (triptans and ergot alkaloids). While mild headaches are effectively treated with NSAIDs, moderate-to-severe migraine headaches warrant the use of a triptan. However, patients exhibit varying treatment responses to triptans, and around 30%–40% of patients are either refractory to them, experience intolerable adverse effects, or have contraindications for the use of triptans., Lack of efficacy of abortive treatments can also lead to overuse headaches and increased risk of transformed migraine (conversion from episodic to chronic migraine).
Ditans are a novel class of anti-migraine drugs that target 5-HT1F receptors localized on the trigeminal pathway and are classified as “neurally acting anti-migraine agents” or “NAAMA.” The Food and Drug Administration (FDA) approved lasmiditan, the first in its class, for abortive migraine therapy. It is a highly selective 5-HT1F receptor agonist with a much higher affinity for 5-HT1F serotonin receptor subtype than 5-HT1B/1D receptors (selectivity ratio >470 fold). This accounts for the absence of vasoconstriction with lasmiditan, unlike triptans., In preclinical studies, lasmiditan decreased the trigeminal ganglion stimulation markers, thus reducing extravasation of dural plasma proteins and c-fos expression. It can prove to be especially valuable for patients who respond poorly to triptans, experience adverse effects, or have cardiovascular contraindications to triptan use. However, data from placebo-controlled trials revealed a high incidence of central nervous system (CNS)-related adverse events, which could be due to rapid penetration of the drug in the CNS. It comes with advice to not drive or operate machinery after use.,
Although a meta-analysis of lasmiditan efficacy has been conducted, it included data from only four trials involving white ethnic groups largely.,,,, Recently, new high-quality randomized controlled trials (RCTs), based on risk of bias assessment, involving different ethnicities have been concluded, which were not part of earlier published meta-analysis., Hence, this systematic review and meta-analysis with trial sequential analysis (TSA) of Phase II/Phase III randomized trials was performed to comprehensively evaluate the efficacy and tolerability profile of lasmiditan therapy for acute episodic migraine and to estimate the therapeutic gain (TG) of lasmiditan therapy.
| » Materials and Methods|| |
PRISMA-2020 checklist was used for drafting the updated systematic review and meta-analysis. We used the Saudi Digital Library to systematically search the electronic databases MEDLINE, Web of Science, and EBSCOhost for indexed, peer-reviewed literature in English from inception till September 2021. Boolean phrase with keywords (”Migraine” OR “Episodic Migraine” OR “Migraineur”) AND (”Ditans” OR “Lasmiditan” OR “COL-144” OR “LY573144”) was used to conduct the search. The NIH U.S. National Library of Medicine (ClinicalTrials.Government) was searched for registered clinical trials on lasmiditan. Reviews were scanned to identify any additional studies.
ENDNote software [Clarivate (formerly Clarivate Analytics), Philadelphia, United States] was used to remove duplicates while Rayyan QCRI (http://rayyan.qcri.org) was employed to screen the studies. Titles and abstracts were screened to select eligible studies. Full text of eligible articles was then reviewed by two authors (MA and AKM). Conflicts were addressed by discussion or consultation with an independent reviewer.
Inclusion and exclusion criteria
Clinical trials fulfilling the following criteria were included: Phase II/Phase III, double-blinded, placebo-controlled, parallel-group, and RCTs among adults of either genders suffering from episodic migraine (<15 migraine attacks per month) as per the International Headache Society (IHS) Criteria 1.1 and 1.2. The experimental arm in the study received lasmiditan in 50/100/200/400 mg oral doses or equivalent intravenous (IV) dose while the control received matched placebo. Preclinical studies, Phase I clinical trials, nonrandomized, and open-labeled trials were not included. Studies on patients diagnosed with chronic migraine, tension headache, or other headache disorders and treated with NSAIDs, triptans, ergot alkaloids, or CGRP-based therapies were excluded. Case reports, case series, reviews, and post hoc analysis or multiple reports of the same study were excluded.
