piperidines and Migraine-Disorders

Migraine is a common neurological disorder that is present in a large proportion of the global population. It is estimated to occur in around 20.7% of women and 10.7% of men in the United States. The pathophysiology of migraine is a major focus of research, and medications have been developed to interrupt the processes that generate headache and other bothersome symptoms of migraine attacks. The triptan class of medications acts as a direct agonist at the 5-HT1B/D receptor but its use is limited by contraindications for those with coronary or cerebrovascular disease. Lasmiditan is a first-in-class agonist at the 5-HT1F serotonin receptor that does not appear to generate vasoconstriction. This article reviews the design, development, and place in therapy for lasmiditan. A narrative review of the literature using the Ovid MEDLINE database was performed. The rationale behind the development of lasmiditan and pre-clinical, proof-of-concept, Phase II, pivotal, Phase III trials and post-hoc data is covered. Additionally, the efficacy and safety of lasmiditan when compared to other acute treatments in migraine is described, including lasmiditan's side effect profile and status as a Schedule V substance. Further, head-to-head studies of lasmiditan compared with other acute treatments are required.

Topics: Adult; Female; Humans; Male; Migraine Disorders; Piperidines; Pyridines; Serotonin Receptor Agonists; Treatment Outcome

Atogepant (Qulipta™) is an orally administered, small-molecule, calcitonin gene-related peptide (CGRP) receptor antagonist being developed by AbbVie for the prophylaxis of migraine. In September 2021, atogepant was approved in the USA for the preventive treatment of episodic migraine in adults. The drug is also in phase 3 clinical development for the preventive treatment of migraine in various other countries. This article summarizes the milestones in the development of atogepant leading to this first approval for the preventive treatment of episodic migraine in adults.

Topics: Calcitonin Gene-Related Peptide Receptor Antagonists; Drug Approval; Drug Interactions; Humans; Migraine Disorders; Piperidines; Pyridines; Pyrroles; Spiro Compounds; United States; United States Food and Drug Administration

Migraine is a common neurovascular disorder that has a severe impact on the individual daily life. Atogepant (AGN-241689) is an orally ingested, small-molecule drugs belonging to calcitonin gene-related peptide receptor antagonist, which has been initiated for the prophylactic treatment of migraine. However, there is no comprehensive literature to study the efficacy and safety of atogepant for the treatment of migraine. In this article, we present a meta-analysis of the available studies.. MEDLINE, Embase, Cochrane Library and ClinicalTrials.gov were searched before October 20, 2021 for any relevant literature. Eventually, three randomized clinical trials (RCTs) with 2,466 patients were included in our study.. We pooled 2,466 patients from 3 RCTs and primary outcome was mean monthly migraine days, the secondary endpoints were monthly headache days, acute medication use days per month and ≥ 50% reduction in monthly migraine days, baseline to end of trials. It was found that atogepant (10 mg, 30 mg, 60 mg once a day) led to a significant reduction in monthly migraine days (P < 0.00001, P < 0.00001, P = 0.007), monthly headache days (P < 0.00001, P < 0.00001, P = 0.001), and monthly medication use days (P < 0.00001, P < 0.00001, P = 0.0001), and an increase in the proportion of people with ≥ 50% reduction in monthly migraine days (P = 0.0008, P = 0.02, P = 0.04) in comparison with placebo. Moreover, there were no significant differences (P > 0.05) in outcomes of adverse events between atogepant and placebo.. Atogepant has shown good efficacy and safety in the prophylactic treatment of migraine, and further studies are expected.

Topics: Analgesics; Humans; Migraine Disorders; Piperidines; Pyridines; Pyrroles; Randomized Controlled Trials as Topic; Spiro Compounds; Treatment Outcome

Atogepant is the latest calcitonin gene-related peptide (CGRP) antagonist approved exclusively for prophylaxis of episodic migraine and is administered orally in doses of 10-60 mg/day. This article aims to provide a systematic review of the efficacy and safety of atogepant in migraine prevention.. The literature was searched in different databases, i.e., the National Institute of Health clinical trials registry, PubMed, and the Cochrane library between 2018 to October 2021 using the keywords atogepant, MK-8031, and migraine. Conference abstracts listed in the Cochrane database (includes Embase) and drug information provided by the US Food and Drug Administration (FDA) label were also reviewed. Only English-language clinical trials were included. The authors retrieved 58 articles. Eventually, two randomized, double-blind, multicenter clinical trials involving 1,727 participants and one open-label trial were analyzed.. The FDA approved atogepant for migraine prevention in September 2021 based on two randomized, double-blind, placebo-controlled trials. Atogepant approved for migraine prevention acts as a CGRP receptor antagonist and is administered orally. Based on the 12-week clinical trials, atogepant was efficacious in prevention of migraine and it was well tolerated. The most common treatment-emergent adverse events were nausea, constipation, and upper respiratory infection.. Atogepant had a statistically significant change from baseline in monthly migraine days, monthly headache days, and acute medication use days.. Atogepant seems to be beneficial for migraine prevention, and it may be of more benefit in individuals who do not wish to take the drug as an injection or do not require a prolonged duration of drug effect. However, head-to-head trials with other CGRP antagonists are required to ascertain its place in migraine prevention.

Topics: Analgesics; Calcitonin Gene-Related Peptide; Double-Blind Method; Headache; Humans; Migraine Disorders; Multicenter Studies as Topic; Piperidines; Pyridines; Pyrroles; Randomized Controlled Trials as Topic; Spiro Compounds; Treatment Outcome

To review the chemistry, pharmacodynamics, pharmacokinetics, efficacy, safety, and tolerability profile of small molecule CGRP receptor antagonists for the preventive treatment of migraine.. We conducted a review of atogepant, rimegepant, and zavegepant for the preventive treatment of migraine. The search was carried out in Medline via PubMed, Embase, and Clinical trials, up to January 2022.. Five hundred ninety-nine studies were found, of which 113 were in Medline via PubMed and 486 in Embase. The review included ten studies. Moreover, 16 clinical trials evaluated atogepant, rimegepant, and zavegepant. Atogepant and rimegepant reduced the number of migraine days per month and improved the Migraine-Specific Quality of Life Questionnaire role function (restrictive domain score). The frequency of adverse events and the treatment discontinuation were similar between the small molecule CGRP receptor antagonists and placebo. Zavegepant is currently being evaluated in a phase-2/3 clinical trial for migraine prevention, with no available findings.. Atogepant and rimegepant were effective and safe for the preventive treatment of migraine in adults. Long-term safety studies and comparisons of atogepant and rimegepant with other established treatments for migraine prevention are required.

Topics: Adult; Analgesics; Calcitonin Gene-Related Peptide Receptor Antagonists; Humans; Migraine Disorders; Piperidines; Pyridines; Pyrroles; Quality of Life; Spiro Compounds

Calcitonin gene-related peptide (CGRP) is probably the most potent vasodilator in cerebral circulation. Forty years after its discovery, the new CGRP-targeted therapy monoclonal antibodies, and the small molecule gepants, are now available for clinical practice. While randomized controlled trials and real-world experience consistently demonstrated the high efficacy and tolerability of monoclonal antibodies, limited evidence is available to characterize gepants fully. Depending on pharmacokinetics, these CGRP receptor antagonists can be used for acute (ubrogepant, rimegepant, and the not yet approved zavegepant) or preventive (atogepant and rimegepant) migraine treatment. Randomized placebo-controlled trials demonstrated gepants efficacy in treating acute attacks to obtain 2 h pain freedom in about 20% of patients and pain relief in about 60%, while up to 60% of treated patients with episodic migraine may experience a 50% reduction in monthly migraine days. The most common treatment-related emergent adverse events were gastrointestinal (nausea, constipation) for the acute or preventive use. No vascular or hepatic concerns have emerged so far. More studies are ongoing to investigate gepant tolerability and safety also if associated with monoclonal antibodies targeting CGRP and other therapeutic classes. Gepants are also under investigation to treat other painful and non-painful conditions. Real-life studies are necessary to confirm the trials' findings and investigate more practical clinical aspects.

Topics: Antibodies, Monoclonal; Calcitonin Gene-Related Peptide; Calcitonin Gene-Related Peptide Receptor Antagonists; Humans; Migraine Disorders; Piperidines; Pyridines; Pyrroles; Randomized Controlled Trials as Topic; Spiro Compounds

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

Topics: Adult; Benzamides; Double-Blind Method; Female; Humans; Middle Aged; Migraine Disorders; Network Meta-Analysis; Piperidines; Pyridines; Pyrroles; Randomized Controlled Trials as Topic

To develop and compare benefit-risk profiles for rimegepant, ubrogepant, and lasmiditan based on a network meta-analysis (NMA) of published clinical trials.. A fixed-effects Bayesian NMA of randomized controlled trials of lasmiditan, rimegepant, and ubrogepant for the acute treatment of adults with migraine were used to determine risk differences for efficacy and safety outcomes of the 3 treatments compared with pooled placebo. Risk differences were used to calculate number needed to treat (NNT) for pain relief and pain freedom at 2 and 2 to 24 hours and freedom from most bothersome symptoms at 2 hours; and number needed to harm (NNH) for dizziness and nausea, relative to placebo.. Results were based on 5 randomized controlled trials (NCT03461757, NCT02828020, NCT02867709, NCT02439320, and NCT02605174). NNT to achieve sustained pain relief at 2 to 24 hours was lowest for rimegepant 75 mg (5; 95% credible interval [Crl]: 4, 7) and ubrogepant 100 mg (5; 95% Crl: 4, 8) and highest for ubrogepant 25 mg (8; 95% Crl: 5, 16). Rimegepant had the lowest NNT to achieve sustained pain freedom at 2 to 24 hours and lasmiditan 50 mg had the highest (7; 95% Crl: 5, 12 vs. 26; 95% Crl: 13, 95). NNH for dizziness and nausea was highest for ubrogepant 25 mg (28; 95% Crl: 15, 62 and 99; 95% Crl: -2580, 2378, respectively). Lasmiditan 200 mg had the lowest NNH for dizziness and rimegepant 75 mg had the lowest NNH for nausea.. The benefit-risk profiles of lasmiditan, rimegepant, and ubrogepant may improve clinical decision-making.

Topics: Adult; Bayes Theorem; Benzamides; Dizziness; Double-Blind Method; Humans; Migraine Disorders; Nausea; Piperidines; Pyridines; Pyrroles; Serotonin Receptor Agonists; Treatment Outcome

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.. 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.. 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.. 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.

Topics: Adult; Benzamides; Humans; Migraine Disorders; Network Meta-Analysis; Piperidines; Pyridines; Pyrroles; Randomized Controlled Trials as Topic; Treatment Outcome

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

Topics: Benzamides; Disability Evaluation; Dose-Response Relationship, Drug; Humans; Migraine Disorders; Pain Measurement; Patient Satisfaction; Piperidines; Pyridines; Randomized Controlled Trials as Topic; Serotonin Receptor Agonists; Time Factors

Migraine has a great impact on public health. Current acute therapies do not satisfy all migraineurs. The novel serotonin 5-HT. To evaluate the clinical efficacy and safety of lasmiditan in treating acute migraine attacks.. The literature search was performed in PubMed, Embase, and the Cochrane Central Register of Controlled Trials for randomized controlled trials (RCTs) which assessed the effect and safety of lasmiditan on migraine. The risk of bias was assessed using the Cochrane Collaboration's risk of bias tool. Results were extracted and pooled as risk ratios (RRs) with a fixed or random-effects model.. Based on the four included RCTs, pooled estimates showed that lasmiditan with the 50 mg, 100 mg, and 200 mg doses was superior to placebo at 2 h after the first dose in terms of pain freedom, absence of migraine-associated symptoms, headache relief, no/mild disability, and global impression of change (very much/much better) (RRs ranged from 1.13 to 1.96), except for nausea-free and vomiting-free. Both lasmiditan 100 mg and 200 mg resulted in significantly fewer patients using rescue medication (100 mg: RR = 0.75, 95% CI (0.61, 0.92),. Lasmiditan with the 50 mg, 100 mg, and 200 mg doses are effective and safe in acute migraine treatment. Lasmiditan 200 mg is more effective than lasmiditan 100 mg in pain freedom, while lasmiditan 100 mg is better tolerated in the short-term follow-up. Further larger sample-size RCTs are required to verify the applicability and tolerability in the long term.

Topics: Adult; Benzamides; Cardiovascular Diseases; Confidence Intervals; Disability Evaluation; Female; Humans; Male; Migraine Disorders; Piperidines; Publication Bias; Pyridines; Receptor, Serotonin, 5-HT1F; Receptors, Serotonin; Risk; Serotonin Receptor Agonists; Treatment Outcome

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.. 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.. 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.. 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.

Topics: Adult; Benzamides; Humans; Migraine Disorders; Piperidines; Pyridines; Serotonin Receptor Agonists; Treatment Outcome

Lasmiditan, a selective 5-HT1F receptor agonist, is a harbinger for the novel ditan class of medications for acute migraine treatment. Lasmiditan activates 5-HT1F receptors on presynaptic trigeminal nerve terminals, which impedes the release of calcitonin gene-related peptide (CGRP) from trigeminal nerve endings and thereby suppresses activation of the trigeminovascular system. Notably, lasmiditan does not result in vasoconstriction, making lasmiditan a migraine-specific acute treatment option for those with cardiovascular risk factors. However, lasmiditan does have centrally mediated side effects. This review will discuss the background of lasmiditan development, its preclinical pharmacology, safety, drug interactions and indications for use.

Topics: Benzamides; Humans; Migraine Disorders; Piperidines; Pyridines; Serotonin Receptor Agonists

Migraine is a leading cause of morbidity and disability worldwide. Triptans were the first migraine-specific drug class developed and have proven efficacy in treatment of this neurological disease. They are however contraindicated in patients with cardiovascular disease and possibly others, owning to their vasoconstrictive properties. This review will focus on lasmiditan, which has been called the first 'ditan' and 'neurally acting anti-migraine agent', designed to selectively agonize the serotonin 5-HT. Lay abstract Migraine is a leading cause of pain and disability worldwide. Triptans (e.g., sumatriptan) were the first migraine-specific drug class developed and have proven to be effective treatments. Triptans are however contraindicated in patients with heart disease and possibly in some subsets of migraine, due to vasoconstriction concerns. This review will focus on lasmiditan, the first 5-HT

Topics: Benzamides; Humans; Migraine Disorders; Piperidines; Pyridines; Receptors, Serotonin; Serotonin Receptor Agonists

Topics: Benzamides; Disability-Adjusted Life Years; Humans; Migraine Disorders; Piperidines; Pyridines; Serotonin Receptor Agonists; Vestibular System

Naratriptan, marketed in a low oral dose of 2.5 mg, is generally regarded as a less-effective triptan with a slower onset of action than most other triptans in the treatment of migraine attacks. In this review, naratriptan will be compared with sumatriptan, the standard triptan.. Papers on pharmacodynamics and pharmacokinetics and results from comparative clinical trials with oral and subcutaneous naratriptan versus other triptans were retrieved from PubMed.. Naratriptan and sumatriptan have similar effects in relevant animal models. In a randomized controlled trial, oral naratriptan 2.5 mg is less effective than oral sumatriptan 100 mg after both 2 h and 4 h. In contrast, oral naratriptan 10 mg has a similar time-effect curve as oral sumatriptan 100 mg, in both its steepness and the efficacy at 2 h and 4 h. Subcutaneous naratriptan 10 mg (88% pain free at 2 h) was in one trial superior to subcutaneous sumatriptan 6 mg (55% pain free at 2 h).. Naratriptan was marketed for the treatment of migraine attacks as the "gentle triptan" in a low oral dose of 2.5 mg, a dose with no more adverse events than placebo. This low dose results in the slow onset of action and low efficacy of oral naratriptan, but in high doses oral naratriptan is similar to oral sumatriptan. Based on one randomized controlled trial, subcutaneous naratriptan has probably the greatest effect of any triptan.

Topics: Animals; Migraine Disorders; Piperidines; Randomized Controlled Trials as Topic; Serotonin Receptor Agonists; Sumatriptan; Tryptamines

Migraine is the second leading cause of years lived with disability after back pain. Poor tolerability, contraindications, drug-drug interactions and efficacy limited to a subpopulation make new approaches necessary for the acute and preventive treatment of migraine. The study of the calcitonin-gene-related peptide (CGRP) pathway over the last decades is a good example of translational medicine leading to directed therapies for patients.. After some of the first-generation CGRP receptor antagonists, gepants, were not fully developed because of hepatotoxicity, the second generation of gepants have shown efficacy, safety and tolerability in recent clinical trials.. Both rimegepant and ubrogepant have published positive randomized placebo-controlled clinical trials data. Vazegepant is the first intranasal gepant for the acute treatment of migraine and has announced a positive phase II/III study. Daily rimegepant use has preliminary data to suggest efficacy. Atogepant has shown efficacy in migraine prevention in a phase II/III study. Most importantly, hepatotoxicity has not been reported in specifically designed phase I studies or long-term extension studies, with rimegepant or ubrogepant, or in a preventive study with atogepant. Given the preventive effect, it seems likely that gepants will not lead to medication overuse headache. They will likely have no cardiovascular warnings. Because of the particular benefit gepants may represent for these groups of patients, specific studies in patients with medication overuse headache, as well as those with comorbid cardiovascular diseases, would be of considerable interest.

Topics: Calcitonin Gene-Related Peptide Receptor Antagonists; Humans; Migraine Disorders; Piperidines; Pyridines; Pyrroles; Randomized Controlled Trials as Topic; Treatment Outcome

The orally disintegrating tablet (ODT) formulation of rimegepant (NURTEC ODT

Topics: Adult; Calcitonin Gene-Related Peptide; Calcitonin Gene-Related Peptide Receptor Antagonists; Drug Approval; Humans; Migraine Disorders; Molecular Conformation; Piperidines; Pyridines

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). 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).. 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).. 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.

Topics: Benzamides; Dizziness; Humans; Migraine Disorders; Nausea; Piperidines; Pyridines; Receptor, Serotonin, 5-HT1F; Receptors, Serotonin; Serotonin Receptor Agonists; Time Factors; Treatment Outcome; Vertigo

Migraine is a leading cause of disability worldwide, but it is still underdiagnosed and undertreated. Research on the pathophysiology of this neurological disease led to the discovery that calcitonin gene-related peptide (CGRP) is a key neuropeptide involved in pain signaling during a migraine attack. CGRP-mediated neuronal sensitization and glutamate-based second- and third-order neuronal signaling may be an important component involved in migraine pain. The activation of several serotonergic receptor subtypes can block the release of CGRP, other neuropeptides, and neurotransmitters, and can relieve the symptoms of migraine. Triptans were the first therapeutics developed for the treatment of migraine, working through serotonin 5-HT

Topics: Animals; Benzamides; Calcitonin Gene-Related Peptide; Humans; Migraine Disorders; Neurons; Piperidines; Pyridines; Receptor, Serotonin, 5-HT1F; Receptors, Serotonin; Serotonin Receptor Agonists; Trigeminal Ganglion; Tryptamines; Vasoconstriction

To evaluate and compare the efficacy and safety of gepants for abortive treatment of migraine by network meta-analysis.. Publications, which were randomized controlled trials (RCTs) about gepants for abortive treatment of migraine, were acquired from Pubmed and Cochrane Library. The literatures screening and quality assessment followed the Cochrane handbook. Review manager 5.3 and Addis v1.16.8 were utilized for data analyzing.. Totally, 15 RCTs were included in the network meta-analysis. The trials enrolled were with high quality. There are 7 treatments were analyzed: BI 44370 TA, MK-3207, olcegepant, rimegepant, telcagepant, ubrogepant, and placebo. Of these trials, 11,118 patients and 10,917 patients were assigned to one of 7 treatments randomly for efficacy assessment and safety assessment, respectively. In meta-analysis of direct comparisons, all gepants were superior to placebo in achieving pain freedom 2 hr postdose and only rimegepant and telcagepant were higher than placebo in incidence of any adverse events. In network meta-analysis, the rank best 3 drugs were olcegepant, BI 44370 TA, and MK-3207 for efficacy outcomes. And the rank best 3 drugs were BI 44370 TA, placebo, and ubrogepant for safety outcomes.. Gepants were effective for abortive treatment of migraine. The most effective treatment of gepants for migraine might be olcegepant which were administrated transvenously. And all of gepants were safe for migraine treatment with single dose.

Topics: Calcitonin Gene-Related Peptide Receptor Antagonists; Humans; Migraine Disorders; Network Meta-Analysis; Piperidines; Randomized Controlled Trials as Topic; Treatment Outcome

The US Food and Drug Administration has approved orally administered 100-mg and 200-mg doses of lasmiditan for the acute treatment of migraine, with or without aura. Having a unique mechanism of action, lasmiditan is the first and only Food and Drug Administration-approved serotonin 5-HT. The objective of this study was to systematically evaluate the efficacy and safety of lasmiditan for the acute treatment of migraine in adult patients.. We systematically searched PUBMED, EMBASE, and Cochrane Library databases. Any relevant articles published before 3 March, 2020 were collected. Inclusion criteria were: (1) randomized clinical trials; (2) enrolled adult participants diagnosed with migraine; (3) compared lasmiditan at 100 mg or 200 mg with placebo; (4) enrolled more than 100 participants; and (5) provided any available data for predefined primary or secondary outcomes.. In this meta-analysis, the use of lasmiditan as an acute treatment for episodic migraine in adults led to a greater percentage of freedom of pain and the absence of the most bothersome symptoms at 2 h post-dose. Lasmiditan 200 mg had superior efficacy to 100-mg dose without a significantly increased risk for adverse events.

Topics: Administration, Oral; Adult; Benzamides; Dose-Response Relationship, Drug; Humans; Migraine Disorders; Piperidines; Pyridines; Randomized Controlled Trials as Topic; Serotonin Receptor Agonists; Treatment Outcome

Topics: Administration, Oral; Benzamides; Humans; Migraine Disorders; Piperidines; Pyridines; Randomized Controlled Trials as Topic; Serotonin Receptor Agonists; Treatment Outcome

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. 5HT

Topics: Benzamides; Calcitonin Gene-Related Peptide Receptor Antagonists; Disability-Adjusted Life Years; Epilepsy; Humans; Migraine Disorders; Piperidines; Pyridines

To describe the new classes of medication for headache management and their roles in clinical practice.. Calcitonin gene-related peptide (CGRP) is a key component in the underlying pathophysiology of migraine. Research focused on targeting CGRP for headache treatment has led to the development of entirely new classes of medications - the gepants and the CGRP monoclonal antibodies (mAbs) - for both acute and preventive treatment. A third class, the ditans, is being developed to target the 5-HT. This article reviews the pathophysiology of migraine that has led to these new pharmacologic developments. Available information from randomized controlled trials, abstracts, press releases, and relevant preclinical studies is summarized for each class of medications.. At the time of this writing, one ditan has been submitted to the U.S. Food and Drug Administration (FDA) for approval. One gepant is anticipated to be submitted within the first quarter of 2019, and others are in clinical trials. Three CGRP mAbs have been FDA approved and are now available in clinical practice, and a fourth was submitted in the first quarter of 2019.. The development of new migraine-specific classes of medications provides more treatment options for both acute and preventive treatment of migraine.

Topics: Analgesics; Antibodies, Monoclonal; Benzamides; Calcitonin Gene-Related Peptide; Calcitonin Gene-Related Peptide Receptor Antagonists; Clinical Trials as Topic; Contraindications, Drug; Drug Approval; Humans; Migraine Disorders; Piperidines; Pyridines; Receptor, Serotonin, 5-HT1F; Receptors, Calcitonin Gene-Related Peptide; Receptors, Serotonin; Serotonin Receptor Agonists; United States; United States Food and Drug Administration; Vasoconstriction; Vasoconstrictor Agents

Lasmiditan (REYVOW™; Eli Lilly and Company) is an orally available serotonin (5-HT)

Topics: Benzamides; Clinical Trials, Phase III as Topic; Drug Approval; Humans; Migraine Disorders; Piperidines; Pyridines; Receptor, Serotonin, 5-HT1F; Receptors, Serotonin; Serotonin Receptor Agonists

Topics: Calcitonin Gene-Related Peptide Receptor Antagonists; Humans; Migraine Disorders; Piperidines; Pyridines; Pyrroles

Migraine is a common and highly disabling neurological disorder whose acute treatment remains problematic and unsatisfactory in a high percentage of cases. Consequently, there remains a need for new symptomatic therapies that can be easily handled by patients (i.e. by oral administration).. This review reports on compounds currently under development for the oral treatment of acute migraine attacks, focusing on Calcitonin-Gene-Related-Peptide receptor antagonists, specifically ubrogepant and rimegepant. This article is based on literature obtained from PubMed and publicly available clinical trial data.. Both reviewed compounds meet the need for rapid and effective pain control, combined with the control of associated bothersome symptoms while also lacking significant adverse events and safety concerns. Though further studies should assess the profile of these compounds comparatively with existing and available treatments (namely triptans), the currently available data points to these new therapies as being very promising new symptomatic oral treatments of migraines.

Topics: Administration, Oral; Humans; Migraine Disorders; Piperidines; Pyridines; Pyrroles; Tryptamines

Migraine is the most common of all neurological disorders. A breakthrough in migraine treatment emerged in the early nineties with the introduction of 5-HT1B/D receptor agonists called triptans. Triptans are used as the standard of care for acute migraine; however, they have significant limitations such as incomplete and inconsistent pain relief, high rates of headache recurrence, class- specific side effects and cardiovascular contraindications. First- and second-generation calcitonin gene-related peptide (CGRP) receptor antagonists, namely gepants, is a class of drugs primarily developed for the acute treatment of migraine. CGRP is the most evaluated target for migraine treatments that are in development.. This article reviews the available data for first- and second-generation CGRP receptor antagonists, the role of CGRPs in human physiology and migraine pathophysiology and the possible mechanism of action and safety of CGRP-targeted drugs.. Available data suggest that second generation of gepants has clinical efficacy similar to triptans and lasmiditan (5-HT1F receptor agonist) and has improved tolerability. Future studies will assess their safety, especially in specific populations such as patients with cardiovascular disease and pregnant women.

Topics: Acute Disease; Animals; Benzamides; Calcitonin Gene-Related Peptide Receptor Antagonists; Drug Development; Humans; Migraine Disorders; Piperidines; Pyridines; Tryptamines

Migraine is a recurrent, disabling, complex and highly prevalent neurological disorder. The mystery behind the cause of migraine is continuously evolving, according to the scientific understanding of the disease. This growing understanding helps to identify novel therapeutic targets for the management of migraine to treat the ailing migraineurs. The role of serotonin (5HT) in migraine is recognized to be the cornerstone for the currently available therapeutic options namely ergot alkaloids and triptans. The role of mediators such as Calcitonin Gene-Related Peptide (CGRP), nitric oxide and excitatory neurotransmitter glutamate, has been realized and ignited the development of drugs targeting these factors. Lasmiditan, known as a Neurally Active Anti- Migraine Agent (NAAMA) is a specific 5HT1F agonist, developed as a new group named as 'ditans'. The drug was designed and developed to meet the unmet needs of currently available medications to circumvent the vascular adverse effects. Having a group of drugs with a nonvascular mechanism of action, devoid of unwanted effects with a different spectrum of indication and contraindications, is the need of the hour to expand the armamentarium available to tackle acute migraine attack.

Topics: Animals; Benzamides; Drug Design; Humans; Migraine Disorders; Molecular Structure; Piperidines; Pyridines; Receptor, Serotonin, 5-HT1F; Receptors, Serotonin; Serotonin; Serotonin 5-HT1 Receptor Agonists; Signal Transduction; Structure-Activity Relationship; Treatment Outcome

Migraine is among the most disabling disorders worldwide, with a significant therapeutic need. Triptans are drugs of choice in the acute attack treatment, but they are contraindicated in patients with vascular conditions due to their potential vasoconstrictive properties. Further limitations include side effects, inconsistency in therapeutic action and possible non-response. Lasmiditan, a highly selective 5-HT1F receptor agonist, is a novel acute anti-migraine substance devoid of vasoconstriction. Areas covered: This article reviews the clinical efficacy and safety of oral and intravenous lasmiditan as a possible acute migraine treatment. We analyze all currently available results in Phase I to III studies. Expert opinion: Lasmiditan is a promising acute migraine therapy, in particular for patients at cardiovascular risk. Phase II and the first Phase III clinical trials show a significant better headache response in comparison to placebo. The efficacy of lasmiditan proves that vasoconstriction is not essential for acute migraine therapy and thereby points, in addition to a well-established trigeminal contribution, to central neuronal mechanisms in migraine pathophysiology. Lasmiditan penetrates the blood-brain barrier and CNS associated adverse events are common, but mostly in mild to moderate severity. The results of long-term Phase III studies will determine if these adverse events represent a limitation in clinical practice.

Topics: Benzamides; Cardiovascular Diseases; Clinical Trials, Phase III as Topic; Drug-Related Side Effects and Adverse Reactions; Humans; Migraine Disorders; Piperidines; Pyridines; Receptor, Serotonin, 5-HT1F; Receptors, Serotonin; Risk Factors; Serotonin Receptor Agonists; Treatment Outcome; Tryptamines

Migraine is a highly prevalent neurovascular disorder.. Of the many factors that have been implicated over the years, 5-hydroxytryptamine (5-HT; serotonin) has long been involved in the pathophysiology of migraine. Certainly, some lines of evidence suggest: (i) a 5-HT depletion from blood platelets resulting in cranial extracerebral vasodilatation; and (ii) the effectiveness of an intravenous (i.v.) infusion of 5-HT to abort migraine in some patients. More direct evidence comes from some drugs that influence 5-HT release and/or interact (as agonists or antagonists) with 5-HT receptors to treat this disorder. Indeed, the development of sumatriptan and second generation triptans in the 1990's led to discover that these drugs produce selective cranial extracerebral vasoconstriction (via 5-HT1B receptors) and inhibition of the trigeminovascular system responses implicated in migraine (via 5-HT1D/5-HT1F receptors). Although the triptans represent the current mainstay of acute antimigraine treatment, a number of patients do not respond well to the triptans and are contraindicated in patients with cardiovascular pathologies.. This mini-review outlines further developments in the design of novel (non-vasoconstrictor) antimigraine treatments acting via 5-HT receptors, including selective agonists at 5-HT1D and 5-HT1F receptors, agonists at 5-HT1B/1D receptors combined with other properties as well as antagonists at 5-HT2B/2C, 5-HT3 and 5-HT7 receptors. It also touches upon the recent development of antagonists and antibodies at calcitonin gene-related peptide (CGRP) and its receptors, which produce a direct blockade of the CGRPergic vasodilator mechanisms involved in migraine. These alternative pharmacological approaches will hopefully lead to less side-effects.

Topics: Benzamides; Drug Design; Humans; Indoles; Migraine Disorders; Piperidines; Protein Binding; Pyridines; Receptor, Serotonin, 5-HT1D; Serotonin; Serotonin 5-HT1 Receptor Agonists

Migraine is one of the most common diseases in the world, with high economical and subjective burden. Migraine acute therapy is nowadays based on specific and non-specific drugs but up to 40% of episodic migraineurs still have unmet treatment needs and over 35% do not benefit from triptans administration. Serotonin-1F receptors have been identified in trigeminal system and became an ideal target for anti-migraine drug development as potential trigeminal neural inhibitors. Lasmiditan, a novel serotonin1F receptor agonist, showed specific affinity in vitro for the receptor without any vasoconstrictive action and inhibited markers associated with electrical stimulation of trigeminal ganglion in migraine animal models. Areas covered: This article reviews both preclinical and clinical studies on lasmiditan as a potential acute therapy for migraine, as well as pharmacokinetic and pharmacodynamic features. It also summarizes safety and tolerability data gathered in the various human studies. Expert opinion: The absence of vasoconstrictive effects makes lasmiditan a promising novel migraine acute therapy. Although preclinical and Phase I and II studies established a significant efficacy, the limited knowledge about pharmacokinetics and metabolism, the high rate of non-serious central nervous system side effects and the lack of larger studies remain still a matter of concern that should be addressed in future studies.

Topics: Animals; Benzamides; Disease Models, Animal; Drug Design; Humans; Migraine Disorders; Piperidines; Pyridines; Receptor, Serotonin, 5-HT1F; Receptors, Serotonin; Serotonin Receptor Agonists

Recent triptan development has focused on new administration methods and formulations, triptan combination therapies, treatment in menstrually related migraines, and novel serotonin receptor subtype agonists (5HTf). Areas covered: Clinical triptan research related to migraine was reviewed, analyzing EMBASE and PUBMED data bases from 01/01/2011 to 06/29/2016, with a focus on clinical trials of class 1 or 2 level of evidence. There have been advances in drug combination therapies, as well as administration devices that aid in ease of use, increase efficacy, and decrease adverse reactions. Some new agents and devices have similar or less efficacy compared to previous generic triptan formulations. New agents have action at the 5HTf receptor subtype, and avoid vascular side effects of classic 5Ht1b/d agonists, however adverse reactions may limit their clinic use. Long half-life triptans, frovatriptan and naratriptan, do appear to have good benefit in menstral related migraine. Expert opinion: Recent advances in triptan development can offer some advantages to migraine therapy and patient preferences, but have a much higher cost compared to individual generic triptan agents. In the coming years, triptan advances with high efficacy, limiting ADRs and cost are welcomed, in this regard the 5HT1b/d triptans are already well established.

Topics: Carbazoles; Humans; Migraine Disorders; Piperidines; Serotonin 5-HT1 Receptor Agonists; Serotonin Receptor Agonists; Tryptamines

The development of sumatriptan, more than 20 years ago, added substantially to the characterization of 5-hydroxytryptamine (5-HT) receptors and their relevance to acute migraine therapy. Recently, 5-HT1F receptor agonists, with no vascular effects, have shown efficacy in the treatment of migraines.. This evaluation reviews the recent advances in acute migraine therapy targeting the 5-HT receptor. Specifically, the authors review the pharmacokinetics, pharmacodynamics, clinical efficacy and safety of 5-HT1F receptor agonists and new formulations of sumatriptan and dihydroergotamine (DHE).. Lasmiditan, a non-vascular acting 5-HT1F receptor agonist, is effective in migraine but causes central nervous system-related adverse events, which may considerably limit its clinical use. The efficacy of transdermal sumatriptan is too low for general use in migraine. Intranasal sumatriptan powder could be a step forward compared with oral sumatriptan, but comparative trials are needed. Orally inhaled DHE has a very quick systemic absorption but the onset of effect in migraine is relatively slow with a maximum effect after 2 h. In contrast, orally inhaled DHE results in a low incidence of recurrence. None of these reviewed treatments are likely to fulfill patients' expectations, and the advancement of acute migraine drugs should likely depend on different mechanisms from current 5-HT-related drugs.

