Long-term efficacy and safety of erenumab in patients with chronic migraine in whom prior preventive treatments had failed: A subgroup analysis.

OBJECTIVE: To assess the long-term efficacy and safety of erenumab in the subgroup of patients with chronic migraine (CM) in whom prior preventive treatments had failed (TF) (≥1, ≥2, and ≥3 TF medication categories) and never failed (preventive naïve or prior preventive treatments had not failed), using the data from a 52-week, open-label treatment period (OLTP) of the parent study. BACKGROUND: Erenumab is a fully human monoclonal antibody that selectively binds to and inhibits the canonical calcitonin gene-related peptide receptor. There are limited long-term data evaluating the efficacy and safety of erenumab in patients with CM in whom prior preventive treatments had failed. METHODS: Patients who had completed the 12-week double-blind treatment period (DBTP) in the parent study were eligible to participate in the 52-week OLTP, during which they received erenumab every 4 weeks. The TF subgroups (≥1, ≥2, and ≥3 TF medication categories) were not mutually exclusive; patients in whom prior preventive treatments from ≥3 medication categories had failed were also counted in the ≥2 and ≥1 medication categories. Endpoints included monthly migraine days (MMD), monthly acute migraine-specific medication days (MSMD), achievement of ≥50%, ≥75%, and 100% reduction from baseline in MMD, and exposure-adjusted patient incidence rates of adverse events (AEs; per 100 patient-years). RESULTS: Erenumab treatment provided sustained mean reductions in MMD and MSMD relative to the parent study baseline throughout the 52 weeks of the OLTP across all TF subgroups. At Week 52, the mean MMD change was -8.6 (SD 6.6) (baseline: 18.4 [SD 4.5] days) in the ≥1 TF subgroup. A post hoc completer analysis (52 weeks [OLTP] erenumab) showed that compared with erenumab 70 mg, the 140 mg dose was associated with numerically greater reductions in the mean MMD (Week 40: -8.6 and -7.2 days; Week 52: -9.7 and -7.9 days [≥1 TF subgroup]) and a higher proportion of patients achieved ≥50%, ≥75%, and 100% response thresholds across all subgroups at Weeks 40 and 52. Overall the exposure-adjusted patient incidence rates of AEs did not increase during the OLTP versus the DBTP (≥1 TF subgroup: 141.9/100 versus 317.9/100 patient-years), and no new safety signals occurred. CONCLUSION: The long-term treatment with erenumab was well tolerated and showed sustained efficacy in patients with CM in whom prior preventive treatments had failed, with numerically greater treatment effects for 140 mg versus 70 mg.

Effects of fremanezumab on the use of acute headache medication and associated symptoms of migraine in patients with episodic migraine.

BACKGROUND: Fremanezumab, a fully humanized monoclonal antibody targeting calcitonin gene-related peptide, has demonstrated efficacy for the preventive treatment of migraine in adults. OBJECTIVE: To evaluate the effect of fremanezumab treatment on acute headache medication use and migraine-associated symptoms in patients with episodic migraine. METHODS: In the Phase 3 HALO trial, patients with episodic migraine were randomized to receive subcutaneous fremanezumab monthly (225 mg at baseline, weeks 4 and 8), fremanezumab quarterly (675 mg at baseline, placebo at weeks 4 and 8), or placebo over a 12-week period. The secondary endpoint was change from baseline in the monthly number of days with use of any acute headache mediation or migraine-specific acute headache medication; exploratory endpoints were change from baseline in the monthly number of days with nausea or vomiting, photophobia, or phonophobia. RESULTS: Of 875 patients randomized, 865 were included in the analysis (monthly, n = 287; quarterly, n = 288; placebo, n = 290). Baseline mean ± standard deviation days with: Any acute headache medication use (monthly: 7.7 ± 3.4; quarterly: 7.8 ± 3.7; placebo: 7.7 ± 3.6), migraine-specific acute headache medication use (6.1 ± 3.1; 6.6 ± 3.1; 7.1 ± 3.0), nausea or vomiting (4.5 ± 3.6; 4.9 ± 3.7; 4.5 ± 3.3) and photophobia and phonophobia (5.5 ± 4.1; 6.3 ± 4.1; 6.0 ± 3.9) were similar among treatment arms. Fremanezumab reduced the number of days of acute headache medication use ([least-squares mean change vs. placebo] monthly: -1.4 [95% confidence interval: -1.84, -0.89], p < 0.001; quarterly: -1.3 [-1.76, -0.82], p < 0.001) and migraine-specific acute headache medication use (monthly: -2.2 [-2.80, -1.56], p < 0.001; quarterly: -2.2 [-2.81, -1.58], p < 0.001) compared with placebo. Fremanezumab also reduced nausea or vomiting, photophobia, and phonophobia compared with placebo. CONCLUSIONS: Fremanezumab reduced the need for acute headache medications, including migraine-specific medications, while treating migraine-associated symptoms in patients with episodic migraine. TRIAL REGISTRATION: Clinicaltrials.gov NCT02629861.

Long-term safety and efficacy of erenumab in patients with chronic migraine: Results from a 52-week, open-label extension study.

