Abstract
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.
Key words
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to Clinical TherapeuticsAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Migraine burden of disease: from the patient's experience to a socio-economic view: supplement article.Headache. 2018; 58: 17-32
- Recent advances in understanding migraine mechanisms, molecules and therapeutics.Trends Mol Med. 2007; 13: 39-44
- Psychosocial difficulties in patients with episodic migraine: a cross-sectional study.Neurol Sci. 2016; 37: 1979-1986
- Mechanism of migraine headache and action of ergotamine tartrate.Arch Neur Psych. 1938; 39: 737-763
- Experimental studies on headache: pain-sensitive structures of the head and their significance in headache.Arch Surg. 1940; 41: 813-856
- Vascular contributions to migraine: time to revisit?.Front Cel Neurosci. 2018; 12: 233
- Advances in pharmacological treatment of migraine.Expert Opin Investig Drugs. 2001; 10: 1831-1845
- The vascular theory of migraine - a great story wrecked by the facts.Brain. 2009; 132: 6-7
- Hypothalamic regulation of headache and migraine.Cephalalgia. 2019; 39: 1710-1719
- Neurobiology in primary headaches.Brain Res Brain Res Rev. 2005; 48: 438-456
- The trigeminovascular pathway: role of CGRP and CGRP receptors in migraine.Headache. 2017; 57: 47-55
- Migraine - current understanding and treatment.N Eng J Med. 2002; 346: 257-270
- The role of CGRP in the pathophysiology of migraine and efficacy of CGRP receptor antagonists as acute antimigraine drugs.Pharmacol Ther. 2009; 124: 309-323
- Cranioselectivity of sumatriptan revisited: pronounced contractions to sumatriptan in small human isolated coronary artery.CNS Drugs. 2014; 28: 273-278
- Comparison of the vasoconstrictor properties of the 5-HT1D-receptor agonists rizatriptan (MK-462) and sumatriptan in human isolated coronary artery: outcome of two independent studies using different experimental protocols.Funct Neurol. 1997; 12: 3-9
- Craniovascular selectivity of eletriptan and sumatriptan in human isolated blood vessels.Neurology. 2000; 55: 1524-1530
- Consensus statement: cardiovascular safety profile of triptans (5-HT agonists) in the acute treatment of migraine.Headache. 2004; 44: 414-425
- Involvement of 5-HT1B receptors in triptan-induced contractile responses in Guinea-pig isolated iliac artery.Naunyn Schmiedebergs Arch Pharmacol. 2004; 370: 54-63
- Peripheral and central trigeminovascular activation in cat is blocked by the serotonin (5HT)-1D receptor agonist 311C90.Headache. 1994; 34: 394-399
- Localization of CGRP, CGRP receptor, PACAP and glutamate in trigeminal ganglion. Relation to the blood–brain barrier.Brain Res. 2015; 1600: 93-109
- Intravital microscopy on a closed cranial window in mice: a model to study trigeminovascular mechanisms involved in migraine.Cephalalgia. 2006; 26: 1294-1303
- mRNA expression of 5-hydroxytryptamine 1B, 1D, and 1F receptors and their role in controlling the release of calcitonin gene-related peptide in the rat trigeminovascular system.Pain. 2012; 153: 830-838
- Vasoactive peptide release in the extracerebral circulation of humans during migraine headache.Ann Neurol. 1990; 28: 183-187
- Sumatriptan causes parallel decrease in plasma calcitonin gene-related peptide (CGRP) concentration and migraine headache during nitroglycerin induced migraine attack.Cephalalgia. 2005; 25: 179-183
- The rat 5-hydroxytryptamine1B receptor is the species homologue of the human 5-hydroxytryptamine1D beta receptor.Mol Pharmacol. 1992; 41: 1-7
- Microiontophoretic application of serotonin (5HT)1B/1D agonists inhibits trigeminal cell firing in the cat.Brain. 1997; 120: 2171-2177
- Is selective 5-HT1F receptor agonism an entity apart from that of the triptans in antimigraine therapy?.Pharmacol Ther. 2018; 186: 88-97
- Lasmiditan mechanism of action - review of a selective 5-HT1F agonist.J Headache Pain. 2020; 21: 71
- Targeted 5-HT1F therapies for migraine.Neurotherapeutics. 2018; 15: 291-303
- Selective serotonin 1F (5-HT(1F)) receptor agonist LY334370 for acute migraine: a randomised controlled trial.Lancet. 2001; 358: 1230-1234
- Emerging therapeutic options for acute migraine: focus on the potential of lasmiditan.Neuropsychiatr Dis Treat. 2014; 10: 547-552
- Pharmacokinetics and pharmacodynamics of new acute treatments for migraine.Expert Opin Drug Metab Toxicol. 2019; 15: 189-198
- Preclinical pharmacological profile of the selective 5-HT1F receptor agonist lasmiditan.Cephalalgia. 2010; 30: 1159-1169