Topics: Animals; Benzamides; Drug Administration Routes; Humans; Migraine Disorders; Piperidines; Pyridines; Receptors, Serotonin; Serotonin Receptor Agonists; Tryptamines

Migraine is a common, disabling condition and a burden for the individual, health services, and society. Many sufferers choose not to, or are unable to, seek professional help and rely on over-the-counter analgesics. Naproxen is a non-steroidal anti-inflammatory drug (NSAID); its efficacy in acute migraine has not been established by systematic reviews. Co-therapy with an antiemetic should help to reduce the nausea and vomiting commonly associated with migraine headaches.. To determine the efficacy and tolerability of naproxen, alone or in combination with an antiemetic, compared with placebo and other active interventions in the treatment of acute migraine headaches in adults.. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) on The Cochrane Library, MEDLINE, EMBASE, and the Oxford Pain Relief Database, together with two online databases (www.gsk-clinicalstudyregister.com and www.clinicaltrials.gov) and reference lists, for studies to 22 May 2013.. We included randomised, double-blind, placebo- or active-controlled studies, with at least 10 participants per treatment arm, using naproxen alone or with an antiemetic to treat a migraine headache episode.. Two review authors independently assessed trial quality and extracted data. We used numbers of participants achieving each outcome to calculate risk ratios and numbers needed to treat (NNT) or harm (NNH) compared with placebo or a different active treatment.. We included six studies using naproxen 275 mg, 500 mg, or 825 mg to treat attacks of moderate or severe pain intensity. Overall, 1241 participants took naproxen (275 mg to 825 mg), 229 took sumatriptan 50 mg, 173 took naratriptan 2.5 mg, and 1092 took placebo. No studies combined naproxen with an antiemetic. Studies using naproxen 275 mg provided no useable data for analysis.Naproxen (500 mg and 825 mg) was better than placebo for pain-free response and headache relief. At two hours, the NNT for pain-free response was 11 (17% response with naproxen, 8% with placebo; risk ratio 2.0 (95% CI 1.6 to 2.6), moderate quality) and for headache relief was 6.0 (45% response with naproxen, 29% with placebo; risk ratio 1.6 (1.4 to 1.8), moderate quality). The NNT for sustained pain-free response during the 24 hours post dose was 19 (12% response with naproxen, 6.7% with placebo), and for sustained headache relief during the 24 hours post dose was 8.3 (30% response with naproxen, 18% with placebo). Analysing only the lower dose of 500 mg of naproxen did not significantly change the results. Adverse events, which were mostly mild or moderate in severity and rarely led to withdrawal, were more common with naproxen than with placebo when the 500 mg and 825 mg doses were considered together, but not when the 500 mg dose was analysed alone.There were insufficient data for analysis of naproxen compared with sumatriptan, and no data suitable for analysis of naproxen compared with naratriptan.. Naproxen is statistically superior to placebo in the treatment of acute migraine, but the NNT of 11 for pain-free response at two hours suggests that it is not a clinically useful treatment. Cochrane reviews examining other commonly used analgesics for acute migraine have reported better (lower) NNT results for the same outcome. Naproxen is not clinically useful as a stand-alone analgesic in acute migraine, as it is effective in fewer than 2 people in 10.

Topics: Adult; Anti-Inflammatory Agents, Non-Steroidal; Antiemetics; Drug Therapy, Combination; Humans; Migraine Disorders; Naproxen; Nausea; Piperidines; Randomized Controlled Trials as Topic; Sumatriptan; Tryptamines; Vomiting

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.

Topics: Animals; Benzamides; Clinical Trials, Phase II as Topic; Dose-Response Relationship, Drug; Humans; Migraine Disorders; Piperidines; Pyridines; Randomized Controlled Trials as Topic; Serotonin Receptor Agonists

The effective anti-migraine drugs triptans, all bind with high affinity to three serotonin (5-HT) subtypes, the 5-HT1B, 5-HT1D and 5-HT1F. 5-HT1B mRNA is densely localized within smooth muscle, and less in the endothelium of cerebral blood vessels. This vascular distribution of 5-HT1B receptor has been shown to mediate the vasoconstrictive properties of the triptans, responsible for potential cardiac adverse events. Activation of 5-HT1D subtype, although effective in animal models of migraine, was not enough efficient to attenuate migraine attacks in clinical trials. The 5-HT1F receptor is located both in vessels and within the trigeminal ganglion (TG) and the trigeminal nucleus caudalis (Sp5C), but with the difference that the 5-HT1F receptor lack vasoconstrictive properties, making it an attractive target for new anti-migraine drugs. Selective activation of 5-HT1F receptor potently inhibited markers associated with electrical stimulation of the TG. Thus 5-HT1F receptor represents an ideal target for anti-migraine drugs. So far two selective 5-HT1F agonists have been tested in human trials for migraine: LY334370 and lasmiditan. Both molecules were efficient in attenuating migraine attacks with efficacy in the same range as oral sumatriptan 100mg, the gold standard for triptans. The LY334370 project withdrew because of toxicity in animals, while lasmiditan is still testing. In this review we present all the available preclinical and clinical data on the 5-HT1F agonists as a potential new class of anti-migraine drugs lacking vascular activity and we discuss related issues on the vascular and neuronal aspects of migraine pathogenesis.

Topics: Animals; Benzamides; Carbazoles; Clinical Trials as Topic; Disease Models, Animal; Drug Evaluation, Preclinical; Fatigue; Fluorobenzenes; Humans; Indoles; Migraine Disorders; Models, Neurological; Molecular Targeted Therapy; Nausea; Paresthesia; Pilot Projects; Piperidines; Pyridines; Randomized Controlled Trials as Topic; Receptor, Serotonin, 5-HT1F; Receptors, Serotonin; Serotonin; Serotonin Receptor Agonists; Treatment Outcome; Vertigo

Naratriptan 2.5 mg is now an over-the-counter drug in Germany. This should increase the interest in drug. The GSK Trial Register was searched for published and unpublished double-blind, randomised, controlled trials (RCTs) concerning the use of naratriptan in migraine. Only 7 of 17 RCTs are published in full. Naratriptan 2.5 mg is superior to placebo for acute migraine treatment in 6 RCTs, but inferior to sumatriptan 100 mg and rizatriptan 10 mg in one RCT each. This dose of naratriptan has no more adverse events than placebo. Naratriptan 1 mg b.i.d. has some effect in the short-term prophylactic treatment of menstruation-associated migraine in 3 RCTs. In 2 RCTs, naratriptan 2.5 mg was equivalent to naproxen sodium 375 mg for migraine-related quality of life. Naratriptan 2.5 mg (34% preference) was superior to naproxen sodium 500 mg (25% preference). Naratriptan 2.5 mg is better than placebo in the acute treatment of migraine. The adverse effect profile of naratriptan 2.5 mg is similar to that of placebo. The efficacy of naratriptan 2.5 mg versus NSAIDs is not sufficiently investigated. Naratriptan, when available OTC is a reasonable second or third choice on the step care ladder in the acute treatment of migraine.

Topics: Double-Blind Method; Germany; Humans; Migraine Disorders; Piperidines; Randomized Controlled Trials as Topic; Registries; Serotonin 5-HT1 Receptor Agonists; Tryptamines

Topics: Humans; Migraine Disorders; Piperidines; Serotonin Receptor Agonists; Tryptamines

In 2006, the triptans sumatriptan 50mg and naratriptan 2.5mg were approved as over-the-counter (OTC) drugs in pharmacies in the UK and Germany, respectively. Both drugs have been used in a large number of patients with migraine and are considered to have good safety profiles. The implications of OTC triptan availability for clinical practice are that more migraine patients will use a triptan and will tend to medicate early when their headache is still mild, which should be beneficial. The problem with OTC access to triptans is medication overuse; therefore, patients should be warned of this and advised to use a triptan on fewer than 10 days per month. Pharmacists should be educated regarding migraine types and symptoms and on contraindications to triptans, so they are then able to discern the patients who should receive triptans and, as importantly, those who should not. The annual cost of migraine is euro27 billion in Europe, $US1.4 billion in the UK and $US16.6 billion in the US. By far the greatest opportunity for cost-savings comes from the potential to reduce costs associated with lost productivity from migraine. OTC availability of triptans will inevitably result in easier access to these medications, which, in turn, may result in improved treatment and lower migraine-related disability. There is currently a lack of empirical evidence that treating migraine effectively does in fact recover lost productivity; well designed studies are required to show this. The availability of triptans OTC is a logical development for the better management of a common, benign, self-limiting but nonetheless burdensome disorder that is currently grossly undertreated. We welcome this development, but recognise that advice at the point of sale is crucial for effective and safe use of these drugs.

Topics: Germany; Humans; Migraine Disorders; Nonprescription Drugs; Piperidines; Serotonin Receptor Agonists; Sumatriptan; Treatment Outcome; Tryptamines; United Kingdom

The clinical efficacy in migraine was compared for oral and subcutaneous sumatriptan and naratriptan. Doses of the two administration forms were chosen as resulting in comparable blood concentrations. Subcutaneous administrations of the drugs were superior for efficacy than the oral forms. This most likely due to a quicker rise in blood concentrations after subcutaneous injections.. In designing new therapies for migraine one should aim at a quick absorption of the drug, which will probably result in an increased efficacy.

Topics: Administration, Oral; Biological Availability; Humans; Infusions, Parenteral; Injections, Subcutaneous; Migraine Disorders; Piperidines; Serotonin Receptor Agonists; Sumatriptan; Time Factors; Treatment Outcome; Tryptamines

The basic CNS neuropharmacology of naratriptan is reviewed here. Naratriptan is a second-generation triptan antimigraine drug, developed at a time when CNS activity was thought not to be relevant to its therapeutic effect in migraine. It was, however, developed to be a more lipid-soluble, more readily absorbed and less readily metabolized variant on preexisting triptans and these variations conferred on it a higher CNS profile. Naratriptan is a 5-HT(1B/1D) receptor agonist with a highly selective action on migraine pain and nausea, without significant effect on other pain or even other trigeminal pain. Probable sites of therapeutic action of naratriptan include any or all of: the cranial vasculature; the peripheral terminations of trigeminovascular sensory nerves; the first-order synapses of the trigeminovascular sensory system; the descending pain control system; and the nuclei of the thalamus. Naratriptan may prevent painful dilatation of intracranial vessels or reverse such painful dilatation. Naratriptan can prevent the release of sensory peptides and inhibit painful neurogenic vasodilatation of intracranial blood vessels. At the first order synapse of the trigeminal sensory system, naratriptan can selectively suppress neurotransmission from sensory fibers from dural and vascular tissue, while sparing transmission from other trigeminal fibers, probably through inhibition of neuropeptide transmitter release. In the periaqueductal gray matter and in the nucleus raphe magnus, naratriptan selectively activates inhibitory neurons which project to the trigeminal nucleus and spinal cord and which exert inhibitory influences on trigeminovascular sensory input. Naratriptan has also a therapeutic effect on the nausea of migraine, possibly exerting its action at the level of the nucleus tractus solitarius via the same mechanisms by which it inhibits trigeminovascular nociceptive input. The incidence of naratriptan-induced adverse effects in the CNS is low and it is not an analgesic for pain other than that of vascular headache. In patients receiving selective serotonin uptake inhibitors (SSRIs) naratriptan may cause serotonin syndrome-like behavioral side effects. The mechanism of action involved in the production of behavioral and other CNS side effects of naratriptan is unknown.

Topics: Analgesia; Animals; Cardiovascular Diseases; Humans; Migraine Disorders; Piperidines; Serotonin Receptor Agonists; Tryptamines

To evaluate the comparative efficacy and tolerability of naratriptan in the treatment of acute attacks of migraine.. Meta-analysis of randomised controlled trials using a random effects model.. A total of 4499 patients suffering from moderate or severe attacks of acute migraine reported in ten trials.. Response rate ratios for headache relief, pain-free response and sustained relief (4-24 hours). Adverse events were estimated with the rate ratio (RR), risk difference and number needed to harm.. Pooled RRs relative to placebo for pain-free response at 2 and 4 hours for naratriptan 2.5 mg were 2.52 (95% CI: 1.78-3.57) and 2.58 (1.99-3.35). Naratriptan 2.5 mg was more effective than naratriptan 1 mg; the corresponding RRs for pain-free response at 2 and 4 hours were 1.54 (95% CI: 1.28-1.86) and 1.35 (1.20-1.51). In contrast, naratriptan 2.5 mg was less effective in pain-free response than either rizatriptan 10 mg at 4 hours (RR: 0.68; 95% CI: 0.55-0.85) or sumatriptan 100 mg at 4 hours (RR: 0.79; 95% CI: 0.67-0.93). However, significantly fewer patients experienced adverse effects with naratriptan 2.5 mg than with rizatriptan 10 mg (RR: 0.73; 95% CI: 0.56-0.97) or sumatriptan 100 mg (RR: 0.68; 95% CI: 0.55-0.86).. Naratriptan is an effective and well-tolerated treatment for acute attacks of migraine. Head-to-head comparisons suggest that naratriptan 2.5 mg is significantly more effective than the 1 mg dose. Rizatriptan 10 mg and sumatriptan 100 mg were superior to naratriptan in terms of headache relief, while zolmitriptan 2.5 mg seemed to have comparable efficacy. Randomised controlled trials have shown that at licensed doses (1 and 2.5 mg), naratriptan is associated with a lower incidence of adverse effects than rizatriptan, sumatriptan and zolmitriptan. The incidence rates of adverse effects were similar to placebo.

Topics: Dose-Response Relationship, Drug; Humans; Indoles; Migraine Disorders; Oxazolidinones; Piperidines; Randomized Controlled Trials as Topic; Serotonin Receptor Agonists; Sumatriptan; Triazoles; Tryptamines

Topics: Anticonvulsants; Botulinum Toxins; Calcitonin Gene-Related Peptide; Central Nervous System; Clinical Trials as Topic; Drug Design; Fructose; Humans; Indoles; Meta-Analysis as Topic; Migraine Disorders; Pain; Piperidines; Pyrrolidines; Serotonin Receptor Agonists; Signal Transduction; Sumatriptan; Topiramate; Triazoles; Trigeminal Nerve; Tryptamines; Vasodilation

Topics: Carbazoles; Evidence-Based Medicine; Humans; Indoles; Migraine Disorders; Oxazolidinones; Piperidines; Pyrrolidines; Receptor, Serotonin, 5-HT1D; Serotonin Receptor Agonists; Sumatriptan; Triazoles; Tryptamines

Topics: Anti-Inflammatory Agents, Non-Steroidal; Diclofenac; Ergotamine; Humans; Ibuprofen; Indoles; Migraine Disorders; Naproxen; ortho-Aminobenzoates; Oxazolidinones; Piperidines; Pyrrolidines; Salicylates; Sumatriptan; Triazoles; Tryptamines

Topics: Acute Disease; Adult; Analgesics, Non-Narcotic; Anti-Inflammatory Agents, Non-Steroidal; Child; Diclofenac; Drug Therapy, Combination; Ergotamine; Humans; Ibuprofen; Indoles; Migraine Disorders; Naproxen; ortho-Aminobenzoates; Oxazolidinones; Piperidines; Pyrrolidines; Salicylates; Serotonin Receptor Agonists; Sumatriptan; Triazoles; Tryptamines

Recent studies of the pathophysiology of migraine provide evidence that the headache phase is associated with multiple physiologic actions. These actions include the release of vasoactive neuropeptides by the trigeminovascular system, vasodilation of intracranial extracerebral vessels, and increased nociceptive neurotransmission within the central trigeminocervical complex. The 5-HT(1B/1D) receptor agonists, collectively known as triptans, are a major advance in the treatment of migraine. The beneficial effects of the triptans in patients with migraine are related to their multiple mechanisms of action at sites implicated in the pathophysiology of migraine. These mechanisms are mediated by 5-HT(1B/1D) receptors and include vasoconstriction of painfully dilated cerebral blood vessels, inhibition of the release of vasoactive neuropeptides by trigeminal nerves, and inhibition of nociceptive neurotransmission. The high affinity of the triptans for 5-HT(1B/1D) receptors and their favorable pharmacologic properties contribute to the beneficial effects of these drugs, including rapid onset of action, effective relief of headache and associated symptoms, and low incidence of adverse effects.

Topics: Carbazoles; Humans; Indoles; Migraine Disorders; Oxazolidinones; Piperidines; Pyrrolidines; Receptor, Serotonin, 5-HT1B; Receptor, Serotonin, 5-HT1D; Receptors, Serotonin; Serotonin Receptor Agonists; Sumatriptan; Triazoles; Tryptamines

Naratriptan is a selective 5-HT(1B/1D) receptor agonist, with a high affinity at the 5-HT(1B), 5-HT(1D) and 5-HT(1F) receptor subtypes. Naratriptan contracts a number of large isolated cerebral arteries from several species, and has little contractile effect on peripheral blood vessels. It has an inhibitory effect on the cranial neurogenic inflammation model. The clinically recommended dose is 2.5 mg. It was found significantly superior to placebo on headache relief and pain free at 2 and 4 hours, and in relieving nausea, photophobia and phonophobia. It also has a good within-patient consistency, and a low recurrence rate. The side-effect profile is that of the triptan class, wih an incidence no different from placebo at the 25 mg dose. The contraindications are similar to any triptan, including coronary disease. Naratriptan is unlikely to affect metabolism of other drugs. In comparison sumatriptan 100 mg, naratriptan 2.5 mg has a slower onset of action and a lower response rate at 4 h, but it has a lower recurrence rate, and is better tolerated.

Topics: Humans; Indoles; Migraine Disorders; Piperidines; Serotonin Receptor Agonists; Tryptamines

Triptans, beginning with sumatriptan, have revolutionized the treatment of migraine. New triptans in several formulations will soon become available in the United States. Although the similarities of these 5-hydroxytryptamine (5-HT) 1B/1D receptor agonists outweigh their differences, important differences in pharmacokinetics and clinical responses do exist. Subcutaneous sumatriptan has the most rapid onset of action and greatest efficacy but the most adverse effects. Intranasal sumatriptan also has rapid onset of action, but at 2 hours its efficacy is comparable to that of oral zolmitriptan. Of the oral triptans, rizatriptan seems to have the greatest early efficacy. Both rizatriptan and zolmitriptan are now available as rapidly dissolving wafers. Almotriptan, the newest of the triptans, has a response rate similar to that of oral sumatriptan and may produce fewer adverse effects. Naratriptan and frovatriptan, with their slow onset, high tolerability, and long half-lives, may have a role in aborting prolonged migraine attacks and in headache prevention. Eletriptan at higher doses (80 mg) has a response rate approaching that of rizatriptan but may be limited by potential side effects. The many triptans available offer the opportunity to individualize migraine treatment, depending on the patient's attack characteristics, tolerance, and preferences.

Topics: Carbazoles; Cardiovascular Diseases; Humans; Indoles; Migraine Disorders; Oxazolidinones; Patient Satisfaction; Piperidines; Pyrrolidines; Serotonin Receptor Agonists; Sumatriptan; Treatment Outcome; Triazoles; Tryptamines

Topics: Clinical Trials as Topic; Female; Humans; Indoles; Male; Migraine Disorders; Oxazolidinones; Piperidines; Prognosis; Recurrence; Serotonin Receptor Agonists; Severity of Illness Index; Sumatriptan; Treatment Outcome; Triazoles; Tryptamines

Topics: Humans; Indoles; Migraine Disorders; Oxazolidinones; Piperidines; Pyrrolidines; Serotonin Receptor Agonists; Sumatriptan; Triazoles; Tryptamines

The current International Headache Society guidelines for migraine clinical trials recommend assessment of pain relief at 2 hours as a primary end point. Patients, however, express a clear preference for more rapid pain relief, with most patients defining rapid relief as occurring within 30 minutes after drug administration. Thus, consideration should be given to establishing clinical trial end points that more accurately reflect the preferences of patients with migraine. In this case, assessment of pain relief at 1 hour would be an appropriate primary end point. Using speed of relief as a criterion for migraine drug selection also is appropriate. The migraine-specific serotonin(1B/1D) agonists, or triptans, are able to meet this faster relief end point and are preferred by patients.

Topics: Analgesics, Non-Narcotic; Carbazoles; Clinical Trials as Topic; Humans; Indoles; Migraine Disorders; Oxazolidinones; Pain Measurement; Patient Satisfaction; Piperidines; Pyrrolidines; Serotonin Receptor Agonists; Sumatriptan; Time Factors; Treatment Outcome; Triazoles; Tryptamines

Topics: Humans; Indoles; Migraine Disorders; Oxazolidinones; Piperidines; Serotonin Receptor Agonists; Sumatriptan; Tryptamines

To compare the efficacy of oral rizatriptan 10 mg with oral doses of sumatriptan, naratriptan, and zolmitriptan on stringent outcome measures.. Retrospective analysis of data from five randomized, placebo-controlled, double-masked clinical trials in which oral rizatriptan was directly compared with oral sumatriptan 100 mg (n = 772), 50 mg (n = 1116), 25 mg (n = 1183), naratriptan 2.5 mg (n = 413), and zolmitriptan 2.5 mg (n = 580) for the acute treatment of a moderate or severe migraine attack.. Percentage of patients pain-free at 2 hours, symptom-free at 2 hours (no pain, nausea, photophobia, phonophobia, vomiting, or functional disability), 24-hour sustained pain-free (no headache at 2 hours, no recurrence, and no additional antimigraine medications for 24 hours).. More patients taking rizatriptan 10 mg were pain-free at 2 hours than were patients taking sumatriptan 100 mg (40% vs 33%, p = 0.019), sumatriptan 50 mg (40% vs 35%, p = 0.009), sumatriptan 25 mg (38% vs 27%, p < 0.001), naratriptan 2.5 mg (45% vs 21%, p < 0.001), and zolmitriptan 2.5 mg (43% vs 36%, p = 0.041). More patients taking rizatriptan 10 mg were symptom-free at 2 hours than were patients taking sumatriptan 100 mg (31% vs 22%, p = 0.002), sumatriptan 50 mg (33% vs 28%, p = 0.003), sumatriptan 25 mg (33% vs 24%, p < 0.001), naratriptan 2.5 mg (30% vs 11%, p < 0.001), and zolmitriptan 2.5 mg (31% vs 24%, p = 0.042). More patients taking rizatriptan 10 mg had a 24-hour sustained pain-free response than did patients taking sumatriptan 100 mg (27% vs 23%, p = 0.112), sumatriptan 50 mg (30% vs 26%, p = 0.015), sumatriptan 25 mg (27% vs 20%, p = 0.005), naratriptan 2.5 mg (29% vs 17%, p = 0.004), and zolmitriptan 2.5 mg (32% vs 24%, p = 0.013).. Oral rizatriptan 10 mg was more effective than oral sumatriptan, naratriptan, and zolmitriptan on stringent outcome measures of pain-free response at 2 hours, symptom-free response at 2 hours, and 24-hour sustained pain-free response.

Topics: Administration, Oral; Humans; Indoles; Migraine Disorders; Oxazolidinones; Patient Satisfaction; Piperidines; Randomized Controlled Trials as Topic; Retrospective Studies; Serotonin Receptor Agonists; Sumatriptan; Triazoles; Tryptamines

The use of triptans has improved the ability to treat migraine successfully compared with older treatments. Speed of relief, consistency of effect, and good tolerability have been the hallmarks of these agents. All of the currently available triptans have comparable efficacy and tolerability. Variables between the agents may lead to one agent or dose form being preferred over another in various clinical scenarios. The triptans that are forthcoming may improve on these options through enhanced efficacy rates, tolerability, and headache recurrence rates. There exist increasing options for migraine treatment that may further improve the clinical effects of the older and newer triptans through early treatment of migraine at the stages of mild migraine pain, or even during the prodromal phase of the attack. Additionally, recent work suggests that mini-prophylaxis of migraine at the menses is a highly successful treatment option with the triptans. In this age of managed care, providing cost-effective treatment of headache will take on increasing importance. Techniques such as stratification of acute treatments may enhance cost-effective care, whereas ready availability of the triptans may lead to significant improvements in utilization of parameters such as office visits, emergency room treatment, and even hospitalization.

Topics: Acute Disease; Blood Flow Velocity; Carbazoles; Clinical Trials as Topic; Drug Administration Routes; Female; Humans; Indoles; Male; Menstruation; Migraine Disorders; Oxazolidinones; Piperidines; Practice Guidelines as Topic; Pyrrolidines; Receptor, Serotonin, 5-HT1B; Receptor, Serotonin, 5-HT1D; Receptors, Serotonin; Serotonin Receptor Agonists; Sumatriptan; Treatment Outcome; Triazoles; Tryptamines; Vasoconstriction; Vasoconstrictor Agents

Two new intranasal migraine medications, sumatriptan and dihydroergotamine mesylate, may offer specific advantages for patients who are seeking alternatives to various oral or parenteral migraine abortive therapies. Placebo-controlled clinical studies demonstrate that both intranasal forms are effective in relieving migraine headache pain, but published clinical trial information comparing these two intranasal medications with current abortive therapies is lacking. Both agents are generally well tolerated by patients, with the exception of mild, local adverse reactions of the nose and throat.

Topics: Administration, Intranasal; Administration, Oral; Analgesics, Non-Narcotic; Clinical Trials as Topic; Dihydroergotamine; Half-Life; Humans; Indoles; Migraine Disorders; Oxazoles; Oxazolidinones; Piperidines; Recurrence; Serotonin Receptor Agonists; Sumatriptan; Triazoles; Tryptamines

Sterile neurogenic inflammation within cephalic tissue, involving vasodilation and plasma protein extravasation, has been proposed as a pathophysiological mechanism in acute migraine. The action of 5-hydroxytryptamine (5-HT1B/1D) agonists--so-called triptans--on receptors located in meningeal arteries (5-HT1B) and trigeminovascular fiber endings (5-HT1D) has an inhibitory effect on this neurogenic inflammation. Recently, a series of second-generation 5-HT1B/1D agonists (almotriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, and zolmitriptan) have been developed and are reviewed in this article. Their in vitro pharmacological properties, pharmacokinetics, clinical efficacy, drug interactions, and adverse effects are evaluated and compared to the golden standard in the treatment of acute migraine, sumatriptan.

Topics: Acute Disease; Carbazoles; Humans; Indoles; Migraine Disorders; Oxazoles; Oxazolidinones; Piperidines; Pyrrolidines; Receptor, Serotonin, 5-HT1B; Receptor, Serotonin, 5-HT1D; Receptors, Serotonin; Serotonin Receptor Agonists; Triazoles; Tryptamines

Migraine headaches are a common medical problem that physicians frequently encounter in their practice. They can be disabling, leading to the individual's suffering if not treated appropriately and quickly. There is a variety of medications and treatment approaches that can be used to relieve pain and any associated symptoms. New medications have become available in recent years to aggressively treat migraine headaches. Called "triptans," these medications have been designed to specifically treat an acute migraine attack and can be effective if used early and properly. Many medications are also available to treat symptoms associated with migraines. Patient education, along with nonpharmacologic approaches, is an element of effective treatment. Biofeedback, relaxation, and physical techniques can be effective adjunctive options. Although nonprescription medications can be helpful initially, more specific treatment is often required. Opioids, phenothiazines, ergotamine, and the triptans are generally used in patients with difficult migraines. The newer agents, the triptans, offer new hope in aggressively treating this painful condition that often has an impact on individuals and their families.

Topics: Analgesics; Ergotamine; Humans; Indoles; Migraine Disorders; Piperidines; Serotonin Receptor Agonists; Sumatriptan; Tryptamines; Vasoconstrictor Agents

To critically evaluate the literature regarding naratriptan's clinical pharmacology, efficacy, safety, and indications.. A MEDLINE search was conducted for the period from January 1990 to June 1998. Key words used included naratriptan, triptan, serotonin agonists, migraine, and migraine therapy. In addition, pertinent references cited in articles obtained from MEDLINE and product information for triptans were reviewed.. All original and review articles and abstracts pertaining to naratriptan were reviewed, as were product information extracts. Clinical trials of naratriptan were critically reviewed and compared with pertinent clinical trials of other oral triptans.. The treatment of migraine has been dramatically improved with the use of sumatriptan, other triptans, and serotonin-receptor subtype 1B and 1D agonists. Drawbacks to these medications, however, have included poorly tolerated adverse effects and the recurrence of the migraine. Naratriptan has been recently approved for acute oral migraine therapy. In two Phase III trials of naratriptan compared with placebo, relief at four hours was obtained in 60% and 68% of patients using the 2.5-mg dose, with recurrence of headache in 24 hours in 27% and 28% of patients. The data on migraine recurrence were similar to those of other oral triptans; the efficacy of naratriptan at two hours was not specifically analyzed. Adverse effects of naratriptan were similar to placebo, and its tolerability seemed superior compared with studies of other oral triptans.. Naratriptan is a promising new oral therapy for acute migraine; it may successfully treat patients who poorly tolerate other triptan therapies or have longer duration migraine headaches.

Topics: Animals; Clinical Trials as Topic; Humans; Indoles; Migraine Disorders; Piperidines; Serotonin Receptor Agonists; Tryptamines; Vasoconstrictor Agents

The efficacy of 5-hydroxytryptamine 1B/1D (5-HT 1B/1D) agonists is related to their inhibitory effects on neurogenic inflammation, mediated through serotoninergic control mechanisms. Recently, a series of oral second generation 5-HT 1B/1D agonists (eletriptan, naratriptan, rizatriptan and zolmitriptan) have been developed and are reviewed in this paper. Their in vitro and in vivo pharmacological properties, clinical efficacy, drug interactions, and adverse effects are evaluated and compared to the gold standard in the treatment of acute migraine, sumatriptan.

Topics: Acute Disease; Animals; Clinical Trials as Topic; Coronary Circulation; Coronary Vasospasm; Drug Design; Drug Interactions; Humans; Inactivation, Metabolic; Indoles; Meninges; Migraine Disorders; Molecular Structure; Nociceptors; Oxazoles; Oxazolidinones; Piperidines; Propranolol; Pyrrolidines; Randomized Controlled Trials as Topic; Rats; Receptor, Serotonin, 5-HT1B; Receptor, Serotonin, 5-HT1D; Receptors, Serotonin; Recurrence; Serotonin Receptor Agonists; Structure-Activity Relationship; Sumatriptan; Treatment Outcome; Triazoles; Tryptamines; Vasoconstrictor Agents

Migraine is a paroxysmal disorder characterized by attacks of headache, nausea, vomiting, photophobia and phonophobia, and malaise. This review summarizes new treatment options for the therapy of acute attacks. Sumatriptan was the first specific serotonin-1B/D agonist for the treatment of acute migraine attacks. Apart from the oral and subcutaneous formulation, it is also available as nasal spray and suppository. The other new migraine drugs zolmitriptan, naratriptan, rizatriptan and eletriptan differ in their pharmacological profiles, which translates into minor differences in efficacy, headache recurrence and side-effects. Importantly, in clinical practice individual patients may show a preference for one treatment over another. New drugs in migraine treatment include substance-P antagonists, nitric oxide synthetase inhibitors and calcitonin gene-related peptide antagonists.

Topics: Humans; Indoles; Migraine Disorders; Oxazoles; Oxazolidinones; Piperidines; Serotonin Receptor Agonists; Sumatriptan; Tryptamines

With the rapid advances in the treatment of acute attacks of migraine in the last few years and a number of new treatments, has come the practical clinical problem of comparing emerging acute attack therapies alone and with regard to current treatments. Acute migraine therapies can usefully be regarded as non-specific and specific, from the perspective of migraine, since some medicines, such as aspirin or paracetamol, are used to treat pain more broadly. In this review I will compare both non-specific and specific compounds. To some extent the introduction into trial then clinical use of sumatriptan, the first of the 5HT1B/1D agonists or triptans, brought new standards in both clinical trial design, and execution and clinical outcome. Thus sumatriptan has become the de facto gold standard and will be thus employed here. To be practical the discussion of the new triptans will be limited to those available widely, naratriptan, rizatriptan and zolmitriptan. There are two broad issues when comparing treatments: what end-point should be considered and then, how can different compounds be compared with respect to that end-point. In terms of end-points those used here relate to pain relief because they have been collected robustly in the clinical studies and, fortunately, rapid pain relief is what patients questioned in population-based studies rate highest in an acute attack medicine. Headache pain has been rated on a scale of nil, mild, moderate and severe and success rated as either a response, nil or mild pain, or headache free, nil pain, at two or four hours. The ideal comparison of the triptans would be a randomized controlled clinical trial directly comparing the medicines in each case. Given that these are not available for all the compounds and the well characterised placebo response in acute migraine studies, summary measures have been developed to express the differences between compounds to try and adjust for the varying placebo effect. The two most widely used are the therapeutic gain, response on active medication minus response on placebo, and the number-needed-to-treat (NNT). The NNT is the reciprocal of the therapeutic gain as a proportion. The strengths and weaknesses of this approach will be discussed, including the importance of the calculation of confidence intervals. It can be concluded that our current instruments are rather blunt and patient preference needs much greater study.

Topics: Acute Disease; Choice Behavior; Dose-Response Relationship, Drug; Humans; Indoles; Migraine Disorders; Models, Biological; Oxazoles; Oxazolidinones; Piperidines; Serotonin Receptor Agonists; Severity of Illness Index; Sumatriptan; Triazoles; Tryptamines

The realisation that serotonin plays a role not only in the carcinoid syndrome but also in migraine, nociception, dumping syndrome, vascular disease and hypertension, has led to an enormous amount of activity in search of serotonin antagonists. Numerous such pharmacological agents have been identified but only few have found their way into clinical use. All of them are competitive serotonin inhibitors, in that they vie for the same receptor as the amine itself and are thus able to block its action as well as imitate its effects. By far the widest use of such inhibitors is in the prevention of migraine, where they have effectively eliminated the dread of an attack from the life of the majority of patients. Whilst useful in the control of diarrhea in patients with carcinoid and dumping syndromes, their role in these diseases is limited. However, the possible role of serotonin in hypertension and nociception opens new avenues in the use of existing serotonin antagonists and calls for the discovery of a new generation of such pharmacological agents for the control of these conditions.

Topics: Cyproheptadine; Depression; Ergotamine; Humans; Hypertension; Ketanserin; Lisuride; Methysergide; Mianserin; Migraine Disorders; Piperidines; Pizotyline; Receptors, Serotonin; Serotonin; Serotonin Antagonists; Vascular Diseases

Topics: Adrenergic beta-Antagonists; Bradykinin; Clonidine; Cycloheptanes; Cyproheptadine; Ergotamine; Histamine; Humans; Methysergide; Migraine Disorders; Norepinephrine; Piperidines; Prostaglandins; Serotonin; Serotonin Antagonists; Thiophenes; Tyramine

Topics: Animals; Blood Pressure; Clinical Trials as Topic; Cycloheptanes; Cyproheptadine; Dogs; Ergolines; Guinea Pigs; Haplorhini; Headache; Histamine H1 Antagonists; Humans; Hypnotics and Sedatives; Lethal Dose 50; Methysergide; Mice; Migraine Disorders; Phenothiazines; Piperidines; Rabbits; Rats; Serotonin Antagonists; Thiophenes; Vascular Headaches

The objectives of this study were to (1) report long-term health-related quality of life (HRQoL) outcomes among patients using rimegepant preventatively in BHV3000-305 (NCT03732638) open-label extension (OLE) and (2) map Migraine-Specific Quality of Life questionnaire version 2.1 (MSQv2) to EQ-5D-3L utility values over the double-blind treatment (DBT; 0-12 weeks) and the OLE (13-64 weeks) to assess the influence of treatment on these values.. This was a post hoc analysis using data from a rimegepant study for the prevention of migraine (BHV3000-305). Adult patients with migraine took either rimegepant 75 mg or placebo every other day (EOD) during the DBT phase. All patients received rimegepant during the OLE. MSQv2 was measured at baseline, weeks 12, 24, and 64. A validated algorithm was used to map MSQv2 scores to EQ-5D utilities.. Baseline data were available for 347 patients treated with placebo and 348 treated with rimegepant in the DBT period, who continued to the OLE. Baseline EQ-5D utilities were similar between trial arms: 0.598 for placebo and 0.614 for rimegepant. EQ-5D improved from baseline to week 12 and utilities increased by + 0.09 for placebo and + 0.10 for rimegepant (p value = 0.011). By 24 weeks, at which point patients who were originally randomized to placebo had received rimegepant 75 mg EOD for 12 weeks, HRQoL measures (MSQv2 and EQ-5D) were similar across groups, demonstrating rapid onset of treatment effect. This HRQoL improvement was durable out to 64 weeks.. Compared to placebo, treatment with rimegepant 75 mg was associated with greater improvement in EQ-5D utilities during the 12-week DBT phase. Patients originally randomized to placebo experienced a similar improvement in EQ-5D utilities after switching to rimegepant during the OLE, demonstrating that benefits are realized within 12 weeks of active treatment. This preventive effect was durable out to 64 weeks and was associated with an additional increase in HRQoL over time.. NCT03732638.

