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The 5-HT1F receptor agonist lasmiditan as a potential treatment of migraine attacks: A review of two placebo-controlled phase II trials

Authors:
Peer Tfelt-Hansen at University of Copenhagen
Peer Tfelt-Hansen
Jes Olesen at Rigshospitalet
Jes Olesen
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Lasmiditan is a novel selective 5-HT(1F) receptor agonist. It is both scientifically and clinically relevant to review whether a 5-HT(1F) receptor agonist is effective in the acute treatment of migraine. Two RCTs in the phase II development of lasmiditan was reviewed. In the intravenous placebo-controlled RCT, lasmiditan doses of 2.5-45 mg were used, and there was a linear association between headache relief (HR) rates and dose levels (P < 0.02). For lasmiditan 20 mg, HR was 64 % and for placebo it was 45 % (NS). In the oral placebo-controlled RCT, lasmiditan doses of 50, 100, 200 and 400 mg were used. For HR, all doses of lasmiditan were superior to placebo (P < 0.05). For lasmiditan 400 mg, HR was 64 % and it was 25 % for placebo. Adverse events (AEs) emerging from the treatment were reported by 22 % of the patients receiving placebo and by 65, 73, 87 and 87 % of patients receiving 50, 100, 200 and 400 mg, respectively. The majority of AEs after lasmiditan 100 and 400 mg were moderate or severe. For the understanding of migraine pathophysiology, it is very important to note that a selective 5-HT(1F) receptor agonist like lasmiditan is effective in the acute treatment of migraine. Thus, migraine can be treated with a drug that has no vasoconstrictor ability. While lasmiditan most likely is effective in the treatment of migraine attacks it had, unfortunately, a high incidence of CNS related AEs in the oral RCT. If confirmed in larger studies in phase III, this might adversely limit the use of this highly specific non-vascular acute treatment of migraine. Larger studies including the parameters of patients' preferences are necessary to accurately position this new treatment principle in relation to the triptans.
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The 5-HT1F receptor agonist lasmiditan as a potential treatment of migraine attacks: A review of two placebo-controlled phase II tria
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... Farkkila et al reported a relatively high incidence of central nervous system (CNS)-related treatment-emergent adverse events (TEAEs) in the ph2 study, 1 which other authors have stated could affect acceptability of the drug. 5,6 However, Kuca et al and Goadsby et al have reported a lower incidence and severity of TEAEs in the ph3 studies. 3,4 In the present manuscript, we review the TEAEs from these lasmiditan studies. ...
... 1,3,4 However, published reviews discussing the ph2 study of oral lasmiditan expressed some concern about the relatively high incidence of CNS-related TEAEs (especially dizziness, vertigo, and fatigue). 5,6 However, the results of 2 ph3 studies have now been reported with the incidence and severity of these TEAEs being relatively lower. 3,4 We explored various factors which may have contributed to this difference between ph2 and ph3 TEAE reporting and found that the best explanation for the difference in the rates of TEAEs may have been related to differences in ICF documents and the methods used to record and code data. ...
Issues Impacting Adverse Event Frequency and Severity: Differences Between Randomized Phase 2 and Phase 3 Clinical Trials for Lasmiditan
Article
Full-text available
  • Jan 2020
Objective: We explore factors that may have contributed to differences in treatment-emergent adverse events in the phase 2 and phase 3 lasmiditan clinical trials. Background: Phase 2 and phase 3 trials showed that the centrally penetrant 5-HT1F agonist, lasmiditan, was effective; higher frequency and severity of adverse events (AEs) were seen in phase 2. Methods: This work represents a hybrid of a review of primary documents and study reports with additional post hoc analyses. Protocols, informed consents, data collection forms, and methodologies were reviewed. This information was supplemented by results from the clinical study reports and post hoc analyses of individual patient data from each trial. Results: For lasmiditan 100 and 200 mg, in phase 2, the incidence of ≥1 AE was 72-86% (26% severe), while in phase 3 was 36-43% (2% severe). The most common AEs in all studies were CNS-related. The phase 2 consent form was more descriptive of AEs than phase 3. In phase 2, patients recorded AEs and severity in a paper diary that warned about drowsiness and dizziness. In phase 3, patients recorded in electronic diaries whether they experienced unusual feelings after dosing with lasmiditan that they had not felt with a migraine before, and were contacted to determine if an AE had occurred. In phase 2, the AE Schwindel was variably translated from German as "vertigo" or "dizziness," while phase 3 vertigo cases were queried to ensure there was a sensation of rotation or movement. History of recurrent dizziness and/or vertigo was exclusionary in phase 3. Conclusions: This work illustrates how informed consent wording, AE collection methods, translation, exclusion criteria, and other factors may be important determinants for reporting of the frequency and severity of AEs in clinical trials.