BACKGROUND: This study reports the long-term safety and efficacy of erenumab in chronic migraine patients. METHODS: This was a 52-week open-label extension study of a 12-week double-blind treatment phase study. During the double-blind treatment phase, patients received placebo or once-monthly erenumab 70 mg or 140 mg. During the open-label treatment phase, the initial monthly dose was erenumab 70 mg. Following protocol amendment, patients continued to receive erenumab 70 mg if they had already completed their Week 28 visit, otherwise, patients switched from 70 mg to 140 mg; if enrolled after the amendment, patients received 140 mg monthly throughout. RESULTS: In all, 451/609 (74.1%) enrolled patients completed the study. The exposure-adjusted patient incidence rate for any adverse event was 126.3/100 patient-years for the overall erenumab group. Overall, the adverse event profile was similar to that observed in the double-blind treatment phase. Adverse event incidence rates did not increase with long-term erenumab treatment compared with the double-blind treatment phase, and no new serious or treatment-emergent events were seen. Efficacy was sustained throughout the 52 weeks. Clinically significant reductions from double-blind treatment phase baseline (about half) were observed for monthly migraine days and migraine-specific medication days. Achievement of ≥50%, ≥75% and 100% reductions from the double-blind treatment phase baseline in monthly migraine days at Week 52 were reported by 59.0%, 33.2% and 8.9% of patients, respectively, for the combined dose group. A numerically greater benefit was observed with 140 mg compared with 70 mg at Weeks 40 and 52. CONCLUSIONS: Sustained efficacy of long-term erenumab treatment in patients with chronic migraine is demonstrated, with safety results consistent with the known safety profile of erenumab and adverse event rates comparable to placebo adverse event rates in the double-blind treatment phase. TRIAL REGISTRATION: This study is registered at ClinicalTrials.gov (NCT02174861).

The spectrum of response to erenumab in patients with chronic migraine and subgroup analysis of patients achieving ≥50%, ≥75%, and 100% response.

OBJECTIVE: To assess the efficacy of erenumab across the spectrum of response thresholds (≥50%, ≥75%, 100%) based on monthly migraine days (MMD) reduction in patients with chronic migraine from a 12-week, randomized study (NCT02066415). METHODS: Patients (n = 667) received (3:2:2) placebo or erenumab 70/140 mg once-monthly. The proportion of patients achieving a given response threshold was assessed. A post-hoc analysis was conducted to contextualize the actual treatment benefit in subgroups of patients achieving (or not) specified response thresholds. Outcome measures included MMD, acute migraine-specific medication treatment days (MSMD) and disability. RESULTS: The proportion of patients responding to erenumab exceeded that of placebo at the ≥50% and ≥75% response thresholds. At month 3, 39.9% and 41.2% of patients on erenumab 70 and 140 mg, respectively, achieved ≥50% response versus placebo (23.5%). Similarly, at month 3, 17.0% and 20.9% of patients on erenumab 70 and 140 mg, respectively, achieved ≥75% response versus placebo (7.8%). Compared with the overall erenumab-treated population (change in MMD: -6.6 [both 70 and 140 mg]), ≥50% responders showed MMD reductions of -12.2/-12.5 for 70 mg/140 mg versus -2.6/-2.2 for those not achieving ≥50% response. ≥75% responders showed MMD reductions of -13.9/-14.8 for 70 mg/140 mg versus -5.0/-4.3 for those not achieving ≥75% response. Relative improvements in MSMD and disability were observed in responders versus overall erenumab-treated population. CONCLUSION: For erenumab-treated patients achieving ≥50% response, the actual reduction in MMD was almost twice that of the overall population. These findings provide context for setting realistic expectations regarding actual treatment benefit experienced by patients responding to treatment.

Interim results of a prospective, randomized, open-label, Phase 3 study of the long-term safety and efficacy of lasmiditan for acute treatment of migraine (the GLADIATOR study).

OBJECTIVES: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: The interim results of this long-term study showed intermittent lasmiditan (100 mg and 200 mg) to be generally well tolerated and efficacious for the acute treatment of migraine over a 1-year period. Trial registration number: NCT02565186; https://clinicaltrials.gov/ct2/show/NCT02565186.

Randomized, double-blind, placebo-controlled, parallel-group, multi-center study of the safety and efficacy of ADAM zolmitriptan for the acute treatment of migraine.

Objective To determine the efficacy, tolerability, and safety of ascending doses of Adhesive Dermally-Applied Microarray (ADAM) zolmitriptan versus placebo for acute migraine treatment. Background ADAM is a novel patient-administered system for intracutaneous drug administration. In a phase 1 pharmacokinetic study, zolmitriptan administered using ADAM had much faster absorption than oral administration with higher exposure in the first two hours. Methods This was a multicenter, randomized, double-blind, placebo-controlled, parallel-group Phase 2b/3 study evaluating ADAM zolmitriptan 1 mg, 1.9 mg, and 3.8 mg versus placebo. Co-primary endpoints were pain freedom and freedom from most bothersome other migraine-associated symptom 2 hours post-dose. Results Of patients treated with ADAM zolmitriptan 3.8 mg or placebo, 41.5% and 14.2%, respectively were pain-free 2 hours post-dose ( p = 0.0001) and 68.3% and 42.9% were free from their most bothersome other symptom ( p = 0.0009). Due to the fixed sequential testing methodology, formal statistical significance was not established for secondary endpoints. However, the proportion of patients who were photophobia-free, phonophobia-free, and nausea-free at 2 hours post-dose was higher in the ADAM zolmitriptan 3.8 mg group compared with placebo, as were the percentages of patients who were pain-free, and who experienced pain relief up to 48 hours post-dose. Systemic adverse events were consistent with previous triptan trials, and included dizziness, paresthesia, muscle tightness, and nausea, all of which occurred in < 5% of patients in any group. Application site reactions were generally mild and resolved within 48 hours, although erythema and bruising persisted for longer periods in some patients. Conclusion ADAM zolmitriptan 3.8 mg provides effective relief of migraine headache and associated most bothersome symptoms compared with placebo, and is well-tolerated. ClinicalTrials.gov NCT02745392.