Topics: Adult; Humans; Migraine Disorders; Piperidines; Pyridines; Quality of Life; Surveys and Questionnaires

Atogepant is an oral, small-molecule, calcitonin gene-related peptide receptor antagonist for the preventive treatment of episodic migraine.. In this 52-week, multicenter, randomized, open-label trial, adults with 4-14 monthly migraine days received atogepant 60 mg once-daily or standard care. Health outcome endpoints collected from participants randomized to atogepant included change from baseline in Migraine-Specific Quality of Life Questionnaire version 2.1 (MSQ v2.1) Role Function-Restrictive (RFR), Role Function-Preventive (RFP) and Emotional Function (EF) domain scores, change in Activity Impairment in Migraine-Diary (AIM-D) Performance of Daily Activities (PDA) and Physical Impairment (PI) domain scores, and change in Headache Impact Test-6 (HIT-6) total score.. Of 744 randomized participants, 521 received atogepant 60 mg in the modified intent-to-treat population. Least-squares mean changes from baseline in MSQ-RFR score were 30.02 (95% confidence interval = 28.16-31.87) at week 12 and 34.70 (95% confidence interval = 32.74-36.66) at week 52. Improvements were also observed in other MSQ domains, AIM-D PDA, PI and HIT-6 total scores. A ≥5-point improvement from baseline in HIT-6 score was observed in 59.9% of participants at week 4 and 80.8% of participants at week 52.. Over 52 weeks, atogepant 60 mg once-daily was associated with sustained improvements in quality of life and reductions in activity impairment and headache impact.

Topics: Calcitonin Gene-Related Peptide Receptor Antagonists; Drug Administration Schedule; Humans; Migraine Disorders; Patient Reported Outcome Measures; Piperidines; Pyridines; Pyrroles; Quality of Life; Spiro Compounds

Atogepant is an oral, small-molecule, calcitonin gene-related peptide receptor antagonist for the preventive treatment of migraine.. In the double-blind, phase 3 ADVANCE trial, participants with 4-14 migraine days/month were randomized to atogepant 10 mg, 30 mg, 60 mg, or placebo once daily for 12 weeks. We evaluated the time course of efficacy of atogepant for the preventive treatment of migraine. Analyses included change from baseline in mean monthly migraine days during each of the three 4-week treatment periods, change in weekly migraine days during weeks 1-4, and proportion of participants with a migraine on each day during the first week.. We analyzed 873 participants (n = 214 atogepant 10 mg, n = 223 atogepant 30 mg, n = 222 atogepant 60 mg, n = 214 placebo). For weeks 1-4, mean change from baseline in mean monthly migraine days ranged from -3.1 to -3.9 across atogepant doses vs -1.6 for placebo (. Atogepant demonstrated treatment benefits as early as the first full day after treatment initiation, and sustained efficacy across each 4-week interval during the 12-week treatment period.

Topics: Analgesics; Double-Blind Method; Humans; Migraine Disorders; Piperidines; Pyridines; Pyrroles; Spiro Compounds; Treatment Outcome

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-HT. 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.. Lasmiditan was efficacious across multiple clinically relevant endpoints in the acute treatment of migraine independent of prior response to triptans.

Topics: Benzamides; Double-Blind Method; Humans; Migraine Disorders; Pain; Piperidines; Pyridines; Serotonin 5-HT1 Receptor Agonists; Serotonin Receptor Agonists; Treatment Outcome; Tryptamines

The objective of this study was to describe patterns in monthly migraine days (MMD) and tablet utilization, and to estimate health-related quality of life (HRQoL) measures in patients treated as needed (PRN) with rimegepant 75 mg over 52-weeks.. Eligible subjects were adults with ≥1 year history of migraine and ≥ 6 MMD at baseline, who used rimegepant 75 mg up to once daily PRN (at their discretion) for up to 52-weeks in an open-label safety study (BHV3000-201; NCT03266588). Mean MMD were calculated at each 4-week period, along with mean monthly tablets taken. Migraine-specific quality of life (MSQv2) data were mapped to EQ-5D utilities and used to characterize HRQoL over time. A published network meta-analysis was used to characterize pain hours as well as time periods spent migraine free.. One thousand forty four subjects were included in this post-hoc analysis. Overall mean MMD were 10.9 at baseline and decreased to 8.9 by week 52. Tablet use remained stable over the follow-up period. A total of 0.08 incremental QALYs were associated with rimegepant use.. For subjects with 6 or more MMD, acute treatment of migraine attacks with rimegepant 75 mg on a PRN basis over one-year of follow-up was found to be associated with reduced MMD frequency without an increase in monthly tablet utilization, and improved HRQoL. There was no evidence of medication-related increases in MMDs when rimegepant 75 mg was used as needed for the acute treatment of migraine over 52-weeks.. ClinicalTrials.gov identifier NCT03266588 .

Topics: Adult; Calcitonin Gene-Related Peptide Receptor Antagonists; Double-Blind Method; Humans; Migraine Disorders; Piperidines; Pyridines; Quality of Life; Treatment Outcome

The robust enrollment in SPARTAN and SAMURAI provided the opportunity to present post-hoc descriptive details on migraine disease characteristics and treatment outcomes after treatment with lasmiditan, a selective serotonin (5-HT. Descriptive data from racial (White [W](. Clinical characteristics were generally similar across populations. W participants had longer migraine history than AA participants, and Non-HL participants had more migraine disability than HL participants. In the lasmiditan single-attack studies, AA participants waited longer than W participants to take study drug. A higher proportion of HL participants rated baseline migraine severity as severe compared to Non-HL participants. Response to lasmiditan was similar across racial and ethnic groups, including pain response, freedom from most bothersome symptom and migraine-related disability, and safety and tolerability. Across multiple outcomes, AA and HL participants tended to report more positive outcomes.. There were few differences in demographic and clinical characteristics across racial and ethnic groups. Similar lasmiditan efficacy and safety outcomes were observed in AA versus W participants, and in HL versus Non-HL participants. Small observed differences may be driven by a tendency toward a more positive response observed across all treatment groups by AA and HL participants.

Topics: Benzamides; Double-Blind Method; Ethnicity; Humans; Migraine Disorders; Piperidines; Pyridines; Serotonin Receptor Agonists; Treatment Outcome

Some patients with migraine, particularly those in primary care, require effective, well-tolerated, migraine-specific oral preventive treatments.. To examine the efficacy of atogepant, an oral, small-molecule, calcitonin gene-related peptide receptor antagonist, using 4 levels of mean monthly migraine-day (MMD) responder rates.. This secondary analysis of a phase 3, double-blind, placebo-controlled randomized clinical trial evaluated the efficacy and safety of atogepant for the preventive treatment of migraine from December 14, 2018, to June 19, 2020, in adults with 4 to 14 migraine-days per month at 128 sites in the US.. Patients were administered 10 mg of atogepant (n = 222), 30 mg of atogepant (n = 230), 60 mg of atogepant (n = 235), or placebo (n = 223) once daily in a 1:1:1:1 ratio for 12 weeks.. These analyses evaluated treatment responder rates, defined as participants achieving 50% or greater (α-controlled, secondary end point) and 25% or greater, 75% or greater, and 100% (prespecified additional end points) reductions in mean MMDs during the 12-week blinded treatment period.. Of 902 participants (mean [SD] age, 41.6 [12.3] years; 801 [88.8%] female; 752 [83.4%] White; 825 [91.5%] non-Hispanic), 873 were included in the modified intention-to-treat population (placebo, 214; 10 mg of atogepant, 214; 30 mg of atogepant, 223; and 60 mg of atogepant, 222). For the secondary end point, a 50% or greater reduction in the 12-week mean of MMDs was achieved by 119 of 214 participants (55.6%) treated with 10 mg of atogepant (odds ratio, 3.1; 95% CI, 2.1-4.6), 131 of 223 participants (58.7%) treated with 30 mg atogepant (odds ratio, 3.5; 95% CI, 2.4-5.3), 135 of 222 participants (60.8%) treated with 60 mg of atogepant (odds ratio, 3.8; 95% CI, 2.6-5.7), and 62 of 214 participants (29.0%) given placebo (P < .001). The numbers of participants who reported a 25% or greater reduction in the 12-week mean of MMDs were 157 of 214 (73.4%) for 10 mg of atogepant, 172 of 223 (77.1%) for 30 mg of atogepant, and 180 of 222 (81.1%) for 60 mg of atogepant vs 126 of 214 (58.9%) for placebo (P < .002). The numbers of participants who reported a 75% or greater reduction in mean MMDs were 65 of 214 (30.4%) for 10 mg of atogepant, 66 of 223 (29.6%) for 30 mg of atogepant, and 84 of 222 (37.8%) for 60 mg of atogepant compared with 23 of 214 (10.7%) for placebo (P < .001). The numbers of participants reporting 100% reduction in mean MMDs were 17 of 214 (7.9%) for 10 mg of atogepant (P = .004), 11 of 223 (4.9%) for 30 mg of atogepant (P = .02), and 17 of 222 (7.7%) for 60 mg of atogepant (P = .003) compared with 2 of 214 (0.9%) for placebo.. At all doses, atogepant was effective during the 12-week double-blind treatment period beginning in the first 4 weeks, as evidenced by significant reductions in mean MMDs at every responder threshold level. Higher atogepant doses appeared to produce the greatest responder rates, which can guide clinicians in individualizing starting doses.. ClinicalTrials.gov Identifier: NCT03777059.

Topics: Adult; Analgesics; Double-Blind Method; Female; Humans; Male; Migraine Disorders; Piperidines; Pyridines; Pyrroles; Spiro Compounds; Treatment Outcome

In controlled clinical trials, compared with placebo, a significantly greater proportion of participants using lasmiditan to treat a migraine attack achieved 2-h pain freedom (PF) and experienced ≥ 1 treatment-emergent adverse event (TEAE).. To better inform clinicians about treatment expectations by evaluating the association between TEAEs and efficacy outcomes after lasmiditan treatment.. Pooled data from SAMURAI, SPARTAN, MONONOFU, and CENTURION were analyzed. A common TEAE (CTEAE) was defined as occurring in ≥ 2% in the overall population. Central nervous system (CNS)-CTEAEs were based on Medical Dictionary for Regulatory Activities.. At 2 h, a significantly higher percentage of lasmiditan 200 mg-treated participants who achieved PF experienced ≥ 1 CTEAE than non-responders who continued to experience moderate/severe pain (48.2% vs. 28.7%, respectively). Correspondingly, a significantly higher percentage of lasmiditan 200 mg-treated participants who experienced ≥ 1 CTEAE achieved PF at 2 h than those who did not (39.0% vs. 30.2%, respectively). Similar results were generally observed with individual CNS-CTEAEs, but for non-CNS-CTEAEs, this pattern was less evident or in the opposite direction. No consistent differences were observed for migraine-related functional disability freedom. The percentage of participants with improved patient global impression of change (PGIC) was greater with a CNS-CTEAE versus no CNS-CTEAE.. Those who had PF at 2 h were more likely to experience a CNS-CTEAE, and those with CNS-CTEAEs were more likely to experience PF. The occurrence of CTEAEs did not seem to negatively affect disability freedom or PGIC.. SAMURAI (NCT02439320), SPARTAN (NCT02605174), MONONOFU (NCT03962738), CENTURION (NCT03670810), ClinicalTrials.gov: NCT02439320, NCT02605174, NCT03962738, NCT03670810.

Topics: Benzamides; Double-Blind Method; Humans; Migraine Disorders; Pain; Piperidines; Pyridines; Randomized Controlled Trials as Topic; Serotonin Receptor Agonists; Treatment Outcome

Perimenstrual migraine attacks in women with menstrual migraine is difficult to treat. This post-hoc analysis evaluated the efficacy of lasmiditan, a high affinity and selective 5-HT. Patients from two randomized, double-blind, placebo-controlled clinical trials (MONONOFU and CENTURION) were instructed to treat an attack with a single dose of study medication within four hours of pain onset. After dosing, the proportion of patients who achieved freedom from migraine-related head pain, most bothersome symptom, and disability was reported at baseline up to 48 hours after dose and pooled data were evaluated.. A total of 303 patients (MONONOFU N = 78; CENTURION N = 225) treated perimenstrual migraine attacks with lasmiditan 50 mg (N = 24), 100 mg (N = 90), 200 mg (N = 110), and placebo (N = 79). More patients achieved migraine-related head pain freedom with lasmiditan 200 mg versus placebo at all time points assessed. At 2 hours, 33.6% of patients in the 200-mg group (p < 0.001), and 16.7% of patients in the 100-mg (p = 0.11) and 50-mg (p = 0.19) groups were pain free, compared with 7.6% in the placebo group.. Lasmiditan treatment of perimenstrual migraine attacks was associated with freedom from migraine-related head pain at two hours, early onset of efficacy, and sustained efficacy.

Topics: Benzamides; Double-Blind Method; Female; Humans; Migraine Disorders; Piperidines; Pyridines; Treatment Outcome

Lasmiditan is the first 5-HT. Patients were randomized 1:1:1 to lasmiditan 200 mg lasmiditan 100 mg, or a control group. The incidence of treatment-emergent adverse events (TEAEs), their severity, and incidence by treated attacks for frequently reported TEAEs (≥ 5%) were evaluated. The duration, onset, and relationship of efficacy with very common TEAEs (≥ 10%) was analyzed.. A total of 281 Chinese patients were included in this post hoc analysis. No deaths and no study drug-related treatment emergent serious adverse events (TESAEs) were reported. The incidence of at least one TEAE was higher in patients receiving lasmiditan 200 mg (73.9%) and 100 mg (66.3%) versus placebo (26.6%). TEAEs were generally mild or moderate in severity, and the incidence of frequently reported TEAEs was generally highest during the first attack. Very common TEAEs with lasmiditan included dizziness, asthenia, somnolence, muscular weakness, fatigue, and nausea. The duration of dizziness was longest during the first attack. There were no cardio-cerebrovascular ischemic events and serotonin syndrome. The presence of very common TEAEs (except nausea), and severe dizziness, did not appear to have a negative influence on the efficacy.. In the Chinese population of the CENTURION study, most of the TEAEs were neurologic, of mild or moderate severity, and self-limiting. The distribution of frequently reported TEAEs at the first attack differed from the primary cohort, while the overall safety profile of lasmiditan in the Chinese population was generally consistent with the CENTURION primary cohort. No new safety concerns were observed in the Chinese population.. NCT03670810.. Although there is significant unmet medical need among patients with migraine, there has been no novel compound for treatment of migraine over past two decades in China. These unmet medical needs persist because the current available medications for the acute treatment of migraine are reported to have safety and tolerability issues. Lasmiditan is a new class of acute migraine medication (5-HT receptor agonist with high selectivity for the 5-HT

Topics: Benzamides; Dizziness; Double-Blind Method; Humans; Migraine Disorders; Nausea; Piperidines; Pyridines; Serotonin Receptor Agonists; Treatment Outcome

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

Topics: Benzamides; Double-Blind Method; Headache; Humans; Japan; Migraine Disorders; Migraine with Aura; Piperidines; Pyridines; Serotonin Receptor Agonists; Treatment Outcome; Tryptamines

Lasmiditan (LTN) is a selective 5-HT. 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.. 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.. 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.. NCT03670810.

Topics: Adult; Benzamides; Double-Blind Method; Humans; Migraine Disorders; Piperidines; Pyridines; Serotonin Receptor Agonists; Treatment Outcome

Atogepant is a potent, selective, oral calcitonin gene-related peptide (CGRP) receptor antagonist in development for migraine prevention. The chemical structure of atogepant is distinct from previous CGRP receptor antagonists, which were associated with elevated serum alanine aminotransferase (ALT) in clinical trials. Here, we report the safety, tolerability, and pharmacokinetics (PKs) of a once-daily supratherapeutic dose (170 mg) of atogepant for 28 days from a randomized, double-blind, placebo-controlled phase I trial in healthy participants. Overall safety, hepatic safety, and plasma PK parameters were evaluated. Thirty-four participants aged 23-55 years enrolled; 28 (82.4%) completed the study in accordance with the protocol. Multiple doses of 170 mg atogepant for 28 consecutive days were generally well-tolerated. All adverse events (AEs; reported in 87.0% of the atogepant group; 72.7%, placebo) were mild in severity except one serious AE of subarachnoid hemorrhage due to a bicycle accident and not considered related to treatment. There were two discontinuations due to AEs, both with atogepant, one considered possibly related to treatment. Over 28 days of treatment, no participant receiving atogepant had an ALT elevation above 1.5 × upper limit of normal. Change from baseline in serum ALT levels was not different between atogepant and placebo. Atogepant is rapidly absorbed (median time to maximum plasma concentration, ~ 2 hours) with an apparent terminal half-life of ~ 11 hours, and no evidence of accumulation after once-daily dosing. Overall, atogepant at a high oral dose is safe and well-tolerated in healthy participants with no clinically meaningful elevations in ALT.

Topics: Administration, Oral; Adult; Alanine Transaminase; Dose-Response Relationship, Drug; Double-Blind Method; Female; Healthy Volunteers; Humans; Liver; Liver Function Tests; Male; Middle Aged; Migraine Disorders; Piperidines; Placebos; Pyridines; Pyrroles; Spiro Compounds; Young Adult

Rimegepant is a calcitonin gene-related peptide receptor antagonist that has shown efficacy and safety in the acute treatment of migraine. We aimed to compare the efficacy of rimegepant with placebo for preventive treatment of migraine.. We did a multicentre, phase 2/3, randomised, double-blind, placebo-controlled trial at 92 sites in the USA. Adults with at least a 1-year history of migraine were recruited. After a 4-week observation period, eligible participants were randomised using an interactive web response system to oral rimegepant 75 mg or matching placebo every other day for 12 weeks (double-blind treatment phase). The primary efficacy endpoint was change from the 4-week observation period in the mean number of migraine days per month in the last 4 weeks of the double-blind treatment phase (weeks 9-12). Participants who received at least one dose of their assigned study medication and who had 14 days or more of data in the observation period and 14 days or more of data for at least one 4-week interval during the double-blind treatment phase were analysed for efficacy. Those who received at least one dose of study medication were analysed for safety. This study is registered with ClinicalTrials.gov, NCT03732638.. Between Nov 14, 2018, and Aug 30, 2019, 1591 participants were recruited and assessed for eligibility, of whom 747 were randomly allocated either rimegepant (n=373) or placebo (n=374). 695 participants were included in the analysis for efficacy, of whom 348 were assigned rimegepant and 347 were allocated placebo. Rimegepant was superior to placebo on the primary endpoint of change in the mean number of migraine days per month during weeks 9-12. The change from the observation period in mean number of migraine days per month during weeks 9-12 was -4·3 days (95% CI -4·8 to -3·9) with rimegepant and -3·5 days (-4·0 to -3·0) with placebo (least squares mean difference -0·8 days, 95% CI -1·46 to -0·20; p=0·0099). 741 participants received study medication and were included in the safety analysis. 133 (36%) of 370 patients who received rimegepant reported an adverse event, compared with 133 (36%) of 371 who received placebo. Seven (2%) participants who received rimegepant and four (1%) who received placebo discontinued the study due to an adverse event; no patients died.. Taken every other day, rimegepant was effective for preventive treatment of migraine. Tolerability was similar to that of placebo, and no unexpected or serious safety issues were noted.. Biohaven Pharmaceuticals.

Topics: Administration, Oral; Adult; Calcitonin Gene-Related Peptide Receptor Antagonists; Double-Blind Method; Drug Evaluation; Female; Humans; Male; Migraine Disorders; Piperidines; Pyridines; Treatment Outcome

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.. 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.. Overall, 1471 patients treated ≥1 migraine attack with the study drug. Both primary endpoints were met for lasmiditan 100 mg and 200 mg (. These results confirm the early and sustained efficacy of lasmiditan 100 mg and 200 mg and demonstrate consistency of response across multiple attacks.

Topics: Benzamides; Double-Blind Method; Humans; Migraine Disorders; Pain; Piperidines; Pyridines; Serotonin Receptor Agonists; Treatment Outcome

Lasmiditan is a selective serotonin (5-HT1F) receptor agonist approved in the US for the acute treatment ofmigraine in adults. This phase I, open-label, two-cohort study assessed the pharmacokinetics (PK), safety, and tolerability of lasmiditan in patients with migraine aged 6 to < 18 years.. Cohort 1 (15 to ≤ 40 kg) and Cohort 2 (> 40 to ≤ 55 kg) received single oral doses of lasmiditan (100 mg and 200 mg, respectively).Blood samples for the assessment of PK and safety parameters were collected over a 24-h period. Follow-up was approximately 14 days after dosing.. Eighteen patients received lasmiditan (11 in Cohort 1, 7 in Cohort 2) and 17 patients completed the study. One patient in Cohort 2 discontinued due to adverse events. Plasma concentrations peaked at 1.5-2 h post dose and then declined, with a terminal half-life of approximately 4 h in both cohorts. While the exposure to lasmiditan was generally similar between cohorts, PK parameters, such as apparent total body clearance and volume of distribution, were greater for the 200 mg cohort relative to the 100 mg cohort. No deaths or serious adverse events were reported. The frequency and severity of adverse events (including somnolence, dizziness, and fatigue) were generally mild and similar to those in adult studies.. The PK results support weight-based dosing of lasmiditan in pediatric patients with migraine and no new safety or tolerability issues were identified. These findings support further investigation of lasmiditan as a potential treatment in pediatric patients with migraine. Clinical Trial Registration Numbers NCT03988088 and EMEA-002166-PIP01-17M02.

Topics: Adolescent; Benzamides; Child; Cohort Studies; Double-Blind Method; Humans; Migraine Disorders; Piperidines; Pyridines; Serotonin Receptor Agonists; Treatment Outcome

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.

Topics: Benzamides; Double-Blind Method; Headache; Humans; Migraine Disorders; Piperidines; Prospective Studies; Pyridines; Serotonin Receptor Agonists; Treatment Outcome

To evaluate the efficacy and safety of lasmiditan in Japanese adults with migraine.. Global clinical studies have demonstrated the efficacy and safety of lasmiditan in the acute treatment of migraine.. 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.. Participants (N = 846) were randomized and treated (N = 691, safety; N = 682, modified intent-to-treat). At 2 h postdose, a significantly higher proportion of participants were headache pain-free in the lasmiditan 200 mg (40.8%, 73/179; odds ratio 3.46 [95% confidence interval 2.17 to 5.54]; p < 0.001; primary objective) and 100 mg groups (32.4%, 67/207; odds ratio 2.41 [1.51 to 3.83]; p < 0.001) compared with the placebo group (16.6%, 35/211), whereas the lasmiditan 50 mg group had a numerically higher proportion of participants headache pain-free (23.5%, 20/85; odds ratio 1.55 [0.83 to 2.87]; p = 0.167) compared with placebo. A statistically significant linear dose-response relationship for pain freedom was achieved at 2 h by a Cochran-Armitage trend test (p < 0.001). Lasmiditan treatment was also associated with headache pain relief, most bothersome symptom freedom, and improvement on disability and Patient Global Impression of Change outcomes. The majority of treatment-emergent adverse events were mild and of short duration, the most common of which were dizziness (39.4%; 188/477), somnolence (19.3%; 92/477), and malaise (10.5%; 50/477) in all lasmiditan groups, with no serious adverse events reported.. Lasmiditan was well tolerated and effective for the acute treatment of Japanese patients with migraine, consistent with global phase 3 studies.

Topics: Adult; Benzamides; Double-Blind Method; Female; Humans; Japan; Male; Middle Aged; Migraine Disorders; Piperidines; Pyridines; Serotonin Receptor Agonists; Treatment Outcome

Limited information is available on acute treatments for migraine in elderly patients. Our objective was to evaluate the tolerability and safety of lasmiditan, a serotonin 1F agonist, for the acute treatment of migraine in elderly compared with nonelderly patients, with special emphasis on cardiovascular-related issues because cardiovascular comorbidities are more common in the elderly population.. These post hoc analyses evaluated the incidence of treatment-emergent adverse events (TEAEs) in elderly (≥65 years of age) versus nonelderly (<65 years of age) lasmiditan-treated patients. Two clinical trials entitled A Study of Two Doses of LAsMiditan (100 mg and 200 mg) Compared to Placebo in the AcUte Treatment of MigRAIne (SAMURAI) and A Study of Three Doses of Lasmiditan (50 mg, 100 mg and 200 mg) Compared to Placebo in the Acute TReaTment of MigrAiNe (SPARTAN) were randomized, double-blind, placebo-controlled, Phase III studies in adults (no upper age limit) who took placebo or lasmiditan 50 (SPARTAN only), 100, or 200 mg for a single migraine attack within 4 hours of the onset of moderate or severe pain. Patients who completed SAMURAI or SPARTAN were eligible to enroll in An Open-label, LonG-term, Safety Study of LAsmiDItan (100 mg and 200 mg) in the Acute Treatment Of MigRaine (GLADIATOR), a Phase III, randomized, open-label, multiattack study of lasmiditan 100 or 200 mg. For pooled SAMURAI+SPARTAN data, treatment × age subgroup interactions were examined using logistic regression analyses. In addition, common cardiovascular event rates were assessed from GLADIATOR during 3 periods: treatment-emergent (<48 hours after dosing), intermediate (48 hours to 1 week after dosing), and remote (>1 week after dosing).. Of 3177 lasmiditan-treated patients in SAMURAI or SPARTAN, 132 (4.2%) were elderly, and of 1262 placebo-treated patients, 54 (4.3%) were elderly. Of 2030 lasmiditan-treated patients in GLADIATOR, 85 (4.2%) were elderly. The incidences of at least 1 TEAE with lasmiditan in nonelderly and elderly patients with migraine were 36% and 35% in pooled SAMURAI+SPARTAN, respectively, and 49% and 38% in GLADIATOR, respectively. No significant treatment × age subgroup interactions were observed in patients with ≥1 TEAE overall or for any individual TEAE in pooled SPARTAN+SAMURAI; however, numerical differences in the incidence of some specific TEAEs were seen. No treatment × age subgroup interactions and no tolerability concerns for individual TEAEs were detected. Cardiovascular TEAEs were much more frequent in the nonelderly population than the elderly population. Cardiovascular events were not reported in the elderly population during the treatment-emergent period or intermediate period. There were 2 cases of increased blood pressure in elderly patients during the remote period.. The incidence of TEAEs was similar for elderly and nonelderly patients, and cardiovascular safety of lasmiditan was generally consistent with that in single-attack studies. No safety signals were observed with the limited number of patients in the elderly population. ClinicalTrials.gov identifiers: NCT02565186 (GLADIATOR), NCT02439320 (SAMURAI), and NCT02605174 (SPARTAN).

Topics: Adult; Aged; Benzamides; Double-Blind Method; Humans; Migraine Disorders; Piperidines; Pyridines; Treatment Outcome

Atogepant is an oral, small-molecule, calcitonin gene-related peptide receptor antagonist that is being investigated for the preventive treatment of migraine.. In a phase 3, double-blind trial, we randomly assigned adults with 4 to 14 migraine days per month in a 1:1:1:1 ratio to receive a once-daily dose of oral atogepant (10 mg, 30 mg, or 60 mg) or placebo for 12 weeks. The primary end point was the change from baseline in the mean number of migraine days per month across the 12 weeks. Secondary end points included headache days per month, a reduction from baseline of at least 50% in the 3-month average of migraine days per month, quality of life, and scores on the Activity Impairment in Migraine-Diary (AIM-D).. A total of 2270 participants were screened, 910 were enrolled, and 873 were included in the efficacy analysis; 214 were assigned to the 10-mg atogepant group, 223 to the 30-mg atogepant group, 222 to the 60-mg atogepant group, and 214 to the placebo group. The mean number of migraine days per month at baseline ranged from 7.5 to 7.9 in the four groups. The changes from baseline across 12 weeks were -3.7 days with 10-mg atogepant, -3.9 days with 30-mg atogepant, -4.2 days with 60-mg atogepant, and -2.5 days with placebo. The mean differences from placebo in the change from baseline were -1.2 days with 10-mg atogepant (95% confidence interval [CI], -1.8 to -0.6), -1.4 days with 30-mg atogepant (95% CI, -1.9 to -0.8), and -1.7 days with 60-mg atogepant (95% CI, -2.3 to -1.2) (P<0.001 for all comparisons with placebo). Results for the secondary end points favored atogepant over placebo with the exceptions of the AIM-D Performance of Daily Activities score and the AIM-D Physical Impairment score for the 10-mg dose. The most common adverse events were constipation (6.9 to 7.7% across atogepant doses) and nausea (4.4 to 6.1% across atogepant doses). Serious adverse events included one case each of asthma and optic neuritis in the 10-mg atogepant group.. Oral atogepant once daily was effective in reducing the number of migraine days and headache days over a period of 12 weeks. Adverse events included constipation and nausea. Longer and larger trials are needed to determine the effect and safety of atogepant for migraine prevention. (Funded by Allergan; ADVANCE ClinicalTrials.gov number, NCT03777059.).

Topics: Adolescent; Adult; Aged; Calcitonin Gene-Related Peptide Receptor Antagonists; Constipation; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Intention to Treat Analysis; Male; Middle Aged; Migraine Disorders; Nausea; Piperidines; Pyridines; Pyrroles; Spiro Compounds; Young Adult

Migraine is a debilitating neurological condition, affecting up to 15% of Americans. Recent estimates from a long-term safety study of rimegepant showed evidence of decreased monthly migraine days (MMD) in people with episodic migraine treated with rimegepant 75 mg. The objective of this study was to characterize migraine-specific quality of life version 2.1 (MSQv2) scores and corresponding mapped EuroQol-5 Dimensions-3 Level (EQ-5D-3L) utility values.. Study participants were randomized into two treatment regimens: individuals with 2-14 MMD received rimegepant 75 mg as needed (PRN), and those with 4-14 MMD at baseline who received rimegepant on a fixed every-other-day schedule plus an as needed dose on days they did not treat (QOD + PRN). MSQv2 was mapped to EQ-5D-3L utilities using a validated algorithm. Outcomes were assessed for the PRN arm at baseline weeks 12, 24, 36, and 52 and for the QOD + PRN arm at baseline and week 12.. At baseline, MSQv2 data were available for 1,800 patients: 1,033 with 2-8 MMD in the PRN group, 481 with 9-14 MMD in the PRN group, and 286 with 4-14 MMD in the QOD + PRN group. For all MSQv2 domains as well as mapped utility values, outcomes improved over each study visit. At baseline, EQ-5D-3L utilities were 0.66, 0.63, and 0.65 for the 2-8 MMD PRN, 9-14 MMD PRN, and 4-14 MMD QOD + PRN groups, respectively. At end-of-study, utilities had increased by + 0.09, + 0.10, and + 0.12 for the three groups, respectively (p < 0.001 for all comparisons with baseline). Similar trends in improvement were observed across MSQv2 subdomains; all differences were statistically significant.. Rimegepant 75 mg, which has been shown to be associated with reduced MMD, is associated with improvement in MSQv2 domains over time, leading to estimated improvement in EQ-5D-3L utilities. While this improvement was observed in all patient-groups, it was most pronounced in those with higher MMD and those taking rimegepant QOD + PRN.. Clinical Trials NCT03266588.

Topics: Algorithms; Humans; Migraine Disorders; Piperidines; Pyridines; Quality of Life; Surveys and Questionnaires

Lasmiditan demonstrated superiority to placebo in the acute treatment of migraine in adults with moderate/severe migraine disability in two similarly designed Phase 3 trials, SAMURAI and SPARTAN. Post-hoc integrated analyses evaluated the efficacy of lasmiditan in patients who reported a good or insufficient response to triptans and in those who were triptan naïve.. Subgroups of patients reporting an overall response of "good" or "poor/none" to the most recent use of a triptan at baseline (defined as good or insufficient responders, respectively) and a triptan-naïve subpopulation were derived from combined study participants randomized to receive lasmiditan 50 mg (SPARTAN only), 100 mg or 200 mg, or placebo, as the first dose. Outcomes including headache pain-freedom, most bothersome symptom-freedom, and headache pain relief 2 hours post-first dose of lasmiditan were compared with placebo. Treatment-by-subgroup analyses additionally investigated whether therapeutic benefit varied according to prior triptan response (good or insufficient).. Regardless of triptan response, lasmiditan showed higher efficacy than placebo (most comparisons were statistically significant). Treatment-by-subgroup analyses found that the benefit over placebo of lasmiditan did not vary significantly between patients with a good response and those with an insufficient response to triptans. Lasmiditan also showed higher efficacy than placebo in triptan-naïve patients.. Lasmiditan demonstrated comparable efficacy in patients who reported a good or insufficient response to prior triptan use. Lasmiditan also showed efficacy in those who were triptan naïve. Lasmiditan may be a useful therapeutic option for patients with migraine.. SAMURAI (NCT02439320); SPARTAN (NCT02605174).

Topics: Adult; Benzamides; Dose-Response Relationship, Drug; Female; Humans; Male; Middle Aged; Migraine Disorders; Piperidines; Pyridines; Serotonin Receptor Agonists; Treatment Outcome; Tryptamines

Lasmiditan (LY573144/COL-144) is a high-affinity, centrally penetrant, selective 5-HT

Topics: Administration, Oral; Adrenergic beta-Antagonists; Adult; Aged; Benzamides; Blood Pressure; Cardiovascular System; Drug Interactions; Drug Therapy, Combination; Fasting; Female; Healthy Volunteers; Heart Rate; Humans; Male; Middle Aged; Migraine Disorders; Piperidines; Propranolol; Pyridines; Serotonin Receptor Agonists

Migraine is recognized as the second leading cause of disability globally. Lasmiditan is a novel, selective serotonin 5-HT. Completers of two single-attack parent studies were offered participation in the 1 year GLADIATOR study, that randomized participants to treatment with lasmiditan 100 mg or 200 mg taken as needed for migraine attacks of at least moderate severity. Changes in MIDAS were modeled using a mixed model repeated measures analysis.. The sample included 1978 patients who received ≥1 lasmiditan dose and were followed for a median of 288 days. Baseline mean MIDAS scores for the lasmiditan 100-mg and 200-mg groups were 29.4 and 28.9, respectively, indicating severe migraine-related disability. Relative to baseline, MIDAS total scores were significantly lower at 3, 6, 9, and 12 months for both dose groups. At 12 months, changes in MIDAS scores were - 12.5 and - 12.2 for lasmiditan 100 mg and 200 mg, respectively, with 49% and 53% of patients, respectively, achieving at least a 50% decrease in MIDAS total score. Statistically significant improvements were also seen for work and/or school absenteeism and presenteeism, monthly headache days, and mean headache pain intensity at all time points up to 1 year. Findings for patients who completed all visits versus those dropping out early were similar. Responses were generally similar for the lasmiditan 100 mg or 200 mg doses, between subgroups defined based on the number of baseline monthly migraine attacks (≤5 vs. >5), and also between subgroups defined by pain-free response (yes/no) during initial attacks.. Long-term treatment with lasmiditan was associated with significant reductions in migraine-related disability, including both work or school absenteeism and presenteeism. The similarity of responses in completers and those who dropped out suggests that selective attrition does not account for the improvements. Benefits were significant at 3 months and maintained through 12 months.. clinicaltrials.govNCT02565186; first posted October 1, 2015.

Topics: Absenteeism; Adult; Benzamides; Disability Evaluation; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Male; Middle Aged; Migraine Disorders; Piperidines; Prospective Studies; Pyridines; Serotonin Receptor Agonists; Time Factors; Treatment Outcome; Young Adult

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.. 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.. 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.. 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.