Efficacy outcome measures
Patients who were headache free, those who reported headache response and relieved from the most bothersome symptom (MBS) at 2 h posttreatment were the efficacy measures included in the meta-analysis. In addition, patients who demonstrated sustained pain freedom at 24 h and 48 h, absence of migraine-related disability at 2 h (level 0 on a 4-point scale), and reporting a global impression of change or improvement as “very much or much better” on a 7-point scale were also included as efficacy measures.
Safety outcome measures
The safety outcome measure was the proportion of participants who experienced treatment-emergent adverse events (TEAEs). Meta-analysis was performed of the most commonly reported TEAEs in the included studies.
Risk of bias assessment
The risk-of-bias tool developed by Cochrane Collaboration was used for assessing the quality of the individual studies. The tool consists of seven domains on which the studies are judged such as random sequencing, allocation concealment, patient and personnel blinding, assessment blinding, data completeness, selective reporting, and other biases. Two authors independently assessed the included studies for each of the domains in the risk of bias tool, and judged as “low, unclear, or high” risk of bias. Disagreements were sorted after discussion. A third independent reviewer was also consulted.
We developed a standardized form and used it for extracting the following data: study details (first author, publication year, design and place, intervention groups, and primary outcome measures) and baseline patient and headache characteristics (age, gender, ethnicity, migraine frequency/month, and migraine severity at baseline). The efficacy and safety outcome measures were also extracted from individual studies. Data were extracted only for the first attack treated. Both published and unpublished data from clinical trial registries were retrieved.
The RevMan 5.4.1 was employed to conduct meat-analysis on the extracted data. Efficacy and adverse event dichotomous data were evaluated by Relative risk (RR) with 95% confidence intervals (CI) using the Mantel–Haenszel method. P < 0.05 was cutoff for significance. Chi-square and I2 statistics were used for evaluating heterogeneity between trials with a fixed or random-effect model. In case of I2 value of more than 50%, the random effect model was preferred. Heterogeneity was reduced by excluding individual studies after performing sensitivity analysis. Type I and Type II errors in the meta-analysis due to sparse data or repetitive testing of accumulating data were evaluated by TSA. Publication bias was assessed with visual representation on funnel plots. TG and numbers needed to treat (NNT) were calculated to estimate each study's absolute magnitude of effect.
| » Results|| |
The PRISMA-2020 flow chart is depicted in [Figure 1]. A literature search of the databases and trial registry for relevant studies yielded 429 records. After removing duplicates, the title and abstract of 209 studies were screened. Reviews, meeting abstracts, editorials, letters to the editor, post hoc analyses of earlier studies, and irrelevant studies were removed. Finally, six randomized clinical trials fulfilled the inclusion criteria. Both the published articles and study results on trial registries were sought for meta-analysis.,,,,,,,,,,,
|Figure 1: PRISMA 2020 flowchart for identifying eligible studies for updated systematic review and meta-analysis.* = Studies identified from previous meta-analysis were eliminated during identification of new studies to avoid repetition|
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Characteristics of the included studies
Of the six studies included, three were Phase II, while three were Phase III RCTs.,,,,,,,,,,, Although all the trials were multicenter, SAMURAI was conducted only in the USA, and MONONOFU was conducted in Japan., While Ferrari et al. employed IV lasmiditan, oral lasmiditan ranging from 50 to 400 mg was the trial drug in five studies. Only a single attack of migraine was treated in five RCTs. Patients enrolled in CENTURION were treated for four attacks of migraine [Table 1].
|Table 1: Characteristics of included studies and baseline characteristics of participants|
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Baseline patient and headache characteristics
A total of 7122 adult patients diagnosed with migraine based on IHS 1.1 and 1.2 criteria were analyzed in the six RCTs, with a mean age of 41.85 ± 11.4 years. Almost 85% of the participants were female. The average frequency of migraine headaches/month over the preceding 3 months was 4.6 ± 1.8. The treated headache was moderate in 65% of patients and severe in 23% of patients. Ferrari et al. included patients with moderate-to-severe headaches but did not mention the number in each category., All the patients received the test drug within 4 h of headache [Table 2].