Efficacy and safety of erenumab (AMG334) in chronic migraine patients with prior preventive treatment failure: A subgroup analysis of a randomized, double-blind, placebo-controlled study.

Background Erenumab was effective and well tolerated in a pivotal clinical trial of chronic migraine. Here, we evaluated efficacy and safety of monthly erenumab (70 mg or 140 mg) versus placebo in the subgroup of patients who had previously failed preventive treatment(s) (≥ 1, ≥ 2 prior failed medication categories) and in patients who had never failed. Methods Subgroup analyses evaluated change from baseline in monthly migraine days; achievement of ≥ 50% and ≥ 75% reduction in monthly migraine days; and change in monthly acute migraine-specific medication days. Adverse events were evaluated for each subgroup. Results Treatment with both doses of erenumab resulted in greater reductions in monthly migraine days (primary endpoint) at Month 3 (treatment difference [95% CI], never failed subgroup: -2.2 [-4.1, -0.3] for 70 mg and -0.5 [-2.4, 1.5] for 140 mg; ≥ 1 prior failed medication categories subgroup: -2.5 [-3.8, -1.2], for 70 mg and -3.3 [-4.6, -2.1] for 140 mg; ≥ 2 prior failed medication categories subgroup: -2.7 [-4.2, -1.2], for 70 mg and -4.3 [-5.8, -2.8] for 140 mg). Similar results were observed in the monthly acute migraine-specific medication days endpoint, and in the achievement of ≥ 50% and ≥ 75% reduction in monthly migraine days. There were no new or unexpected safety issues. Conclusion Erenumab showed consistent efficacy in chronic migraine patients who had failed prior preventive treatments and was well tolerated across subgroups.

ARISE: A Phase 3 randomized trial of erenumab for episodic migraine.

Background Calcitonin gene-related peptide plays an important role in migraine pathophysiology. Erenumab, a human monoclonal antibody that inhibits the calcitonin gene-related peptide receptor, is being evaluated for migraine prevention. Methods In this randomized, double-blind, placebo-controlled, phase 3 study, 577 adults with episodic migraine were randomized to placebo or 70 mg erenumab; 570 patients were included in efficacy analyses. Primary endpoint was change in monthly migraine days. Secondary endpoints were ≥50% reduction in monthly migraine days, change in acute migraine-specific medication treatment days, and ≥5-point reduction in Physical Impairment and Impact on Everyday Activities domain scores measured by the Migraine Physical Function Impact Diary. All endpoints assessed change from baseline at month 3. Results Patients receiving erenumab experienced -2.9 days change in monthly migraine days, compared with -1.8 days for placebo, least-squares mean (95% CI) treatment difference of -1.0 (-1.6, -0.5) ( p < 0.001). A ≥ 50% reduction in monthly migraine days was achieved by 39.7% (erenumab) and 29.5% (placebo) of patients (OR:1.59 (95% CI: 1.12, 2.27) ( p = 0.010). Migraine-specific medication treatment days were reduced by -1.2 (erenumab) and -0.6 (placebo) days, a treatment difference of -0.6 (-1.0, -0.2) ( p = 0.002). The ≥5-point reduction rates in Migraine Physical Function Impact Diary - Physical Impairment were 33.0% and 27.1% (OR:1.33 (0.92, 1.90) ( p = 0.13) and in Migraine Physical Function Impact Diary - Everyday Activities were 40.4% and 35.8% (OR:1.22 (0.87, 1.71) ( p = 0.26). Safety and adverse event profiles of erenumab were similar to placebo. Most frequent adverse events were upper respiratory tract infection, injection site pain, and nasopharyngitis. Conclusions As a preventive treatment of episodic migraine, erenumab at a dosage of 70 mg monthly significantly reduced migraine frequency and acute migraine-specific medication use. (Funded by Amgen). Trial registration ClinicalTrials.gov, NCT02483585.

Needle-free subcutaneous sumatriptan (Sumavel DosePro): bioequivalence and ease of use.