Topics: Adolescent; Adult; Aged; Benzamides; Double-Blind Method; Female; Humans; Male; Middle Aged; Migraine Disorders; Outcome Assessment, Health Care; Piperidines; Pyridines; Receptor, Serotonin, 5-HT1F; Receptors, Serotonin; Serotonin Receptor Agonists; Time Factors; Young Adult

Evaluate the safety and tolerability of oral rimegepant when used for acute treatment concomitantly with a monoclonal antibody (mAb) targeting the calcitonin gene-related peptide (CGRP) ligand or receptor (CGRP mAb) for the preventive treatment of migraine.. The efficacy of CGRP mAbs for the preventive treatment of migraine and the small molecule CGRP receptor antagonist rimegepant for acute treatment has been demonstrated in randomized controlled clinical trials. Over the past few years, the US Food and Drug Administration has approved 4 CGRP mAbs for the preventive treatment of migraine and 2 small molecule CGRP receptor antagonists for the acute treatment of migraine. A previous case report of 2 patients receiving concomitant treatment with rimegepant and erenumab suggested that rimegepant may be safely used as acute treatment in patients who are also receiving a preventive regimen involving CGRP mAbs. We report here 13 additional patients with migraine who simultaneously used rimegepant and either erenumab, fremanezumab, or galcanezumab and assess the rate of on-treatment adverse events (AEs).. This was a substudy nested within a multicenter, open-label, long-term safety study in adults with 2-14 monthly migraine attacks of moderate to severe pain intensity. A subgroup experiencing 2-8 monthly attacks and taking a stable dose of a CGRP mAb also took rimegepant 75 mg as needed up to once daily for acute treatment for 12 weeks.. The 13 patients (11 women [85%]; mean age 49.9 years) enrolled in the substudy were being treated with CGRP mAbs (erenumab [n = 7], fremanezumab [n = 4], or galcanezumab [n = 2]). Mean (SD) time in the rimegepant treatment period was 9.6 (4.6) weeks. Mean (SD) 4-week rimegepant exposure was 7.8 (5.5) doses; a total of 224 doses were taken. Five (38%) patients reported ≥1 on-treatment AE. Of these, 2 (15%) patients had mild or moderate nasopharyngitis; no other AEs occurred in ≥2 patients. Three patients had AEs of mild or moderate severity that were considered potentially treatment-related. No patients had serious AEs, AEs leading to discontinuation, or aminotransferase levels >3× the upper limit of normal.. Rimegepant, when used as an oral acute treatment in patients receiving CGRP mAbs as preventive treatment, was well tolerated; no safety issues were identified. Studies involving larger patient populations are needed to confirm these findings.

Topics: Administration, Oral; Adult; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Calcitonin Gene-Related Peptide; Calcitonin Gene-Related Peptide Receptor Antagonists; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Male; Middle Aged; Migraine Disorders; Piperidines; Pyridines

Rimegepant is an oral calcitonin gene-related peptide (CGRP) receptor antagonist developed with a novel quick-dissolve oral tablet formulation for the acute treatment of migraine by Biohaven Pharmaceuticals, under license from Bristol Myers Squibb. The completed phase II and III trials showed its efficacy in terms of pain freedom, pain relief, release of migraine symptoms and lifestyle recovery, with an effect sustained up to 48 h. Significant clinical efficacy has been reported with a rimegepant single dose. Rimegepant was well tolerated and the few adverse events were mild or moderate and did not cause trial discontinuation. It received Food and Drug Administration (FDA) approval on February 27, 2020, for the acute treatment of migraine headache. Three clinical trials are currently ongoing to evaluate: i) the long-term safety as migraine acute treatment; ii) the efficacy and safety as a preventive treatment for migraine; and iii) the efficacy and safety for refractory trigeminal neuralgia. Future studies should be designed also to evaluate potential drug-drug interactions.

Topics: Calcitonin Gene-Related Peptide Receptor Antagonists; Humans; Migraine Disorders; Piperidines; Pyridines

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].

Topics: Adult; Benzamides; Double-Blind Method; Female; Humans; Male; Middle Aged; Migraine Disorders; Piperidines; Pyridines; Recurrence; Serotonin Receptor Agonists

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.. 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.. 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.

Topics: Adolescent; Adult; Aged; Benzamides; Dose-Response Relationship, Drug; Female; Humans; Male; Middle Aged; Migraine Disorders; Piperidines; Prospective Studies; Pyridines; Serotonin Receptor Agonists; Treatment Outcome; Young Adult

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.

Topics: Adult; Benzamides; Cardiovascular Diseases; Double-Blind Method; Female; Headache; Humans; Male; Middle Aged; Migraine Disorders; Piperidines; Pyridines; Receptor, Serotonin, 5-HT1F; Receptors, Serotonin; Serotonin Receptor Agonists; Treatment Outcome

To expand on available information on the efficacy of oral lasmiditan for the acute treatment of migraine with particular focus on the timing of the effect and on its impact on migraine-associated symptoms.. Lasmiditan is a novel selective 5-hydroxytryptamine 1F receptor agonist that lacks vasoconstrictive activity. In 2 phase 3 studies, SAMURAI and SPARTAN, lasmiditan met primary and key secondary efficacy endpoints at 2 hours following initial dose.. Integrated analyses were completed from 2 phase 3 clinical trials, SPARTAN and SAMURAI. Baseline data and data collected every 30 minutes up to 2 hours after taking lasmiditan (50, 100, or 200 mg) or placebo were analyzed to determine the onset of efficacy. A total of 5236 patients were randomized to be treated with placebo (N = 1493), lasmiditan 50 mg (N = 750), lasmiditan 100 mg (N = 1498), or lasmiditan 200 mg (N = 1495). Data were analyzed to determine the onset of improvement for the following efficacy measures: pain freedom, most bothersome symptom freedom, pain relief, freedom from associated individual symptoms (photophobia, phonophobia, or nausea), total migraine freedom (defined as pain freedom and freedom from associated symptoms), and freedom from migraine-related functional disability. Time to meaningful headache relief and time to first become pain free were also analyzed.. Significantly higher rates of pain freedom (100 mg, 10.0%, P = .012; 200 mg, 15.5%, P < .001; Placebo, 7.0%) and total migraine freedom (100 mg, 8.9%, P = .017; 200 mg, 12.4%, P < .001; Placebo, 6.1%) were achieved starting at 60 minutes in 100- and 200-mg lasmiditan-treated groups compared with placebo group. Rates of freedom from most bothersome symptom (100 mg, 11.1%, P = .015; 200 mg, 13.0%, P < .001; Placebo, 7.9%), and pain relief (100 mg, 17.5%, P = .007; 200 mg, 19.1%, P < .001; Placebo, 13.4%) were significantly higher starting as early as 30 minutes in lasmiditan 100- and 200-mg lasmiditan-treated groups. A significantly higher percentage of patients in the 200-mg lasmiditan-treated group achieved freedom from photophobia (13.7%, P = .005; Placebo, 9.2%) and phonophobia (17.4%, P = .042; Placebo, 13.4%) starting at 30 minutes. A significantly greater proportion of patients in the 200-mg lasmiditan-treated group achieved freedom from migraine-related functional disability starting at 60 minutes (16.4%, P < .001; Placebo, 11.1%). All efficacy measures, except for freedom from nausea, were statistically significant after lasmiditan treatment (50, 100, or 200 mg) compared with placebo at 90 and 120 minutes. Finally, patients taking lasmiditan had a higher likelihood of achieving meaningful headache relief and becoming headache pain free within 24 hours compared with those taking placebo (P < .001).. Patients treated with lasmiditan for a migraine attack reported an earlier onset of efficacy compared with those treated with placebo. Some of the efficacy measures such as pain relief demonstrated improvement as early as the first assessment at 30 minutes after 100- or 200-mg lasmiditan treatment.

Topics: Administration, Oral; Adult; Benzamides; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Male; Middle Aged; Migraine Disorders; Piperidines; Pyridines; Serotonin Receptor Agonists; Treatment Outcome

Lasmiditan, a serotonin 5-HT1F receptor agonist, was effective for acute treatment of patients with migraine in a phase 3 double-blind randomized controlled study. The current study was designed to replicate these findings in a generalizable population of patients with migraine, including those with a cardiovascular medical history. This prospective, double-blind, phase 3 multicentre study randomly assigned patients with migraine with and without aura (1:1:1:1 ratio) to oral lasmiditan 200 mg, 100 mg, 50 mg, or placebo. Patients were instructed to dose at home within 4 h of onset of migraine attack of at least moderate intensity and not improving. The primary objective was to assess the proportion of patients' headache pain-free and most bothersome symptom-free at 2 h post-dose for each dose of lasmiditan versus placebo (NCT02605174). Patients (n = 3005) were assigned and treated (n = 2583, safety population): 1938 lasmiditan (200 mg n = 528, 100 mg n = 532, and 50 mg n = 556 included in primary analysis) and 645 placebo (540 included in primary analysis). Most patients (79.2%) had ≥1 cardiovascular risk factor at baseline, in addition to migraine. Lasmiditan was associated with significantly more pain freedom at 2 h (lasmiditan 200 mg: 38.8%, odds ratio 2.3, 95% confidence interval 1.8-3.1, P < 0.001; 100 mg: 31.4%, odds ratio 1.7, 1.3-2.2, P < 0.001; 50 mg: 28.6%, odds ratio 1.5, 1.1-1.9, P = 0.003 versus placebo 21.3%) and freedom from most bothersome symptom at 2 h (lasmiditan 200 mg: 48.7%, odds ratio 1.9, 95% confidence interval 1.4-2.4, P < 0.001; 100 mg: 44.2%, odds ratio 1.6, 1.2-2.0, P < 0.001; 50 mg: 40.8%, odds ratio 1.4, 1.1-1.8, P = 0.009 versus placebo 33.5%). Treatment-emergent adverse events were reported in 253 of 649 (39.0%), 229 of 635 (36.1%), and 166 of 654 (25.4%) of patients on lasmiditan 200, 100, and 50 mg, respectively, versus 75 of 645 (11.6%) on placebo. Most adverse events were CNS-related and included dizziness, somnolence and paraesthesia. Lasmiditan was effective at 2 h post-dose for acute treatment of migraine at all oral doses tested. Efficacy and safety were consistent with the previous phase 3 study.

Topics: Adult; Benzamides; Cardiovascular Diseases; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Male; Migraine Disorders; Piperidines; Pyridines; Risk Factors; Serotonin Receptor Agonists; Time Factors; Young Adult

SAMURAI and SPARTAN were double-blind, placebo-controlled Phase 3 studies conducted in the United States, as well as the United Kingdom and Germany (SPARTAN only). Individuals with migraine were randomized to receive oral lasmiditan 50 mg (SPARTAN only), 100 mg, 200 mg, or placebo within 4 hours of onset of a migraine attack. The aim of this analysis was to characterize dizziness reported with lasmiditan treatment.. Data from SAMURAI and SPARTAN were pooled for the current post hoc analyses. Onset time and duration of dizziness were analyzed using descriptive statistics. Subgroup analyses based on presence/absence of dizziness were performed for the endpoints of interference with daily activity, patient global impression of change (PGIC), pain at 2 hours, and most bothersome symptom (MBS) at 2 hours based on adverse events occurring within 2 hours of taking study drug.. Dizziness incidence was as follows: Placebo (N = 1262), 2.9% (0.1% severe); lasmiditan 50 mg (N = 654), 8.6% (0.3% severe); lasmiditan 100 mg (N = 1265), 14.9% (0.7% severe); and lasmiditan 200 mg (N = 1258), 16.8% (1.4% severe). Among participants who received lasmiditan as their first dose, risk factors for dizziness were higher lasmiditan dosage, being non-Hispanic/Latino, mild or moderate severity of migraine attack, and lower body mass index. The median time to onset of dizziness was generally 30-40 minutes, and the median duration was 1.5-2 hours. The presence of dizziness did not appear to have a negative influence on lasmiditan's effect on daily activity, PGIC, freedom from pain, or MBS. Overall, 21 participants experienced vertigo: Lasmiditan 50 mg, n = 2 (0.3%); 100 mg, n = 11 (0.9%); 200 mg, n = 7 (0.6%); and placebo, n = 1 (<0.1%).. The incidence of dizziness with lasmiditan increased with dose. Dizziness was generally mild or moderate in severity and of quick onset and short duration. The presence of dizziness did not influence drug efficacy.

Topics: Acute Disease; Adult; Benzamides; Dizziness; Double-Blind Method; Female; Humans; Male; Middle Aged; Migraine Disorders; Outcome Assessment, Health Care; Piperidines; Pyridines; Severity of Illness Index; Vertigo

We assessed the safety profile of lasmiditan, a selective 5-HT. 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.. 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.. 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.. SAMURAI (NCT02439320) and SPARTAN (NCT02605174).

Topics: Administration, Oral; Adult; Benzamides; Double-Blind Method; Fatigue; Female; Humans; Male; Middle Aged; Migraine Disorders; Piperidines; Pyridines; Serotonin Receptor Agonists; Time Factors; Treatment Outcome; Vertigo

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-HT. 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.. 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. 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.. SAMURAI: NCT02439320; SPARTAN: NCT02605174.

Topics: Adult; Benzamides; Double-Blind Method; Female; Humans; Male; Middle Aged; Migraine Disorders; Piperidines; Pyridines; Serotonin Receptor Agonists; Treatment Outcome

Calcitonin gene-related peptide receptor has been implicated in the pathogenesis of migraine. Rimegepant is an orally administered, small-molecule, calcitonin gene-related peptide receptor antagonist that may be effective in acute migraine treatment.. In a multicenter, double-blind, phase 3 trial, we randomly assigned adults with at least a 1-year history of migraine and two to eight migraine attacks of moderate or severe intensity per month to receive rimegepant orally at a dose of 75 mg or matching placebo for the treatment of a single migraine attack. The primary end points were freedom from pain and freedom from the most bothersome symptom (other than pain) identified by the patient, both of which were assessed 2 hours after the dose of rimegepant or placebo was administered.. A total of 1186 patients were randomly assigned to receive rimegepant (594 patients) or placebo (592 patients); of these, 537 patients in the rimegepant group and 535 patients in the placebo group could be evaluated for efficacy. The overall mean age of the patients evaluated for efficacy was 40.6 years, and 88.7% were women. In a modified intention-to-treat analysis, the percentage of patients who were pain-free 2 hours after receiving the dose was 19.6% in the rimegepant group and 12.0% in the placebo group (absolute difference, 7.6 percentage points; 95% confidence interval [CI], 3.3 to 11.9; P<0.001). The percentage of patients who were free from their most bothersome symptom 2 hours after the dose was 37.6% in the rimegepant group and 25.2% in the placebo group (absolute difference, 12.4 percentage points; 95% CI, 6.9 to 17.9; P<0.001). The most common adverse events were nausea and urinary tract infection.. Treatment of a migraine attack with the oral calcitonin gene-related peptide receptor antagonist rimegepant resulted in a higher percentage of patients who were free of pain and free from their most bothersome symptom than placebo. (Funded by Biohaven Pharmaceuticals; ClinicalTrials.gov number, NCT03237845.).

Topics: Administration, Oral; Adult; Analgesics; Calcitonin Gene-Related Peptide Receptor Antagonists; Double-Blind Method; Female; Humans; Male; Middle Aged; Migraine Disorders; Nausea; Piperidines; Placebos; Pyridines

Rimegepant, a small molecule calcitonin gene-related peptide receptor antagonist, has shown efficacy in the acute treatment of migraine using a standard tablet formulation. The objective of this trial was to compare the efficacy, safety, and tolerability of a novel orally disintegrating tablet formulation of rimegepant at 75 mg with placebo in the acute treatment of migraine.. In this double-blind, randomised, placebo-controlled, multicentre phase 3 trial, adults aged 18 years or older with history of migraine of at least 1 year were recruited to 69 study centres in the USA. Participants were randomly assigned to receive rimegepant (75 mg orally disintegrating tablet) or placebo and instructed to treat a single migraine attack of moderate or severe pain intensity. The randomisation was stratified by the use of prophylactic medication (yes or no), and was carried out using an interactive web response system that was accessed by each clinical site. All participants, investigators, and the sponsor were masked to treatment group assignment. The coprimary endpoints were freedom from pain and freedom from the most bothersome symptom at 2 h postdose. The efficacy analyses used the modified intention-to-treat population, which included all patients who were randomly assigned, had a migraine attack with pain of moderate or severe intensity, took a dose of rimegepant or placebo, and had at least one efficacy assessment after administration of the dose. The safety analyses included all randomly assigned participants who received at least one dose of study medication. This study is registered with ClinicalTrials.gov, number NCT03461757, and is closed to accrual.. Between Feb 27 and Aug 28, 2018, 1811 participants were recruited and assessed for eligibility. 1466 participants were randomly assigned to the rimegepant (n=732) or placebo (n=734) groups, of whom 1375 received treatment with rimegepant (n=682) or placebo (n=693), and 1351 were evaluated for efficacy (rimegepant n=669, placebo n=682). At 2 h postdose, rimegepant orally disintegrating tablet was superior to placebo for freedom from pain (21% vs 11%, p<0·0001; risk difference 10, 95% CI 6-14) and freedom from the most bothersome symptom (35% vs 27%, p=0·0009; risk difference 8, 95% CI 3-13). The most common adverse events were nausea (rimegepant n=11 [2%]; placebo n=3 [<1%]) and urinary tract infection (rimegepant n=10 [1%]; placebo n=4 [1%]). One participant in each treatment group had a transaminase concentration of more than 3 × the upper limit of normal; neither was related to study medication, and no elevations in bilirubin greater than 2 × the upper limit of normal were reported. Treated participants reported no serious adverse events.. In the acute treatment of migraine, a single 75 mg dose of rimegepant in an orally disintegrating tablet formulation was more effective than placebo. Tolerability was similar to placebo, with no safety concerns.. Biohaven Pharmaceuticals.

Topics: Administration, Sublingual; Adult; Calcitonin Gene-Related Peptide Receptor Antagonists; Double-Blind Method; Female; Humans; Male; Middle Aged; Migraine Disorders; Piperidines; Pyridines; Tablets

To study the efficacy and safety of lasmiditan for acute treatment of migraine in patients using migraine preventive medications.. 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.. 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.. 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 < 0.05). Primary efficacy outcome (pain-free at 2 h), key secondary outcome (most bothersome symptom-free at 2 h) and all other efficacy outcomes were not significantly different between patients using or not using migraine preventives (all interaction p-values ≥0.1). Rates of adverse events were similar for patients using and not using preventive medications.. Lasmiditan was more effective than placebo for the acute treatment of migraine in patients concurrently using migraine preventive medications. Lasmiditan efficacy and safety measures were similar for patients using and not using preventive medications.. SAMURAI (NCT02439320) and SPARTAN (NCT02605174). Registered 18 March 2015.

Topics: Adult; Benzamides; Benzimidazoles; Biphenyl Compounds; Botulinum Toxins, Type A; Double-Blind Method; Female; Humans; Male; Middle Aged; Migraine Disorders; Piperidines; Pyridines; Tetrazoles; Treatment Outcome

To assess the efficacy and safety of lasmiditan in the acute treatment of migraine.. Adult patients with migraine were randomized (1:1:1) to a double-blind dose of oral lasmiditan 200 mg, lasmiditan 100 mg, or placebo and were asked to treat their next migraine attack within 4 hours of onset. Over 48 hours after dosing, patients used an electronic diary to record headache pain and the presence of nausea, phonophobia, and photophobia, one of which was designated their most bothersome symptom (MBS).. Of the 1,856 patients who treated an attack, 77.9% had ≥1 cardiovascular risk factors in addition to migraine. Compared with placebo, more patients dosed with lasmiditan 200 mg were free of headache pain at 2 hours after dosing (32.2% vs 15.3%; odds ratio [OR] 2.6, 95% confidence interval [CI] 2.0-3.6,. Lasmiditan dosed at 200 and 100 mg was efficacious and well tolerated in the treatment of acute migraine among patients with a high level of cardiovascular risk factors.. NCT02439320.. This study provides Class I evidence that for adult patients with migraine, lasmiditan increases the proportion of subjects who are headache pain free at 2 hours after treating a migraine attack.

Topics: Acute Disease; Administration, Oral; Adult; Benzamides; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Male; Middle Aged; Migraine Disorders; Piperidines; Pyridines; Treatment Outcome

This study explored whether antagonism of orexin receptors might be an effective mechanism for migraine prevention.. We conducted a randomized, double-blind, placebo-controlled, pilot trial. Patients experiencing four to 14 days with migraine during a one-month baseline period were randomized to the orexin receptor antagonist filorexant 10 mg nightly or placebo for three months. Efficacy was assessed by mean monthly migraine days (headache plus at least one associated migraine symptom) and headache days. Safety and tolerability were assessed by adverse event reports and laboratory tests.. Of 120 patients treated with filorexant and 115 treated with placebo, 97 (81%) and 101 (88%), respectively, completed the trial. There was no statistically significant difference between treatments for change from baseline in mean monthly migraine days (filorexant = -1.7, placebo = -1.3, difference = -0.4 (95% CI: -1.3, 0.4)) or headache days (filorexant = -1.7, placebo = -1.2, difference = -0.5 (95% CI: -1.4, 0.4)). Filorexant was generally well tolerated but was associated with a higher proportion of patients who reported adverse events than placebo (47% vs 37%), particularly somnolence (13% vs 4%).. These data fail to provide evidence that antagonism of orexin receptors with filorexant, when administered at night, is effective for migraine prophylaxis.

Topics: Adult; Double-Blind Method; Female; Humans; Male; Migraine Disorders; Orexin Receptor Antagonists; Piperidines; Pyrimidines

BMS-927711 is a potent, selective, competitive human calcitonin gene-related peptide (CGRP) receptor antagonist that has shown in vivo efficacy without vasoconstrictor effect. The objective of the current study was to determine an effective and tolerable dose range of BMS-927711 for the acute treatment of migraine.. In this randomized, double-blind, placebo controlled, dose-ranging study, 885 patients were randomized using an adaptive design to one of the following dose groups: BMS-927711 (10, 25, 75, 150, 300, or 600 mg); sumatriptan 100 mg (active comparator); and placebo. Patients were treated for a single migraine attack. The primary endpoint was pain freedom at two hours post-dose.. Of patients who took the study drug, 799 had one post-randomization efficacy evaluation. Significantly more patients in the BMS-927711 75 mg (31.4%, P = 0.002), 150 mg (32.9%, P < 0.001), and 300 mg (29.7%, P = 0.002) groups and the sumatriptan group (35%, P < 0.001) had pain freedom at two hours post-dose versus placebo (15.3%). For the secondary endpoint of sustained pain freedom from two to 24 hours post-dose, BMS-927711 doses (25-600 mg) were also statistically significant compared with placebo. No deaths or treatment-related serious adverse events (AEs) were reported, and no patients discontinued because of AEs.. BMS-927711 is superior to placebo at several different doses (75 mg, 150 mg, and 300 mg) and has an excellent tolerability profile.

Topics: Acute Disease; Adolescent; Adult; Aged; Calcitonin Gene-Related Peptide; Calcitonin Gene-Related Peptide Receptor Antagonists; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Male; Middle Aged; Migraine Disorders; Piperidines; Placebos; Pyridines; Serotonin 5-HT1 Receptor Agonists; Sumatriptan; Treatment Outcome; Young Adult

Triptans, serotonin 5-HT1B/1D receptor agonists, exert their action by targeting serotonin 5-HT1B/1D receptors, are used for treatment of migraine attack. Presently, 5 different triptans, namely sumatriptan, zolmitriptan, eletriptan, rizatriptan, and naratriptan, are marketed in Japan. In the present study, we retrospectively analyzed the relationships of clinical efficacy (headache relief) in Japanese and 5-HT1B/1D receptor occupancy (Φ1B and Φ1D). Receptor occupancies were calculated from both the pharmacokinetic and pharmacodynamic data of triptans.. To evaluate the total amount of exposure to drug, we calculated the area under the plasma concentration-time curve (AUCcp) and the areas under the time curves for Ф1B and Ф1D (AUCФ1B and AUCФ1D). Moreover, parameters expressing drug transfer and binding rates (Acp, AФ1B, AФ1D) were calculated.. Our calculations showed that Фmax1B and Фmax1D were relatively high at 32.0-89.4% and 68.4-96.2%, respectively, suggesting that it is likely that a high occupancy is necessary to attain the clinical effect. In addition, the relationships between therapeutic effect and AUCcp, AUCΦ1B, AUCΦ1D, and Acp · AUCcp differed with each drug and administered form, whereas a significant relationship was found between the therapeutic effect and AΦ1B · AUCΦ1B or AΦ1D · AUCΦ1D that was not affected by the drug and the form of administration.. These results suggest that receptor occupancy can be used as a parameter for a common index to evaluate the therapeutic effect. We considered that the present findings provide useful information to support the proper use of triptans.

Topics: Humans; Migraine Disorders; Oxazolidinones; Piperidines; Pyrrolidines; Serotonin 5-HT1 Receptor Agonists; Sumatriptan; Treatment Outcome; Triazoles; Tryptamines

Although naratriptan is not approved for prophylactic use in migraine, naratriptan has been shown to be significantly more effective than placebo for short-term prevention of menstrually related migraine (MRM). The tolerability of naratriptan administered intermittently for prophylaxis for MRM over the long term has not been assessed.. To assess the tolerability of naratriptan 1 mg given twice daily for 6 days per month, administered for up to 1 year for short-term prevention of MRM in an open-label study.. Patients were eligible for the study if they were between 18 and 65 years of age and had at least a 1-year history of migraine, with or without aura, as defined by 1988 International Headache Society criteria; reported a history of MRM; and had at least 1 MRM attack during their last menstrual cycle. MRM was defined as any migraine beginning during the perimenstrual period (PMP). By definition, the PMP consisted of Days -2, -1, 1, 2, 3, and 4, with Day 1 being the first day of menstrual flow. During each menstrual cycle occurring over a 1-year period, patients began short-term treatment with naratriptan 1 mg twice daily (BID) 3 days before the expected onset of MRM and treated for a total of 6 days. Naratriptan 2.5 mg could be taken for breakthrough MRM attacks. Tolerability and safety measures included adverse events, standard clinical laboratory tests, electrocardiograms (ECGs), and vital signs. The secondary endpoints were the percentage of PMPs without MRM; headache disability as measured by the Headache Impact Test (HIT), and psychological health as measured by the Beck Depression Inventory version 2 (BDI-II).. The number of patients who took at least 1 dose of study medication (safety population) was 457, and the numbers of patients completing 6 months and 12 months of treatment were 318 and 131, respectively. Note that 171 (37%) patients were asked to leave the study once target enrollment numbers were met. The only adverse event occurring at an incidence of more than 2% during the 6-day treatment periods when naratriptan 1 mg BID was taken with or without an additional 2.5-mg dose for breakthrough attacks was ear, nose, throat infection (3%). No specific adverse event considered at least possibly to be related to study medication occurred in more than 2% of patients. No serious drug-related adverse events were reported. Furthermore, no patient experienced clinically relevant drug-related changes in 12-lead ECGs, vital signs, or clinical laboratory tests. Patients in both the 6- and 12-month populations did not experience an MRM in approximately 50% of treated PMPs. Health outcomes results suggested that naratriptan reduced headache impact when used for up to 12 months for the short-term prevention of MRM.. Naratriptan 1 mg BID, with the optional use of an additional 2.5-mg dose for breakthrough attacks, was well tolerated when used for 6 continuous days per month for up to 1 year for short-term prevention of MRM.

Topics: Adult; Female; Humans; Menstruation; Middle Aged; Migraine Disorders; Piperidines; Serotonin Receptor Agonists; Treatment Outcome; Tryptamines

Menstrual migraines are particularly difficult-totreat. Few studies on the use of triptans in short-term prophylaxis of menstrually related migraine have been recently conducted, but evidences of triptans' efficacy in the specific case of pure menstrual migraine (PMM) are lacking. The aim of this study is to explore the efficacy and tolerability of naratriptan as short-term prophylaxis of pure menstrual migraine (PMM) attacks. A multi-centre, open, non comparative, pilot six-month study was conducted in women, aged 18 years or older, with regular menstrual cycles and with a history of migraine without aura exclusively associated to the perimenstrual period. After an observation period of three months, patients took for three consecutive menstrual cycles oral naratriptan 1 mg twice daily, starting two days before the expected onset of menstruation and continuing for six days. Ninety-eight women with a history of PMM were screened for study participation, and 61 entered the study. Fifty-nine comprised the intent-to-treat population. The mean number of PMM attacks decreased from 3.5+/-1.4 in the 3-month observation period to 1.6+/-1.3 in the 3-month treatment with naratriptan. The pecentage of responders (subjects who recorded a decrease-equal or more than 50%-in the mean number of attacks) was 61.4%. A tendency towards a decrease in headache severity and in the presence of associated symptoms was observed during treatment. At least one adverse event during the treatment period was reported by 19 patients (31.1%). No serious adverse events occurred. Naratriptan may be an effective and safe treatment option in the short-prophylaxis of PMM.

Topics: Adolescent; Adult; Drug Evaluation; Dysmenorrhea; Female; Follow-Up Studies; Humans; Indoles; Middle Aged; Migraine Disorders; Pain Measurement; Piperidines; Serotonin Receptor Agonists; Time Factors; Treatment Outcome; Tryptamines

Topics: Adult; Dopamine Antagonists; Drug Therapy, Combination; Female; Humans; Indoles; Middle Aged; Migraine Disorders; Piperidines; Prochlorperazine; Prospective Studies; Serotonin Receptor Agonists; Tryptamines

The aim of this study was to investigate the efficacy of orally administered 2.5 mg naratriptan in the treatment of menstrually related migraine (MRM). A high percentage of women suffering from migraine report increased frequency of attacks in association with menstruation that may be more severe, of longer duration and more difficult to treat than at other times. This was a phase IIIb, randomized, double-blind, placebo-controlled clinical trial. Subjects were given either 2.5 mg naratriptan or placebo to treat a single MRM episode, defined as starting between days -2 and +4 relative to the start of menstruation. The primary efficacy measure was the percentage of subjects who were free of pain 4 h after treatment, the absence of pain at 30 min, 1 and 2 h being secondary efficacy measures. Other secondary measures were the absence of associated symptoms, sustained headache relief 24 h after a single dose of the study medication, recourse to a second dose of study medication or escape medication, pain intensity 4-24 h after first treatment, the ability to carry out work or daily activities, and patient satisfaction. Adverse events were also monitored. A total of 275 women were enrolled in the trial and 229 (115 naratriptan group, 114 placebo group) provided data on the effects of the study medication on MRM. A higher percentage of subjects in the naratriptan group (58%) reported complete pain relief 4 h after medication than in the placebo group (30%) (P<0.001). Significant differences between the naratriptan and placebo groups and in favor of naratriptan were also found for: total pain relief at 2 h (P=0.004), sustained pain-free response within 4-24 h (P<0.001), absence of all associated symptoms at 2 and 4 h (P=0.004), ability to work and carry out daily activities at 2 h (P=0.036), and patient overall satisfaction (P<0.001). Three adverse events were recorded that might potentially be attributable to naratriptan. Naratriptan given orally at a dose of 2.5 mg is effective in the acute treatment of MRM as early as 2 h after treatment.

Topics: Administration, Oral; Double-Blind Method; Female; Humans; Menstruation; Migraine Disorders; Pain Measurement; Patient Satisfaction; Piperidines; Retrospective Studies; Time Factors; Treatment Outcome; Tryptamines; Vasoconstrictor Agents

Calcitonin gene-related peptide (CGRP) may have a causative role in migraine. We therefore hypothesized that a CGRP-receptor antagonist might be effective in the treatment of migraine attacks.. In an international, multicenter, double-blind, randomized clinical trial of BIBN 4096 BS, a highly specific and potent nonpeptide CGRP-receptor antagonist, 126 patients with migraine received one of the following: placebo or 0.25, 0.5, 1, 2.5, 5, or 10 mg of BIBN 4096 BS intravenously over a period of 10 minutes. A group-sequential adaptive treatment-assignment design was used to minimize the number of patients exposed.. The 2.5-mg dose was selected, with a response rate of 66 percent, as compared with 27 percent for placebo (P=0.001). The BIBN 4096 BS group as a whole had a response rate of 60 percent. Significant superiority over placebo was also observed with respect to most secondary end points: the pain-free rate at 2 hours; the rate of sustained response over a period of 24 hours; the rate of recurrence of headache; improvement in nausea, photophobia, phonophobia, and functional capacity; and the time to meaningful relief. An effect was apparent after 30 minutes and increased over the next few hours. The overall rate of adverse events was 25 percent after the 2.5-mg dose of the drug and 20 percent for the BIBN 4096 BS group as a whole, as compared with 12 percent for placebo. The most frequent side effect was paresthesia. There were no serious adverse events.. The CGRP antagonist BIBN 4096 BS was effective in treating acute attacks of migraine.

Topics: Acute Disease; Adult; Calcitonin Gene-Related Peptide Receptor Antagonists; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Male; Middle Aged; Migraine Disorders; Piperazines; Piperidines; Quinazolines; Time Factors

To evaluate the effect of acute treatment on ictal behavioral functioning of patients with migraine via ambulatory accelerometry.. The inability to carry out daily activities often complicates migraine attacks. Research into the effects of pharmacological drugs on this outcome parameter in the acute treatment of migraine has been based on subjective reports only.. In a double-blind, double-dummy, crossover study, 12 patients with migraine treated 2 migraine attacks with the nonspecific antimigraine drug, naproxen (500-mg capsule) or the more specific antimigraine drug, naratriptan (2.5-mg tablet). The clinical symptoms of headache, nausea, vomiting, photophobia, and phonophobia, and the subjective symptoms reflecting mood, sleepiness, and level of functioning were measured by use of a daily log.. During the first 6 hours after intake of the study medication, the objective behavioral parameters showed no significant effect of time and no significant differences between naproxen and naratriptan, but naratriptan was significantly more efficacious than naproxen in relieving headache, nausea, and vomiting; the interval between treatment and relief was significantly shorter after intake of naratriptan.. Consciously perceived clinical and subjective symptoms do not necessarily run in parallel with their behavioral equivalents. It, thus, may be important to assess the effects of treatment on behavioral functioning in the evaluation of the general efficacy of antimigraine drugs in the acute treatment of a migraine attack.

Topics: Activities of Daily Living; Acute Disease; Adult; Anti-Inflammatory Agents, Non-Steroidal; Cross-Over Studies; Double-Blind Method; Humans; Indoles; Middle Aged; Migraine Disorders; Naproxen; Piperidines; Serotonin Receptor Agonists; Treatment Outcome; Tryptamines

This was a randomized, double-blind study designed to evaluate the comparative efficacy and tolerability of the 40-mg dose of eletriptan and the 2.5-mg dose of naratriptan. Patients (n = 548) meeting International Headache Society (IHS) criteria for migraine were randomized to treat a single migraine attack with either eletriptan 40 mg, naratriptan 2.5 mg, or placebo. Headache response rates at 2 h and 4 h, respectively, were 56% and 80% for eletriptan, 42% and 67% for naratriptan (P < 0.01 for both time-points vs. eletriptan), and 31% and 44% for placebo (P < 0.0001 vs. both active drugs at both time-points). Eletriptan also showed a significantly greater pain-free response at 2 h (35% vs. 18%; P < 0.001) as well as lower use of rescue medication (15% vs. 27%; P < 0.01) and higher sustained headache response at 24 h (38%) compared with naratriptan (27%; P < 0.05) and placebo (19%; P < 0.01). Both eletriptan and naratriptan were well tolerated. The results confirm previous meta-analyses that have suggested the superiority of eletriptan vs. naratriptan in the acute treatment of migraine.