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... It has been described that in up to 25% of the migraineurs none of the triptans is effective [274,275]. On the flip side, continued migraine treatment with triptans can be result in medication overuse headache [276] and a certain propensity for recurrence. ...
Migraine drugs
Article
Full-text available
  • Apr 2023
According to recent studies, migraine affects more than 1 billion people worldwide, making it one of the world’s most prevalent diseases. Although this highly debilitating illness has been known since ancient times, the first therapeutic drugs to treat migraine, ergotamine (Gynergen) and dihydroergotamine (Dihydergot), did not appear on the market until 1921 and 1946, respectively. Both drugs originated from Sandoz, the world’s leading pharmaceutical company in ergot alkaloid research at the time. Historically, ergot alkaloids had been primarily used in obstetrics, but with methysergide (1-methyl-lysergic acid 1′-hydroxy-butyl-(2S)-amide), it became apparent that they also held some potential in migraine treatment. Methysergide was the first effective prophylactic drug developed specifically to prevent migraine attacks in 1959. On the basis of significantly improved knowledge of migraine pathophysiology and the discovery of serotonin and its receptors, Glaxo was able to launch sumatriptan in 1992. It was the first member from the class of triptans, which are selective 5-HT1B/1D receptor agonists. Recent innovations in acute and preventive migraine therapy include lasmiditan, a selective 5-HT1F receptor agonist from Eli Lilly, the gepants, which are calcitonin gene-related peptide (CGRP) receptor antagonists discovered at Merck & Co and BMS, and anti-CGRP/receptor monoclonal antibodies from Amgen, Pfizer, Eli Lilly, and others. Graphical abstract
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... On the other hand, the 5-HT 1F receptor is prominently expressed in the neocortex, hippocampus, and dorsal raphe nucleus (Agosti, 2007;Muchimapura et al. 2003). Potent agonists for 5-HT 1F receptors can be effective in the treatment of migraine (Neeb et al., 2010;Tfelt-Hansen and Olesen, 2012). However, the effect of 5-HT 1D and 5-HT 1F receptors on learning and memory has not been reported. ...
The role of hippocampal 5-HT1D and 5-HT1F receptors on learning and memory in rats
Article
Full-text available
  • Feb 2023
  • N Schmied Arch Pharmacol
Serotonin is a neurotransmitter, which is involved in memory via its receptors. The 5-HT1D and 5-HT1F receptors mainly exist in the hippocampus, which plays an important role in memory processing. However, few studies have assessed the effect of these serotonin receptors on memory. We evaluated the effect of a 5-HT1D receptor agonist, PNU142633, 5-HT1D receptor antagonist, BRL15572 hydrochloride, and 5-HT1F receptor agonist, LY344864, on the recognition and avoidance memory in the hippocampus area. Fifty adult male Wistar rats weighing 200–250 g were divided into the control, sham-operated, PNU, BRL, and LY groups (n=10 per group). Bilateral guide cannulas were implanted into the dentate gyrus area of the hippocampus. The drugs were administered at the dose of 1 μg/μl before the novel object recognition (NOR) and passive avoidance learning (PAL) tests. The results showed that in the NOR test, the administration of PNU and LY had no significant effect on recognition index; however, the recognition index was increased by BRL. In the PAL test, the administration of PNU had no significant effect on recognition index, but the administration of BRL and LY increased the time spent in the dark compartment of the apparatus and decreased the step-through latency into the dark compartment apparatus. It can be concluded that the inhibition of the hippocampal 5-HT1D receptor improved cognition memory but impaired avoidance memory. Activation of the hippocampal 5-HT1F receptor had no effect on cognitive memory but impaired avoidance memory.