BACKGROUND: Subcutaneous (s.c.) injection of sumatriptan is currently associated with needle aversion in some patients, and sharps disposal issues. OBJECTIVES: To investigate whether a needle-free system can deliver s.c. sumatriptan. If so, to examine whether needle-free administration is bioequivalent to a 26-gauge needle-based auto-injector. Lastly, to assess the needle-free system for clinical acceptability and ease of use during migraine attacks. METHODS: Two clinical trials. Study A: Pharmacokinetics and bioequivalence was studied in normal adult volunteers (n = 57 total), directly comparing needle-free (Sumavel DosePro) with needle-based (Imitrex STATdose System) administration of 6 mg s.c. sumatriptan. An incomplete, randomized, partial factorial, crossover design was used. Each subject received 2 administrations of each product, at 2 of the 3 anatomical sites (abdomen, thigh or arm). There were appropriate "washout" periods between each. Pharmacokinetic sampling was at standard time points, and tests for bioequivalence then followed. Study B: The term "ease of use" was used for clinical acceptability and utility of the needle-free system when it was assessed among 52 outpatients treating migraine attacks. Instructional materials were used as would be provided after ordinary prescription. The primary endpoint was successful use of the needle-free system to administer sumatriptan at the first attempt, including appropriate injection site selection. Second and subsequent uses of the needle-free system were also documented. RESULTS: For administration sites in the thigh and the abdomen, but not the arm, the needle-free and needle-based systems were bioequivalent (for all pharmacokinetic endpoints the mean ratios between the 2 devices were always between 90.1% and 115%). Among outpatients treating a migraine attack with the needle-free system, 51 of 52 on first attempt used the needle-free system successfully when treating a migraine attack. CONCLUSIONS: Sumavel DosePro needle-free delivery system is a new presentation of s.c. sumatriptan that delivers drug effectively, is bioequivalent to the existing needle auto-injector when used at the thigh or abdomen, and is easy to use.

Erenumab in chronic migraine with medication overuse: Subgroup analysis of a randomized trial.

OBJECTIVE: To determine the effect of erenumab, a human anti-calcitonin gene-related peptide receptor monoclonal antibody, in patients with chronic migraine and medication overuse. METHODS: In this double-blind, placebo-controlled study, 667 adults with chronic migraine were randomized (3:2:2) to placebo or erenumab (70 or 140 mg), stratified by region and medication overuse status. Data from patients with baseline medication overuse at baseline were used to assess changes in monthly migraine days, acute migraine-specific medication treatment days, and proportion of patients achieving ≥50% reduction from baseline in monthly migraine days. RESULTS: Of 667 patients randomized, 41% (n = 274) met medication overuse criteria. In the medication overuse subgroup, erenumab 70 or 140 mg groups had greater reductions than the placebo group at month 3 in monthly migraine days (mean [95% confidence interval] -6.6 [-8.0 to -5.3] and -6.6 [-8.0 to -5.3] vs -3.5 [-4.6 to -2.4]) and acute migraine-specific medication treatment days (-5.4 [-6.5 to -4.4] and -4.9 [-6.0 to -3.8] vs -2.1 [-3.0 to -1.2]). In the placebo and 70 and 140 mg groups, ≥50% reductions in monthly migraine days were achieved by 18%, 36% (odds ratio [95% confidence interval] 2.67 [1.36-5.22]) and 35% (odds ratio 2.51 [1.28-4.94]). These clinical responses paralleled improvements in patient-reported outcomes with a consistent benefit of erenumab across multiple measures of impact, disability, and health-related quality of life. The observed treatment effects were similar in the non-medication overuse subgroup. CONCLUSIONS: Erenumab reduced migraine frequency and acute migraine-specific medication treatment days in patients with chronic migraine and medication overuse, improving disability and quality of life. CLINICALTRIALSGOV IDENTIFIER: NCT02066415. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that erenumab reduces monthly migraine days at 3 months in patients with chronic migraine and medication overuse.

In-office discussions of migraine: results from the American Migraine Communication Study.

BACKGROUND: Research indicates that successful migraine assessment and treatment depends on information obtained during patient and healthcare professional (HCP) discussions. However, no studies outline how migraine is actually discussed during clinical encounters. OBJECTIVE: Record naturally occurring HCP-migraineur interactions, analyzing frequency and impairment assessment, and preventive treatment discussions. DESIGN: HCPs seeing high volumes of migraineurs were recruited for a communication study. Patients likely to discuss migraine were recruited immediately before their normally scheduled appointment and, once consented, were audio- and video-recorded without a researcher present. Separate post-visit interviews were conducted with patients and HCPs. All interactions were transcribed. PARTICIPANTS: Sixty patients (83% female; mean age 41.7) were analyzed. Patients were diagnosed with migraine 14 years and experienced 5 per month, on average. APPROACH: Transcripts were analyzed using sociolinguistic techniques such as number and type of questions asked and post-visit alignment on migraine frequency and impairment. American Migraine Prevalence and Prevention Study guidelines were utilized. RESULTS: Ninety-one percent of HCP-initiated, migraine-specific questions were closed-ended/short answer; assessments focused on frequency and did not focus on attention on impairment. Open-ended questions in patient post-visit interviews yielded robust impairment-related information. Post-visit, 55% of HCP-patient pairs were misaligned regarding frequency; 51% on impairment. Of the 20 (33%) patients who were preventive medication candidates, 80% did not receive it and 50% of their visits lacked discussion of prevention. CONCLUSIONS: Sociolinguistic analysis revealed that HCPs often used narrowly focused, closed-ended questions and were often unaware of how migraine affected patients' lives as a result. It is recommended that HCPs assess impairment using open-ended questions in combination with the ask-tell-ask technique.