Topics: Adult; Double-Blind Method; Female; Humans; Indoles; Male; Middle Aged; Migraine Disorders; Patient Satisfaction; Piperidines; Pyrrolidines; Serotonin Receptor Agonists; Time Factors; Treatment Outcome; Tryptamines

Chronic migraine (CM) patients frequently overuse symptomatic medications (SM). These medications may create a cycle of rebound, worsening of headache and withdrawal symptoms that perpetuate the headache itself. In addition, the overuse of such substances is believed to counteract the efficacy of preventive treatments. We conducted a prospective randomized open-label trial comparing approaches to out-patient management in 150 CM patients (125 women, 25 men; ages 18-80 years, mean 40.3 +/- 13.8) with overuse of SM. In each group, 50 patients received education and orientation and were then abruptly withdrawn from all SM. Immediately following withdrawal, the first group took prednisone (60 mg/ day 2 days, 40 mg/day 2 days and 20 mg/day 2 days) for 6 days, the second group did not have any regular medications to take and the third group took naratriptan (2.5 mg twice a day) during this initial period. All patients had similar profiles of headache characteristics and consumption (quality and quantity) of SM before initiation of the treatment, but most were not severe headache sufferers, heavy SM overusers or were overusing opioids. After 5 weeks the headache frequency and intensity, the prevalence and frequency of withdrawal symptoms and consumption of rescue medications during the first 6 days were compared between groups. In addition, adherence to treatment (who returned or not and for which reasons, between groups) and headache frequency, week by week, among the groups of patients were also compared. Forty-four (88%) patients from the prednisone group, 41 (82%) from the 'nothing' group and 35 (70%) from the naratriptan group adhered to the treatment and returned. The were no differences between groups with regard to treatment adherence (P = 0.072), headache frequency as well as intensity (P = 0.311) and decreasing of days with headache after 5 weeks and weekly (P = 0.275). However, the incidence of withdrawal symptoms and consumption of rescue drugs was higher among the patients who did not take regular medications during the first 6 days (P = 0.0001 and P = 0.006). We concluded that CM patients with moderate overuse of SM other than opioids may be detoxified on an out-patient basis regardless of the strategy adopted with regard to the use of regular drugs during the initial days of withdrawal, but prednisone and naratriptan may be useful for reducing withdrawal symptoms and rescue medication consumption. Further controlled studies are necessary to confir

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Ambulatory Care; Chi-Square Distribution; Female; Headache Disorders; Humans; Indoles; Male; Middle Aged; Migraine Disorders; Piperidines; Prednisone; Prospective Studies; Statistics, Nonparametric; Substance Withdrawal Syndrome; Tryptamines

Naratriptan is a novel 5-HT1 agonist developed to treat acute migraine. The study objective was to characterize the pharmacokinetics of oral naratriptan in adolescent migraine patients outside a migraine attack. Subjects received a single 2.5 mg naratriptan tablet. Serial serum samples for naratriptan concentrations were collected over 24 hours. Blood pressure, pulse rate, and 12-lead ECG were recorded at baseline and at regular intervals after dosing. Seven patients--3 males and 4 females, 12 to 16 years of age--received drug and completed the study. The geometric mean and 95% confidence interval maximum concentration (Cmax) was 8.0 ng/mL (5.9-10.7), elimination half-life (t1/2) was 4.9 hours (4.5-5.4), area under the concentration-time curve (AUC) was 74.6 ng.h/mL (56.6-98.2), and apparent total clearance (Cl/F) was 558.8 mL/min (424.3-735.9). The median time to maximal concentration (tmax) was 4 hours, with a range of 1.5 to 4. Blood pressure, pulse rate, and ECG parameters did not change significantly from baseline. No serious adverse events or subject withdrawal after drug administration occurred. Oral naratriptan pharmacokinetic parameters in adolescents were similar to values reported in adults. Naratriptan doses for adolescents older than 12 years of age would be expected to be similar to adult doses.

Topics: Adolescent; Area Under Curve; Child; Female; Humans; Indoles; Male; Migraine Disorders; Piperidines; Serotonin Receptor Agonists; Tryptamines

To determine the efficacy of naratriptan 1-mg and 2.5-mg tablets twice daily compared with placebo as short-term prophylaxis of menstrually associated migraine.. Approximately 60% of women with migraine report headaches associated with their menstrual cycles. Results from an open-label study suggest that short-term administration of sumatriptan is useful in the prophylaxis of menstrually associated migraine.. A randomized, double-blind, three-arm, parallel-group, placebo-controlled study was conducted in women aged 18 years or older with a history of migraine with or without aura, as defined by the International Headache Society, of at least 6 months. Two dose strengths of naratriptan (1 mg, 2.5 mg) or identical-appearing placebo tablets (1:1:1) were administered twice daily for 5 days starting 2 days prior to the expected onset of menses across four perimenstrual periods. End points included the number of menstrually associated migraines, total migraine days, peak headache severity, lost work/activity time, migraine-related quality of life, and incidence of adverse events.. Overall, the intent-to-treat population comprised 206 women (naratriptan 1 mg, n = 70; naratriptan 2.5 mg, n = 70, and placebo, n = 66); 171 women treated four perimenstrual periods. Significantly more perimenstrual periods per subject treated with naratriptan, 1 mg, were headache-free compared with placebo (50% versus 25%, P =.003). Naratriptan, 1 mg, significantly reduced the number of menstrually associated migraines (2.0 versus 4.0, P <.05) and menstrually associated migraine days (4.2 versus 7.0, P <.01) compared with placebo. More patients treated with naratriptan, 1 mg, were headache-free across all treated perimenstrual periods compared with placebo (23% versus 8%). No difference in headache severity was observed in breakthrough headaches. The incidence and severity of adverse events was similar across treatment groups. Naratriptan, 2.5 mg, was not statistically superior to placebo for any measure.. Naratriptan, 1 mg, with tolerability similar to placebo, is an effective, short-term, prophylactic treatment for menstrually associated migraine.

Topics: Adult; Double-Blind Method; Female; Humans; Indoles; Menstruation; Migraine Disorders; Piperidines; Quality of Life; Serotonin Receptor Agonists; Treatment Outcome; Tryptamines

Lanepitant, a potent non-peptide neurokinin-1 receptor antagonist, inhibits neurogenic dural inflammation, and may have a role in migraine therapy. This study evaluated the effect of lanepitant taken daily for migraine prevention. Patients with migraine headaches with and without aura by International Headache Society classification criteria were enrolled in a 12-week double-blind, parallel design study comparing the effect of 200 mg qd lanepitant (n = 42) and placebo (n = 42) on reduction of migraine frequency. The primary outcome measure was response rate, i.e. the proportion of patients with a 50% reduction in days of headache. Of the 84 patients enrolled, 90.5% were female. The endpoint response rate for lanepitant-treated patients (41.0%) was not statistically significantly (P = 0.065) greater than that for placebo-treated patients (22.0%). No efficacy variables differed significantly between treatments, except for response rates at month 3 (P = 0.045). Higher plasma concentrations were no more effective than lower concentrations. In this study lanepitant was not effective in preventing migraine, but was well tolerated. These results do not support a role for NK-1 antagonism in migraine prevention.

Topics: Adult; Double-Blind Method; Drug Administration Schedule; Female; Humans; Indoles; Male; Middle Aged; Migraine Disorders; Neurokinin-1 Receptor Antagonists; Piperidines; Recurrence; Treatment Outcome

Migraine drugs can produce adverse cardiac effects. The authors have demonstrated previously that ergotamine can lead to a significant reduction of hyperemic myocardial blood flow, but little is known about the effect of the newer serotonin analogues. Coronary artery constriction caused by serotonin or its analogues is mediated mainly by 5HT2 receptors. The selective 5HT1B/1D agonist naratriptan has no significant activity at 5HT2 receptors; however, like all 5HT1B/1D agonists developed for the acute treatment of migraine, naratriptan could potentially constrict coronary arteries by activation of 5HT1B receptors.. The effects on myocardial blood flow of subcutaneous naratriptan 1.5 mg compared with placebo were assessed under resting and hyperemic conditions with PET using oxygen-15 labeled water during two separate visits. This study was a randomized, double-blind, placebo-controlled crossover trial in 34 migraine subjects with no evidence of ischemic heart disease, studied outside a migraine attack.. Naratriptan did not differ significantly from placebo in its effects on resting myocardial blood flow, but did evoke a small, significant fall in hyperemic myocardial blood flow (-13% versus placebo) and an increase in hyperemic coronary resistance (+19% versus placebo) without any signs or symptoms suggestive of myocardial ischemia. Naratriptan did not significantly affect the coronary vasodilator reserve (hyperemic/resting blood flow) compared with placebo.. These results show that at therapeutic doses, naratriptan exerts only a minor effect on myocardial blood flow, coronary vasodilator reserve, or coronary resistance among subjects with no evidence of ischemic heart disease. These results should not be extrapolated to patients with coronary artery disease, in whom all 5HT1 agonists for migraine are contraindicated.

Topics: Adult; Coronary Circulation; Female; Heart; Humans; Indoles; Male; Middle Aged; Migraine Disorders; Myocardium; Piperidines; Serotonin Receptor Agonists; Tomography, Emission-Computed; Tryptamines; Vascular Resistance; Vasodilation

To assess patient satisfaction with and preference for naratriptan hydrochloride therapy over previous "nontriptan" therapy for migraines.. Open-label study conducted at 15 primary care clinics.. One hundred forty-three adults meeting International Headache Society diagnostic criteria for migraine who were not using triptans as first-line therapy for migraines were enrolled; 115 completed the study. INTERVENTION AND OUTCOME ASSESSMENTS: At baseline, satisfaction with current migraine therapy was assessed. Patients were provided with naratriptan hydrochloride, 2.5 mg, to treat 3 migraines and diaries to record headache symptoms and response to treatment. After treating 3 migraines, satisfaction with naratriptan therapy and preference for either previous or naratriptan therapy were assessed.. Eighty-nine (62%) of 143 patients had previous exposure to triptans, with lack of prescribing (55%) as the primary reason for not continuing their use as first-line therapy. Medications used for first-line therapy included simple analgesics (59%), combination products (46%), and narcotics (13%). After treating 3 migraines with naratriptan, satisfaction with migraine therapy increased from 47% to 75%. Sixty-three percent of patients preferred naratriptan therapy over their previous nontriptan therapy, 27% preferred their previous therapy, and 10% had no preference. The main reasons for preference for naratriptan therapy were "relieves pain effectively" (86%) and "restores ability to function/perform task" (81%).. Naratriptan for first-line migraine therapy was preferred by most patients over previous nontriptan therapy.

Topics: Adult; Aged; Female; Humans; Indoles; Male; Middle Aged; Migraine Disorders; Patient Satisfaction; Piperidines; Serotonin Receptor Agonists; Treatment Outcome; Tryptamines; Vasoconstrictor Agents

This study sought to compare the efficacy of several doses of naratriptan tablets with that of sumatriptan tablets and placebo in the acute treatment of a single migraine attack.. This was a randomized, double-blind, placebo-controlled, parallel-group, dose-ranging study. Patients received either naratriptan tablets (1, 2.5, 5, 7.5, or 10 mg), sumatriptan tablets (100 mg), or placebo.. A total of 643 patients took part in the study. Two hours after dosing, headache relief was reported by significantly more patients treated with any dose of naratriptan (52%-69%) or sumatriptan (60%) than with placebo (31%) (P < 0.05). Four hours after dosing, headache relief was reported by significantly more patients treated with any dose of naratriptan (63%-80%) or sumatriptan (80%) than with placebo (39%) and by significantly more patients treated with sumatriptan 100 mg (80%) than with naratriptan 1 mg (64%), 2.5 mg (63%), or 5 mg (65%) (P < 0.05). Twenty-four-hour overall efficacy (headache relief maintained through 24 hours postdose with no worsening, no use of rescue medication, and no recurrence) was reported by more patients treated with any dose of naratriptan (39%-58%) or sumatriptan (44%) than with placebo (22%). Headache recurrence was reported in 17% to 32% of naratriptan-treated patients, 44% of sumatriptan-treated patients, and 36% of placebo recipients. The overall incidence of adverse events was similar in patients treated with naratriptan 1 mg (20%), naratriptan 2.5 mg (21%), and placebo (23%). For naratriptan 5, 7.5, and 10 mg, the incidence of adverse events was 32%, 37%, and 35%, respectively, and for sumatriptan 100 mg it was 26%.. Our results suggest that the 2.5-mg dose of naratriptan tablets offers the optimal efficacy-to-tolerability ratio at the dose range between 1 and 10 mg. Although naratriptan 2.5 mg was less effective than sumatriptan 100 mg at 4 hours after dosing, the 2 medications showed similar efficacy at 24 hours.

Topics: Dose-Response Relationship, Drug; Double-Blind Method; Humans; Indoles; Migraine Disorders; Patient Satisfaction; Piperidines; Placebos; Serotonin Receptor Agonists; Tablets; Tryptamines; Vasoconstrictor Agents

This randomized, double-blind, crossover study was undertaken to compare the incidence of headache recurrence after treatment with naratriptan or sumatriptan in migraine patients with a history of frequent headache recurrence (recurrence in > or =50% of successfully treated attacks).. Although the selective 5-hydroxytryptamine, (5-HT1) agonist sumatriptan is effective and well tolerated for acute treatment of migraine in most patients, headache recurrence within 24 hours of initial successful treatment with sumatriptan and other medications has been reported in approximately 35% of patients. The novel 5-HT1 agonist naratriptan possesses pharmacologic and pharmacokinetic characteristics that may address the issue of headache recurrence.. Men and women aged 18 to 65 years with a > or =1-year history of migraine with or without aura were randomly assigned to treat 1 moderate or severe migraine attack in a nonclinical setting with one 2.5-mg naratriptan tablet and 1 attack with one 100-mg sumatriptan tablet. A pain-free interval of > or =24 hours was required between attacks. At 4 hours, patients not using rescue medication and experiencing headache recurrence could take a second, identical dose of study medication to treat recurrence. No more than 2 tablets of study medication were permitted in any 24-hour period.. A total of 253 patients treated > or =1 migrane attack and were included in the safety analysis; the 225 patients who treated both attacks were included in the efficacy analysis. Of the 164 naratriptan-treated and 181 sumatriptan-treated patients experiencing headache relief after > or =1 attack, headache recurrence 4 to 24 hours after treatment was reported by 74 naratriptan-treated patients (45%) and 101 sumatriptan-treated patients (57%; not statistically significant). (One naratriptan- and 3 sumatriptan-treated patients who experienced headache relief did not record recurrence status and were not included in the denominator for the percentage calculation.) In a subset of patients experiencing headache relief after 2 attacks, headache recurrence 4 to 24 hours after initial dosing was reported by 55 naratriptan- and 77 sumatriptan-treated patients (41% and 57%, respectively; P = 0.005). The overall incidence of adverse events was 22% after treatment with naratriptan and 33% after treatment with sumatriptan. This incidence did not increase after use of a second dose of naratriptan (20%) or sumatriptan (31%).. These data suggest that naratriptan is a long-acting and well-tolerated addition to currently available medications for the treatment of acute migraine.

Topics: Adolescent; Adult; Aged; Cross-Over Studies; Double-Blind Method; Female; Humans; Indoles; Middle Aged; Migraine Disorders; Piperidines; Recurrence; Serotonin Receptor Agonists; Sumatriptan; Tryptamines; Vasoconstrictor Agents

The primary objective of this prospective, open, non controlled, multicenter study was to collect data on migraine patient's health related quality of life before and after treatment of their migraine attacks b naratriptan orl 2.5 mg over a 12 week period.. The impact on health related quality of life was evaluated by the mean change from pre-treatment scores on the French migraine health related quality of life specific questionnaire (QVM).. 244 patients have been included in the study. A statistically significant score improvement in health related quality of life, as measured by the global score and the four scores related to the four dimensions of the QVM questionnaire (functional, psychological, social and therapeutic) was observed compared to the pre-treatment score values. At the end of the treatment period, 67% of patients preferred naratriptan oral 2.5 mg to their usual treatment.. Those data suggest that the use of naratriptan oral 2.5 mg for the treatment of migraine attacks during a 12 week period may be associated with a significant improvement in migraine patient's quality of life.

Topics: Administration, Oral; Adult; Female; Humans; Indoles; Male; Middle Aged; Migraine Disorders; Piperidines; Quality of Life; Treatment Outcome; Tryptamines; Vasoconstrictor Agents

Rizatriptan (MAXALT(TM), Merck & Co., Inc.) is a selective 5-HT(1B/1D) receptor agonist with rapid oral absorption and early onset of action for the acute treatment of migraine. This randomized, double-masked, double-dummy, placebo-controlled study compared rizatriptan 10 mg to naratriptan (NARAMIG(TM), AMERGE(TM), both Glaxo Wellcome plc) 2.5 mg in 522 patients treating a single migraine attack. Rizatriptan was more effective than naratriptan. Rizatriptan provided earlier headache relief than naratriptan (hazard ratio 1.62, p < 0.001), acting as early as 30 min. More patients were pain free at 2 h on rizatriptan than on naratriptan (44.8 vs. 20.7%, p < 0.001). Rizatriptan also provided earlier relief of associated migraine symptoms within 2 h than naratriptan and more patients had normal function at 2 h (39.3 vs. 22.6%, p < 0. 001). Both active treatments were effective compared to placebo. Both active treatments were well tolerated. The most common side effects with rizatriptan were dizziness, asthenia/fatigue, nausea and somnolence, while the most common side effects with naratriptan were dizziness and asthenia/fatigue.

Topics: Adult; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Indoles; Male; Middle Aged; Migraine Disorders; Piperidines; Recurrence; Serotonin Receptor Agonists; Treatment Outcome; Triazoles; Tryptamines

Lanepitant is a high-affinity, selective neurokinin-1 receptor (NK-1) and is effective in the dural inflammation model of acute migraine. Lanepitant 30, 80, and 240 mg given orally was evaluated in a double-blind, placebo-controlled crossover study to determine its effect in reducing migraine pain and severity of associated symptoms. Outpatients treated four migraine headaches of moderate or severe pain intensity with study drug according to a randomization schedule. They recorded their pain intensity and severity of migraine-associated symptoms at 30, 60, 90, and 120 min. Although 53 patients were randomly allocated to a treatment sequence, only 40 patients completed all treatments. There was no statistically significant difference in improvement in migraine pain at any time for any of the treatments. Additionally, there was no change in severity of migraine-associated symptoms associated with lanepitant therapy. No adverse events could be attributed to lanepitant. Lanepitant was ineffective orally in treating acute migraine in this trial. This may be due to poor bioavailability during a migraine attack. Alternatively, the neurogenic inflammation hypothesis may not apply to migraine.

Topics: Acute Disease; Administration, Oral; Age of Onset; Analysis of Variance; Cross-Over Studies; Double-Blind Method; Female; Humans; Indoles; Male; Migraine Disorders; Neurokinin-1 Receptor Antagonists; Piperidines; Treatment Outcome

The efficacy and tolerability of naratriptan tablets (2.5 mg, 1 mg, and 0.25 mg) compared with placebo in the acute treatment of migraine were evaluated in a randomized, double-blind, four-period crossover study. Five hundred eighty-six assessable patients received naratriptan 2.5 mg, 595 received 1 mg, 591 received 0.25 mg, 602 received placebo. Headache relief (moderate or severe pain reduced to mild or none) 4 hours postdose was reported in 68% of patients after treatment with naratriptan 2.5 mg compared with 57% after 1 mg, 39% after 0.25 mg, and 33% after placebo (p < 0.001 naratriptan 2.5 mg and 1 mg versus placebo and 1 mg and 2.5 mg versus 0.25 mg). Headache relief was maintained 8, 12, and 24 hours postdose with no use of rescue medication or a second dose of study medication by significantly (p < 0.001) greater percentages of patients after treatment with naratriptan 2.5 mg or 1 mg compared with naratriptan 0.25 mg or placebo. Naratriptan was also more effective than placebo in reducing clinical disability and the incidences of nausea, photophobia, and phonophobia. The overall incidence of adverse events and the incidences of specific adverse events did not differ in the naratriptan groups compared with placebo. No clinically relevant changes in ECG, blood pressure, or laboratory findings were reported. These data demonstrate that naratriptan is effective and well tolerated for the acute treatment of migraine. The 2.5-mg dose was associated with superior efficacy, whereas its adverse event profile was similar to that of placebo.

Topics: Adolescent; Adult; Aged; Cross-Over Studies; Double-Blind Method; Female; Gastrointestinal Diseases; Humans; Hyperesthesia; Indoles; Male; Middle Aged; Migraine Disorders; Piperidines; Recurrence; Serotonin Receptor Agonists; Treatment Outcome; Tryptamines

In a randomized general practice study, the prophylactice effect of femoxetive (a 5HT uptake inhibitor) was compared with placebo in migraine patients. Treatment, with separate randomization schedules in each practice, was allocated to 65 patients. Each patient was treated for 16 weeks with 200 mg increasing during the first nine days to 600 mg daily. No effect of femoxetine could be demonstrated in attack frequency and headache index. Separate analysis of maximum reduction in serotonin concentration during treatment revealed no difference in efficacy when compared with placebo. This supports earlier studies that femoxetine generally exerts no prophylactic effect on migraine, and the hypothesis that platelet 5HT might be of major importance in the pathogenesis of migraine is not supported.

Topics: Adolescent; Adult; Clinical Trials as Topic; Female; Humans; Male; Middle Aged; Migraine Disorders; Piperidines

The amplitude of visual evoked potentials (VEPs) for flickering light has been reported to be increased in migraine. In the present study, we have examined whether the VEPs are attenuated when the clinical state of the patient improves during a double-blind experiment with propranolol and femoxetine. VEPs for sinusoidally-modulated light were measured by spectral analysis, and an index depicting the visual reaction type was calculated. The group mean VEP index closely followed the group mean attack frequency, but individual variance was considerable. The changes were most evident in VEPs elicited by stimuli of about 20 Hz. During the treatments, the VEP and headache were also significantly correlated among subjects. The results suggest a close relationship between the enlarged VEPs and the headache mechanisms.

Topics: Adult; Anti-Inflammatory Agents, Non-Steroidal; Double-Blind Method; Evoked Potentials, Visual; Female; Humans; Male; Middle Aged; Migraine Disorders; Piperidines; Propranolol; Visual Pathways

The prophylactic effect in migraine of femoxetine, a 5-HT-uptake inhibitor, was compared to that of placebo in a double-blind group-comparative study. A total of 59 patients, referred to the department from general practitioners, was stratified according to age, sex, duration, and frequency of attacks and then allocated at random to treatment with either femoxetine or placebo. Each patient was treated for 12 weeks with 200 mg in the first week and 300 in the remaining weeks. Ten patients on femoxetine and four patients on placebo failed to complete the study. Headache index as well as number and severity of attacks showed a significant reduction with time. The patients on femoxetine showed the greatest improvement over time. It was, however, not statistically significant. Direct comparison between femoxetine and placebo revealed no statistically significant difference. Three patients in the femoxetine group withdrew due to side-effects combined with lack of therapeutic effect. Other side-effects were slight and infrequent. They did not interfere with the treatment. These results indicate that femoxetine could be useful in migraine as a prophylactic drug.

Topics: Adult; Clinical Trials as Topic; Double-Blind Method; Female; Humans; Male; Middle Aged; Migraine Disorders; Piperidines; Placebos; Random Allocation; Serotonin; Serotonin Antagonists

The prophylactic effect of the 5-HT uptake inhibitor femoxetine was compared with propranolol (Frekven R) in a double-blind crossover trial of 6 months duration. Forty-nine patients commenced the trial. Twelve patients withdrew because of drug failure or failure to attend checkups (6), side effects (4) or other non-drug related causes (2). In the 37 patients who completed the trial there was no significant difference between propranolol 160 mg and femoxetine 400 mg with respect to the number of headache days or the number of migraine attacks during the last 2 months of each treatment, Propranolol, however, was superior to femoxetine when the headache index was used (P less than 0.05). The study has shown that partial depletion of thrombocyte 5-HT by a 5-HT uptake inhibitor does not lead to a marked improvement in all patients contrary to what might be expected from the 5-HT hypothesis of migraine. Nevertheless, due to the infrequent subjective side effects associated with femoxetine treatment it may be a valuable prophylactic drug to a subgroup of migraine patients.

Topics: Adult; Aged; Clinical Trials as Topic; Double-Blind Method; Female; Humans; Male; Middle Aged; Migraine Disorders; Piperidines; Propranolol; Serotonin Antagonists

Topics: Adult; Aged; Anti-Inflammatory Agents; Antiemetics; Benzimidazoles; Clinical Trials as Topic; Craniocerebral Trauma; Dihydroxyphenylalanine; Dysmenorrhea; Esophagoscopy; Female; Humans; Male; Middle Aged; Migraine Disorders; Nausea; Piperidines; Premedication; Radiotherapy; Renal Dialysis; Vomiting

Topics: Adult; Antidepressive Agents; Benzocycloheptenes; Clinical Trials as Topic; Drug Evaluation; Female; Humans; Male; Middle Aged; Migraine Disorders; Piperidines; Placebos; Psychological Tests; Thiophenes

Topics: Acoustic Stimulation; Adult; Benzocycloheptenes; Cerebrovascular Circulation; Clinical Trials as Topic; Electroencephalography; Female; Fingers; Humans; Male; Middle Aged; Migraine Disorders; Photic Stimulation; Piperidines; Placebos; Plethysmography; Problem Solving; Thiophenes; Vasomotor System

Topics: Adolescent; Adult; Clinical Trials as Topic; Cycloheptanes; Female; Humans; Male; Middle Aged; Migraine Disorders; Piperidines; Prochlorperazine; Serotonin Antagonists; Thiophenes

Topics: Adjustment Disorders; Benzocycloheptenes; Clinical Trials as Topic; Female; Humans; Male; Methysergide; Migraine Disorders; Piperidines; Placebos; Serotonin Antagonists; Thiophenes

Topics: Antidepressive Agents; Benzocycloheptenes; Clinical Trials as Topic; Depression; Humans; Migraine Disorders; Piperidines; Psychiatric Status Rating Scales; Thiophenes

Topics: Adult; Benzocycloheptenes; Clinical Trials as Topic; Drug Evaluation; Female; Humans; Middle Aged; Migraine Disorders; Piperidines; Placebos; Serotonin Antagonists; Thiophenes

Topics: Adult; Benzocycloheptenes; Clinical Trials as Topic; Drug Evaluation; Female; Humans; Male; Middle Aged; Migraine Disorders; Piperidines; Serotonin Antagonists; Thiophenes

Topics: Clinical Trials as Topic; Cycloheptanes; Evaluation Studies as Topic; Histamine H1 Antagonists; Humans; Methysergide; Migraine Disorders; Piperidines; Placebos; Serotonin Antagonists; Thiophenes

Topics: Animals; Blood Pressure; Clinical Trials as Topic; Cycloheptanes; Cyproheptadine; Dogs; Ergolines; Guinea Pigs; Haplorhini; Headache; Histamine H1 Antagonists; Humans; Hypnotics and Sedatives; Lethal Dose 50; Methysergide; Mice; Migraine Disorders; Phenothiazines; Piperidines; Rabbits; Rats; Serotonin Antagonists; Thiophenes; Vascular Headaches

Topics: Adolescent; Adult; Body Weight; Clinical Trials as Topic; Cycloheptanes; Feeding and Eating Disorders; Female; Headache; Humans; Male; Methysergide; Middle Aged; Migraine Disorders; Piperidines; Thiophenes; Time Factors

Topics: Body Weight; Clinical Trials as Topic; Cycloheptanes; Ergotamine; Humans; Migraine Disorders; Piperidines; Thiophenes

Topics: Adult; Aged; Antidepressive Agents; Benzocycloheptenes; Depression; Female; Humans; Male; Middle Aged; Migraine Disorders; Piperidines; Thiophenes

Topics: Adolescent; Adult; Aged; Benzocycloheptenes; Body Weight; Child; Child, Preschool; Clinical Trials as Topic; Fatigue; Female; Humans; Male; Middle Aged; Migraine Disorders; Piperidines; Placebos; Thiophenes; Wakefulness

Topics: Adult; Benzocycloheptenes; Clinical Trials as Topic; Female; Humans; Male; Middle Aged; Migraine Disorders; Piperidines; Serotonin Antagonists; Thiophenes

Topics: Adolescent; Adult; Body Weight; Clinical Trials as Topic; Cycloheptanes; Female; Humans; Male; Middle Aged; Migraine Disorders; Piperidines; Sleep; Thiophenes

Topics: Benzocycloheptenes; Diagnosis, Differential; Headache; Humans; Migraine Disorders; Piperidines; Placebos; Thiophenes; Time Factors

Topics: Adult; Clinical Trials as Topic; Ergotamine; Female; Histamine H1 Antagonists; Humans; Migraine Disorders; Piperidines; Placebos

This post-hoc analysis from three phase 3 treatment trials of rimegepant 75 mg - an oral small molecule calcitonin gene-related peptide receptor antagonist for acute and preventive treatment of migraine - assessed efficacy in adults with migraine based on triptan treatment experience.. Participants were assigned to one of four groups based on triptan treatment experience: insufficient response (e.g. lack of efficacy and/or poor tolerability) to 1 triptan, insufficient response to ≥2 triptans, current triptan users, and triptan-naïve participants. The co-primary efficacy endpoints were pain freedom and most bothersome symptom freedom at two hours postdose.. In the three trials (N = 3507; rimegepant n = 1749, placebo n = 1758), 1235 (35.2%) participants had a history of insufficient response to 1 triptan (n = 910 [25.9%]) or ≥2 triptans (n = 325 [9.3%]), and 2272 (64.8%) had no history of insufficient response to triptans (current use = 595 [17.0%], naïve = 1677 [47.8%]). Rimegepant was effective on the co-primary endpoints in all subgroups (. Rimegepant was effective for the acute treatment of migraine in adults with a history of insufficient response to 1 or ≥2 triptans and in current triptan users. Efficacy on co-primary endpoints did not differ based on the number of insufficient triptan responses.Trial registration: Clinicaltrials.gov: NCT03235479, NCT03237845, NCT03461757.

Topics: Adult; Clinical Trials, Phase III as Topic; Humans; Migraine Disorders; Piperidines; Randomized Controlled Trials as Topic; Serotonin 5-HT1 Receptor Agonists; Tryptamines

Topics: Humans; Migraine Disorders; Piperidines; Pyridines

Topics: Administration, Oral; Calcitonin Gene-Related Peptide; Humans; Migraine Disorders; Piperidines

Lasmiditan is a novel selective 5-HT. Electrical stimulation of the dura mater or the superior salivatory nucleus in anaesthetised rats evoked trigeminovascular or trigeminal-autonomic reflex activation at the level of the trigeminocervical complex. Additionally, cranial autonomic manifestations in response to trigeminal-autonomic reflex activation were measured, via anterior choroidal blood flow alterations. These responses were then challenged with lasmiditan. We explored the tissue distribution of mRNA for 5-HT. Lasmiditan dose-dependently reduced trigeminovascular activation in a preclinical model of migraine. Lasmiditan also reduced superior salivatory nucleus-evoked activation of the trigeminal-autonomic reflex, but had no effect on cranial autonomic activation. mRNA profiling in human tissue showed expression of the 5-HT. Our data suggest that lasmiditan acts, at least in part, as an anti-migraine agent by reducing trigeminovascular activation. Furthermore, our results highlight a clear action for lasmiditan in a preclinical model of cluster headache. Given the proven translational efficacy of this model, our data support the potential utility of lasmiditan as a therapeutic option for the acute treatment of cluster headache attacks.. This article is part of a themed issue on Advances in Migraine and Headache Therapy (BJP 75th Anniversary). To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.3/issuetoc.

Topics: Animals; Benzamides; Cluster Headache; Migraine Disorders; Nociception; Piperidines; Pyridines; Rats; Receptor, Serotonin, 5-HT1F; Receptors, Serotonin; RNA, Messenger; Serotonin

Topics: Analgesics; Humans; Migraine Disorders; Piperidines; Pyridines; Pyrroles; Spiro Compounds

Until recently, only nonspecific and not always well-tolerated medications were available for migraine prophylaxis. Currently, specific drugs such as calcitonin gene-related peptide (CGRP) monoclonal antibodies and second-generation gepants are marketed for migraine treatment. Atogepant, an orally active small molecule, is a potent, selective antagonist of the CGRP receptor and is the only gepant authorized exclusively for episodic migraine prophylaxis in adults.. Using literature obtained from PubMed, Scopus, Web of Science, Cochrane, and ClinicalTrials.gov (up to February 13. From pivotal trials, the efficacy and tolerability of atogepant in episodic migraine prophylaxis seem comparable to those of CGRP monoclonal antibodies, even if comparative studies have not been conducted. To date, limited information is available on atogepant, including the optimal dose and duration of therapy; hence, it is difficult to establish whether it could be a first-line drug for migraine prophylaxis. Furthermore, it is important to evaluate if atogepant use is associated with the risk of cardiovascular and cerebrovascular events, which could result from potent and persistent blockade of vasodilation by CGRP.

Topics: Adult; Antibodies, Monoclonal; Calcitonin Gene-Related Peptide; Calcitonin Gene-Related Peptide Receptor Antagonists; Humans; Migraine Disorders; Piperidines; Pyridines; Pyrroles; Spiro Compounds

This study investigated the mechanism of action of atogepant, a small-molecule CGRP receptor antagonist recently approved for the preventive treatment of episodic migraine, by assessing its effect on activation of mechanosensitive C- and Aδ-meningeal nociceptors following cortical spreading depression.. Single-unit recordings of trigeminal ganglion neurons (32 Aδ and 20 C-fibers) innervating the dura was used to document effects of orally administered atogepant (5 mg/kg) or vehicle on cortical spreading depression-induced activation in anesthetized male rats.. Bayesian analysis of time effects found that atogepant did not completely prevent the activation of nociceptors at the tested dose, but it significantly reduced response amplitude and probability of response in both the C- and the Aδ-fibers at different time intervals following cortical spreading depression induction. For C-fibers, the reduction in responses was significant in the early phase (first hour), but not delayed phase of activation, whereas in Aδ-fibers, significant reduction in activation was apparent in the delayed phase (second and third hours) but not early phase of activation.. These findings identify differences between the actions of atogepant, a small molecule CGRP antagonist (partially inhibiting both Aδ and C-fibers) and those found previously for fremanezumab, a CGRP-targeted antibody (inhibiting Aδ fibers only) and onabotulinumtoxinA (inhibiting C-fibers only)- suggesting that these agents differ in their mechanisms for the preventive treatment of migraine.

Topics: Animals; Bayes Theorem; Calcitonin Gene-Related Peptide; Male; Migraine Disorders; Nerve Fibers, Unmyelinated; Nociceptors; Piperidines; Pyridines; Pyrroles; Rats; Rats, Sprague-Dawley; Spiro Compounds

Topics: Analgesics; Calcitonin Gene-Related Peptide; Calcitonin Gene-Related Peptide Receptor Antagonists; Humans; Migraine Disorders; Piperidines; Pyridines; Pyrroles; Spiro Compounds

Atogepant is a selective oral, small-molecule calcitonin gene-related peptide (CGRP) receptor antagonist that has been approved for preventive treatment of migraine. CGRP is a neuropeptide involved in vasodilation and cerebrovascular regulation. CGRP is the most potent vasoactive constituent of the cerebrovascular trigeminal neuronal system and has a key role in migraine. Medications targeting CGRP are being used as migraine preventive and abortive treatments.

Topics: Analgesics; Calcitonin Gene-Related Peptide; Calcitonin Gene-Related Peptide Receptor Antagonists; Humans; Migraine Disorders; Piperidines; Pyridines; Pyrroles; Spiro Compounds

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.. 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.

Topics: Benzamides; Controlled Clinical Trials as Topic; Humans; Migraine Disorders; Piperidines; Pyridines; Pyrroles

Orexin 1 receptors (Orx1R) and cannabinoid 1 receptors (CB1R) are implicated in migraine pathophysiology. This study evaluated the potential involvement of Orx1R and CB1R within the ventrolateral periaqueductal gray matter (vlPAG) in the modulation of anxiety-like behavior and social interaction of migraineurs rats. A rat model of migraine induced by recurrent administration of nitroglycerin (NTG) (5 mg/kg/i.p.). The groups of rats (n = 6) were then subjected to intra-vlPAG microinjection of orexin-A (25, 50 pM), and Orx1R antagonist SB334867 (20, 40 nM) or AM 251 (2, 4 μg) as a CB1R antagonist. Behavioral responses were evaluated in elevated plus maze (EPM), open field (OF) and three-chambered social test apparatus. NTG produced a marked anxiety like behaviors, in both EPM and OF tasks. It did also decrease social performance. NTG-related anxiety and social conflicts were attenuated by orexin-A (25, 50 pM). However, NTG effects were exacerbated by SB334867 (40 nM) and AM251 (2, 4 μg). The orexin-A-mediated suppression of NTG-induced anxiety and social conflicts were prevented by either SB334867 (20 nM) or AM251 (2 μg). The findings suggest roles for Orx1R and CB1R signaling within vlPAG in the modulation of migraine-induced anxiety-like behavior and social dysfunction in rats.