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... Hence, it cannot be claimed that lasmiditan is superior to triptans. [29] 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. [16,25] Further randomized controlled trials comparing lasmiditan and triptans are needed to compare the treatments. ...
Lasmiditan abortive therapy for episodic migraine in Phase II/ III randomized clinical trials: A meta‑analysis
Article
Full-text available
  • Feb 2023
  • INDIAN J PHARMACOL
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.
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... Lasmiditan acts on the trigeminal nerve system to inhibit neurotransmitter release without causing vasoconstriction [10,11] and therefore is not contraindicated for patients with a history of CVD. Lasmiditan has been studied in two phase 2 [12] and three phase 3 global studies [13][14][15][16] and has been approved as an oral acute treatment for migraine in the United States. Consistent with the global studies, the phase 2 randomized clinical trial (MONONOFU study) demonstrated that lasmiditan is well tolerated and effective for acute treatment of Japanese patients with migraine [17]. ...
Lasmiditan for single migraine attack in Japanese patients with cardiovascular risk factors: subgroup analysis of a phase 2 randomized placebo-controlled trial
Article
Full-text available
Background: Some migraine treatments are contraindicated for patients with cardiovascular disease (CVD) or risk factors (CVRFs). We report safety and efficacy of lasmiditan, a new oral acute migraine treatment with no cardiovascular contraindication, in Japanese patients with CVRFs. Research design and methods: MONONOFU was a multicenter, randomized, double-blind, placebo-controlled, phase 2 study of Japanese patients with migraine (met International Headache Society criteria, Migraine Disability Assessment score ≥11, disabling migraine for ≥1 year). Eligible patients were randomized (7:3:7:6) to placebo or lasmiditan 50, 100, 200 mg. This prespecified analysis described CVDs, CVRFs, and cardiovascular treatment-emergent adverse events (TEAEs). Efficacy (proportion pain-free, experienced pain relief, most bothersome symptom-free, or disability-free 2 hours post-dose) was evaluated within CVRF subgroups (≤1, ≥2). Results: Of 846 randomized patients, 691 were analyzed (CVRF≤1: 375; CVRF≥2: 316). The proportion of lasmiditan-treated patients with ≥1 TEAE was not related to CVRF numbers. Eighteen (3.8%) lasmiditan-treated and three (1.4%) placebo-treated patients reported likely cardiovascular TEAEs. Lasmiditan was more effective than placebo at relieving pain, symptoms, and disability in both CVRF subgroups. There was no consistent relationship between CVRF subgroups and efficacy. Conclusions: Lasmiditan was well tolerated and effective in Japanese patients with migraine and CVRFs. Trial registration: ClinicalTrials.gov: NCT03962738.
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... Furthermore, lasmiditan also showed benefits over placebo at 2 h in terms of the proportion of patients in global impression of change ratings and disability level ratings. The findings of this systematic review confirmed that lasmiditan was superior to placebo in relieving migraine, however, as feared earlier, there was some concern about the relatively high incidence of CNS-related AEs (especially dizziness, nausea, and fatigue) as the published reviews discussing by Peer C et al [23] and David K et al [24]. The CNS-related AEs were reported in all included studies, and remarkably increased with increasing doses compared with placebo. ...
Short-term efficacy and safety of lasmiditan, a novel 5-HT1Freceptor agonist, for the acute treatment of migraine: A systematic review and meta-analysis
Article
Full-text available
  • Jun 2020
  • J HEADACHE PAIN
Background: Migraine has been recognized as one of common diseases in the world whose current treatment options are not ideal. Lasmiditan, an oral 5-hydroxytryptamine (HT)1F receptor 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). Methods: PubMed, 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). Results: Four 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). Conclusions: This 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.
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... bind to PACAP type 1 receptor (PAC1), and/or VIP/PACAP receptor 1/2 (VPAC1/2)). However, as the clinical studies measure efficacy e.g. based on pain relief rates, headache severity scores, number of severe headache days, percent symptom/pain-free (Derosier et al., 2012;Matharu et al., 2017;Tfelt-Hansen and Olesen, 2012), the following question arises: Where do the anti-headache drugs act and how? (Dussor, 2014). Animal research has been conducted with the intent to obtain results that can answer the question but multiple aspects of the question remain unsolved. ...