Sumatriptan-naproxen for acute treatment of migraine: a randomized trial.

CONTEXT: Multiple pathogenic mechanisms may be involved in generating the migraine symptom complex, and multimechanism-targeted therapy may confer advantages over monotherapy. OBJECTIVE: To evaluate the efficacy and safety of a fixed-dose tablet containing sumatriptan succinate and naproxen sodium relative to efficacy and safety of each monotherapy and placebo for the acute treatment of migraine. DESIGN, SETTING, AND PARTICIPANTS: Two replicate, randomized, double-blind, single-attack, parallel-group studies conducted among 1461 (study 1) and 1495 (study 2) patients at 118 US clinical centers who were diagnosed as having migraine and received study treatment for a moderate or severe migraine attack. INTERVENTIONS: Patients were randomized in a 1:1:1:1 ratio to receive a single tablet containing sumatriptan, 85 mg, and naproxen sodium, 500 mg; sumatriptan, 85 mg (monotherapy); naproxen sodium, 500 mg (monotherapy); or placebo, to be used after onset of a migraine with moderate to severe pain. MAIN OUTCOME MEASURES: Primary outcome measures included the percentages of patients with headache relief 2 hours after dosing, absence of photophobia, absence of phonophobia, and absence of nausea for the comparison between sumatriptan-naproxen sodium and placebo, and the percentages of patients with sustained pain-free response for the comparison between sumatriptan-naproxen sodium and each monotherapy. RESULTS: Sumatriptan-naproxen sodium was more effective than placebo for headache relief at 2 hours after dosing (study 1, 65% vs 28%; P<.001 and study 2, 57% vs 29%; P<.001), absence of photophobia at 2 hours (58% vs 26%; P<.001 and 50% vs 32%; P<.001), and absence of phonophobia at 2 hours (61% vs 38%; P<.001 and 56% vs 34%; P<.001). The absence of nausea 2 hours after dosing was higher with sumatriptan-naproxen sodium than placebo in study 1 (71% vs 65%; P = .007), but in study 2 rates of absence of nausea did not differ between sumatriptan-naproxen sodium and placebo (65% vs 64%; P = .71). For 2- to 24-hour sustained pain-free response, sumatriptan-naproxen sodium was superior at P<.01 (25% and 23% in studies 1 and 2, respectively) to sumatriptan monotherapy (16% and 14% in studies 1 and 2), naproxen sodium monotherapy (10% and 10% in studies 1 and 2), and placebo (8% and 7% in studies 1 and 2). The incidence of adverse events was similar between sumatriptan-naproxen sodium and sumatriptan monotherapy. CONCLUSION: Sumatriptan, 85 mg, plus naproxen sodium, 500 mg, as a single tablet for acute treatment of migraine resulted in more favorable clinical benefits compared with either monotherapy, with an acceptable and well-tolerated adverse effect profile. TRIAL REGISTRATION: clinicaltrials.gov Identifiers: NCT00434083 (study 1); NCT00433732 (study 2).

Assessing the ability of topiramate to improve the daily activities of patients with migraine.

OBJECTIVE: To assess the impact of topiramate on the daily activities of patients with migraine. PATIENTS AND METHODS: We performed a randomized, double-blind, placebo-controlled multicenter trial Initiated on March 1, 2001, and completed on April 4, 2002. Patient-reported data from the Migraine Specific Questionnaire (MSQ) and the Medical Outcomes Study 36-item Short-Form Health Survey (SF-36) were collected at baseline and at weeks 8, 16, and 26 from an intent-to-treat population receiving either topiramate, 50, 100, or 200 mg/d, or placebo. Two activity-related MSQ domains (role restrictive [MSQ-RR] and role prevention [MSQ-RP]) and 2 activity-related SF-36 domains (role physical [SF36-RP] and vitality [SF36-VT]) were the prospectively designated secondary outcome measures. The changes in MSQ and SF-36 scores for each treatment group were calculated by measuring the area under the curve from week 8 (the beginning of the maintenance period) through week 26 of the double-blind phase, relative to the prospective baseline. A mixed-effect piecewise linear regression model was used to estimate average domain score over time. RESULTS: Patients receiving topiramate, 100 or 200 mg/d, had significantly reduced mean monthly (28-day) migraine frequency (P = .008 and P < .001, respectively) compared with placebo, but not patients receiving topiramate, 50 mg/d (P = .48). Topiramate significantly improved mean MSQ-RR domain scores (50 mg/d [P = .02], 100 mg/d [P< .001], and 200 mg/d [P < .001]) and mean MSQ-RP domain scores (50 mg/d [P = .007], 100 mg/d [P = .001], and 200 mg/d [P= .002]) vs placebo. Topiramate, 100 and 200 mg/d, significantly improved mean SF36-RP domain scores vs placebo (P = .02). Topiramate (all doses) improved SF36-VT domain scores, although not significantly vs placebo. Changes in prospectively designated domain scores were significantly correlated with changes in mean monthly migraine frequency (P < or = .001 [MSQ domains], P < or = .002 [SF-36 domains]). CONCLUSION: Patient-reported migraine-specific outcomes measured by the MSQ-RR and MSQ-RP domains improved significantly for those receiving topiramate (all doses) vs placebo. The SF36-RP domain scores improved significantly for patients receiving 100 or 200 mg/d of topiramate. Improvements in all 4 prospectively selected MSQ and SF-36 domains were significantly correlated with decreases in mean monthly migraine frequency.