Topics: Animals; Anxiety; Behavior, Animal; Benzoxazoles; Male; Migraine Disorders; Naphthyridines; Orexin Receptors; Periaqueductal Gray; Piperidines; Pyrazoles; Rats; Rats, Wistar; Receptor, Cannabinoid, CB1; Receptors, Neuropeptide; Social Behavior; Urea

Topics: Benzamides; Budgets; Humans; Migraine Disorders; Piperidines; Pyridines; Serotonin Receptor Agonists; Surveys and Questionnaires; United States

Topics: Administration, Oral; Calcitonin Gene-Related Peptide Receptor Antagonists; Drug Interactions; Humans; Migraine Disorders; Piperidines; Pyridines; Pyrroles; Receptors, Calcitonin Gene-Related Peptide; Signal Transduction; Spiro Compounds; Treatment Outcome

To review the pharmacology, pharmacokinetics, efficacy, safety, and place in therapy of rimegepant for treatment of migraine.. A comprehensive PubMed and Cochrane search (1985 to May 2020) was performed utilizing the keywords. All English-language trials evaluating oral rimegepant were included for this review.. Rimegepant orally disintegrating tablet (ODT) is Food and Drug Administration approved for the treatment of migraine. According to data from 3 phase 3 randomized controlled trials, rimegepant has been shown to significantly improve freedom from pain at 2 hours after the dose and freedom from the most bothersome symptom 2 hours postdose. Additional outcomes improved include freedom from photophobia and phonophobia at 2 hours postdose and pain relief 2 hours after the dose. Adverse effects of rimegepant include nausea, urinary tract infection, and dizziness.. Orally disintegrating rimegepant provides a novel mechanism of action for the treatment of acute migraine. When patients experience inadequate relief from other therapies, have contraindications to triptans, or are unable to tolerate the adverse effects of triptans, rimegepant is a promising therapeutic option.. Rimegepant ODT is an efficacious migraine treatment option with a novel mechanism of action, convenient dosage form, and limited adverse effect profile.

Topics: Acute Disease; Administration, Oral; Calcitonin Gene-Related Peptide; Calcitonin Gene-Related Peptide Receptor Antagonists; Clinical Trials as Topic; Humans; Migraine Disorders; Nausea; Pain; Pain Management; Piperidines; Pyridines; Solubility; Tablets; Treatment Outcome

OnabotulinumtoxinA and agents that block calcitonin gene‒receptor peptide action have both been found to have anti-migraine effects, but they inhibit different populations of meningeal nociceptors. We therefore tested the effects of combined treatment with onabotulinumtoxinA and the calcitonin gene‒receptor peptide antagonist atogepant on activation/sensitization of trigeminovascular neurons by cortical spreading depression.. Single-unit recordings were obtained of high-threshold and wide-dynamic-range neurons in the spinal trigeminal nucleus, and cortical spreading depression was then induced in anesthetized rats that had received scalp injections of onabotulinumtoxinA 7 days earlier and intravenous atogepant infusion 1 h earlier. The control group received scalp saline injections and intravenous vehicle infusion.. OnabotulinumtoxinA/atogepant pretreatment prevented cortical spreading depression-induced activation and sensitization in both populations (control: Activation in 80% of high-threshold and 70% of wide-dynamic-range neurons, sensitization in 80% of high-threshold and 60% of wide-dynamic-range neurons; treatment: activation in 10% of high-threshold and 0% of wide-dynamic-range neurons, sensitization in 0% of high-threshold and 5% of wide-dynamic-range neurons).. We propose that the robust inhibition of high-threshold and wide-dynamic-range neurons by the combination treatment was achieved through dual blockade of the Aδ and C classes of meningeal nociceptors. Combination therapy that inhibits meningeal C-fibers and prevents calcitonin gene‒receptor peptide from activating its receptors on Aδ-meningeal nociceptors may be more effective than a monotherapy in reducing migraine days per month in patients with chronic migraine.

Topics: Analgesics; Animals; Botulinum Toxins, Type A; Calcitonin; Humans; Migraine Disorders; Nerve Fibers, Unmyelinated; Piperidines; Pyridines; Pyrroles; Rats; Rats, Sprague-Dawley; Spiro Compounds

Topics: Calcitonin Gene-Related Peptide Receptor Antagonists; Double-Blind Method; Humans; Migraine Disorders; Piperidines; Pyridines

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.

Topics: Adult; Calcitonin Gene-Related Peptide; Calcitonin Gene-Related Peptide Receptor Antagonists; Humans; Migraine Disorders; Piperidines; Pyridines; Receptors, Calcitonin Gene-Related Peptide

Topics: Calcitonin Gene-Related Peptide Receptor Antagonists; Humans; Migraine Disorders; Piperidines; Pyridines; Receptors, Calcitonin Gene-Related Peptide

Clinical data on the transfer of triptans into human breast milk remain scarce. In a lactation study including 19 breastfeeding women with migraine, we examined the excretion of six different triptans into milk. Following intake of a single dose, each participant collected seven breast milk samples at predefined intervals up to 24 hours after dose. Triptan concentrations in milk were measured using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Infant drug exposure was estimated by calculating the relative infant dose (RID). Twenty-two breast milk sample sets were obtained for sumatriptan (n = 8), rizatriptan (n = 5), zolmitriptan (n = 4), eletriptan (n = 3), almotriptan (n = 1) and naratriptan (n = 1). Based on the average concentration in milk throughout the day, estimated mean RIDs (with range in parenthesis) were as follows: eletriptan 0.6% (0.3%-0.8%), sumatriptan 0.7% (0.2%-1.8%), rizatriptan 0.9% (0.3%-1.4%), almotriptan 1.8% (-), zolmitriptan 2.1% (0.7%-5.3%) and naratriptan 5.0% (-). Infant drug exposure through breastfeeding appears to be low and indicates that use of the triptans in this study is compatible with breastfeeding. Naratriptan may not be first choice in breastfeeding mothers initiating triptans during the neonatal period.

Topics: Adult; Breast Feeding; Female; Humans; Infant; Infant, Newborn; Migraine Disorders; Milk, Human; Oxazolidinones; Piperidines; Pyrrolidines; Triazoles; Tryptamines

Rimegepant is an orally administered small-molecule calcitonin gene-related peptide (CGRP) receptor antagonist, with demonstrated efficacy in the acute treatment of migraine. Recent estimates from a single-arm trial (BHV3000-201) have also shown evidence of long-term preventive effects in monthly migraine days (MMDs) and health-related quality of life (HRQoL). This study aimed to compare MMDs and HRQoL data for oral rimegepant to those obtained in placebo-controlled trials for injectable anti-CGRP monoclonal antibodies (mAbs) galcanezumab and erenumab.. Matching-adjusted indirect comparisons (MAICs) were conducted using rimegepant subject-level data and published aggregate-level results from mAb trials. Rimegepant baseline characteristics were matched to the pooled subject characteristics from EVOLVE-I/II (galcanezumab vs. placebo; n = 1773) and STRIVE (ereumab vs. placebo; n = 955) by reweighting the rimegepant subjects to more closely match the distributions observed in these trials. To align with inclusion criteria of the mAb trials, only the subset of rimegepant subjects with a history of 4-14 MMDs were included (n = 257). Weighted mean differences were used to calculate adjusted change in MMDs, Migraine Disability Assessment Test (MIDAS) score, and Migraine-Specific Quality of Life Questionnaire version 2 (MSQv2) scores from baseline to week 12.. When matched to the EVOLVE trials, rimegepant was superior to placebo with a mean difference in MMD change from baseline [95% confidence interval] of -1.16 [-1.80, -0.52] and was not statistically significantly different from galcanezumab 0.59 [-0.13, 1.32]. When matched to the STRIVE trial, rimegepant was superior to placebo -1.59 [-2.15, -1.03] and was not statistically significantly different from erenumab -0.06 [-0.61, 0.50]. Rimegepant showed superior MIDAS and MSQv2 results compared with placebo in both EVOLVE trials and in the STRIVE trial, no statistically significant differences from galcanezumab and erenumab regarding MIDAS, and favorable results compared with erenumab across all MSQv2 domains, while being generally similar to galcanezumab across all MSQv2 domains.. When adjustments were made to reflect baseline characteristics in published literature, supporting data from BHV3000-201 suggest that rimegepant every other day is an effective therapy in reducing disability and MMDs and enhancing migraine-specific HRQoL. These data support the preventive benefit observed in randomized trials of rimegepant and further validate its efficacy for both acute and preventive treatment of migraine.

Topics: Administration, Oral; Adult; Antibodies, Monoclonal, Humanized; Calcitonin Gene-Related Peptide; Female; Humans; Male; Middle Aged; Migraine Disorders; Piperidines; Placebos; Pyridines; Quality of Life; Surveys and Questionnaires; Treatment Outcome

Recently, the FDA approved ubrogepant and rimegepant as oral drugs to treat migraines by targeting the calcitonin-gene related peptide receptor (CGRPR). Unfortunately, there is no high-resolution complex structure with these two drugs; thus the detailed interaction between drugs and the receptor remains elusive. This study uses molecular docking and molecular dynamics simulation to model the drug-receptor complex and analyze their binding interactions at a molecular level. The complex crystal structure (3N7R) of the gepant drugs' predecessor, olcegepant, was used for our molecular docking of the two drugs and served as a control system. The three systems, with ubrogepant, rimegepant, and crystal olcegepant, were subject to 3 × 1000 ns molecular dynamics simulations and followed by the simulation interaction diagram (SID), structural clustering, and MM-GBSA binding energy analyses. Our MD data revealed that olcegepant binds most strongly to the CGRPR, followed by ubrogepant and then rimegepant, largely due to changes in hydrophobic and electrostatic interactions. The order of our MM-GBSA binding energies of these three compounds is consistent with their experimental IC

Topics: Calcitonin Gene-Related Peptide; Humans; Migraine Disorders; Molecular Docking Simulation; Molecular Dynamics Simulation; Pharmaceutical Preparations; Piperidines; Pyridines; Pyrroles; Receptors, Calcitonin Gene-Related Peptide

Topics: Adult; Calcitonin Gene-Related Peptide Receptor Antagonists; Dihydroergotamine; Humans; Migraine Disorders; Piperidines; Pyridines; Vasoconstrictor Agents

Migraine is a common neurovascular disease which has been classified as the sixth most disabling disorder. Current migraine therapy was triptans, however, riptans can cause contraction of blood vessels. Therefore, novel drugs without cardiovascular effects emerged, such as CGRP and selective 5-HT

Topics: Animals; Body Weight; Dose-Response Relationship, Drug; Drug Design; Eating; Female; Haplorhini; HEK293 Cells; Humans; Inflammation; Male; Migraine Disorders; Molecular Structure; Piperidines; Pyridines; Rats; Rats, Sprague-Dawley; Rats, Wistar; Receptor, Serotonin, 5-HT1F; Receptors, Serotonin; Structure-Activity Relationship

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.. 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.. 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 < 0.001 for all combinations). In addition, more patients who were pain free experienced both 2 h MBS freedom and 2 h functional disability freedom (83.6%) compared to those with mild pain (10.8%; p < 0.001). The proportion of patients with pain freedom who did not achieve either MBS or disability freedom (4.6%) was lower than in patients with mild pain (52.4%). Lastly, 55.2% of patients experienced mild pain before disability freedom compared to 72.1% who experienced pain freedom and disability freedom at the same time.. 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.. SAMURAI ( NCT02439320 ); SPARTAN ( NCT02605174 ).

Topics: Benzamides; Double-Blind Method; Freedom; Headache; Humans; Migraine Disorders; Piperidines; Pyridines; Treatment Outcome

We explore factors that may have contributed to differences in treatment-emergent adverse events in the phase 2 and phase 3 lasmiditan clinical trials.. Phase 2 and phase 3 trials showed that the centrally penetrant 5-HT. 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.. 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.. 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.

Topics: Adult; Benzamides; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Drug-Related Side Effects and Adverse Reactions; Female; Forms as Topic; Humans; Informed Consent; Male; Middle Aged; Migraine Disorders; Patient Reported Outcome Measures; Piperidines; Pyridines; Serotonin Receptor Agonists; Translating

Topics: Benzamides; Drug Approval; Humans; Migraine Disorders; Piperidines; Pyridines; Serotonin Receptor Agonists; United States; United States Food and Drug Administration

Topics: Animals; Benzamides; Drug Development; Humans; Migraine Disorders; Piperidines; Pyridines; Serotonin Receptor Agonists

Status migrainosus is a condition with limited epidemiological knowledge, and no evidence-based treatment guideline or rational-driven assessment of successful treatment outcome. To fill this gap, we performed a prospective observational study in which we documented effectiveness of treatment approaches commonly used in a tertiary headache clinic.. Patients with episodic and chronic migraine who experienced continuous and prolonged attacks for more than 72 hours were treated with dexamethasone (4 mg orally twice daily for 3 days), ketorolac (60 mg intramuscularly), bilateral nerve blocks (1-2% lidocaine, 0.1-0.2 ml for both supraorbital and supratrochlear nerves, 1 ml for both auriculotemporal nerves, and 1 ml for both greater occipital nerves), or naratriptan (2.5 mg twice daily for 5 days). Hourly (for the first 24 hours) and daily (for first 30 days) change in headache intensity was documented using appropriate headache diaries.. Fifty-four patients provided eligible data for 60 treatment attempts. The success rate of rendering patients pain free within 24 hours and maintaining the pain-free status for 48 hours was 4/13 (31%) for dexamethasone, 7/29 (24%) for nerve blocks, 1/9 (11%) for ketorolac and 1/9 (11%) for naratriptan. These success rates depended on time to remission, as the longer we allowed the treatments to begin to work and patients to become pain free (i.e. 2, 12, 24, 48, 72, or 96 hours), the more likely patients were to achieve and maintain a pain-free status for at least 48 hours.. These findings suggest that current treatment approaches to terminating status migrainosus are not satisfactory and call attention to the need to develop a more scientific approach to define a treatment response for status migrainosus.

Topics: Adult; Dexamethasone; Female; Humans; Ketorolac; Male; Middle Aged; Migraine Disorders; Nerve Block; Pain Management; Piperidines; Treatment Outcome; Tryptamines

Topics: Calcitonin Gene-Related Peptide Receptor Antagonists; Humans; Migraine Disorders; Piperidines; Pyridines; Pyrroles; Spiro Compounds

Topics: Acute Disease; Adult; Benzamides; Clinical Trials as Topic; Humans; Migraine Disorders; Piperidines; Pyridines; Serotonin Receptor Agonists; Treatment Outcome

Topics: Administration, Oral; Calcitonin Gene-Related Peptide Receptor Antagonists; Humans; Migraine Disorders; Piperidines; Pyridines

Topics: Animals; Benzamides; Humans; Migraine Disorders; Piperidines; Pyridines; Pyrroles

Topics: Calcitonin Gene-Related Peptide Receptor Antagonists; Humans; Migraine Disorders; Piperidines; Pyridines

Topics: Calcitonin Gene-Related Peptide Receptor Antagonists; Double-Blind Method; Humans; Migraine Disorders; Piperidines; Pyridines; Tablets

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.

Topics: Adult; Benzamides; Dose-Response Relationship, Drug; Humans; Migraine Disorders; Piperidines; Pyridines; Randomized Controlled Trials as Topic; Serotonin Receptor Agonists; United States

Topics: Administration, Oral; Calcitonin Gene-Related Peptide; Dose-Response Relationship, Drug; Drug Approval; Drug Interactions; Humans; Migraine Disorders; Piperidines; Pyridines

Topics: Benzamides; Humans; Migraine Disorders; Piperidines; Pyridines; Pyrroles

Topics: Analgesics; Benzamides; Calcitonin Gene-Related Peptide; Cost-Benefit Analysis; Drug Costs; Humans; Migraine Disorders; Piperidines; Pyridines; Pyrroles; Quality-Adjusted Life Years; Receptor, Serotonin, 5-HT1F; Receptors, Serotonin; Serotonin 5-HT1 Receptor Agonists; Signal Transduction; Systematic Reviews as Topic; Time Factors; Treatment Outcome

Topics: Antibodies, Monoclonal; Calcitonin Gene-Related Peptide; Calcitonin Gene-Related Peptide Receptor Antagonists; Humans; Migraine Disorders; Piperidines; Pre-Exposure Prophylaxis; Pyridines; Receptors, Calcitonin Gene-Related Peptide

Topics: Double-Blind Method; Freedom; Humans; Migraine Disorders; Pain; Piperidines; Pyridines; Tablets

Topics: Calcitonin Gene-Related Peptide Receptor Antagonists; Freedom; Humans; Migraine Disorders; Pain; Piperidines; Pyridines

Serotonin (5-HT) plays a role in migraine pathophysiology, but whether brain 5-HT is involved in the conversion from episodic to chronic migraine is unknown. Here, we investigated brain 5-HT levels, as indexed by 5-HT. Sixteen chronic migraine patients underwent a dynamic PET scan after injection of [. The finding of low 5-HT

Topics: Adult; Brain; Carbon Radioisotopes; Cross-Sectional Studies; Female; Heterozygote; Humans; Male; Middle Aged; Migraine Disorders; Piperidines; Positron-Emission Tomography; Protein Binding; Receptors, Serotonin, 5-HT4; Serotonin; Young Adult

κ opioid receptor (KOR) antagonists are potential pharmacotherapies for the treatment of migraine and stress-related mood disorders including depression, anxiety, and drug abuse, thus the development of novel KOR antagonists with an improved potency/selectivity profile and medication-like duration of action has attracted the interest of the medicinal chemistry community. In this paper, we describe the discovery of 1-(6-ethyl-8-fluoro-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)quinolin-2-yl)- N-(tetrahydro-2 H-pyran-4-yl)piperidin-4 amine (CYM-53093, BTRX-335140) as a potent and selective KOR antagonist, endowed with favorable in vitro ADMET and in vivo pharmacokinetic profiles and medication-like duration of action in rat pharmacodynamic experiments. Orally administered CYM-53093 showed robust efficacy in antagonizing KOR agonist-induced prolactin secretion and in tail-flick analgesia in mice. CYM-53093 exhibited a broad selectivity over a panel of off-target proteins. This compound is in phase 1 clinical trials for the treatment of neuropsychiatric disorders wherein dynorphin is thought to contribute to the underlying pathophysiology.

Topics: Aminoquinolines; Animals; Caco-2 Cells; Dogs; Drug Design; Escherichia coli; Humans; Madin Darby Canine Kidney Cells; Male; Mice, Inbred C57BL; Microsomes, Liver; Migraine Disorders; Molecular Structure; Narcotic Antagonists; Oxadiazoles; Piperidines; Quinolines; Rats, Sprague-Dawley; Receptors, Opioid, kappa; Salmonella typhimurium; Small Molecule Libraries; Structure-Activity Relationship

The recent expansion of electronic health and medical record systems may present an opportunity to generate robust post-approval safety data and obviate the limitations of prospective pregnancy exposure registries. We examined and compared, over the same time frame, the outcomes of triptan exposure in pregnancy using (1) a retrospective claims database and (2) a previously completed pregnancy registry.. Using the Marketscan database, the risk of major birth defects was ascertained in live-born infants whose birth mothers were exposed to sumatriptan, naratriptan, or sumatriptan/naproxen during pregnancy. The frequencies of outcomes observed were compared with the findings of the 16-year sumatriptan, naratripan, and sumatriptan/naproxen prospective pregnancy registry.. About 5120 pregnancies were identified in the retrospective claims cohort in contrast to 617 included in the prospective registry during the same time frame. The proportion of major birth defects among first-semester sumatriptan exposures was 4.0%, which is exactly the same as the proportion of major birth defects reported for first-semester sumatriptan exposures in the registry. There were very few non-livebirth outcomes in both the claims analyses and registry.. These results confirm broad agreement between the database analysis and the registry regarding the safety of triptans during pregnancy. Of note, the number of triptan-exposed pregnancies identified in this large US database was about 7-fold that included in the prospective registry over the same time frame. The findings of this study support an approach of using existing health care database (s) in the post-approval assessment of medication exposure in pregnancy.

Topics: Abnormalities, Drug-Induced; Administrative Claims, Healthcare; Adolescent; Adult; Databases, Factual; Drug Combinations; Electronic Health Records; Female; Humans; Infant, Newborn; Migraine Disorders; Naproxen; Piperidines; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Prospective Studies; Registries; Retrospective Studies; Sumatriptan; Tryptamines; United States; Young Adult

Objective Naratriptan has been reported to reduce the frequency of cluster headache. The purpose of this study was to determine whether naratriptan is effective as a prophylactic treatment for cluster headache in Japan. Methods We retrospectively reviewed all 43 patients with cluster headache who received preventive treatment with naratriptan from April 2009 to April 2015. The International Classification of Headache Disorders, 3rd Edition (beta version) (ICHD-3 beta) was used to diagnose cluster headache. This study was conducted at 3 centers (Department of Neurology, Saitama Medical University; Saitama Neuropsychiatric Institute; Saitama Medical University International Medical Center). Patients were recruited from these specialized headache outpatient centers. Naratriptan was taken before the patient went to bed. Results The study population included 30 men (69.8%) and 13 women (30.2%). Twenty-two cases received other preventive treatments (51.2%), while 21 cases only received naratriptan (48.8%). Among the 43 cases, 37 patients (86.0%) achieved an improvement of cluster headache on naratriptan. Conclusion Naratriptan has been suggested as a preventive medicine for cluster headache because of the longer the biological half-life in comparison to other triptans. The internal use of naratriptan 2 hours before attacks appears to achieve a good response in patients with cluster headache.

Topics: Adult; Aged; Cluster Headache; Female; Humans; Japan; Male; Middle Aged; Migraine Disorders; Piperidines; Retrospective Studies; Serotonin Receptor Agonists; Tryptamines; Vasoconstrictor Agents; Young Adult

Topics: Cluster Headache; Humans; Indoles; Migraine Disorders; Piperidines; Tryptamines

Topics: Calcitonin Gene-Related Peptide; Calcitonin Gene-Related Peptide Receptor Antagonists; Female; Humans; Male; Migraine Disorders; Piperidines; Pyridines

Topics: Analgesics; Humans; Migraine Disorders; Piperidines; Pyrimidines

There is evidence to suggest that a dysregulation of endocannabinoid signaling may contribute to the etiology and pathophysiology of migraine. Thus, patients suffering from chronic migraine or medication overuse headache showed alterations in the activity of the arachidonoylethanolamide (AEA) degrading enzyme fatty acid amide hydrolase (FAAH) and a specific AEA membrane transporter, alongside with changes in AEA levels. The precise role of different endocannabinoid system components is, however, not clear. We have therefore investigated mice with a genetic deletion of the two main cannabinoid receptors CB1 and CB2, or the main endocannabinoid degrading enzymes, FAAH and monoacylglycerol lipase (MAGL), which degrades 2-arachidonoylglycerol (2-AG), in a nitroglycerine-induced animal model of migraine. We found that nitroglycerin-induced mechanical allodynia and neuronal activation of the trigeminal nucleus were completely abolished in FAAH-deficient mice. To validate these results, we used two structurally different FAAH inhibitors, URB597 and PF3945. Both inhibitors also dose-dependently blocked nitroglycerin-induced hyperalgesia and the activation of trigeminal neurons. The effects of the genetic deletion of pharmacological blockade of FAAH are mediated by CB1 receptors, because they were completely disrupted with the CB1 antagonist rimonabant. These results identify FAAH as a target for migraine pharmacotherapy.

Topics: Amidohydrolases; Analgesics; Animals; Arachidonic Acids; Benzamides; Cannabinoid Receptor Antagonists; Carbamates; Disease Models, Animal; Dose-Response Relationship, Drug; Endocannabinoids; Enzyme Inhibitors; Hyperalgesia; Male; Mice, Inbred C57BL; Mice, Knockout; Migraine Disorders; Monoacylglycerol Lipases; Nitroglycerin; Pain Measurement; Piperidines; Polyunsaturated Alkamides; Pyrazoles; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Rimonabant; Touch; Trigeminal Nuclei

An asymmetric synthesis of novel heterocyclic analogue of the CGRP receptor antagonist rimegepant (BMS-927711, 3) is reported. The cycloheptane ring was constructed by an intramolecular Heck reaction. The application of Hayashi-Miyaura and Ellman reactions furnished the aryl and the amine chiral centers, while the separable diastereomeric third chiral center alcohols led to both carbamate and urea analogues. This synthetic approach was applicable to both 6- and 5-membered heterocycles as exemplified by pyrazine and thiazole derivatives.

Topics: Calcitonin Gene-Related Peptide Receptor Antagonists; Cycloheptanes; Migraine Disorders; Molecular Structure; Piperidines; Pyridines; Stereoisomerism

Topics: Calcitonin Gene-Related Peptide; Calcitonin Gene-Related Peptide Receptor Antagonists; Humans; Migraine Disorders; Piperidines; Pyridines

Infusion of glyceryltrinitrate (GTN), a nitric oxide (NO) donor, in awake, freely moving rats closely mimics a universally accepted human model of migraine and responds to sumatriptan treatment. Here we analyse the effect of nitric oxide synthase (NOS) and calcitonin gene-related peptide (CGRP) systems on the GTN-induced neuronal activation in this model.. The femoral vein was catheterised in rats and GTN was infused (4 µg/kg/min, for 20 minutes, intravenously). Immunohistochemistry was performed to analyse Fos, nNOS and CGRP and Western blot for measuring nNOS protein expression. The effect of olcegepant, L-nitro-arginine methyl ester (L-NAME) and neurokinin (NK)-1 receptor antagonist L-733060 were analysed on Fos activation.. GTN-treated rats showed a significant increase of nNOS and CGRP in dura mater and CGRP in the trigeminal nucleus caudalis (TNC). Upregulation of Fos was observed in TNC four hours after the infusion. This activation was inhibited by pre-treatment with olcegepant. Pre-treatment with L-NAME and L-733060 also significantly inhibited GTN induced Fos expression.. The present study indicates that blockers of CGRP, NOS and NK-1 receptors all inhibit GTN induced Fos activation. These findings also predict that pre-treatment with olcegepant may be a better option than post-treatment to study its inhibitory effect in GTN migraine models.

Topics: Animals; Calcitonin Gene-Related Peptide; Calcitonin Gene-Related Peptide Receptor Antagonists; Dipeptides; Disease Models, Animal; Enzyme Inhibitors; Humans; Male; Migraine Disorders; Neurokinin-1 Receptor Antagonists; Neurons; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase Type I; Nitroglycerin; Piperazines; Piperidines; Posterior Horn Cells; Proto-Oncogene Proteins c-fos; Quinazolines; Rats; Rats, Sprague-Dawley; Receptors, Neurokinin-1; Trigeminal Nerve; Vasodilator Agents; Wakefulness

Familial hemiplegic migraine type 1 (FHM-1) is a monogenic subtype of migraine with aura caused by missense mutations in the CACNA1A gene, which encodes the pore-forming α1 subunit of voltage-gated neuronal CaV2.1 (P/Q-type) calcium channels. Transgenic knock-in mice expressing the CACNA1A R192Q mutation that causes FHM-1 in patients show a greater susceptibility to cortical spreading depression, the likely underlying mechanism of typical human migraine aura. The aim of this study was to compare neuronal activation within the trigeminal pain pathways in response to nociceptive trigeminovascular stimulation in wild-type and R192Q knock-in mice. After sham surgery or electrical stimulation of the superior sagittal sinus for 2h, or stimulation preceded by treatment with naratriptan, mice underwent intracardiac perfusion, and the brain, including the brainstem, was removed. Fos expression was measured in the trigeminocervical complex (TCC) and the lateral (ventroposteromedial, ventrolateral), medial (parafascicular, centromedian) and posterior thalamic nuclei. In the TCC of wild-type animals, the number of Fos-positive cells increased significantly following dural stimulation compared to the sham control group (P<0.001) and decreased after naratriptan treatment (P<0.05). In R192Q knock-in mice, there was no significant difference between the stimulated and sham (P=0.10) or naratriptan pre-treated groups (P=0.15). The number of Fos-positive cells in the R192Q stimulated group was significantly lower compared to the wild-type stimulated mice (P<0.05). In the thalamus, R192Q mice tended to be more sensitive to stimulation compared to the sham control in the medial and posterior nuclei, and between the two strains of stimulated animals there was a significant difference in the centromedian (P<0.005), and posterior nuclei (P<0.05). The present study suggests that the FHM-1 mutation affects more rostral brain structures in this experimental paradigm, which offers a novel perspective on possible differential effects of mutations causing migraine in terms of phenotype-genotype correlations.

Topics: Animals; Calcium Channels; Cerebellar Ataxia; Electric Stimulation; Gene Knock-In Techniques; Mice; Mice, Inbred C57BL; Mice, Transgenic; Migraine Disorders; Mutation, Missense; Neural Pathways; Neurons; Nociception; Piperidines; Proto-Oncogene Proteins c-fos; Serotonin 5-HT1 Receptor Agonists; Superior Sagittal Sinus; Thalamic Nuclei; Trigeminal Caudal Nucleus; Trigeminal Nuclei; Tryptamines

Topics: Adolescent; Carbazoles; Delayed-Action Preparations; Female; Follow-Up Studies; Humans; Male; Migraine Disorders; Piperidines; Serotonin Receptor Agonists; Time Factors; Tryptamines; Weather

The purpose of this study was to develop and manufacture novel freeze-dried orally disintegrating tablets (ODTs) for migraine therapy containing taste-masked naproxen sodium and naratriptan hydrochloride. The formulation was optimized based on freeze-drying of sucrose solutions with different binders (hydroxyethylstarch, sodium alginate, methylcellulose, and gelatin) and varying amounts of Eudragit® E-coated naproxen sodium granules. Excellent product performance of the ODTs in terms of hardness and disintegration time (<10 s) independent of the mass of particles embedded was found for the solution consisting of sucrose and hydroxyethylstarch. Poloxamer 188, menthol flavor, naratriptan hydrochloride, and taste-masked naproxen sodium granules corresponding to 200 mg of naproxen were then added, and the final batches of ODTs for migraine therapy were produced. The ODTs were fully characterized, and subsequently stored for 1 month at room temperature and at 40°C. The amount of free naproxen sodium after freeze-drying and storage was below the threshold bitterness value, and the coating remained intact. Additionally, the particle size distribution of taste-masked granules was preserved, and more than 90 % naproxen sodium was released after 30 min. Naratriptan hydrochloride was dissolved immediately after disintegration, hence facilitating buccal absorption of the active pharmaceutical ingredient.

Topics: Administration, Oral; Anti-Inflammatory Agents, Non-Steroidal; Drug Compounding; Drug Storage; Excipients; Freeze Drying; Migraine Disorders; Naproxen; Particle Size; Piperidines; Polymethacrylic Acids; Solubility; Tablets; Taste; Tryptamines; Vasoconstrictor Agents

Topics: Calcitonin Gene-Related Peptide; Calcitonin Gene-Related Peptide Receptor Antagonists; Female; Humans; Male; Migraine Disorders; Piperidines; Pyridines

Myocardial infarction as the most severe clinical manifestation of coronary atherosclerosis is the major cause of death in western countries. Although rupture of an atherosclerotic plaque is generally causal for this event, in recent years differential diagnoses have been discussed to further optimize diagnosis and treatment of myocardial ischemia. The "universal definition of myocardial infarction" defines five subtypes of myocardial infarction: in particular, type 2 myocardial infarction includes other diseases related to myocardial ischemia such as hyper- or hypotension, coronary artery spasms, arrhythmia, etc. Some medications for the acute therapy of migraine like triptans can lead to myocardial infarction.

Topics: Combined Modality Therapy; Drug Substitution; Female; Humans; Middle Aged; Migraine Disorders; Myocardial Infarction; Myocardial Ischemia; Piperidines; Self Medication; Substance-Related Disorders; Tryptamines

Topics: Acute Coronary Syndrome; Aged; Editorial Policies; Female; Humans; Medical Records, Problem-Oriented; Migraine Disorders; Periodicals as Topic; Piperidines; Publishing; Research Report; Switzerland; Tryptamines; Vasoconstrictor Agents; Writing

We report on an angioedema patient with a genetic defect in complement 1 inhibitor, manifesting migraine-like episodes of headache, effective prophylaxis with Danazol, and triptan for a treatment of acute clinical episode. The patient was 44-yr-old Korean man with abdominal pain and headache, who was brought into the Emergency Department of Seoul National University Hospital, Seoul. He suffered from frequent attacks of migraine-like headache (3-7 per month), pulsating in nature associated with nausea. Severities were aggravated by activity and his headache had shown recent progression with abdominal pain. No remarkable findings were observed on radiologic examination, brain magnetic resonance images and intracranial and extracranial magnetic resonance angiography. Danazol 200 mg every other day was subsequently used. Following administration of Danazol, symptoms showed improvement and the patient was discharged. While taking Danazol, the migraine-like episodes appeared to be prevented for about 2 yr. At the eighth month, he suffered a moderate degree of migraine-like headache; however, administration of naratriptan 2.5 mg resolved his problem. A case of genetic defect of C1-INH deficiency presented with headache episodes, and was controlled by Danazol and triptan. It suggests that pathogenic mechanism of headache in hereditary angioedema may be mediated by the neurogenic inflammatory-like physiology of migraine.

Topics: Adult; Angioedemas, Hereditary; Brain; Complement C1 Inhibitor Protein; Danazol; Estrogen Antagonists; Humans; Magnetic Resonance Angiography; Male; Migraine Disorders; Piperidines; Radionuclide Imaging; Tryptamines; Vasoconstrictor Agents

Calcitonin gene-related peptide (CGRP) receptor antagonists have demonstrated clinical efficacy in the treatment of acute migraine. Herein, we describe the design, synthesis, and preclinical characterization of a highly potent, oral CGRP receptor antagonist BMS-927711 (8). Compound 8 has good oral bioavailability in rat and cynomolgus monkey, attractive overall preclinical properties, and shows dose-dependent activity in a primate model of CGRP-induced facial blood flow. Compound 8 is presently in phase II clinical trials.

Topics: Administration, Oral; Calcitonin Gene-Related Peptide; Clinical Trials as Topic; Drug Discovery; Humans; Magnetic Resonance Spectroscopy; Migraine Disorders; Piperidines; Pyridines

The aim of this case/non-case study was to assess and compare the risk of drug dependence associated with different migraine-specific drugs, i.e., ergot derivatives and triptans, using the French pharmacovigilance database.. Reports on drug side effects recorded in this database between January 1985 and June 2007 were analyzed, and triptans (almotriptan, eletriptan, naratriptan, sumatriptan, and zolmitriptan) as well as ergot derivatives used in acute migraine were examined. For all reports, cases were defined as those reports corresponding to "drug abuse," "physical or mental drug dependence," and "pharmacodependence," whereas "non-cases" were defined as all the remaining SED reports. The method's reliability was assessed by calculating the risk associated with a negative (amoxicillin) and a positive (benzodiazepines) control. The risk of dependence associated with each drug and control was evaluated by calculating the odds ratio (OR) with a confidence interval of 95%.. Among the 309,178 reports recorded in the database, drug dependence accounted for 0.8% (2,489) of the reports, with 10.9% (449) involving a triptan, and 9.33% (332) an ergot derivative. The risk of dependence was similar for triptans and ergot derivatives and did not differ from that of benzodiazepines. In the triptan group, the risk (odds ratio [95% CI]) ranged from 10.3 [4.8-22.3] for sumatriptan to 21.5 for eletriptan [10.1-45.6], while in the ergot derivative group, it ranged from 12 [8-17.9] for ergotamine to 20.6 [8-53] for dihydroergotamine.. These findings confirm the hypothesis that triptans and ergot derivatives are associated with an increased risk of drug dependence.

Topics: Claviceps; Dihydroergotamine; Ergotamine; Humans; Migraine Disorders; Oxazolidinones; Piperidines; Pyrrolidines; Risk; Substance-Related Disorders; Sumatriptan; Tryptamines

A 60-year-old female with sudden onset of abdominal pain and hematochezia was diagnosed with histology-proven ischemic colitis. She used naratriptan on a regular basis for migraine. By exclusion of other causes for colonic ischemia and the absence of cardiovascular risk factors, naratriptan was considered the causal agent. Discontinuation resulted in a complete clinical recovery. With the increasing use of triptans, health care providers should be aware of the possible serious ischemic events associated with these drugs.