The trigeminovascular system and biomarkers in migraine and cluster headache
Thesis
  • Nov 2018
The etiology of migraine and cluster headache remains unclear but a neurovascular origin has been suggested e.g. with involvement of the trigeminovascular system. Headache classification criteria are available, but a risk of misdiagnosis and delayed diagnosis exist which postpone effective treatment of the patients. Use of biomarkers would, therefore, be beneficial in the diagnostic process. An increased understanding of pathophysiological mechanisms and confounding would be valuable on the path to discover valid biomarkers. The overall aims of the PhD thesis were to increase the knowledge of the trigeminovascular system, to reveal signaling molecule profiles and to discover potential biomarkers in migraine and cluster headache. In PAPER I (https://doi.org/10.1177/0271678X17747188), the relationship between cerebral blood flow (CBF) and primary headaches, with particular focus on migraine and cluster headache, was examined by conducting a literature review. As CBF is regulated by multiple factors, it allowed us to reveal potential interconnections between multiple aspects of the pathophysiology. We observed an association between signaling molecule fluctuations in blood and the disease state or headache phases in migraine. However, inconsistencies between studies existed. In PAPER II, ... (coming up). In PAPER III (https://doi.org/10.1016/j.neuroscience.2018.10.004), the protein expression of calcitonin gene-related peptide (CGRP), pituitary adenylate cyclase-activating peptide 38 (PACAP-38) and selected headache targets in the rat and human trigeminal ganglia (TG) was investigated by means of histological techniques and western blotting. The investigated neuropeptides and headache targets were mapped to specific cell types in the rat and human TG. Potential sites of action for anti-headache drugs were identified and when comparing the rat and human TG, an overlap in expression to specific cell types was observed. In PAPER IV (https://doi.org/10.1111/head.13499), the idea about identifying homogenous subgroups within and across headache categories, based on a variety of factors, is presented. Subsequently, differential biochemical profiles and networks will be investigated across the identified clusters. Overall, the intent is to reduce within- and between-study heterogeneity to promote discovery of valid biomarkers.
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Lasmiditan: Acute Migraine Treatment Without Vasoconstriction. A Review
Article
  • Jun 2021
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-HT 1F 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.
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Lasmiditan: an additional therapeutic option for the acute treatment of migraine
Article
  • Apr 2021
Introduction: Migraine is currently listed as the second cause of ‘years lived with disability’ and the sixth cause of global disability. Despite the burden associated to the disease, availability of specific drugs is still limited. Areas covered: The authors have evaluated lasmiditan, the first ‘ditan’ approved by the Food and Drugs Administration in 2019, from a global perspective: basic chemistry, pharmacodynamic and pharmacokinetic profiles, efficacy in migraine as a 5-HT1F receptor selective agonist, tolerability and clinical safety, and impact on migraine-related disability. Our evaluation considered original papers and review articles published from 2010 to 2020. Expert opinion: Available data point to the efficacy of lasmiditan in reducing migraine pain and the most bothersome symptoms within 2 hours from oral administration. Moreover, lasmiditan has a positive effect on migraine-related disability. Its side effects mostly reflect an involvement of the central nervous system or the vestibular system, while cardiovascular side effects are rare and mild. Lasmiditan can be safely prescribed in patients who have failed non-steroid anti-inflammatory drugs or triptans or with cardiovascular risk factors. Caution is advised in frequent users, due to lack of reliable data on its abuse potential. Further data are necessary to determine the usability of lasmiditan in particular populations, e.g. children and adolescents, pregnancy.