The influence of estrogen on migraine: a systematic review.

CONTEXT: Menstrual migraine affects approximately 50% to 60% of female migraineurs, but knowledge regarding the role of hormones, especially estrogen, appears incomplete. OBJECTIVE: To conduct a systematic review to determine the role of hormones on menstrual migraine. EVIDENCE ACQUISITION: MEDLINE (January 1966 through September 1, 2005) and EMBASE Drugs and Pharmacology (January 1991 through September 1, 2005) were searched for articles published in the English language using the keywords migraine, estrogen, menstrual migraine, pure menstrual migraine, true menstrual migraine, menstrually-associated migraine, menstrually-related migraine, pregnancy, breast-feeding, perimenopause, menopause, nitric oxide, and estrogen receptors. A total of 643 unique articles were reviewed for relevance, scientific rigor, and generalizability. For each relevant citation, the bibliography was reviewed to identify additional sources of pertinent data. EVIDENCE SYNTHESIS: The influence of estrogen on migraine is evident by a 3-fold greater prevalence among women compared with men, and by significant changes in migraine incidence with changes in female reproductive status. Menstrual migraines are usually more resistant to treatment, generally not associated with aura, of longer duration, and associated with more functional disability compared with attacks at other times of the month. Biochemical and genetic evidence suggest central and peripheral roles for estrogen in the pathophysiology of menstrual migraine, with potential interactions with excitatory circuits, including serotonergic components. Although evidence for estrogen as a preventive treatment for menstrual migraine is inconsistent, serotonin receptor agonists (triptans) provide acute relief and also may have a role in prevention. CONCLUSIONS: Epidemiological, pathophysiological, and clinical evidence link estrogen to migraine headaches. Triptans appear to provide acute relief and also may be useful for headache prevention. Clear, focused, and evidence-based treatment algorithms are needed to support primary care physicians, neurologists, and gynecologists in the treatment of this common condition.

Two replicate randomized, double-blind, placebo-controlled trials of the time to onset of pain relief in the acute treatment of migraine with a fast-disintegrating/rapid-release formulation of sumatriptan tablets.

BACKGROUND: The gastric stasis that commonly accompanies migraine headache may impair absorption of conventional oral tablets in the stomach. A fast-disintegrating/rapid-release formulation of sumatriptan has been developed to enhance tablet disintegration and drug dispersion and potentially improve absorption. OBJECTIVE: Two studies were conducted comparing the time to onset of relief from moderate or severe migraine pain with the fast-disintegrating/rapid-release formulation of sumatriptan tablets 50 and 100 mg and placebo. METHODS: These were 2 identically designed randomized, double-blind, parallel-group studies. Sumatriptan 50 or 100 mg or placebo was taken on an outpatient basis to treat a single moderate or severe migraine attack. Using a personal digital assistant, patients recorded the time of dosing and the time at which pain severity reached none or mild (ie, pain relief) or none (ie, pain free) in real time so that the time to onset of relief could be measured as a continuous variable. Onset of relief was defined as the earliest time point at which a statistically significant difference in pain relief compared with placebo was achieved and maintained through 2 hours after dosing. Before dosing and at pre-determined time points after dosing, patients also provided an assessment of migraine pain as none, mild, moderate, or severe. At a clinic visit within 1 week after treatment of the migraine attack, patients were queried about adverse events. For each adverse event, investigators recorded whether study medication was considered the cause. Data analyses were undertaken for each study individually and, in post hoc analyses of the primary and key secondary end points, on pooled data from both studies. RESULTS: The 2 studies comprised 2696 patients: 902 received sumatriptan 50 mg, 902 received sumatriptan 100 mg, and 892 received placebo. Patients' mean age ranged from 40.2 to 40.8 years across treatment groups, and most patients were female (83%-87%) and white (92%-93%). In the analysis of pooled data, sumatriptan tablets provided significantly more effective pain relief compared with placebo as early as 20 minutes after dosing with the 100-mg dose and as early as 30 minutes after dosing with the 50-mg dose (P < or = 0.05). Similar results were observed for the individual studies: in study 1, sumatriptan tablets were significantly more effective than placebo at 25 minutes with the 100-mg dose and at 50 minutes with the 50-mg dose; in study 2, sumatriptan tablets were significantly more effective than placebo at 17 minutes for the 100-mg dose and at 30 minutes for the 50-mg dose (P < or = 0.05). In the pooled data, the cumulative percentages of patients with pain relief by 2 hours after dosing were 72% for the 100-mg dose and 67% for the 50-mg dose, compared with 42% for placebo (P < or = 0.001, both sumatriptan doses vs placebo). The cumulative percentages of patients with a pain-free response by 2 hours were 47% for the 100-mg dose, 40% for the 50-mg dose, and 15% for placebo (P < or = 0.001, both sumatriptan doses vs placebo). In the individual studies, significantly more patients receiving either sumatriptan dose were migraine free 2 hours after dosing and had sustained pain relief and a sustained pain-free response over 24 hours compared with placebo (P < or = 0.001, both sumatriptan doses vs placebo). The only drug-related adverse events reported in >2% of patients in any treatment group in either study were nausea (both studies: 3% sumatriptan 100 mg, 2% sumatriptan 50 mg, 1% placebo) and paresthesia (study 1: <1% sumatriptan 100 mg, <1% sumatriptan 50 mg, 0% placebo; study 2: 3% sumatriptan 100 mg, 1% sumatriptan 50 mg, <1% placebo). CONCLUSIONS: In these studies, sumatriptan tablets in a fast-disintegrating/rapid-release formulation were effective for the acute treatment of moderate to severe migraine pain, were generally well tolerated, and achieved an onset of pain relief as early as 20 minutes for 100 mg and as early as 30 minutes for 50 mg.

