Goadsby, Peter J.

Background 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. Methods 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. Results 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. Conclusions BMS-927711 is superior to placebo at several different doses (75 mg, 150 mg, and 300 mg) and has an excellent tolerability profile.

Background: This study evaluated the CGRP receptor antagonist MK-3207 for acute treatment of migraine. Methods: Multicenter, double-blind, randomized, placebo-controlled, parallel-group, two-stage adaptive study with two interim efficacy analyses to facilitate optimal dose selection. Migraine patients were initially randomized to MK-3207 2.5, 5, 10, 20, 50 and 100 mg or placebo to treat a moderate/severe migraine. One or more doses were to be discontinued based on the first interim analysis and a lower or higher dose could be added based on the second interim analysis. The primary endpoint was two-hour pain freedom. Results: A total of 547 patients took study medication. After the first interim analysis, the two lowest MK-3207 doses (2.5, 5 mg) were identified as showing insufficient efficacy. Per the pre-specified adaptive design decision rule, only the 2.5-mg group was discontinued and the five highest doses (5, 10, 20, 50, 100 mg) were continued into the second stage. After the second interim efficacy analysis, a 200 mg dose was added due to insufficient efficacy at the top three (20, 50, 100 mg) doses. A positive dose-response trend was demonstrated when data were combined across all MK-3207 doses for two-hour pain freedom ( p < .001). The pairwise difference versus placebo for two-hour pain freedom was significant for 200 mg ( p < .001) and nominally significant for 100 mg and 10 mg ( p < .05). The incidence of adverse events appeared comparable between active treatment groups and placebo, and did not appear to increase with increasing dose. Conclusions: MK-3207 was effective and generally well tolerated in the acute treatment of migraine.

Background: Medically intractable chronic migraine (CM) is a disabling illness characterized by headache ≥15 days per month. Methods: A multicenter, randomized, blinded, controlled feasibility study was conducted to obtain preliminary safety and efficacy data on occipital nerve stimulation (ONS) in CM. Eligible subjects received an occipital nerve block, and responders were randomized to adjustable stimulation (AS), preset stimulation (PS) or medical management (MM) groups. Results: Seventy-five of 110 subjects were assigned to a treatment group; complete diary data were available for 66. A responder was defined as a subject who achieved a 50% or greater reduction in number of headache days per month or a three-point or greater reduction in average overall pain intensity compared with baseline. Three-month responder rates were 39% for AS, 6% for PS and 0% for MM. No unanticipated adverse device events occurred. Lead migration occurred in 12 of 51 (24%) subjects. Conclusion: The results of this feasibility study offer promise and should prompt further controlled studies of ONS in CM.

Chronic migraine has been linked to the excessive use of acute headache medications. Medication overuse (MO) is commonly considered the most significant risk factor for the progression of migraine from an episodic to a chronic condition. Managing MO is a challenge. Discontinuation of the acute medication can result in withdrawal headache, nausea, vomiting and sleep disturbances. This review summarizes the results from two similarly designed, randomized, placebo- controlled, multicentre studies of chronic migraine conducted in the USA and European Union. Both studies demonstrate the efficacy and safety of the migraine preventive medication, topiramate, for the treatment of chronic migraine in patient populations both with and without MO. These studies may have important implications for the future of chronic migraine management, suggesting that detoxification prior to initiating prophylactic therapy may not be required in all patients if MO is present.

Thirty to forty percent of migraineurs do not respond to any given triptan treatment. We identified clinical variables that significantly predict therapeutic non-response and evaluated the efficacy of eletriptan (20, 40 and 80 mg) and sumatriptan (100 mg) vs. placebo in a subgroup of patients with all predictor variables. First-attack data were pooled from 10 randomized, double-blind, placebo-controlled migraine trials ( n = 8473). Multivariate regression analyses identified three significant baseline predictors of failure to achieve 2-h pain-free response: severe headache pain, presence of photophobia/phonophobia and presence of nausea. Time of dosing following headache onset did not influence 2-h pain-free response. Among patients with all three risk factors ( n = 2010; 24± of total sample), 2-h pain-free response was significantly higher in patients receiving all three doses of eletriptan or sumatriptan vs. placebo (all P< 0.01). Thus, eletriptan and sumatriptan are efficacious in difficult-to-treat patients at high risk for non-response to triptans.