Sex differences in response to triptans

ObjectiveTo examine the effect of sex on clinical response to triptans and to determine whether these differences are related to pharmacokinetics of triptans in men and women, we performed a systematic review and meta-analysis.MethodsWe searched clinical trials distinguishing clinical response to or pharmacokinetic parameters of triptans between sexes in PubMed, MEDLINE, Cochrane Library, Embase and Web of Science up to Dec 12, 2019. Analysis was based on data extracted from published reports. Male-to-female pooled risk ratios (RR) were calculated for clinical outcomes and pooled ratio of means (RoM) for pharmacokinetic outcomes, using random-effects models.ResultsOut of 1,188 publications on clinical trials with triptans, 244 were identified with sex-related search terms. Only 19 publications presented sex-specific results, comprising n = 2,280 men and n = 13,899 women. No sex differences were revealed for 2-hour headache and pain-free responses, but men had a lower risk for headache recurrence (male-to-female RR 0.64, 95% confidence interval [CI]: 0.55–0.76, Q = 0.81) and adverse events (RR 0.82, 95% CI: 0.72–0.93, Q = 4.93). Men had lower drug exposure with lower area under the curve (RoM 0.69, 95% CI: 0.60–0.81, Q = 18.06) and peak drug concentration (RoM 0.72, 95% CI: 0.64–0.82, Q = 8.24) than women.ConclusionsRemarkably few publications about sex differences in triptan response are available. The limited number of eligible studies show sex differences in adverse event frequency, which may be partly due to drug exposure differences. This higher drug exposure in women is not reflected in different response rates. Despite higher exposure, women have higher headache recurrence rates possibly due to longer attack duration related to sex hormonal changes.

Effect of a rescue or recurrence dose of lasmiditan on efficacy and safety in the acute treatment of migraine: Findings from the Phase 3 trials (SAMURAI and SPARTAN)

Background We studied the efficacy and safety of a second dose of lasmiditan for acute treatment of migraine. Methods SAMURAI and SPARTAN were double-blind, placebo-controlled Phase 3 studies in which individuals with migraine were randomized to oral lasmiditan 50mg (SPARTAN only), 100mg, 200mg, or placebo. Study drug was to be taken within 4 hours (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 2h and took a second dose 2-24h post-first dose) or recurrence (patient pain-free at 2h, but experienced recurrence of mild, moderate, or severe migraine pain and took a second dose 2-24h 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. Results 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 2h 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 2h 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. Conclusions 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.

Effect of a rescue or recurrence dose of lasmiditan on efficacy and safety in the acute treatment of migraine: Findings from the Phase 3 trials (SAMURAI and SPARTAN)

Background We studied the efficacy and safety of a second dose of lasmiditan for acute treatment of migraine. Methods SAMURAI and SPARTAN were double-blind, placebo-controlled Phase 3 studies in which individuals with migraine were randomized to oral lasmiditan 50mg (SPARTAN only), 100mg, 200mg, or placebo. Study drug was to be taken within 4 hours (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 2h and took a second dose 2-24h post-first dose) or recurrence (patient pain-free at 2h, but experienced recurrence of mild, moderate, or severe migraine pain and took a second dose 2-24h 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. Results 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 2h 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 2h 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. Conclusions 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.

Effect of a rescue or recurrence dose of lasmiditan on efficacy and safety in the acute treatment of migraine: Findings from the Phase 3 trials (SAMURAI and SPARTAN)

Background We studied the efficacy and safety of a second dose of lasmiditan for acute treatment of migraine. Methods SAMURAI and SPARTAN were double-blind, placebo-controlled Phase 3 studies in which individuals with migraine were randomized to oral lasmiditan 50mg (SPARTAN only), 100mg, 200mg, or placebo. Study drug was to be taken within 4 hours (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 2h and took a second dose 2-24h post-first dose) or recurrence (patient pain-free at 2h, but experienced recurrence of mild, moderate, or severe migraine pain and took a second dose 2-24h 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. Results 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 2h 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 2h 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. Conclusions 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.

LO18: The effectiveness of parenteral agents to reduce relapse in patients with acute migraine in emergency settings: a systematic review

Introduction: Although a variety of parenteral agents exist for the treatment of acute migraine, relapse after an emergency department (ED) visit is still a common occurrence. The objective of this systematic review was to update a previous review examining the effectiveness of parenteral agents for the treatment of acute migraine in the ED or equivalent acute care setting; our review focused on those studies aiming a reduction in relapse after an ED visit. Methods: A comprehensive search of 10 electronic databases and grey literature was conducted to identify comparative studies to supplement the previous systematic review. Two independent reviewers completed study selection, quality assessment, and data extraction. Any discrepancies were resolved by third party adjudication. Relative risks (RR) with 95% confidence intervals (CIs) were calculated using a random effects model and heterogeneity (I2) was reported. Results: Titles and abstracts of 5039 unique studies were reviewed, of which, 51 studies were included. Sixty-four studies from the original review were included, resulting in a total of 115 included studies. Relapse was reported in 44 (38%) included studies and occurred commonly in patients receiving placebo or no interventions (median = 39%; IQR: 14%, 47%). Overall, no differences in headache relapse were found between patients receiving sumatriptan or placebo (RR = 1.09; 95% CI: 0.55, 2.17; I2 = 93%; n = 8). Conversely, patients receiving neuroleptic agents experienced fewer relapses compared to placebo (RR = 0.27; 95% CI: 0.12, 0.58; I2 = 0%; n = 3); however, patients receiving neuroleptics reported an increase in adverse events (RR = 1.87; 95% CI: 1.17, 3.00; I2 = 0%; n = 3). Compared to placebo, patients receiving dexamethasone were less likely to experience a headache recurrence (RR = 0.71; 95% CI: 0.53, 0.95; I2 = 60%, n = 9); however, no differences were found in reported adverse events (RR = 1.09; 95% CI: 0.81, 1.47; I2 = 0%; n = 3). Conclusion: Relapse is a common occurrence for patients with migraine headaches. This review found patients receiving neuroleptics or dexamethasone experienced fewer headache recurrences. Conversely, triptan agents appear to have minimal effect on reducing the risk for headache recurrence following discharge from an acute care setting. Limited available data on adverse events is an important limitation to inform decision-making. Guidelines should be revised to reflect these results.