Global trends in migraine care: results from the MAZE survey.

INTRODUCTION: Many patients with migraine do not consult a physician, or do not achieve adequate relief after consulting a physician because of undertreatment. The objective of the Migraine and Zomig Evaluation study was to provide insights into the management of migraine in the general population. METHODS: In phase I, 5553 members of the general public in the UK, France, Germany, Italy, and the US were interviewed by telephone and classified according to International Headache Society criteria. The Migraine Disability Assessment Scale (MIDAS) questionnaire was used to assess the impact of migraine on work, home and social lives. In phase II, 516 patients with clinically diagnosed migraine were interviewed to assess the impact of migraine on daily life, attitudes towards migraine, perceptions of current treatments and aspirations for future treatments. RESULTS: In phase I, the average prevalence of migraine over the five countries was 9%. Migraine posed a significant burden in terms of the impact on patients' daily lives, and attack severity and frequency. However, medical consultation rates were low; reasons for this included patients not recognising that they had migraine or having low expectations about treatment benefits. On average, only 10% of patients who had consulted a physician had been prescribed a triptan. Only 22% of participants in phase II thought that migraine did not markedly affect their lives. In each of the five countries, > or = 50% of patients required bed rest to manage migraine attacks, demonstrating the impact of migraine-related disability on patients' lives. Assessment of MIDAS scores confirmed the debilitating effect of migraine; > 50% of respondents had a MIDAS grade of III or IV, indicating moderate or severe disability. Less than one-third of patients reported that their current medication was consistently effective and only 36% were 'very satisfied' with their current therapy. High efficacy and rapid pain relief were rated as the most important attributes of migraine medications. When asked which formulation they would like to see more of, most patients chose a tablet that dissolves in the mouth without the need to take liquids. CONCLUSIONS: These results show that migraine patients worldwide are still not receiving adequate treatment and there remains a significant unmet need in migraine care. The challenge for the future is to diagnose migraine early and offer patients effective migraine-specific therapies. Physicians particularly need to reach patients who do not realise they have migraine and those who have lapsed from care.

Migraine matters: the role of triptans in relieving the burden in managed care.

OBJECTIVE: To provide managed care pharmacists with information regarding the prevalence and burden of migraine in the United States, approaches to diagnosing and managing migraine, and implications for managed care organizations. SUMMARY: Migraine is a common chronic condition that imparts tremendous disability to those afflicted. Economic costs associated with migraine are staggering, with the majority of costs resulting from lost workdays. Barriers to the proper management of migraine patients include misdiagnosis and a limited understanding of available pharmacological and nonpharmacological treatment options. Use of screening tools in primary care may help diagnose migraine and point to appropriate treatment plans. The use of migraine-specific therapies is discussed, with special emphasis on triptans, which have demonstrated efficacy and modest side effects. Use of triptans has been shown to reduce migraine-associated disability and overall costs associated with migraine. Studies comparing the effectiveness and costs of individual triptans are also described. CONCLUSIONS: Migraine-associated pain and disability can be significantly reduced with proper treatment. Use of diagnostic tools, such as ID Migraine, can facilitate the identification of migraine patients who need treatment. A stratified care approach with appropriate treatment can improve the lives of migraine sufferers as well as reduce migraine-associated costs for managed care organizations.

Topiramate for migraine prevention: a randomized controlled trial.

CONTEXT: Small open-label and controlled trials suggest that the antiepileptic drug topiramate is effective for migraine prevention. OBJECTIVE: To assess the efficacy and safety of topiramate for migraine prevention in a large controlled trial. DESIGN, SETTING, AND PATIENTS: A 26-week, randomized, double-blind, placebo-controlled study was conducted during outpatient treatment at 52 North American clinical centers. Patients were aged 12 to 65 years and had a 6-month history of migraine (International Headache Society criteria) and 3 to 12 migraines a month but no more than 15 headache days a month during a 28-day prospective baseline phase. INTERVENTIONS: After a washout period, patients meeting entry criteria were randomized to topiramate (50, 100, or 200 mg/d) or placebo. Topiramate was titrated by 25 mg/wk for 8 weeks to the assigned or maximum tolerated dose, whichever was less. Patients continued receiving that dose for 18 weeks. MAIN OUTCOME MEASURES: The primary efficacy measure was change from baseline in mean monthly migraine frequency. Secondary efficacy measures included responder rate (proportion of patients with > or =50% reduction in monthly migraine frequency), reductions in mean number of monthly migraine days, severity, duration, and days a month requiring rescue medication, and adverse events. The month of onset of preventive treatment action was assessed. RESULTS: Of 483 patients randomized, 468 provided at least 1 postbaseline efficacy assessment and comprised the intent-to-treat population. Mean monthly migraine frequency decreased significantly for patients receiving topiramate at 100 mg/d (-2.1, P =.008) and topiramate at 200 mg/d (-2.4, P<.001) vs placebo (-1.1). Statistically significant reductions (P<.05) occurred within the first month with topiramate at 100 and 200 mg/d. The responder rate was significantly greater with topiramate at 50 mg/d (39%, P =.01), 100 mg/d (49%, P<.001), and 200 mg/d (47%, P<.001) vs placebo (23%). Reductions in migraine days were significant for the 100-mg/d (P =.003) and 200-mg/d (P<.001) topiramate groups. Rescue medication use was reduced in the 100-mg/d (P =.01) and 200-mg/d (P =.005) topiramate groups. Adverse events resulting in discontinuation in the topiramate groups included paresthesia, fatigue, and nausea. CONCLUSION: Topiramate showed significant efficacy in migraine prevention within the first month of treatment, an effect maintained for the duration of the double-blind phase.