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Lasmiditan for the Treatment of Migraines With or Without Aura in Adults
Article
  • Oct 2020
Migraines are a common form of primary headache, affecting women more than men (17.4% and 5.7% of US population, respectively, a total of 12%) that carry significant morbidity and disability, as well as a hefty healthcare price tag. They are most prevalent in women of reproductive ages and are estimated to be the 6th disease in order of causing global burden. They are estimated to cause 45.1 million years lived with disability, or 2.9% of global years lost to disability. Migraine treatment divides into acute, abortive treatment for relief of an ongoing migraine attack, and prophylactic therapy to reduce the occurrence of migraines, specifically for patients suffering from chronic and frequent episodic migraines. Traditional abortive treatment usually begins with NSAID and non-specific analgesics that are effective in curbing mild to moderate attacks. 5HT1-agonists, such as triptans, are often used for second-line and for severe attacks. Triptans are generally better tolerated in the longterm than NSAIDs and other analgesics, though they carry a significant side-effect profile and are contraindicated in large parts of the population. Prophylactic therapy is usually reserved for patients with frequent recurrence owing to medication side effects and overall poor adherence to the medication schedule. Importantly, medication overuse may actually lead to the development of chronic migraines from previously episodic attacks. Recent research has shed more light on the pathophysiology of migraine and the role of CGRP in the trigeminovascular system. Recent pharmacological advances were made in developing more specific drugs based on this knowledge, including CGRP neutralizing antibodies, receptor antagonists, and the development of ditans. These novel drugs are highly specific to peripheral and central 5-HT1F receptors and effective in the treatment of acute migraine attacks. Binding these receptors reduces the production of CGRP and Glutamate, two important ligands in the nociceptive stimulus involved with the generation and propagation of migraines. Several large clinical studies showed Lasmiditan to be effective in the treatment of acute migraine attacks. Importantly, due to its receptor specificity, it lacks the vasoconstriction that is associated with triptans and is thus safer is larger parts of the population, specifically in patients with cardiac and vascular disease. Though more research is required, specifically with aftermarket surveillance to elucidate rare potential side effects, Lasmiditan is a targeted anti-migraine drug that is both safe and effective, and carries an overall superior therapeutic profile to its predecessors. It joins the array of medications that target CGRP signaling, such as gepants and CGRP-antibodies, to establish a new line of care for this common disabling condition.
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Evidence for a Vascular Factor in Migraine
Article
Full-text available
  • Apr 2011
  • ANN NEUROL
It has been suggested that migraine is caused by neural dysfunction without involvement of vasodilatation. Because dismissal of vascular mechanisms seemed premature, we examined diameter of extra- and intracranial vessels in migraine without aura patients. A novel high-resolution direct magnetic resonance angiography imaging technique was used to measure arterial circumference of the extracranial middle meningeal artery (MMA) and the intracranial middle cerebral artery (MCA). Data were obtained at baseline, during migraine attack, and after treatment with the migraine abortive drug sumatriptan (a 5-hydroxytryptamine agonist). We found dilatation of both MMA and MCA during migraine attack (p = 0.001). Sumatriptan administration caused amelioration of headache (p < 0.001) and contraction of MMA (p < 0.001), but MCA remained unchanged (p = 0.16). Exploratory analysis revealed that in migraine attacks with half-sided headache, there was only dilatation on the headache side of MMA of 12.49% (95% confidence interval [CI], 4.16-20.83%) and of MCA of 12.88% (95% CI, 3.49-22.27%) and no dilatation on the non headache side of MMA (95% CI, -4.27 to 11.53%) and MCA (95% CI, -6.7 to 14.28%). In double-sided headache we found bilateral vasodilatation of both MMA and MCA (p < 0.001). These data show that migraine without aura is associated with dilatation of extra- and intracerebral arteries and that the headache location is associated with the location of the vasodilatation. Furthermore, contraction of extracerebral and not intracerebral arteries is associated with amelioration of headache. Collectively, these data suggest that vasodilatation and perivascular release of vasoactive substances is an integral mechanism of migraine pathophysiology.