Topics: Colitis, Ischemic; Female; Humans; Middle Aged; Migraine Disorders; Piperidines; Tryptamines; Vasoconstrictor Agents

A patient who just found out that she is pregnant and suffers from migraine headaches informs me that she has been taking naratriptan. She indicates that she is planning on breastfeeding her baby and might need to continue treatment. How safe are the medications from this class of drugs during pregnancy and breastfeeding?. Accumulated data suggest that exposure to sumatriptan during pregnancy does not increase the risk of birth defects above the baseline rate. There are currently insufficient data to confirm the safety of other triptans; however, evidence to date is reassuring. Information regarding safety of triptans while breastfeeding is limited but also reassuring, as the minimal amounts excreted into the milk are insufficient to cause any adverse effects on the breastfeeding infant.

Topics: Breast Feeding; Female; Humans; Migraine Disorders; Piperidines; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Risk Factors; Serotonin 5-HT1 Receptor Agonists; Sumatriptan; Tryptamines

Topics: Benzamides; Clinical Trials as Topic; Humans; Migraine Disorders; Piperidines; Pyridines; Receptor, Serotonin, 5-HT1F; Receptors, Serotonin; Serotonin; Serotonin Receptor Agonists

This case report describes for the first time acute coronary syndrome in a 67-year old patient after oral intake of naratriptan for migraine. So far in the literature, only sumatriptan, zolmitriptan and frovatriptan have been described to cause acute coronary syndromes. A 67-year old Swiss woman with thoracic pain after intake of 2.5 mg naratriptan presented with T-wave inversions in the ECG and a positive troponin-T at our hospital. Coronary angiography showed normal coronary arteries. Naratriptan-induced coronary vasospasms were thought to have caused the acute coronary syndrome.Triptans should not be prescribed in patients with pre-existing coronary heart disease. However, triptans can also cause acute coronary syndromes in patients without coronary heart disease--as described in our case report. Severe or persistent thoracic pain after intake of triptans should therefore be investigated accordingly.

Topics: Acute Coronary Syndrome; Aged; Electrocardiography; Female; Humans; Migraine Disorders; Piperidines; Serotonin Agents; Treatment Outcome; Troponin T; Tryptamines

The efficacy of triptans in the treatment of migraine was recently contested. How high is then the maximum effect of a triptan? After subcutaneous naratriptan 10 mg a 88% pain-free response was observed. This result was obtained despite the fact that more half of the patients had a migraine duration of > 4 h. These results indicate that subcutaneous naratriptan in a high dose can overcome central sensitization that occurs in migraine attacks.

Topics: Dose-Response Relationship, Drug; Humans; Injections, Subcutaneous; Migraine Disorders; Pain Measurement; Piperidines; Randomized Controlled Trials as Topic; Sumatriptan; Treatment Outcome; Tryptamines

Molecules of eletriptan hydrobromide monohydrate (systematic name: (1S,2R)-1-methyl-2-{5-[2-(phenylsulfonyl)ethyl]-1H-indol-3-ylmethyl}pyrrolidinium bromide monohydrate), C(22)H(27)N(2)O(2)S(+) x Br(-) x H(2)O, (I), and naratriptan hydrochloride (systematic name: 1-methyl-4-{5-[2-(methylsulfamoyl)ethyl]-1H-indol-3-yl}piperidinium chloride), C(17)H(26)N(3)O(2)S(+) x Cl(-), (II), adopt conformations similar to other triptans. The C-2 and C-5 substituents of the indole ring, both of which are in a region of conformational flexibility, are found to be oriented on either side of the indole ring plane in (I), whilst they are on the same side in (II). The N atom in the C-2 side chain is protonated in both structures and is involved in the hydrogen-bonding networks. In (I), the water molecules create helical hydrogen-bonded chains along the c axis. In (II), the hydrogen bonding of the chloride ions results in macrocyclic R(4)(2)(20) and R(4)(2)(24) ring motifs that form sheets in the bc plane. This structural analysis provides an insight into the molecular structure-activity relationships within this class of compound, which is of use for drug development.

Topics: Analgesics; Crystallography, X-Ray; Halogens; Humans; Hydrogen Bonding; Migraine Disorders; Molecular Structure; Piperidines; Pyrrolidines; Salts; Structure-Activity Relationship; Tryptamines

Spreading depression (SD) has long been associated with the underlying pathophysiology of migraine. Evidence that the N-methyl-D-aspartate (NMDA) glutamate receptor (NMDA-R) is implicated in the generation and propagation of SD has itself been available for more than 15 years. However, to date, there are no reports of NMDA-R antagonists being developed for migraine therapy. In this study, an uncompetitive, pan-NMDA-R blocker, memantine, approved for clinical use, and two antagonists with selectivity for NMDA-R containing the NR2B subunit, (1S,2S)-1-(4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidino)-1-propanol (CP-101,606) and (+/-)-(R*,S*)-alpha-(4-hydroxyphenyl)-beta-methyl-4-(phenylmethyl)-1-piperidine propanol (Ro 25-6981), were investigated to assess their protective effects against SD in the rat. Under isoflurane anesthesia, d.c. potential and the related cortical blood flow and partial pressure of O2 (pO2) were recorded simultaneously at separate cortical sites. Drugs (1, 3, and 10 mg/kg i.p.) were given 1 h or 30 min before KCl application to the brain surface. Core temperature and arterial pCO2,pO2, and pH measurements confirmed physiological stability. KCl induced 7.7+/-1.8 (mean+/-S.D.) SD events with d.c. amplitude of 14.9+/-2.8 mV. Memantine and CP-101,606 dose-dependently decreased SD event number (to 2.0+/-1.8 and 2.3+/-2.9, respectively) and SD amplitude at doses relevant for therapeutic use. Ro 25-6981 also decreased SD events significantly, but less effectively (to 4.5+/-1.6), without affecting amplitude. These results indicate that NR2B-containing NMDA receptors are key mediators of SD, and as such, memantine- and NR2B-selective antagonists may be useful new therapeutic agents for the treatment of migraine and other SD-related disorders (e.g., stroke and brain injury). Whether chronic, rather than acute, treatment may improve their efficacy remains to be determined.

Topics: Animals; Cerebrovascular Circulation; Cortical Spreading Depression; Dizocilpine Maleate; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Male; Memantine; Migraine Disorders; Oxygen; Phenols; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate

Chronic migraine (CM) is a common disorder, affecting 2% to 3% of the general population. Glutamate is implicated in cortical spreading depression, trigeminovascular activation, central sensitization, and may be linked to migraine chronification. Triptans brought a novel option for the acute migraine treatment. As the development of central sensitization impacts upon the effectiveness of triptan therapy, we hypothesized that glutamate might be related to triptan response mechanisms.. We studied 19 patients diagnosed with CM according to the International Headache Society (2004) criteria. Patients were divided in those overusing analgesics (NSAIDs); those without overuse, and those overusing triptans.. Cerebrospinal fluid (CSF) glutamate levels were similar in patients overusing acute medications (0.335 +/- 0.225 micromol) compared to those without overuse (0.354 +/- 0.141 micromol), P= NS). In contrast, patients overusing triptans had CSF glutamate levels significantly lower than that observed in nonoverusers (0.175 +/- 0.057 vs 0.354 +/- 0.141 micromol, P= 0.015), and significantly higher than controls (0.175 +/- 0.057 vs 0.109 +/- 0.066 micromol, P= 0.039). In triptan overusers, CSF glutamate levels, although lower, were not significantly different from patients overusing other types of analgesics.. Our study showed lower glutamate levels in CSF of CM patients overusing triptans. Glutamate may be implicated in triptan response mechanisms, triptans may work in part by reducing extracellular glutamate levels in the brain.

Topics: Aged; Anti-Inflammatory Agents, Non-Steroidal; Female; Glutamic Acid; Headache Disorders; Headache Disorders, Secondary; Humans; Male; Middle Aged; Migraine Disorders; Piperidines; Serotonin Receptor Agonists; Triazoles; Tryptamines

Migraine is a prevalent neurological disorder that can be alleviated by specific treatment for acute headaches, in particular, the triptans, including naratriptan. France has developed official guidelines for the use of triptans as part of migraine management. This pharmacoepidemiological study sought to evaluate how naratriptan is prescribed and used in community medicine in France.. The protocol called for general practitioners to be randomly selected from a list of all physicians in France and for each to include two patients with migraine. Data came from questionnaires completed by the physician and by the patient (including HIT-6 and QVM to assess headache impact and quality of life) as well as a patient diary.. In all, 2530 physicians included 3863 patients: 54.3% were treated with naratriptan, 22.4% with another triptan and 23.3% with a non-triptan medication. Of the patients receiving naratriptran, 82.3% were women. Migraine impact was greater and quality of life worse in the patients receiving triptans than those treated with other medications (p<0.0001). Naratriptan was prescribed as second-line treatment following failure of an NSAID in 44.2% of patients taking it; 55.3% of them were prescribed a single dose per headache. Overall, initial treatment was taken right at the beginning of the migraine attack in 70.5% of headaches.. Data from this cross-sectional study indicate that triptans in general and naratriptan in particular are most often prescribed for patients with the most severe migraines. Consistent with official French guidelines, physicians often recommend taking naratriptan after and only if a NSAID fails to provide relief. Nonetheless, one patient in three starts treatment late, which may significantly reduce the efficacy rate, increase the risk of recurrence and side effects, and prolong the headache.. Naratriptan is generally prescribed in accordance with official guidelines. Delay in taking medication by around one third of patients probably reduces its efficacy.

Topics: Adult; Drug Prescriptions; Drug Utilization; Family Practice; Female; France; Humans; Male; Migraine Disorders; Piperidines; Surveys and Questionnaires; Tryptamines

In this report, a case with vitamin B12 deficiency showing a temporary confusion depending on the usage of naratriptan during the migraine attack was presented.

Topics: Confusion; Female; Humans; Magnetic Resonance Imaging; Middle Aged; Migraine Disorders; Piperidines; Serotonin Receptor Agonists; Tryptamines; Vitamin B 12 Deficiency

Six migraine patients experienced significant topiramate-related cognitive and language dysfunction that improved with donepezil treatment and allowed uninterrupted topiramate use. These patients represent the first report of topiramate-related cognitive and language dysfunction that improved with a cholinesterase inhibitor. Although, the mechanism responsible for this effect is uncertain, cholinesterase inhibition resulting in cholinergic augmentation and enhanced cognition probably account for some if not most of the improvement.

Topics: Adult; Cholinesterase Inhibitors; Cognition Disorders; Donepezil; Female; Fructose; Humans; Indans; Language Disorders; Male; Middle Aged; Migraine Disorders; Piperidines; Topiramate; Treatment Outcome

Topics: Acetaminophen; Age Factors; Analgesics; Anti-Inflammatory Agents, Non-Steroidal; Child; Ergot Alkaloids; Humans; Ibuprofen; Life Style; Migraine Disorders; Oxazolidinones; Parents; Patient Education as Topic; Pediatrics; Piperidines; Pyrrolidines; Risk Factors; Serotonin Receptor Agonists; Sumatriptan; Taste Disorders; Triazoles; Tryptamines; Vasoconstrictor Agents

Triptans, serotonin 5-HT(1B/1D), receptor agonists, which are so effective in acute migraine, are considered to act directly on the trigeminovascular system. Using an in vivo model of trigeminovascular nociception, we report a potentially novel action for the triptans within the somatosensory thalamus. Both microiontophoretically applied and intravenous naratriptans potently and reversibly modulate nociceptive neurotransmission by trigeminovascular thalamic neurons in the ventroposteromedial nucleus (VPM) driven by stimulation of the superior sagittal sinus. Naratriptan also suppresses l-glutamate activated trigeminovascular VPM neurons. Co-ejection of naratriptan with the 5-HT(1B/1D) receptor antagonist GR127935 antagonized this effect. (S)-WAY 100135 the 5-HT(1A) receptor antagonist also partially inhibited the effect of naratriptan in the VPM when co-ejected with it. Taken together, the new data suggest a potential effect of triptans in the VPM nucleus of the thalamus acting through 5-HT(1A/1B/1D) mechanisms, and offer an entirely new direction for the development of and understanding of the effects of anti-migraine medicines.

Topics: Afferent Pathways; Animals; Cerebral Arteries; Drug Interactions; Glutamic Acid; Male; Migraine Disorders; Nociceptors; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, Serotonin; Serotonin; Serotonin Antagonists; Serotonin Receptor Agonists; Synaptic Transmission; Trigeminal Nerve; Tryptamines; Ventral Thalamic Nuclei

In our continuing effort to identify CGRP receptor antagonists for the acute treatment of migraine, we have undertaken a study to evaluate alternative 4-substituted piperidines to the lead dihydroquinazolinone 1. In this regard, we have identified the piperidinyl-azabenzimidazolone and phenylimidazolinone structures which, when incorporated into the benzodiazepine core, afford potent CGRP receptor antagonists (e.g., 18 and 29). These studies produced a potent analog (18) which overcomes the instability issues associated with the lead structure 1. A general pharmacophore for the 4-substituted piperidine component of these CGRP receptor antagonists is also presented.

Topics: Benzodiazepines; Calcitonin Gene-Related Peptide Receptor Antagonists; Cyclic AMP; Drug Stability; Humans; Migraine Disorders; Piperidines; Protein Binding; Structure-Activity Relationship

The treatment of migraine consists of the acute treatment of the migraine attack and prophylactic measures for either pharmacological or non-pharmacological management. Since the retreat of the ergotamines one can only choose between one of the well-established analgesics and one of seven triptans for the treatment of the migraine attack. Although neither a new triptan nor an innovative new application form has been introduced, the year 2006 will be remembered as the year when the first triptan (naratriptan) was released as a prescription-free over-the-counter drug and when the first sumatriptan generics were marketed in Germany. In addition to the beta-blockers metoprolol and propranolol and the calcium antagonist flunarizine two antiepileptic drugs, topiramate and valproic acid, have been rated as first-line prophylactic drugs in Germany. Due to an extensive and successful study program topiramate has been officially approved in Germany.

Topics: Anticonvulsants; Humans; Migraine Disorders; Piperidines; Serotonin Agents; Tryptamines

Currently, direct comparisons between 5-HT(1B/d) receptor agonists are used to assess differences and similarities in antimigraine response. Such comparisons depend on the selected sampling time and do not allow evaluation of entire response profiles. A thorough evaluation of drug properties requires that the time course of the response be taken into account. In this investigation we show the advantages of a model-based approach to compare the efficacy of two triptans (sumatriptan vs. naratriptan).. A Markov model was used to describe the course of a migraine attack over three clinically identified stages. Drug effects were modelled as concentration-dependent increases in transition rates and were parameterised as potency (EC(50)) and maximum effect (E(max)). Parameters were estimated using headache measurements from efficacy studies. Model estimates were then used to compare the pharmacodynamics of the two drugs in a time-independent manner.. Efficacy parameters could be derived, allowing for comparison between compounds. The potency ratio (EC50(suma)/EC50(nara)) for headache relief was 3.3 (0.9, 12). The ratio of maximum effects (Emax(suma)/Emax(nara)) for this endpoint was 0.74 (0.55, 0.97). To interpret these efficacy measures and explore their value for the development of antimigraine drugs, results were evaluated against the reported in vitro potency at 5-HT(1B) and 5-HT(1D) receptors.. Comparison of the effects of two or more drugs based on preset sampling times does not allow proper assessment of the antimigraine properties in vivo. Disease dynamics must be considered to evaluate treatment response adequately and optimise the dosing regimen in migraine.

Topics: Dose-Response Relationship, Drug; Humans; Markov Chains; Migraine Disorders; Models, Biological; Piperidines; Serotonin Receptor Agonists; Sumatriptan; Treatment Outcome; Tryptamines

It has been suggested that triptans achieving higher central nervous system (CNS) levels should have an advantage in efficacy, if central actions are important. Objective.-Our aim was to correlate the efficacy and tolerability results of triptans with their lipophilicity.. Data for response and pain free at 2 hours, recurrence, adverse events (AE), CNS AE, and chest symptoms taken from Ferrari et al's meta-analysis publications for the recommended doses of oral triptans were correlated with their lipophilicity coefficients (logD(pH)7.4 = -2.1 almotriptan < -1.5 sumatriptan < -1.0 zolmitriptan < -0.7 rizatriptan < -0.2 naratriptan < 0.5 eletriptan).. We found no significant correlation between lipophilicity coefficients and any of the analyzed parameters. There was, however, some correlation between lipophilicity and CNS AE (P = .09, r = 0.74) and, to a lesser degree, with a reduction in recurrence rate (r = -0.36). The r values for response and pain free with placebo correction ranged from 0.04 to 0.34, suggesting almost no correlation between lipophilicity and efficacy variables.. According to this analysis, a higher lipophilicity does not seem crucial to improve triptan efficacy. This physico-chemical property, however, correlates with higher CNS AE and, possibly, lower recurrence rates.

Topics: Central Nervous System Diseases; Chemical Phenomena; Chemistry, Physical; Humans; Indoles; Migraine Disorders; Oxazolidinones; Piperidines; Serotonin Receptor Agonists; Statistics as Topic; Sumatriptan; Treatment Outcome; Triazoles; Tryptamines

Activation of vanilloid receptors has commonly been used to facilitate neurogenic inflammation and plasma exudation to model components of the pathogenesis of migraine; however, these studies have been performed mainly in species lacking the emetic reflex. In the present studies, therefore, we used Suncus murinus, a species of insectivore capable of emesis, to investigate if the vanilloid receptor agonist resiniferatoxin is capable of modeling the emesis associated with migraine. Resiniferatoxin (100 nmol/kg, s.c.) induced an emetic response that was antagonized significantly (P<0.05) by ruthenium red (1-3 micromol), (2R-trans)-4-[1-[3,5-bis(trifluromethyl)benzoyl]-2-(phenylmethyl)-4-piperidinyl]-N-(2,6-dimethylphenyl)-1-acetamide (S)-hydroxybutanedioate (R116301; 10-100 micromol/kg), and scopolamine (1 micromol/kg), but not by dihydroergotamine (0.3-3 micromol/kg), sumatriptan (1-10 micromol/kg), methysergide (1-10 micromol/kg), tropanyl 3,5-dichlorobenzoate (MDL72222; 3-30 micromol/kg), ondansetron (0.3-3 micromol/kg), metoclopramide (3-30 micromol/kg), domperidone (3-30 micromol/kg), diphenhydramine (1-10 micromol/kg), or indomethacin (3-30 micromol/kg). The failure of a wide range of representative anti-migraine drugs to reduce retching and vomiting limits the use of this model to identify/investigate novel treatments for the emesis (and nausea) associated with migraine attacks in humans. However, the results provide further evidence for the involvement of a novel vanilloid receptor in resiniferatoxin-induced emesis and implicate both tachykinins and acetylcholine in the pathway(s) activated by resiniferatoxin in S. murinus.

Topics: Animals; Antiemetics; Butanols; Capsaicin; Cyclooxygenase Inhibitors; Dihydroergotamine; Diphenhydramine; Diterpenes; Domperidone; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Humans; Indomethacin; Malates; Methysergide; Metoclopramide; Migraine Disorders; Ondansetron; Piperidines; Ruthenium Red; Scopolamine; Serotonin Antagonists; Serotonin Receptor Agonists; Shrews; Sumatriptan; Time Factors; Tropanes; Vomiting

Ischemic colitis has not been reported in association with naratriptan therapy. We describe the occurrence of ischemic colitis in a patient who was treated with abortive doses of naratriptan for migraine and was also taking long-term oral contraceptives. Concurrent use of naratriptan and oral contraceptives should probably be avoided.

Topics: Adult; Colitis, Ischemic; Contraceptives, Oral; Drug Interactions; Female; Humans; Indoles; Migraine Disorders; Piperidines; Tryptamines

Managed care and other decision makers need sound comparative information to support the formulary selection process and reimbursement decisions for the treatment of migraine. The objective of this study was to compare currently marketed triptan therapies using number-needed-to-treat (NNT) and doses-needed-to-treat (DNT) measures. DNT was further used to derive triptan treatment cost to achieve 100 successfully treated patients such that the cost-effectiveness of each treatment regime could be compared from the payer perspective.. Using published meta-analysis data to categorize patients as treatment success or failure, an NNT and a DNT were derived for each triptan. Treatment success was defined as achieving a 2-hour pain response, sustained through 24 hours postdose. Costs were derived by multiplying DNT by the average wholesale price (AWP) minus 15% for each triptan.. Eletriptan 40 mg had the lowest NNT, with 361 patients needing to be treated in order to have 100 patients achieve clinical benefit; rizatriptan 5 mg had the highest NNT (597 patients). Eletriptan 40 mg required 388 doses to successfully treat 100 patients.the lowest number of doses of the triptans considered; rizatriptan 5 mg required the highest number (662 doses). Eletriptan 40 mg had the lowest total triptan cost of USD 5,630 to successfully treat 100 patients. The highest total triptan cost of treatment was USD 11,136 for naratriptan 2.5 mg.. Eletriptan 40 mg provides the best value in terms of the lowest DNT, assuming an approximately equal AWP discount for each triptan. Eletriptan 40 mg also was found to have the lowest total triptan cost to successfully treat 100 patients. Future research should further explore the utility of DNT in managed care decision making.

Topics: Algorithms; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Costs; Humans; Managed Care Programs; Migraine Disorders; Piperidines; Pyrrolidines; Recurrence; Serotonin Receptor Agonists; Time Factors; Treatment Outcome; Triazoles; Tryptamines

The aim of the study was to predict pain relief of migraine in patients following naratriptan oral (tablet) administration by using uncertainty analysis. The analysis was based on phase I pharmacokinetic naratriptan data, sumatriptan pharmacodynamic data, and naratriptan preclinical (animal) potency information, together with general knowledge as to how migraine affects oral absorption.. A previously developed pharmacokinetic (PK)/pharmacodynamic (PD) model for naratriptan disposition and effect was used. The uncertain parameters in the model, which were associated with absorption and scaling between first-in-class compound sumatriptan and naratriptan, were modeled using fuzzy sets theory. Global sensitivity analysis was then used to investigate the impact of each PK/PD parameter on the responses.. Acknowledging parametric uncertainty did not improve prediction of the probability of pain relief. Global sensitivity analysis demonstrated that predictions were heavily influenced by interindividual variability in pharmacodynamics, as the dose response relationship was relatively insensitive to the pharmacokinetics.. To predict the probability of pain relief following oral (tablet) administration of naratriptan, a simple dose response, instead of the PK/PD model, would have yielded very similar predictions. The naratriptan PK/PD model may be improved by either refining the PD model or better still by specifying the interindividual error by additional data collecting with an improved design.

Topics: Algorithms; Analgesics; Female; Humans; Male; Migraine Disorders; Models, Biological; Piperidines; Serotonin Receptor Agonists; Software; Sumatriptan; Tryptamines; Vasoconstrictor Agents

The triptans are agonists at serotonin (5-HT)1B/1D receptors; however, they are also active at 5-HT1A and 5-HT1F receptors. We conducted this series of experiments to further elucidate the site of action of naratriptan using a well-established animal model of trigeminovascular stimulation. Following electrical stimulation of the superior sagittal sinus of the cat, single cell responses (n=83) were recorded in the trigeminal nucleus caudalis. Most cells (91%) also responded to electrical and mechanical stimulation of cutaneous or mucosal facial receptive fields. The microiontophoretic application of naratriptan resulted in a significant suppression of the response to sagittal sinus stimulation (response suppressed by 47 +/- 4%, P<0.001). The effect of naratriptan was significantly attenuated by application of either the 5-HT(1B/1D) receptor antagonist GR-127935 (P<0.001) or the 5-HT1A antagonist WAY-100635 (P<0.05). The response of single cells to receptive field stimulation was also suppressed by microiontophoretic application of naratriptan, but by only 20 +/- 3%. Intravenous administration of naratriptan resulted in a similar selective suppression of sagittal sinus vs. receptive field responses in trigeminal neurones. These results indicate that naratriptan has a central effect in the trigeminovascular system, selectively inhibiting afferent activity in craniovascular neurones, via both 5-HT(1B/1D) and 5-HT1A receptors.

Topics: Action Potentials; Animals; Cats; Cerebrovascular Circulation; Electric Stimulation; Indoles; Microelectrodes; Migraine Disorders; Neurons; Physical Stimulation; Piperidines; Receptors, Serotonin, 5-HT1; Serotonin Antagonists; Serotonin Receptor Agonists; Trigeminal Caudal Nucleus; Tryptamines

Topics: Acute Disease; Calcitonin Gene-Related Peptide; Calcitonin Gene-Related Peptide Receptor Antagonists; Female; Humans; Male; Migraine Disorders; Piperazines; Piperidines; Quinazolines; Receptors, Calcitonin Gene-Related Peptide

Pooled data from multiple clinical trials can provide information for medical decision-making that typically cannot be derived from a single clinical trial. By increasing the sample size beyond that achievable in a single clinical trial, pooling individual-patient data from multiple trials provides additional statistical power to detect possible effects of study medication, confers the ability to detect rare outcomes, and facilitates evaluation of effects among subsets of patients. Data from pharmaceutical company-sponsored clinical trials lend themselves to data-pooling, meta-analysis, and data mining initiatives. Pharmaceutical company-sponsored clinical trials are arguably among the most rigorously designed and conducted of studies involving human subjects as a result of multidisciplinary collaboration involving clinical, academic and/or governmental investigators as well as the input and review of medical institutional bodies and regulatory authorities. This paper describes the aggregation, validation and initial analysis of data from the sumatriptan/naratriptan aggregate patient (SNAP) database, which to date comprises pooled individual-patient data from 128 clinical trials conducted from 1987 to 1998 with the migraine medications sumatriptan and naratriptan. With an extremely large sample size (>28000 migraineurs, >140000 treated migraine attacks), the SNAP database allows exploration of questions about migraine and the efficacy and safety of migraine medications that cannot be answered in single clinical trials enrolling smaller numbers of patients. Besides providing the adequate sample size to address specific questions, the SNAP database allows for subgroup analyses that are not possible in individual trial analyses due to small sample size. The SNAP database exemplifies how the wealth of data from pharmaceutical company-sponsored clinical trials can be re-used to continue to provide benefit.

Topics: Clinical Trials as Topic; Data Collection; Databases, Factual; Humans; Indoles; Logistic Models; Migraine Disorders; Piperidines; Sumatriptan; Tryptamines

Topics: Drug Administration Schedule; Humans; Indoles; Migraine Disorders; Pain Measurement; Piperidines; Secondary Prevention; Serotonin Receptor Agonists; Treatment Outcome; Tryptamines; Vasoconstrictor Agents

To review the efficacy of naratriptan as preventive treatment in 27 patients with chronic migraine refractory to other commonly used preventive therapies.. The treatment of chronic migraine often poses a major challenge to the clinician. Even when given expert care, patients with chronic migraine may continue to have daily or near-daily headaches.. Clinical records and headache calendars were reviewed of 27 patients fulfilling the following inclusion criteria: (1) aged 18 to 65 years; (2) diagnosis of chronic migraine (formerly transformed migraine), according to the criteria proposed by Silberstein et al; (3) previous failure of at least 4 preventive medications prescribed as part of a management program that included nonpharmacological measures, preventive medication, acute care medication, and detoxification from overused medication; and (4) have used daily naratriptan for no less than 2 consecutive months. The dose of naratriptan prescribed was 2.5 mg twice daily. We considered the following outcomes: (1) frequency of headache, (2) intensity of pain, (3) number of days per month with severe headache, (4) headache index (frequency times intensity), and (5) proportion of patients who reverted to an episodic pattern of pain after 6 months of treatment.. There was a statistically significant reduction in the frequency of headache days 2 months (15.3 days versus 24.1 days at baseline, P<.001), 6 months (9.1 days, P<.001), and 1 year (7.3 days, P<.001) after daily treatment with naratriptan was initiated. There was also a statistically significant reduction in the number of days per month of severe pain at 1 month (5.6 days versus 12.5 days at baseline, P<.01), 2 months (5.7 days, P<.01), 6 months (2.8 days, P<.01), and 1 year (2.6 days, P<.01). Similarly, there was a statistically significant reduction in the headache index at 2 months (33 versus 56.4 at baseline, P<.001), 6 months (19.5, P<.001), and 1 year (17.2, P<.001). Of the 20 patients who continued to use naratriptan daily for at least 6 months, 13 (65%) reverted to an episodic pattern of pain (migraine). At 1 year, 11 (55%) still continued to experience episodic headache, 1 (5%) relapsed to chronic migraine, and 2 (10%) were lost to follow-up. No patients had intolerability to naratriptan during the treatment period, and no one stopped treatment due to adverse events.. Naratriptan may have a role in the preventive treatment of intractable chronic migraine. Prospective, controlled studies should be considered.

Topics: Adolescent; Adult; Female; Humans; Indoles; Male; Middle Aged; Migraine Disorders; Pain, Intractable; Piperidines; Retrospective Studies; Serotonin Receptor Agonists; Tryptamines

The objective of this study was to provide an epidemiological description of naratriptan use in ambulatory medicine. 1695 patients were recruited by 384 primary care physicians and 111 neurologists, and followed for 12 weeks. Physicians had to document the migraine history, and to report symptoms and health care in a structured case report form. Patients were to document each episode of migraine (EM) in a diary. At baseline, 45 p.cent of the patients reported their migraine treatment as unsatisfactory. Ninety-eight percent of included patients were migraineurs according to criteria of the International Headache Society (IHS), including migrainous disorders. Ninety-two percent of naratriptan prescriptions were established in the second intention in patients with migraine, according to the IHS classification, including migrainous disorders. A total of 79 p.cent of patients had complied with the good practices for all EMs. More appropriate health education strategies should target the small group of patients who over-use naratriptan, and patients with aura. However, this study shows that naratriptan tends to be correctly prescribed by physicians, and used by patients with acute migraine.

Topics: Acute Disease; Adult; Ambulatory Care; Female; Follow-Up Studies; Humans; Indoles; Male; Migraine Disorders; Piperidines; Prospective Studies; Tryptamines; Vasoconstrictor Agents

Compound 1a (LY334370), a selective 5-HT(1F) receptor agonist (SSOFRA), inhibited dural inflammation in the neurogenic plasma protein extravasation model of migraine and demonstrated clinical efficacy for the acute treatment of migraine. Although 1a was greater than 100-fold selective over both the 5-HT(1B) and 5-HT(1D) receptors, it exhibited appreciable 5-HT(1A) receptor affinity. Described here is the synthesis and evaluation of a series of pyrrolo[2,3-c]pyridine and pyrrolo[3,2-b]pyridine (2a and 3a) as well as pyrrolo[3,2-d]pyrimidine (4a) analogues of 1a, compounds prepared in an effort to identify SSOFRAs with improved selectivity over other 5-HT(1) receptor subtypes. The pyrrolo[3,2-b]pyridine analogue 3a showed high 5-HT(1F) receptor affinity but offered no improvement in selectivity compared to 1a. However, the C-5 acetamide derivative, 3b, was greater than 100-fold selective over the 5-HT(1A), 5-HT(1B), and 5-HT(1D) receptors. SAR studies of this series determined that alkylamides in particular exhibited high selectivity for the 5-HT(1F) receptor. Replacement at C-5 with other substituents decreased affinity or selectivity. These SAR studies identified SSOFRAs that demonstrated oral activity in the neurogenic plasma protein extravasation model, a model indicative of antimigraine activity.

Topics: Administration, Oral; Animals; Blood Proteins; Bridged Bicyclo Compounds, Heterocyclic; Cell Line; In Vitro Techniques; Migraine Disorders; Piperidines; Polyunsaturated Alkamides; Pyridines; Pyrroles; Rabbits; Radioligand Assay; Receptor, Serotonin, 5-HT1F; Receptors, Serotonin; Saphenous Vein; Serotonin Receptor Agonists; Structure-Activity Relationship; Trigeminal Nerve; Vasoconstriction

The effects of naratriptan, rizatriptan, and sumatriptan on arteriovenous oxygen saturation difference and carotid hemodynamics were compared in the anesthetized pig. Oxygen and carbon dioxide partial pressures in systemic arterial and jugular venous blood as well as hemoglobin oxygen saturation were determined by conventional blood gas analysis. Vehicle (n = 19) or naratriptan, rizatriptan, or sumatriptan (0.63, 2.5, 10, 40, 160, 630, and 2,500 microg/kg i.v.; n = 7/group) were infused cumulatively. In naratriptan-, rizatriptan-, and sumatriptan-treated animals, jugular venous oxygen saturation decreased dose dependently (geometric mean ED50 values of 3.1, 17.9, and 16.0 microg/kg, respectively) concomitantly with increases in carotid vascular resistance. Rizatriptan significantly and dose dependently, from 160 microg/kg, increased PvCO2 (P < 0.05 versus vehicle). Naratriptan and sumatriptan also tended to increase PvCO2 albeit nonstatistically significantly. All three triptans consistently evoked quantitatively similar carotid vasoconstriction, whereas decreases in jugular venous oxygen saturation (VOS) and increases in PvCO2 had different magnitudes and occurred only in around one-half of the animals studied. Maximal variations in PvCO2 were found to correlate highly with those in PvO2 (P = 0.002), but maximal variations in carotid resistance failed to correlate with those in PvCO2 (P = 0.76) or PvO2 (P = 0.28). The results demonstrate that the triptans investigated robustly produced carotid vasoconstriction, but elicited less consistent decreases in VOS and increases in jugular PvCO2, possibly suggestive of distinct mechanisms. Collectively, the data suggest that triptan-induced increases in arteriovenous oxygen saturation difference and carbon dioxide partial pressure in venous blood draining the head are class effects.

Topics: Anesthesia; Animals; Blood Gas Analysis; Hemodynamics; Indoles; Jugular Veins; Male; Migraine Disorders; Oxygen; Piperidines; Sumatriptan; Swine; Triazoles; Tryptamines; Vasoconstriction; Vasoconstrictor Agents

Topics: Administration, Oral; Controlled Clinical Trials as Topic; Delayed-Action Preparations; Female; Headache; Humans; Indoles; Male; Migraine Disorders; Oxazolidinones; Piperidines; Placebos; Pyrrolidines; Serotonin Receptor Agonists; Sumatriptan; Time Factors; Tryptamines

Topics: Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Humans; Indoles; Migraine Disorders; Oxazolidinones; Piperidines; Pyrrolidines; Receptors, Serotonin, 5-HT1; Serotonin Receptor Agonists; Sumatriptan; Triazoles; Tryptamines

Many migraine patients are unable to function normally during a migraine attack. Assessments of treatment efficacy have tended to focus on migraine symptoms, rather than looking at functional impact. This study compared the efficacy of different oral triptans for restoring normal function in migraine sufferers.. Retrospective subgroup analysis of data from five randomized, placebo-controlled, double-blind clinical trials in which oral rizatriptan was directly compared with oral sumatriptan 100 mg (772 attacks), 50 mg (2,227 attacks), and 25 mg (1,182 attacks), naratriptan 2.5 mg (413 attacks), and zolmitriptan 2.5 mg (578 attacks) for the acute treatment of a moderate or severe migraine attack. Functional disability was evaluated by patients on a 4-grade scale ('normal', 'mild impairment', 'severe impairment', 'requires bedrest') at baseline and at 0.5, 1, 1.5, 2, 3 and 4 h after dosing. This analysis looked at the percentage of patients who had normal functional ability at 2 h, the last time point before escape medications were allowed, in the subgroup of patients who had some level of disability at baseline.. Most patients in each trial and treatment group had some level of disability at baseline (range = 94-100%). At 2 h, more patients on rizatriptan 10 mg were able to function normally compared with sumatriptan 100 mg (39 vs. 32%, odds ratio = 1.4, p = 0.021), sumatriptan 50 mg (47 vs. 42%, odds ratio = 1.2, p = 0.033), sumatriptan 25 mg (48 vs. 36%, odds ratio = 1.7, p < 0.001), naratriptan 2.5 mg (39 vs. 22%, odds ratio = 2.5, p < 0.001), and zolmitriptan 2.5 mg (45 vs. 36%, odds ratio = 1.6, p = 0.008).. In direct head-to-head comparative clinical trials, oral rizatriptan 10 mg enabled more migraine sufferers to function normally at 2 h after dosing than oral sumatriptan, naratriptan, and zolmitriptan.