|Table 2: Comparison of efficacy outcomes between lasmiditan and placebo groups|
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Risk of bias assessment
Selection bias was evaluated as “low risk” as random sequence generation and allocation concealment was described by the included studies. All included studies had quadruple masking of patients, health-care providers, investigators, and assessors. Thus, performance and detection bias were also classified as “low risk.” Attrition bias and reporting bias risks were classified “low risk” as participants in the studies used a headache diary (e-diary or paper diary) to record symptoms at regular intervals. There was insignificant loss of data in all the included RCTs [Figure 2].
|Figure 2: Risk of bias summary: Review authors' judgments about each risk of bias item for each included study|
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Headache-free at 2 h
All the studies reported headache freedom at 2 h. Almost 30% treated with lasmiditan were headache-free 2 h posttreatment, and TG was 15% while the NNT = 7 [Table 2]. Forest plot of the data, favored lasmiditan over placebo for achieving headache-free state at 2 h (RR = 1.99, 95% CI [1.69, 2.35], P < 0.0001, I2 = 68%). Sensitivity analysis showed that heterogeneity decreased to an insignificant level (I2 = 39%) when a study by Ashina et al. was excluded. Lasmiditan was superior to placebo at all doses for achieving headache freedom. TG increased from 8% with 50 mg to 13% for 400 mg dose [Table 2] and [Figure 3].
|Figure 3: Forest plot of comparison of the number of patients headache-free at 2 h interval postdosing|
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Headache response at 2 h
Significantly greater proportion of patients reported headache response at 2 h postdose with lasmiditan compared to placebo (RR = 1.45, 95% CI [1.36, 1.55], P < 0.00001, I2 = 55%). Although heterogeneity was moderate, it was further reduced by removing Färkkilä et al.'s study from analysis (I2 = 25%). The TG of lasmiditan for headache response was 19% with NNT = 5. Lasmiditan was favored over placebo in all subgroups of comparison, and TG increased with increasing dose (11%–39%) [Table 2].
Most bothersome symptom-free at 2 h
Patients on lasmiditan had a greater chance of being MBS-free at 2 h posttreatment (RR = 1.34, 95% CI [1.26–1.42], P < 0.00001, I2 = 0%). Studies by Ferrari et al. and Färkkilä et al. demonstrated improvement of specific symptoms (vomiting, photophobia, and phonophobia) but did not identify the most bothersome symptom and was not included in the meta-analysis, [Table 2].
Five studies reported on sustained-pain freedom till 24 h, while four studies reported on sustained-pain freedom till 48 h. Lasmiditan was superior to placebo for sustained pain freedom at 24 and 48 h, RR = 1.88, 95% CI (1.68, 2.10), P < 0.00001, I2 = 68% and RR = 1.73, 95% CI (1.54, 1.95), P < 0.00001, I2 = 58%, respectively. Heterogeneity was moderate for which Goadsby et al.'s study was excluded for 24 h assessment and Ashina et al. for 48 h assessment to yield I2 = 30% and I2 = 35%, respectively., Response was similar between 50 mg dose and placebo at 48 h assessment (RR = 1.27, 95% CI [0.97, 1.65], P = 0.08, I2 = 0%) [Table 2].
Global impression at 2 h
Pooled data from all the six trials revealed that 38% of patients reported improvement as much or very much better at 2 h (RR = 1.68, 95% CI [1.57–1.79], P < 0.00001, I2 = 46%). TG (16%) was similar for the 100 mg and 200 mg doses of lasmiditan over placebo [Table 2].
Disability at 2 h
All the trials reported disability level 2 h posttreatment. However, Ferrari et al. reported combined patients with “no” or “mild” disability and were not included for meta-analysis., Although 29% of patients treated with lasmiditan had no disability 2 h posttreatment (RR = 1.50, 95% CI [1.39–1.62], P < 0.00001, I2 = 8%) the TG was only 10%. There was no significant difference between the different doses of lasmiditan in achieving “no disability” at 2 h (χ2 = 4.00, P = 0.26, I2 = 24.9%) on the fixed-effect model [Table 2].