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Mechanism of migraine headache and action of ergotamine tartrate
Article
  • Jan 1938
The observation that administration of ergotamine tartrate regularly and promptly ends the migraine headache introduced a new approach to the experimental study of this syndrome (Tzanck,¹ Lennox and von Storch,² O'Sullivan³). With this effective tool the attack can be sufficiently shortened to permit convenient analysis of certain changes that take place in the transition from the peak to the termination of the headache. Because ergotamine tartrate predominantly affects smooth muscle, inquiry concerning its action during migraine headache was centered on the cranial blood vessels. The experiments described here were performed when the phenomena which characterize the onset of an attack, namely, scotomas, blurring of vision, paresthesias and aphasia, had already passed and had been supplanted by headache. Hence these results have no bearing on preheadache phenomena. They concern only the origin of migraine pain. MATERIAL Experimental analyses were made during thirty-two attacks of migraine occurring in sixteen
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Triptans in Migraine
Article
  • Dec 2000
Triptans are a new class of compounds developed for the treatment of migraine attacks. The first of the class, sumatriptan, and the newer triptans (zolmitriptan, naratriptan, rizatriptan, eletriptan, almotriptan and frovatriptan) display high agonist activity at mainly the serotonin 5-HT1b and 5-HT1d receptor subtypes. As expected for a class of compounds developed for affinity at a specific receptor, there are minor pharmacodynamic differences between the triptans. Sumatriptan has a low oral bioavailability (14%) and all the newer triptans have an improved oral bioavailability and for one, risatriptan, the rate of absorption is faster. The half-lives of naratriptan, eletriptan and, in particular, frovatriptan (26 to 30h) are longer than that of sumatriptan (2h). These pharmacokinetic improvements of the newer triptans so far seem to have only resulted in minor differences in their efficacy in migraine. Double-blind, randomised clinical trials (RCTs) comparing the different triptans and triptans with other medication should ideally be the basis for judging their place in migraine therapy. In only 15 of the 83 reported RCTs were 2 triptans compared, and in 11 trials triptans were compared with other drugs. Therefore, in all placebo-controlled randomised clinical trials, the relative efficacy of the triptans was also judged by calculating the therapeutic gain (i.e. percentage response for active minus percentage response for placebo). The mean therapeutic gain with subcutaneous sumatriptan 6mg (51%) was more than that for all other dosage forms of triptans (oral sumatriptan 100mg 32%; oral sumatriptan 50mg 29%; intranasal sumatriptan 20mg 30%; rectal sumatriptan 25mg 31%; oral zolmitriptan 2.5mg 32%; oral rizatriptan 10mg 37%; oral eletriptan 40mg 37%; oral almotriptan 12.5mg 26%). Compared with oral sumatriptan 100mg (32%), the mean therapeutic gain was higher with oral eletriptan 80mg (42%) but lower with oral naratriptan 2.5mg (22%) or oral frovatriptan 2.5mg (16%). The few direct comparative randomised clinical trials with oral triptans reveal the same picture. Recurrence of headache within 24 hours after an initial successful response occurs in 30 to 40% of sumatriptan-treated patients. Apart from naratriptan, which has a tendency towards less recurrence, there appears to be no consistent difference in recurrence rates between the newer triptans and sumatriptan. Rizatriptan with its shorter time to maximum concentration (tmax) tended to produce a quicker onset of headache relief than sumatriptan and zolmitriptan. The place of triptans compared with non-triptan drugs in migraine therapy remains to be established and further RCTs are required.
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Preclinical pharmacological profile of the selective 5-HTIF receptor agonist lasmiditan
Article
  • Sep 2010
Introduction: Lasmiditan (also known as COL-144 and LY573144; 2,4,6-trifluoro-N-[6-[(1-methylpiperidin-4-yl)carbonyl]pyridin-2yl]benzamide) is a high-affinity, highly selective serotonin (5-HT) 5-HT(1F) receptor agonist. Results: In vitro binding studies show a K(i) value of 2.21 nM at the 5-HT(1F) receptor, compared with K(i) values of 1043 nM and 1357 nM at the 5-HT(1B) and 5-HT(1D) receptors, respectively, a selectivity ratio greater than 470-fold. Lasmiditan showed higher selectivity for the 5-HT(1F) receptor relative to other 5-HT(1) receptor subtypes than the first generation 5-HT(1F) receptor agonist LY334370. Unlike the 5-HT(1B/1D) receptor agonist sumatriptan, lasmiditan did not contract rabbit saphenous vein rings, a surrogate assay for human coronary artery constriction, at concentrations up to 100 µM. In two rodent models of migraine, oral administration of lasmiditan potently inhibited markers associated with electrical stimulation of the trigeminal ganglion (dural plasma protein extravasation, and induction of the immediate early gene c-Fos in the trigeminal nucleus caudalis). Conclusions: Lasmiditan presents a unique pyridinoyl-piperidine scaffold not found in any other antimigraine class. Its chemical structure and pharmacological profile clearly distinguish it from the triptans. The potency and selectivity of lasmiditan make it ideally suited to definitively test the involvement of 5-HT(1F) receptors in migraine headache therapy.