Topics: Administration, Oral; Adolescent; Adult; Aged; Female; Humans; Indoles; Male; Middle Aged; Migraine Disorders; Oxazolidinones; Piperidines; Randomized Controlled Trials as Topic; Retrospective Studies; Serotonin Receptor Agonists; Sumatriptan; Treatment Outcome; Triazoles; Tryptamines

Topics: Colitis, Ischemic; Female; Humans; Indoles; Middle Aged; Migraine Disorders; Piperidines; Serotonin Receptor Agonists; Tryptamines; Vasoconstrictor Agents

To compare patient self-reported tablet consumption of rizatriptan 10 mg per attack (24 hours) with that of sumatriptan 50 mg, zolmitriptan 2.5 mg, and naratriptan 2.5 mg on an unselected, prescription-based, Spanish migraine population.. One hundred twenty community pharmacies recruited patients with migraine, who used their pharmacies, to fill a triptan prescription. In diaries, patients recorded baseline pain intensity and the number of triptan tablets and additional medication taken per attack. Patients treated a maximum of three attacks. Analysis of variance or the Student t test and chi-square or Fisher exact tests were used for univariate comparisons. Hochberg corrections were used for multiple-group comparisons. A generalized estimating equation method was used to correct for within-subject correlation. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were calculated.. Two hundred thirty-one patients (84% women) treated 589 evaluable migraine attacks (sumatriptan, n = 135; naratriptan, n = 90; zolmitriptan, n = 149; rizatriptan, n = 149). Triptan tablet consumption per attack (mean +/- SD) for rizatriptan (1.24 +/- 0.56) was significantly lower than that of sumatriptan (1.75 +/- 1.2; P< .05), zolmitriptan (1.61 +/- 0.86; P < .05), or naratriptan (1.46 +/- 0.62; P= .05). The average number of triptan tablets taken and additional medication use increased according to baseline pain severity. More attacks were treated with one tablet of rizatriptan (81.2%) than with one tablet of sumatriptan (51.9%), zolmitriptan (55.7%), or naratriptan (60%). The probability of using more than one triptan tablet per attack (24 hours) was more than three times greater for sumatriptan (adjusted OR = 3.71; CI, 2.05 to 6.7; P = .001) and zolmitriptan (adjusted OR = 3.32; CI, 1.82 to 6.17; P = .001), and more than two times greater for naratriptan (adjusted OR = 2.66; CI, 1.36 to 5.21; P =.004) than for rizatriptan.. Rizatriptan was associated with significantly lower triptan tablet use and additional medication use per attack than the other triptans. Additional randomized studies are needed to confirm the conclusions of this study.

Topics: Female; Humans; Indoles; Male; Migraine Disorders; Oxazolidinones; Piperidines; Prospective Studies; Serotonin Receptor Agonists; Sumatriptan; Tablets; Triazoles; Tryptamines

Modulatory effects of the new antimigraine drug naratriptan, a 5-HT(1)-receptor-agonist, on neurons of the nucleus raphé magnus were examined in rat by extracellular recordings. In the nucleus raphé magnus neuronal activity decreased in on-cells and increased in off-cells after intravenous administration of naratriptan. The modulatory effects of naratriptan were similar to the well-known effects of morphine on neurons in the nucleus raphé magnus. The results of this study suggest central actions of naratriptan and may point to an involvement of the endogenous pain control system in the antinociceptive effects of the 5-HT(1)-receptor-agonist.

Topics: Animals; Indoles; Male; Migraine Disorders; Neurons; Piperidines; Raphe Nuclei; Rats; Rats, Wistar; Serotonin Receptor Agonists; Tryptamines

To evaluate the cost-effectiveness of naratriptan for the treatment of migraine in Canada.. The substantial disability brought on by migraine, coupled with the high prevalence of this disorder, leads to substantial costs. Naratriptan is a newly developed triptan shown to be effective in the treatment of migraine.. Monte Carlo modeling techniques were used to simulate the experience of Canadian migraineurs over the course of 1 year. Data from a multinational study comparing oral naratriptan 2.5 mg to customary therapies were used in the cost-effectiveness analysis.. Naratriptan leads to an annual reduction in symptom duration of 225 hours compared to customary therapy not including other triptans. Reductions in lost productivity yield savings of Can $390 (1998 Canadian dollars) relative to customary therapy, which exceed the increase in drug costs resulting in overall savings of Can $109 per year.. The use of naratriptan in the treatment of migraine is an economically attractive option, leading to savings in overall costs. Increases in drug costs seem acceptable in light of reductions in symptom duration.

Topics: Canada; Cost-Benefit Analysis; Humans; Indoles; Migraine Disorders; Piperidines; Serotonin Receptor Agonists; Tryptamines; Vasoconstrictor Agents

To compare the effects of oral rizatriptan, sumatriptan, naratriptan, and zolmitriptan on the relief and emergence of nausea during a migraine attack.. Data from five randomized, placebo-controlled, double-blind clinical trials in which oral rizatriptan 10 mg was directly compared with oral sumatriptan 100 mg (N = 772), 50 mg (N = 1168), 25 mg (N = 1180), naratriptan 2.5 mg (N = 406), or zolmitriptan 2.5 mg (N = 571) for the acute treatment of a migraine attack were retrospectively analyzed. Migraine was diagnosed according to International Headache Society criteria. Presence or absence of nausea was recorded at baseline and at 0.5, 1, 1.5, and 2 hours after dosing. The end points analyzed were relief of nausea in those who had it at baseline and emergence of nausea in those who were free of it at baseline. Treatments were compared using odds ratios estimated from logistic regression models at 2 hours, and averaged odds ratios for the first 2 hours posttreatment.. Approximately 60% of patients in each treatment group had nausea at baseline. In those patients with nausea at baseline, significantly more patients treated with rizatriptan 10 mg were free of nausea at 2 hours compared with sumatriptan 100 mg (66% versus 58%, P =.043), sumatriptan 50 mg (68% versus 57%, P =.010), sumatriptan 25 mg (68% versus 59%, P =.017), and naratriptan 2.5 mg (59% versus 45%, P =.014). Averaging over the four posttreatment time points in the first 2 hours, significantly more patients treated with rizatriptan 10 mg were free of nausea compared with sumatriptan 100 mg (P =.004), sumatriptan 50 mg (P =.001), and naratriptan 2.5 mg (P =.015). No significant differences in nausea relief were seen between rizatriptan 10 mg and zolmitriptan 2.5 mg, either at 2 hours (65% versus 61%, P =.210) or over the first 2 hours (P =.781). Rates of treatment-emergent nausea at 2 hours ranged from 11% to 18% with placebo, from 5% to 13% with rizatriptan 10 mg, and from 10% to 20% with other comparator triptans.. Oral rizatriptan 10 mg was more effective than oral sumatriptan and naratriptan at eliminating nausea within 2 hours in patients who had it at baseline. Rates of emergent nausea in patients who were free of it at baseline were low, and no consistent differences were observed between active treatments.

Topics: Administration, Oral; Adult; Double-Blind Method; Humans; Indoles; Migraine Disorders; Nausea; Oxazolidinones; Piperidines; Randomized Controlled Trials as Topic; Serotonin Receptor Agonists; Sumatriptan; Triazoles; Tryptamines; Vasoconstrictor Agents

Topics: Contraindications; Coronary Circulation; Dose-Response Relationship, Drug; Humans; Indoles; Injections, Subcutaneous; Migraine Disorders; Piperidines; Product Surveillance, Postmarketing; Risk Factors; Serotonin Receptor Agonists; Sumatriptan; Tryptamines; Vasoconstrictor Agents

Topics: Headache Disorders; Humans; Indoles; Migraine Disorders; Piperidines; Primary Health Care; Serotonin Receptor Agonists; Sumatriptan; Treatment Outcome; Tryptamines; Vasoconstrictor Agents

Topics: Administration, Oral; Biological Availability; Clinical Trials as Topic; Dose-Response Relationship, Drug; Humans; Indoles; Migraine Disorders; Piperidines; Serotonin Receptor Agonists; Structure-Activity Relationship; Sumatriptan; Treatment Outcome; Tryptamines; Vasoconstrictor Agents

Four drugs in the triptan class are now available for the treatment of acute migraine--sumatriptan, rizatriptan, naratriptan, and zolmitriptan. For clinicians prescribing these drugs, data on the comparative advantages and disadvantages of each medication can aid in drug selection. For example, in 2 recently conducted clinical trials, rizatriptan was found to have several advantages over naratriptan and zolmitriptan. Compared with both drugs, rizatriptan provided more rapid relief of headache pain and associated nausea, and allowed patients to return to normal activities more quickly. These are important advantages for patients, particularly when migraine affects their ability to function on the job or at home.

Topics: Adolescent; Adult; Aged; Female; Humans; Male; Middle Aged; Migraine Disorders; Oxazolidinones; Piperidines; Serotonin Receptor Agonists; Time Factors; Treatment Outcome; Triazoles; Tryptamines; Vasoconstrictor Agents; Young Adult

Development of a rapid, sensitive and selective method for the determination of antimigraine drugs from human serum is essential for understanding the pharmacokinetics of these drugs when administered concurrently. Solid phase extraction (SPE) using Oasis HLB was used to extract the drugs (sumatriptan, naratriptan, zolmitriptan and rizatriptan) and the internal standard bufotenine from serum. A method based on liquid chromatography/tandem mass spectrometry (LC/MS/MS) was developed and validated to simultaneously quantitate these antimigraine drugs from human serum. The precursor and major product ions of the analytes were monitored on a triple quadrupole mass spectrometer with positive ion electrospray ionization (ESI) in the multiple reaction monitoring (MRM) mode. The base peak in all the analytes is formed by alpha cleavage associated with protonation of the secondary amine. Mechanisms for the formation of the collision-induced dissociation products of these antimigraine compounds are proposed. Linear calibration curves were generated from 1-100 ng/mL with all coefficients of determination greater than 0.99. The inter- and intraday precision (%RSD) were less than 9.3% and accuracy (%error) was less than 9.8% for all components. The limits of detection (LOD) for the method were 250 pg/mL for sumatriptan and 100 pg/mL for the remaining analytes based on a signal-to-noise ratio of 3.

Topics: Bufotenin; Chromatography, High Pressure Liquid; Humans; Indoles; Mass Spectrometry; Migraine Disorders; Molecular Structure; Oxazoles; Oxazolidinones; Piperidines; Sensitivity and Specificity; Serotonin Receptor Agonists; Sumatriptan; Triazoles; Tryptamines; Vasoconstrictor Agents

To evaluate clinical parameters that may affect the incidence of headache recurrence or the time to headache recurrence, or both, in migraineurs treated with naratriptan, 2.5-mg tablets.. The incidence of headache recurrence within 24 hours of treatment with naratriptan, 2.5-mg tablets (17%-28%), is lower than that reported for other currently available selective serotonin agonists. Identifying clinical parameters that influence headache recurrence may further reduce the incidence of headache recurrence or prolong the time to recurrence, or both, for naratriptan-treated patients.. We examined the effects of three clinical parameters (predose pain severity, headache duration prior to treatment, and relief status 4 hours post dose) on the incidence of and time to headache recurrence across four placebo-controlled naratriptan clinical trials. The impact of these parameters on headache recurrence was examined individually and in combination.. Predose pain severity had no effect on the incidence of headache recurrence (overall 23%; moderate 22%, severe 23%). The median time to recurrence was longer for patients with moderate pain before treatment compared with patients with severe pain before treatment (14.5 hours versus 9.3 hours, respectively). Overall time to headache recurrence was 11.8 hours. Patients with headache recurrence reported a longer time until they treated the headache compared with patients without headache recurrence (median, 145 minutes versus 97.5 minutes). Patients who treated headache pain within 3 hours of onset had a lower incidence of headache recurrence (20%) than patients who treated their headache more than 3 hours after onset (28%). Patients with no pain 4 hours post dose had a lower incidence of and a longer time to headache recurrence compared with patients with mild pain 4 hours post dose (17% versus 32%; median, 17.8 hours versus 8.1 hours, respectively). The interaction of all three clinical parameters was significant in predicting headache recurrence.. The overall incidence of headache recurrence is low after naratriptan, 2.5 mg, compared with other currently available selective serotonin agonists. Predose pain severity, time to treatment, and 4-hour relief status appear related to the incidence of or time to headache recurrence, or both. Treating less severe migraine attacks, treating earlier within an attack, and obtaining complete relief post dose may enhance the low incidence of headache recurrence and achieve longer times to recurrence with naratriptan, 2.5 mg.

Topics: Acute Disease; Adult; Aged; Female; Humans; Indoles; Male; Middle Aged; Migraine Disorders; Piperidines; Recurrence; Retrospective Studies; Serotonin Receptor Agonists; Tryptamines

Topics: Humans; Indoles; Migraine Disorders; Piperidines; Serotonin Receptor Agonists; Tryptamines; Vasoconstrictor Agents

Topics: Absenteeism; Adult; Cost-Benefit Analysis; Efficiency; Female; Humans; Indoles; Injections, Subcutaneous; Male; Migraine Disorders; Oxazoles; Oxazolidinones; Piperidines; Randomized Controlled Trials as Topic; Self Administration; Serotonin Receptor Agonists; Sumatriptan; Treatment Outcome; Triazoles; Tryptamines; Workplace

Topics: Humans; Indoles; Migraine Disorders; Piperidines; Serotonin Receptor Agonists; Tryptamines; Vasoconstrictor Agents

This open-label study was conducted to evaluate the tolerability and efficacy of the 5HT1 agonist naratriptan with repeated use in the acute treatment of migraine attacks for 1 year. Four hundred and seventeen (417) migraine patients treated 15,301 migraine attacks over the course of the study.. The results show that 84% of attacks treated with a single 2.5 mg dose of naratriptan were not associated with the occurrence of an adverse event. The percentage of attacks associated with an adverse event did not increase with number of doses used to treat a given attack (1 vs. 2) or duration of use (0-6 months vs. > 6-12 months). The only adverse events experienced in > 2% of attacks throughout the 1-year study were nausea (3% of attacks), hyposalivation (2% of attacks), and drowsiness/sleepiness (2% of attacks). Headache relief 4 h post-dose was reported in a median 70% of moderate or severe attacks and a median 86% of mild attacks treated with naratriptan tablets 2.5 mg. The percentages of patients reporting headache relief did not diminish as a function of increased duration of treatment (0-6 months vs. > 6-12 months) or frequency of use (for > 36 vs. < 36 attacks). The mean number of tablets taken per attack was 1.2. A second naratriptan 2.5 mg tablet was taken for headache recurrence in a mean 16% (median 8%) of attacks.. The results of this study demonstrate that naratriptan tablets 2.5 mg taken for acute migraine attacks over a 1-year period are well-tolerated and effective.

Topics: Adult; Dose-Response Relationship, Drug; Female; Humans; Indoles; Male; Middle Aged; Migraine Disorders; Patient Satisfaction; Piperidines; Retreatment; Salvage Therapy; Serotonin Receptor Agonists; Tablets; Time Factors; Tryptamines

1997, sumatriptan-treated migraineurs had significantly higher depression PCRs (22.3%) compared with non-triptan users (19.3%), a difference of 6.4% (95% confidence interval (CI) 4.6-8.4%, P < 0.001). In the year (April 1997 to March 1998) following the launch of the TELs, depression PCRs were significantly higher among patients using these compounds compared with sumatriptan-treated patients (5.1%, CI 1.8-12.0%, P < 0.05). However, after taking account of prior depression (odds ratio (OR) 6.45, 95% CI 3.63-11.43), TELs were not significantly associated with depression (OR 0.27, 95% CI 0.03-2.13). Furthermore, rates of newly diagnosed depression after treatment were similar in the two triptan groups (sumatriptan 4.2%; TELs 3.9%). Although, the TELs are being prescribed to patients with higher pre-existing rates of depression, they are not associated with subsequently increased consulting for depressive illness compared with patients taking sumatriptan. This study highlights the potential to use GPRD to test targeted hypotheses exploring pharmacovigilance issues for patients using new medicines.

Topics: Cohort Studies; Depression; Female; Humans; Indoles; Male; Migraine Disorders; Oxazolidinones; Piperidines; Referral and Consultation; Regression Analysis; Serotonin Receptor Agonists; Sumatriptan; Tryptamines

Topics: Adult; Female; Headache; Humans; Indoles; Middle Aged; Migraine Disorders; Oxazoles; Oxazolidinones; Piperidines; Serotonin Receptor Agonists; Tryptamines

Topics: Clinical Trials as Topic; Humans; Indoles; Migraine Disorders; Piperidines; Tryptamines; Vasoconstrictor Agents

Naratriptan, launched by Glaxo Wellcome under the trade name Naramig, is a potent and selective agonist of 5-HT1B and 5-HT1D vascular receptors. Available as tablets of 2.5 mg, it is indicated in the acute treatment of migraine, with or without aura. A single oral dose of 2.5 mg naratriptan is characterized by a satisfactory clinical efficacy (already significant after one hour, maximum after 4 hours and persisting during 24 hours), a reduction by half of the recurrence of the migraine crisis within the 24 hours and an excellent tolerance profile.

Topics: Drug Administration Schedule; Humans; Indoles; Migraine Disorders; Piperidines; Serotonin Receptor Agonists; Tryptamines

Topics: Humans; Indoles; Migraine Disorders; Piperidines; Receptor, Serotonin, 5-HT1B; Receptor, Serotonin, 5-HT1D; Receptors, Serotonin; Risk Factors; Serotonin Receptor Agonists; Sumatriptan; Tryptamines; Vasoconstrictor Agents

A series of 4-hydroxy-1-[3-(5-(1,2,4-triazol-4-yl)-1H-indol-3-yl)propyl] piperidines was investigated as potential selective h5-HT1D agonists for the treatment of migraine. The 4-[(N-benzyl-N-methyl)amino]methyl analog 12a was found to be a full agonist at the h5-HT1D receptor with good binding selectivity over the h5-HT1B receptor.

Topics: Animals; CHO Cells; Cricetinae; Humans; Migraine Disorders; Piperidines; Receptor, Serotonin, 5-HT1D; Receptors, Serotonin; Serotonin Receptor Agonists

Topics: Acute Disease; Clinical Trials as Topic; Humans; Indoles; Migraine Disorders; Oxazoles; Oxazolidinones; Piperidines; Serotonin Receptor Agonists; Sumatriptan; Tryptamines

Topics: Drug Approval; Humans; Indoles; Migraine Disorders; Piperidines; Serotonin Receptor Agonists; Tryptamines; United States; United States Food and Drug Administration

This open-label study was conducted to examine the long-term tolerability and efficacy of the novel 5HT1 agonist naratriptan tablets 2.5 mg used to treat all migraine attacks for 6 months. Patients could reduce the dose to 1 mg in the event of intolerable adverse events. The results demonstrate that the majority (median 83%) of attacks treated with naratriptan tablets 2.5 mg were not associated with an adverse event. Among attacks treated with naratriptan tablets 2.5 mg (+ optional 2.5 mg for headache recurrence), the most frequently reported adverse event was nausea (4% of attacks after a single naratriptan dose). Both the overall incidence of adverse events and the incidences of specific adverse events were no higher during months 4-6 of treatment compared with months 1-3. Only 5 of 414 patients elected to reduce their naratriptan dose to 1 mg. Headache relief 4 h postdose was reported in a mean of 68% of 6770 moderate or severe migraine attacks treated with naratriptan tablets 2.5 mg. The median number of naratriptan tablets used per attack was 1.0 (mean 1.25); patients treated only a median 7% of attacks (mean 13%) with a 2nd naratriptan tablet for headache recurrence. Patients rated naratriptan tablets as good or excellent in 61% of 7566 treated attacks. In summary, the data from this study demonstrate that naratriptan tablets 2.5 mg were very well tolerated and effective for the acute treatment of migraine for 6 months in a situation closely resembling actual clinical use.

Topics: Adolescent; Adult; Aged; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Indoles; Long-Term Care; Male; Middle Aged; Migraine Disorders; Piperidines; Serotonin Receptor Agonists; Treatment Outcome; Tryptamines; Vasoconstrictor Agents

The antimigraine drugs ergotamine and sumatriptan may cause angina-like symptoms, possibly resulting from coronary artery constriction. We compared the coronary vasoconstrictor potential of a number of current and prospective antimigraine drugs (ergotamine, dihydroergotamine, methysergide and its metabolite methylergometrine, sumatriptan, naratriptan, zolmitriptan, rizatriptan, avitriptan).. Concentration-response curves to the antimigraine drugs were constructed in human isolated coronary artery segments to obtain the maximum contractile response (Emax) and the concentration eliciting 50% of Emax (EC50). The EC50 values were related to maximum plasma concentrations (Cmax) reported in patients, obtaining Cmax/EC50 ratios as an index of coronary vasoconstriction occurring in the clinical setting. Furthermore, we studied the duration of contractile responses after washout of the acutely acting antimigraine drugs to assess their disappearance from the receptor biophase. Compared with sumatriptan, all drugs were more potent (lower EC50 values) in contracting the coronary artery but had similar efficacies (Emax <25% of K+-induced contraction). The Cmax of avitriptan was 7- to 11-fold higher than its EC50 value, whereas those of the other drugs were <40% of their respective EC50 values. The contractile responses to ergotamine and dihydroergotamine persisted even after repeated washings, but those to the other drugs declined rapidly after washing.. All current and prospective antimigraine drugs contract the human coronary artery in vitro, but in view of low efficacy, these drugs are unlikely to cause myocardial ischemia at therapeutic plasma concentrations in healthy subjects. In patients with coronary artery disease, however, these drugs must remain contraindicated. The sustained contraction by ergotamine and dihydroergotamine seems to be an important disadvantage compared with sumatriptan-like drugs.

Topics: Adolescent; Adult; Aged; Angina Pectoris; Child; Coronary Vessels; Dihydroergotamine; Ergotamine; Female; Humans; In Vitro Techniques; Indoles; Male; Methysergide; Middle Aged; Migraine Disorders; Piperidines; Sulfonamides; Sumatriptan; Triazoles; Tryptamines; Vasoconstrictor Agents

Topics: Administration, Oral; Adult; Contraindications; Female; Humans; Indoles; Migraine Disorders; Patient Selection; Piperidines; Serotonin Receptor Agonists; Sumatriptan; Time Factors; Tryptamines

Topics: Adrenergic beta-Antagonists; Amitriptyline; Anti-Inflammatory Agents, Non-Steroidal; Antidepressive Agents, Tricyclic; Calcium Channel Blockers; Dihydroergotamine; Drug Interactions; Ergotamine; Humans; Indoles; Methysergide; Migraine Disorders; Naproxen; Oxazoles; Oxazolidinones; Piperidines; Propranolol; Selective Serotonin Reuptake Inhibitors; Serotonin Receptor Agonists; Sumatriptan; Time Factors; Timolol; Triazoles; Tryptamines; Valproic Acid; Vasoconstrictor Agents

One of the outstanding therapeutic revolutions of this last decade has been the introduction of selective serotonin agonists in the acute treatment of migraine. After sumatriptan, introduced in Belgium in 1992, other "triptans" are emerging. The efficacy and the pharmacoeconomic profile of zolmitriptan, the second "triptan" now available in Belgium, are reviewed and the arrival of a third triptan, naratriptan is announced.

Topics: Chemistry, Pharmaceutical; Humans; Indoles; Migraine Disorders; Oxazoles; Oxazolidinones; Piperidines; Serotonin Receptor Agonists; Sumatriptan; Tryptamines

LY303870 is a competitive, high affinity NK-1 receptor antagonist. It was tested in the trigeminal stimulation-induced neurogenic dural inflammation model of migraine. The neurogenic inflammation theory of migraine pain proposes that substance P, acting through NK-1 receptors, causes dural inflammation which enhances migraine pain. LY303870 administration potently inhibited neurogenic dural inflammation as measured by plasma protein extravasation caused by electrical stimulation of the trigeminal ganglion in guinea pigs. It was active in this model when administered via intravenous, oral or inhalation routes. LY306155, the enantiomer of LY303870 with lower affinity for the NK-1 receptor, was much less potent than LY303870 in this model. LY303870, at oral doses of 1, 10 and 100 microg/kg, produced a long, dose-dependent inhibition of dural inflammation, demonstrating a suitable duration of action for a potential use in acute migraine and migraine prophylaxis.

Topics: Animals; Disease Models, Animal; Dose-Response Relationship, Drug; Dura Mater; Electric Stimulation; Guinea Pigs; Indoles; Male; Migraine Disorders; Neurokinin-1 Receptor Antagonists; Piperidines; Stereoisomerism; Sumatriptan

The actions of several serotonergic ligands in use or under development for the treatment of migraine headaches were examined at recombinant human 5-HT1A receptors stably expressed in Chinese Hamster Ovary cells. Affinities (K(i)s) at this site were determined in competition binding experiments with [3H]-8-OH-DPAT ([3H](+/-)8-hydroxy-N,N-dipropylaminotetralin), whilst agonist efficacy was measured by stimulation of [35S]-GTP gamma S (guanylyl-5'-[gamma[35S]thio]-triphosphate) binding. Of the prophylactic antimigraine drugs tested, methysergide and lisuride behaved as efficacious agonists (Emax > or = 90% relative to 5-HT) whereas pitozifen and (-)propranolol acted as a partial agonist (60%) and an antagonist, respectively. This suggests that there is no correlation between agonism at 5-HT1A receptors and prophylactic antimigraine action. In contrast, serotonin, dihydroergotamine, sumatriptan, naratriptan and alniditan, which are effective in acute interruption of migraine attacks, each displayed high efficacy (Emax = 100, 100, 92.6, 79.3, 79.1% respectively) and marked affinity (Ki = 18.7, 0.6, 127, 26.4 and 3.0 nM respectively) at 5-HT1A receptors. EC50 values for agonist stimulation of [35S]-GTP gamma S binding correlated with respective Ki values at 5-HT1A receptors (r = 0.93) and the stimulation of [35S]-GTP gamma S binding by these compounds was antagonised by the selective 5-HT1A antagonist WAY 100,635 (N-{2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl}-N-(2-pyridinyl) cyclo-hexanecarboxamide; 100 nM). These data suggest that agonism at 5-HT1A receptors may be involved in some actions of drugs used in acute antimigraine therapy. In comparison with the above compounds, novel ligands targeted at 5-HT1B/1D receptors, such as GR125,743 (N-[4-methoxy-3-(4-methyl-piperazin-1-yl)phenyl] -3-methyl-4-(4-pyridyl)benzamide) and GR 127,935 (N-[4-methoxy-3-(4-methylpiperazin-1-yl)-phenyl]-2'-methyl-4'-(5-m ethyl-1, 2,4-oxadiazol-3-yl)-biphenyl-4-carboxamide), only weakly activated [35S]-GTP gamma S binding (32.4 and 32.1% efficacy) and displayed moderate affinity at 5-HT1A receptors (Kis 53.1 and 49.8 nM) suggesting that they constitute useful tools to differentiate 5-HT1A and 5-HT1B/1D receptor-mediated actions. In conclusion, the present data indicates that several antimigraine agents exhibit marked 5-HT1A receptor activity and that although this is unlikely to be important for prophylactic action it may be relevant to the ancilliary properties of drugs used for a

Topics: 8-Hydroxy-2-(di-n-propylamino)tetralin; Animals; Benzopyrans; Binding, Competitive; Cell Membrane; Cricetinae; Dihydroergotamine; Guanosine 5'-O-(3-Thiotriphosphate); Guinea Pigs; Humans; In Vitro Techniques; Indoles; Lisuride; Methysergide; Migraine Disorders; Piperazines; Piperidines; Pizotyline; Propranolol; Propylamines; Protein Binding; Pyridines; Pyrimidines; Receptors, Serotonin; Receptors, Serotonin, 5-HT1; Recombinant Proteins; Serotonin; Serotonin Antagonists; Serotonin Receptor Agonists; Sumatriptan; Tryptamines

The preparation of a series of N-heteroarylpiperidine ether-based human NK1 antagonists is described. Two of the compounds 3-[-(2S,3S)-3-(((3,5-bis(trifluoromethyl)phenyl)methyl)oxy)- 2-phenylpiperidino}methyl]-1,2,4-triazole (11) and 5-[¿(2S,3S)-3-(((3,5-bis(trifluoromethyl)-phenyl)methyl)oxy)-2- phenylpiperidino}methyl]-3-oxo-1,2,4-triazolone (12)), in particular, are orally bioavailable and exhibited significant improvements in potency, both in vitro and in vivo, over the lead (carboxamidomethyl)piperidine ether 1. Rat liver microsome studies on a selected number of compounds from this series show the triazolone heterocycle to be considerably more stable than the others. Furthermore, both 11 and 12 have been profiled in a number of assays that may be predictive of the clinical utility of substance P antagonists.

Topics: Animals; Biological Availability; Drug Stability; Ferrets; Guinea Pigs; Humans; Inflammation; Macaca mulatta; Male; Microsomes, Liver; Migraine Disorders; Neurokinin-1 Receptor Antagonists; Piperidines; Rats; Receptors, Neurokinin-1; Triazoles; Vomiting

Topics: Analgesics; Animals; Binding, Competitive; Brain; Male; Migraine Disorders; Piperidines; Pizotyline; Rats; Rats, Inbred Strains; Receptors, Serotonin; Serotonin; Serotonin Antagonists; Thiophenes

Pipethiadene, a prophylactic of vasomotoric headaches of the series of 4,9-dihydrothieno(2,3-c)-2-benzothiepine derivatives, shows a peripheralpharmacological profile of an antiallergic agent. The experiments in rats showed a high antianaphylactic effect of pipethiadene in the passive cutaneous anaphylaxis (PCA) test. Pipethiadene also exerted intensive antianaphylactoid action in rats on the liberator of histamine, compound 48/80, on dextran, and in the use of a combination of ovalbumin with indomethacin. In comparative pharmacological experiments with pizotifen and cyproheptadine an attempt was made to estimate the relative role of histamine and 5-hydroxytryptamine 5-HT) mediators in the employed experimental procedures in rats.

Topics: Anaphylaxis; Animals; Cyproheptadine; Female; Guinea Pigs; Mice; Migraine Disorders; Passive Cutaneous Anaphylaxis; Piperidines; Pizotyline; Rats

The characteristics of warning symptoms preceding the migraine headache attack in 49 patients with complete migraine are described. These symptoms are divided into non-evolutive and evolutive warning symptoms, based on specific characteristics of each. Non-evolutive symptoms precede the attack by 8 to 48 h in 88% of our patients and have a constant and modest intensity. Evolutive warning symptoms appear within a few minutes up to 6 h before the attack. These symptoms become more and more pronounced towards the onset of the headache. There was no striking similarity between symptoms during the attack and the warning symptoms. In a number of patients with complete migraine, migraine attacks can be prevented by taking domperidone, a peripheral dopamine antagonist, at the time of the non-evolutive warning symptoms. These data suggest that the mechanism leading to a migraine attack can be operative 8-48 h before the headache begins and is possibly dopaminergically mediated.

Topics: Adolescent; Adult; Aged; Cisapride; Domperidone; Female; Humans; Male; Middle Aged; Migraine Disorders; Piperidines

The prophylactic effect of a 5-HT uptake inhibitor, femoxetine, was compared with that of propranolol in a double-blind crossover study of 6-months duration. 29 patients commenced the experiment. 3 subjects withdrew because of side effects and 2 because the program was inconvenient for them. In the 24 patients who continued the study to the end, the periods of propranolol (administered 160 mg daily) and of femoxetine (given 400 mg daily) differed significantly from each other with respect to the attack frequency and headache index. A significant reduction in the use of medication relieving attacks was observed during the propranolol treatment as compared with the pre-treatment period. The study showed that partial depletion of thrombocyte 5-HT uptake inhibitor did not lead to a marked improvement in headache, contrary to what might be expected on the grounds of the 5-HT hypothesis of migraine.

Topics: Adult; Anti-Inflammatory Agents, Non-Steroidal; Double-Blind Method; Female; Humans; Male; Middle Aged; Migraine Disorders; Piperidines; Propranolol; Serotonin Antagonists; Time Factors

Reports have indicated that patients with migraine have abnormalities in platelet function and in the metabolism of vasoactive monoamines. On the basis of these findings, a number of compounds with a stabilizing effect on the level of free vasoactive monoamines in plasma or with anti-platelet effects have been evaluated with regard to their prophylactic effect in migraine. Femoxetine, a new phenylpiperidine derivative and a potent selective serotonin uptake inhibitor, has been suggested as a useful prophylactic drug in migraine. The present studies were designed to evaluate platelet function and blood serotonin levels in patients with migraine before and during femoxetine treatment. During the treatment of 11 patients with migraine with 300 mg femoxetine daily, blood serotonin decreased from 0.17 +/- 0.06 microgram/ml (mean +/- SD) to 0.06 +/- 0.02 microgram/ml. In 8 patients treated with 300 mg femoxetine daily for 12 weeks, 14C-serotonin uptake into platelets in vitro was reduced significantly. Unlike most drugs used in migraine prophylaxis, femoxetine did not influence platelet aggregation in vitro. The demonstration of a certain prophylactic effect of femoxetine in some patients lends support to theories of a serotonin involvement in the pathogenesis of migraine. It does not, however, exclude the possibility of a platelet abnormality as the primary cause of migraine. A hypothesis combining the 2 theories is put forward.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Blood Platelets; Female; Humans; Middle Aged; Migraine Disorders; Piperidines; Platelet Function Tests; Serotonin

Topics: Adult; Aged; Anthracenes; Female; Humans; Male; Middle Aged; Migraine Disorders; Piperidines

Topics: Humans; Migraine Disorders; Piperidines; Tranquilizing Agents

Topics: Adult; Benzocycloheptenes; Female; Histamine H1 Antagonists; Humans; Male; Migraine Disorders; Piperidines; Serotonin Antagonists; Thiophenes

Topics: Administration, Oral; Adult; Benzocycloheptenes; Facial Neuralgia; Female; Histamine; Humans; Male; Middle Aged; Migraine Disorders; Piperidines; Sex Factors; Thiophenes

Topics: Adult; Aged; Benzocycloheptenes; Drug Tolerance; Female; Humans; Male; Middle Aged; Migraine Disorders; Piperidines; Thiophenes

Topics: Adolescent; Adult; Benzocycloheptenes; Drug Tolerance; Female; Humans; Male; Middle Aged; Migraine Disorders; Piperidines; Syndrome; Thiophenes

Topics: Benzocycloheptenes; Humans; Migraine Disorders; Piperidines; Thiophenes

Topics: Administration, Oral; Body Weight; Cycloheptanes; Follow-Up Studies; Humans; Migraine Disorders; Piperidines; Thiophenes; Time Factors

Topics: Adult; Chemical Phenomena; Chemistry; Cycloheptanes; Evaluation Studies as Topic; Facial Neuralgia; Female; Histamine; Humans; Male; Middle Aged; Migraine Disorders; Piperidines; Serotonin; Serotonin Antagonists; Thiophenes; Vascular Headaches

Topics: Benzocycloheptenes; Diagnosis, Differential; Ergotamine; Headache; Humans; Methysergide; Migraine Disorders; Pain; Piperidines; Thiophenes

Topics: Benzocycloheptenes; Humans; Migraine Disorders; Piperidines; Thiophenes

Topics: Adult; Amides; Ammonia; Clopamide; Diuretics; Female; Humans; Hypertension; Lymphedema; Male; Middle Aged; Migraine Disorders; Piperidines

Topics: Body Temperature; Cycloheptanes; Cyproheptadine; Ergolines; Female; Humans; Menstruation; Methysergide; Migraine Disorders; Phenothiazines; Piperidines; Progesterone; Reserpine; Serotonin Antagonists; Skin Temperature; Thermography; Thiophenes; Urea

Topics: Adult; Aged; Asthma; Biliary Tract Diseases; Dioxoles; Drug Tolerance; Duodenal Diseases; Dysmenorrhea; Esophagitis; Female; Gastritis; Heart Diseases; Humans; Kidney Calculi; Male; Middle Aged; Migraine Disorders; Muscles; Piperidines; Spasm

Topics: Adult; Aged; Bile; Biliary Dyskinesia; Cholelithiasis; Female; Humans; Liver Diseases; Male; Middle Aged; Migraine Disorders; Piperidines