- Recent advances in pharmacotherapy for episodic migraine.CNS Drugs. 2019; 33: 1053-1071
- Migraine therapy: relationship between serotonergic contractile receptors in canine and rabbit saphenous veins to human cerebral and coronary arteries.Cephalalgia. 1997; 17: 631-638
- Characterization of binding, functional activity, and contractile responses of the selective 5-HT1F receptor agonist lasmiditan.Br J Pharmacol. 2019; 176: 4681-4695
- 5-HT(1F) receptor agonists: a new treatment option for migraine attacks?.Neurotherapeutics. 2010; 7: 176-182
- Lasmiditan acts specifically on the 5-HT1F receptor in the central nervous system.Cephalalgia. 2016; 36: 103
- Lasmiditan inhibits CGRP release in the mouse trigeminovascular system.Cephalalgia. 2017; 37: 362
- Evidence for serotonin (5-HT)1B, 5-HT1D and 5-HT1F receptor inhibitory effects on trigeminal neurons with craniovascular input.Neuroscience. 2003; 122: 491-498
- Colocalization of 5-HT1F receptor and calcitonin gene-related peptide in rat vestibular nuclei.Neurosci Lett. 2009; 465: 151-156
- Acute migraine therapy: new drugs and new approaches.Curr Treat Options Neurol. 2011; 13: 1-14
- Pathophysiological mechanisms in migraine and the identification of new therapeutic targets.CNS Drugs. 2019; 33: 525-537
- 5-hydroxytryptamine 1F receptor agonist induces mitochondrial biogenesis and promotes recovery from spinal cord injury.J Pharmacol Exp Ther. 2020; 372: 216-223
- Mitochondrial migraine: disentangling the angiopathy paradigm in m.3243A>G patients.JIMD Rep. 2019; 46: 52-62
- COL-144, an orally bioavailable selective 5-HT1F receptor agonist for acute migraine therapy.Cephalalgia. 2009; 29: 24-25
- Lasmiditan for the treatment of migraine.Expert Opin Investig Drugs. 2017; 26: 227-234
- Acute treatment of migraine with the selective 5-HT1F receptor agonist lasmiditan - a randomised proof-of-concept trial.Cephalalgia. 2010; 30: 1170-1178
- Efficacy and tolerability of lasmiditan, an oral 5-HT(1F) receptor agonist, for the acute treatment of migraine: a phase 2 randomised, placebo-controlled, parallel-group, dose-ranging study.Lancet Neurol. 2012; 11: 405-413
- Lasmiditan is an effective acute treatment for migraine: a phase 3 randomized study.Neurology. 2018; 91: e2222-e2232
- Phase 3 randomized, placebo-controlled, double-blind study of lasmiditan for acute treatment of migraine.Brain. 2019; 142: 1894-1904
- Interim results of a prospective, randomized, open-label, phase 3 study of the long-term safety and efficacy of lasmiditan for acute treatment of migraine (the GLADIATOR study).Cephalalgia. 2019; 39: 1343-1357
- Lasmiditan for the acute treatment of migraine: subgroup analyses by prior response to triptans.Cephalalgia. 2020; 40: 19-27
- Therapeutic novelties in migraine: new drugs, new hope?.J Headache Pain. 2019; 20 ([Erratum J Headache Pain. 20:55]): 37
- Emerging drugs for migraine treatment: an update.Expert Opin Emerg Drugs. 2018; 23: 301-318
- Onset of efficacy following oral treatment with lasmiditan for the acute treatment of migraine: integrated results from 2 randomized double-blind placebo-controlled phase 3 clinical studies.Headache. 2019; 59: 1788-1801
- Lasmiditan in patients with common migraine comorbidities: a post hoc efficacy and safety analysis of two phase 3 randomized clinical trials.Curr Med Res Opin. 2020; 36: 1791-1806
- Sustained responses to lasmiditan: results from post-hoc analyses of two phase 3 randomized clinical trials for acute treatment of migraine.Cephalalgia. 2019; 39: 1569-1576
- Safety findings from phase 3 lasmiditan studies for acute treatment of migraine: results from SAMURAI and SPARTAN.Cephalalgia. 2019; 39: 957-966
- Effect of a rescue or recurrence dose of lasmiditan on efficacy and safety in the acute treatment of migraine: findings from the phase 3 trials (SAMURAI and SPARTAN).BMC Neurol. 2019; 19: 191
- Efficacy and safety of lasmiditan in patients using concomitant migraine preventive medications: findings from SAMURAI and SPARTAN, two randomized phase 3 trials.J Headache Pain. 2019; 20: 84
- Lasmiditan for acute treatment of migraine in patients with cardiovascular risk factors: post-hoc analysis of pooled results from 2 randomized, double-blind, placebo-controlled, phase 3 trials.J Headache Pain. 2019; 20: 90
- Improvement in function after lasmiditan treatment: post hoc analysis of data from phase 3 studies.Neurol Ther. 2020; 9: 459-471
- Characterization of dizziness after lasmiditan usage: findings from the SAMURAI and SPARTAN acute migraine treatment randomized trials.Headache. 2019; 59: 1052-1062