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The role of CGRP in the pathophysiology of migraine and efficacy of CGRP receptor antagonists as acute antimigraine drugs
Article
  • Dec 2009
Migraine is a highly prevalent neurovascular disorder that can be provoked by infusion of calcitonin gene-related peptide (CGRP). CGRP, a neuropeptide released from activated trigeminal sensory nerves, dilates intracranial and extracranial blood vessels and centrally modulates vascular nociception. On this basis, it has been proposed that: (i) CGRP may play an important role in the pathophysiology of migraine; and (ii) blockade of CGRP receptors may abort migraine.With the advent of potent and selective CGRP receptor antagonists, the importance of CGRP in the pathophysiology of migraine and the therapeutic principle of CGRP receptor antagonism were clearly established. Indeed, both olcegepant (BIBN4096BS, given intravenously) and telcagepant (MK-0974, given orally) have been shown to be safe, well tolerated and effective acute antimigraine agents in phase I, phase II, and for telcagepant phase III, studies. However, recent data reported elevated liver transaminases when telcagepant was dosed twice daily for three months for the prevention of migraine rather than acutely.The potential for a specific acute antimigraine drug, without producing vasoconstriction or vascular side effects and with an efficacy comparable to triptans, is enormous. The present review will discuss the role of CGRP in the pathophysiology of migraine and the various treatment modalities that are currently available to target this neuropeptide.
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Randomized controlled trial of the CGRP receptor antagonist MK-3207 in the acute treatment of migraine
Article
  • Mar 2011
  • CEPHALALGIA
This study evaluated the CGRP receptor antagonist MK-3207 for acute treatment of migraine. Multicenter, double-blind, randomized, placebo-controlled, parallel-group, two-stage adaptive study with two interim efficacy analyses to facilitate optimal dose selection. Migraine patients were initially randomized to MK-3207 2.5, 5, 10, 20, 50 and 100 mg or placebo to treat a moderate/severe migraine. One or more doses were to be discontinued based on the first interim analysis and a lower or higher dose could be added based on the second interim analysis. The primary endpoint was two-hour pain freedom. A total of 547 patients took study medication. After the first interim analysis, the two lowest MK-3207 doses (2.5, 5 mg) were identified as showing insufficient efficacy. Per the pre-specified adaptive design decision rule, only the 2.5-mg group was discontinued and the five highest doses (5, 10, 20, 50, 100 mg) were continued into the second stage. After the second interim efficacy analysis, a 200 mg dose was added due to insufficient efficacy at the top three (20, 50, 100 mg) doses. A positive dose-response trend was demonstrated when data were combined across all MK-3207 doses for two-hour pain freedom (p < .001). The pairwise difference versus placebo for two-hour pain freedom was significant for 200 mg (p < .001) and nominally significant for 100 mg and 10 mg (p < .05). The incidence of adverse events appeared comparable between active treatment groups and placebo, and did not appear to increase with increasing dose. MK-3207 was effective and generally well tolerated in the acute treatment of migraine.
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BI 44370 TA, an oral CGRP antagonist for the treatment of acute migraine attacks: Results from a phase II study
Article
  • Dec 2010
  • CEPHALALGIA
Four hundred and sixty-one adult subjects with migraine were randomised to one of five treatments, the oral antagonist at the calcitonin gene-related peptide (CGRP) receptor BI 44370 TA (50 mg, 200 mg, 400 mg), active comparator eletriptan 40 mg or placebo. The analysis included 341 subjects who took study medication. The primary endpoint, pain-free after two hours, was reached by significantly more subjects in the BI 44370 TA 400 mg (20/73 = 27.4%) and eletriptan 40 mg (24/69 = 34.8%) groups compared to placebo (6/70 = 8.6%, p = .0016), but not by subjects in the BI 44370 TA 200 mg group (14/65 = 21.5%). The effect of 50 mg BI 44370 TA (5/64 = 7.8%) was similar to that of placebo. Analysis of secondary endpoints supported the conclusion from the primary analysis. The frequency of adverse events was low in all groups. Efficacy of BI 44370 TA was shown in a dose-dependent manner in the treatment of acute migraine attacks.
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