TEAEs were reported by all the six included studies in our meta-analysis. Meta-analysis revealed a higher incidence of at least one TEAE among the lasmiditan group (RR = 2.57, 95% CI [2.10–3.14], P < 0.00001, I2 = 90%). The very high level of heterogeneity can be explained by the difference in collecting data among the studies. Although Färkkilä et al., Goadsby et al., and Ashina et al. reported treatment-related serious adverse events (SAEs), only Ashina et al. reported withdrawal of therapy as a result of adverse events.,, Although six SAEs were reported in the lasmiditan group, it was not statistically significant. Färkkilä et al. reported that a woman receiving 200 mg dose of lasmiditan was admitted overnight for dizziness but recovered completely the next day after receiving saline infusion. Goadsby et al. reported dystonic reaction (with 100 mg) and presyncope (with 200 mg) associated with residual effects while Ashina et al. reported asthma (100 mg), hemiplegic migraine and serotonin syndrome (200 mg).,, None of the studies reported any death due to the drug [Table 3].
|Table 3: Comparison of treatment emergent adverse events between lasmiditan and placebo groups|
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Adverse events with lasmiditan were mostly CNS-related. Dizziness was reported by 20% of patients (RR = 6.03, 95% CI [4.76–7.65]) followed by almost 7% of patients reporting somnolence (RR = 3.16, 95% CI [2.35–4.26]) and 7% reporting paresthesia (RR = 4.72, 95% CI [3.28–6.78]). Fatigue was reported in 6% cases, nausea in 5% cases, and vertigo in 3% cases [Table 3]. Lethargy, hypoesthesia, asthenia, malaise, and muscular weakness were also significantly greater in the lasmiditan group. Cardiovascular-related adverse events were mostly palpitations in all the six studies (RR = 3.37, 95% CI [1.82–6.23], P < 0.001, I2 = 0%). No vasoconstriction-related adverse event like angina was reported in any of the studies [Table 3].
Trial sequential analysis
For performing the TSA, the Type I error was fixed at 1%, the Type II error at 10%, and the power of the study was set at 90%. The cumulative Z-score crossed all set boundaries (conventional testing and α-spending), yielding substantial evidence for lasmiditan efficacy in relieving headache at 2 h [Figure 4]. A similar TSA was obtained for other efficacy outcome measures.
|Figure 4: Trial sequential analysis for the proportion of patients headache-free at 2 h. The Cumulative Z-score (blue line) crossed the conventional boundary (horizontal red lines) and the trial sequential monitoring boundary (upper O'Brien Flemming, α = 1%, β = 10%, red vertical line). Required information size was calculated as 1161 patients|
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A study of the funnel plot of all the included studies did not present any apparent asymmetry [Figure 5].
|Figure 5: Funnel plot of comparison: Headache-free at 2 h postdosing. No obvious asymmetry|
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| » Discussion|| |
Unlike, the triptans which bind to 5-HT1B/1D and 5-HT1F receptors, this new class of drug is highly selective. Lasmiditan binds to 5-HT1F and has low cross-reactivity for other serotonin receptors. 5-HT1F is mainly localized in the nucleus caudalis and trigeminal ganglion. Stimulation of the 5-HT1F receptor hyperpolarizes the nerve terminals, thereby inhibiting trigeminal impulses. Although 5-HT1F receptors are present on the middle cerebral artery, they possess no vasoconstrictor activity. Several compounds were developed as the 5-HT1F agonists or the “ditans.” Among drugs used in clinical trials (lasmiditan and LY334370), trials with LY334370 had to be prematurely stopped because of reports of hepatotoxicity in dogs. The FDA approved lasmiditan (REYVOW™) in 2019 as a result of positive efficacy and safety data from Phase III studies (SAMURAI and SPARTAN).,,
This updated meta-analysis of six high-quality Phase II and III double-blinded placebo-controlled RCTs confirmed that lasmiditan is superior to placebo for managing acute migraine attacks in patients of episodic migraine. We performed TSA to adjust for random errors and found reliable and conclusive evidence in our meta-analysis [Figure 4]. The efficacy outcomes following the treatment of a single and first attack of migraine were evaluated. A significantly greater number of migraineurs reported freedom from headache and headache response with lasmiditan, at all doses, compared to placebo. Headache response was described as declining severity of headache (to “mild” or “no headache”) 2 h posttreatment. There was a dose-effect response, and a linear association was seen between an increasing dose of lasmiditan and response to treatment [Table 2].