Migraine in women.

PURPOSE OF REVIEW: This article discusses hormonal milestones and the influence that hormonal fluctuations make in the frequency and severity of migraine in women and includes information on acute, short-term, and preventive strategies for hormonally influenced migraine and the situations in which hormonal therapies may be offered. RECENT FINDINGS: Genomic patterns in adolescent girls differentiate between menstrually related migraine and non-menstrually related migraine. The age at initiation of estrogen replacement therapy appears to be significant with respect to stroke. No increase in stroke occurred in women on low-dose (50 µg or less) transdermal estrogen replacement compared to women not using estrogen replacement. Childhood maltreatment is more common in women with migraine and depression than in women with migraine alone. SUMMARY: Management of hormonally influenced migraine involves a clear identification of the relationship between migraine and hormone change. A thorough history and detailed diary are critical in identifying this relationship and in predicting response or following response to hormonal therapies. The evolution of migraine in an individual may be strongly driven by hormonal shifts. Although limited, clinical evidence suggests that oral contraceptive use in young women with episodic migraine may transform their pattern into chronic migraine. Thus, particular attention to changes in migraine patterns following either endogenous or exogenous hormonal changes is crucial. Providing reassurance and education that migraine is a biological disorder and providing an understanding of the role of estrogen in the frequency and severity of migraine can guide treatment choices. Pharmacologic treatments include acute therapy, with short-term and standard prevention offered where appropriate. Hormonal therapies are not first-line therapies but may be important choices for a woman with migraine whose estrogen fluctuation is continually exacerbating migraine attacks. Given the many hormonal stages during the life of a woman with migraine, therapies may vary according to hormonal stage and status. Overall wellness should also be emphasized; regular exercise, balanced diet, smoking cessation, weight control, and sleep hygiene are important in the management of migraine.

Needle-free subcutaneous sumatriptan for triptan users requiring a change in migraine therapy: efficacy and impact on patient-rated functionality, satisfaction, and confidence.

OBJECTIVE: To evaluate efficacy of, satisfaction with, and confidence in SDP (SUMAVEL DosePro *) among triptan users requiring a change in therapy. SDP is a needle-free, subcutaneous sumatriptan product that confers relief as early as 10 minutes postdose. RESEARCH DESIGN AND METHODS: In an open-label study, SDP was administered for ≤4 migraine attacks over ≤60 days by migraineurs currently treated with triptans (any form/dosage). In the 90 patients with baseline Migraine-ACT scores ≤2 (indicating the need for a change in therapy), efficacy data were collected from patient diaries, and satisfaction was measured with the revised Patient Perception of Migraine Questionnaire (PPMQ-R). CLINICAL TRIAL REGISTRATION NUMBER: NCT01016834 on clinicaltrials.gov. RESULTS: Across all attacks, the rates of pain relief were 30.7%, 66.4%, 80.1%, 81.6%, and 77.6% at 0.25, 0.5, 1, 2, and 24 hours postdose, respectively. Corresponding results for pain-free response were 0.7%, 14.8%, 35.0%, 48.0, and 65.7%. Sustained 24-hour pain relief was observed in 61.0% of attacks. PPMQ-R scores (transformed to 0-100 scales, mean ± SD) improved from baseline to end of treatment for Efficacy (52.5 ± 17.8 versus 74.8 ± 23.4, p < 0.0001) and Functionality (46.2 ± 22.3 versus 71.3 ± 25.2, p < 0.0001) with no deterioration in Tolerability (80.6 ± 14.7 versus 83.5 ± 17.7, p = 0.12). PPMQ-R Overall Satisfaction score increased from baseline to end of treatment (55.1 ± 23.2 versus 74.6 ± 27.7, p < 0.0001). The percentage of patients (90% confidence interval) confident or very confident in treating migraine attacks increased from 22.2% (15.2, 30.6) at baseline to 57.8% (48.6, 66.6) at end of treatment. Results should be interpreted in the context of the open-label design of the original study. CONCLUSION: With SDP, triptan users requiring a change in therapy experienced increased efficacy, satisfaction with therapy, and confidence in treatment without deterioration in tolerability.