- Evaluation of 2-hour post-dose efficacy of lasmiditan for the acute treatment of difficult-to-treat migraine attacks.Headache. 2020; 60: 1601-1615
- Trajectory of migraine-related disability following long-term treatment with lasmiditan: results of the GLADIATOR study.J Headache Pain. 2020; 21: 20
- Long-term safety and efficacy of lasmiditan for acute treatment of migraine: final results of the GLADIATOR study.Cephalalgia Rep. 2020; 3: 1-5
- Short-term efficacy and safety of lasmiditan, a novel 5-HT1F receptor agonist, for the acute treatment of migraine: a systematic review and meta-analysis.J Headache Pain. 2020; 21: 66
- Issues impacting adverse event frequency and severity: differences between randomized phase 2 and phase 3 clinical trials for lasmiditan.Headache. 2020; 60: 576-588
- Lasmiditan for acute treatment of migraine in adults: a systematic review and meta-analysis of randomized controlled trials.CNS Drugs. 2020; 34: 1015-1024
- The efficacy of lasmiditan for the treatment of migraine: a meta-analysis of randomized controlled studies.Clin Neuropharmacol. 2020; 43: 191-195
- Pain freedom at 2 to 8 hours with lasmiditan: a comparison with rimegepant and ubrogepant.Headache. 2020; 60 (Online ahead of print): 1793-1796
- Lasmiditan: first approval.Drugs. 2019; 79: 1989-1996
- The pharmacological profile and clinical prospects of the oral 5-HT1F receptor agonist lasmiditan in the acute treatment of migraine.Ther Adv Neurol Disord. 2015; 8: 46-54
- Profiling lasmiditan as a treatment option for migraine.Expert Opin Pharmacother. 2020; 21: 147-153
- Lasmiditan inhibits calcitonin gene-related peptide release in the rodent trigeminovascular system.Pain. 2020; 161: 1092-1099
- Lasmiditan for the acute treatment of migraine.Headache. 2020; 60: 1225-1226
- Effects of lasmiditan on simulated driving performance: results of two randomized, blinded, crossover studies with placebo and active controls.Hum Psychopharmacol. 2020; 35e2732
- Current management: migraine headache.CNS Spectr. 2017; 22: 1-13
- Examination of unmet treatment needs among persons with episodic migraine: results of the American Migraine Prevalence and Prevention (AMPP) study.Headache. 2013; 53: 1300-1311
- Side effects associated with current and prospective antimigraine pharmacotherapies.Expert Opin Drug Metab Toxicol. 2018; 14: 25-41
- Pharmacological treatment of migraine: CGRP and 5-HT beyond the triptans.Pharmacol Ther. 2020; 211: 107528
- Drugs targeting 5-hydroxytryptamine receptors in acute treatments of migraine attacks. A review of new drugs and new administration forms of established drugs.Expert Opin Investig Drugs. 2014; 23: 375-385
- Migraine.N Engl J Med. 2020; 383: 1866-1876
- Novel therapies in acute migraine management: small-molecule calcitonin gene-receptor antagonists and serotonin 1F receptor agonist.Ann Pharmacother. 2020; (1060028020963574)
- Triptans and CNS side-effects: pharmacokinetic and metabolic mechanisms.Cephalalgia. 2004; 24: 417-424
- Adverse reactions related to drugs for headache treatment: clinical impact.Eur J Clin Pharmacol. 2005; 60: 893-900
- What do patients with migraine want from acute migraine treatment?.Headache. 2002; 42: 3-9
- What do patients want from acute migraine treatment?.Cephalalgia. 2004; 24: 8-15
- What do patients consider to be the most important outcomes for effectiveness studies on migraine treatment? Results of a Delphi study.PLoS One. 2014; 9e98933
- Abuse potential of lasmiditan: a phase 1 randomized, placebo- and alprazolam-controlled crossover study.J Clin Pharmacol. 2020; 60: 495-504
- Medication overuse and chronic migraine: a critical review according to clinical pharmacology.Expert Opin Drug Metab Toxicol. 2015; 11: 1127-1144
- Evaluation of LY573144 (lasmiditan) in a preclinical model of medication overuse headache.Cephalalgia. 2020; 40: 903-912
- Polypharmacy among headache patients: a cross-sectional study.CNS Drugs. 2018; 32: 567-578
- Serotonin syndrome: pathophysiology, clinical features, management, and potential future directions.Int J Tryptophan Res. 2019; 12 (1178646919873925)
- Lasmiditan: its development and potential use.Clin Pharmacol Drug Dev. 2020; 9: 292-296
- Effects of lasmiditan on cardiovascular parameters and pharmacokinetics in healthy subjects receiving oral doses of propranolol.Clin Pharmacol Drug Dev. 2020; 9: 629-638
- The potential of lasmiditan in migraine.Ther Adv Neurol Disord. 2020; 13 (1756286420967847)
Article info
Publication history
Published online: February 16, 2021
Accepted:
January 25,
2021
Identification
Copyright
© 2021 Elsevier Inc.