Moreover, a more significant number of headache-free patients at 2 h did not require a repeat dose and experienced sustained headache freedom at 24 and 48 h. This sustained response in headache freedom was also dose related. In addition, lasmiditan was superior for associated symptoms such as photophobia or phonophobia. Almost 47% of patients who identified their most-bothersome symptom were relieved at 2 h with lasmiditan. Patient's global impression of improvement and patients having “no disability” was significantly higher in the lasmiditan group for all doses [Table 2].
In a long-term open-labeled study (GLADIATOR), similar consistent results were seen in patients treated intermittently for multiple attacks of migraine over 1 year in both the 100 and 200 mg lasmiditan group for pain-freedom (29.4%) and MBS-freedom (38.8%) at 2 h.
To estimate the absolute magnitude of effect and aid in decision-making, we calculated the TG (percentage difference between lasmiditan and placebo) and NNT (number of cases receiving treatment, before at least one case benefits from treatment) from the pooled data on headache relief. The TG with lasmiditan was highest for headache response at 2 h (TG = 19%, NNT = 5) [Table 2]. However, earlier studies have revealed a TG of 33% for oral sumatriptan and 51% for subcutaneous sumatriptan. Hence, it cannot be claimed that lasmiditan is superior to triptans. Ashina et al. preclassified the patients based on prior response to triptans into triptan-sufficient responders, triptan-insufficient responders (TIR), and triptan-naïve patients at baseline and found lasmiditan to be efficacious for the TIR population., Further randomized controlled trials comparing lasmiditan and triptans are needed to compare the treatments.
The proportion of cases reporting TEAEs was significantly greater with lasmiditan (39.3%) compared to placebo (17.8%). Higher doses resulted in greater incidence of adverse events. However, significant heterogeneity was reported among the studies in the meta-analysis. Although six treatment-related SAEs such as dystonic reactions, presyncope asthma, hemiplegic migraine, serotonin syndrome, and hospital admission for dizziness were reported were reported, only Ashina et al. reported discontinuation of therapy due to TEAEs. Most common TEAEs were CNS related, with dizziness being reported in almost 20% of patients on lasmiditan. Other CNS-related adverse events were somnolence, paresthesia, fatigue, nausea, asthenia, hypoesthesia, vertigo, and lethargy [Table 3]. Lasmiditan is a highly lipid-soluble drug and easily enters the CNS. This property can explain the high incidence of CNS-TEAEs. Lasmiditan has been approved with precaution not to operate machinery and drive within 8 h of dosing. However, none of the trials reported any accidents or injuries as a result of CNS-TEAEs. Ashina et al. and Sakai et reported a higher incidence of muscular weakness (reported by more than 2% of the population)., This could be because of a larger proportion of Asian ethnicities enrolled in these trials. Interestingly, Ashina et al. treated four migraine attacks and found that the incidence of TEAEs declined with subsequent use of lasmiditan. Similar safety findings were also reported in the long-term safety study GLADIATOR.
Although patients were cardiovascular-risk factors were enrolled in the studies, only mild-to-moderate cardiovascular TEAEs, most commonly palpitations, were reported [Table 3]. Events due to vasoconstriction, such as angina, and hypertension, were not reported following lasmiditan, making it a promising alternative for patients with cardiovascular contraindications to triptans.
| » Conclusion|| |
We found lasmiditan to be effective and safe for abortive treatment of episodic migraine, but with a high incidence of CNS-related adverse events. Whether lasmiditan is suitable for long-term use remains to be seen. Moreover, future RCTs are needed for head-on comparison of lasmiditan with other standard drugs used for abortive therapy to evaluate the superior treatment option.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
[Table 1], [Table 2], [Table 3]