Overview of Triptans in the Treatment of Acute Migraine

The advent of triptans for effective relief of migraine represented a therapeutic breakthrough. Triptans are serotonin (5-hydroxytryptamine, or 5-HT) agonists with high affinity for 5-HT1B and 5-HT1D receptors. There are, at present, seven commonly used triptans: almotriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan, and zolmitriptan. Some controversy still surrounds the mode of action of this class. When first studied, it was thought that triptans provided relief from migraine through cranial vasoconstriction, probably via action at postsynaptic 5-HT1B receptors on the smooth-muscle cells of blood vessels. More recently, however, triptans have also been demonstrated to block release of vasoactive peptides from the perivascular trigeminal neurons owing to their action at presynaptic 5-HT1D receptors on the nerve terminal. Triptans may also facilitate descending pain inhibitory systems. However, it is not certain whether or not the activation of vascular 5-HT1B receptors is essential for relieving migraine. Many drug characteristics need to be taken into account when selecting the best triptan for an individual patient. Clinical characteristics of the migraine attack and the patient’s lifestyle and medical history are also important. Despite their biochemical similarity, triptans have distinct pharmacokinetic and pharmacodynamic profiles. Frovatriptan and naratriptan, for example, have a longer half-life and therefore a delayed onset of action and prolonged duration compared with the other triptans, which are fast acting, with a rapid dose-dependent efficacy and higher risk of adverse events and migraine recurrence. Migraine recurrence is affected by the pharmacological and pharmacokinetic properties of the triptan but is unrelated to initial clinical efficacy. Triptans with a longer half-life and largest 5-HT1B receptor affinity have the lowest rates of headache recurrence.

Treatment of hemicrania continua with radiofrequency ablation and long-term follow-up

Objective The objective of this research is to describe novel procedural treatments for hemicrania continua that allow patients to remain off indomethacin. Methods Case reports are presented. Results We describe four distinct patients with indomethacin-responsive hemicrania continua who were unable to discontinue the use of indomethacin without headache recurrence. No other medications were effective for their syndrome. Secondary causes of headache were ruled out in each case. Each patient underwent diagnostic blockade of either the atlanto-axial joint, C2 dorsal root ganglion or sphenopalantine ganglion depending on their clinical examination and presence of cranial autonomic symptoms. A positive response led to a radiofrequency ablation of the C2 ventral ramus, C2 dorsal root ganglion or sphenopalantine ganglion, which provided headache relief in all case patients as complete as indomethacin. Long-term follow-up of these patients has shown that all have remained essentially headache free without the need for indomethacin. One patient has needed repeat radiofrequency procedures with consistent response. Conclusion Hemicrania continua is defined by its sensitivity to indomethacin but very few patients are able to discontinue the medication without headache recurrence. As the risks of chronic indomethacin use are substantial, alternative treatments are necessary to protect patient health. We are now able to suggest several radiofrequency ablation procedures as effective as indomethacin with long-term follow-up.

The place of corticosteroids in migraine attack management: A 65-year systematic review with pooled analysis and critical appraisal

Background and objectives Headaches recur in up to 87% of migraine patients visiting the emergency department (ED), making ED recidivism a management challenge. We aimed herein to determine the role of corticosteroids in the acute management of migraine in the ED and outpatient care. Methods Advanced search strategies employing PubMed/MEDLINE, Web of Science, and Cochrane Library databases inclusive of a relevant gray literature search was employed for Clinical Studies and Systematic Reviews by combining the terms “migraine” and “corticosteroids” spanning all previous years since the production of synthetic corticosteroids ca. 1950 until August 30, 2014. Methods were in accordance with MOOSE guidelines. Results Twenty-five studies ( n = 3989, median age 37.5 years, interquartile range or IQR 35–41 years; median male:female ratio 1:4.23, IQR 1:2.1–6.14; 52% ED-based, 56% randomized-controlled) and four systematic reviews were included. International Classification of Headache Disorders criteria were applied in 64%. Nineteen studies (76%) indicated observed outcome differences favoring benefits of corticosteroids, while six (24%) studies indicated non-inferior outcomes for corticosteroids. Median absolute risk reduction was 30% (range 6%–48.2%), and 11% (6%–48.6%) for 24-, and 72-hour headache recurrence, respectively. Parenteral dexamethasone was the most commonly (56%) administered steroid, at a median single dose of 10 mg (range 4–24 mg). All meta-analyses revealed efficacy of adjuvant corticosteroids to various abortive medications—indicating generalizability. Adverse effects were tolerable. Higher disability, status migrainosus, incomplete pain relief, and previous history of headache recurrence predicted outcome favorability. Conclusions Our literature review suggests that with corticosteroid treatment, recurrent headaches become milder than pretreated headaches and later respond to nonsteroidal therapy. Single-dose intravenous dexamethasone is a reasonable option for managing resistant, severe, or prolonged migraine attacks.