Research Submission. ISSN doi: /head Published by Wiley Periodicals, Inc.

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1 Headache 213 The Authors Headache published by Wiley Periodicals, Inc. on behalf of American Headache Society ISSN doi: /head Published by Wiley Periodicals, Inc. Research Submission Comparing the Efficacy of Eletriptan for Migraine in Women During Menstrual and Non-Menstrual Time Periods: A Pooled Analysis of Randomized Controlled Trials Rahul Bhambri, PharmD; Vincent T. Martin, MD; Younos Abdulsattar, PharmD, BCPS; Stephen Silberstein, MD; Mary Almas, MS; Anjan Chatterjee, MD, MPH*; Elodie Ramos, PhD Objective. To assess the efficacy and tolerability of eletriptan in treating migraine attacks occurring within the defined menstrual time period of 1 day before and 4 days after onset of menstruation (menses days 1 to +4) compared with attacks occurring during non-menstrual time periods (occurring outside of menses days 1 to +4). Background. Migraine attacks during menses have been associated with longer duration, higher recurrence rates, greater treatment resistance, and greater functional disability than those not associated with menses. The efficacy of eletriptan in treating migraine attacks associated with menstruation vs those outside a defined menstrual period has not been evaluated. Methods. Data were pooled from 5 similarly designed, double-blind, randomized, placebo-controlled trials of eletriptan 2 mg/4 mg/8 mg. Two groups were defined for this analysis: women with a single index migraine beginning during the menstrual (group 1) and non-menstrual (group 2) time periods. End points of interest were headache response at 2 hours, migraine recurrence and sustained responses for nausea, photo/phonophobia, and function. Logistic regression was used to compare group 1 vs group 2 and each eletriptan dose (2, 4, or 8 mg) vs placebo. Adverse events were also assessed. Results. Of 3217 subjects pooled from 5 studies, 2216 women were either in group 1 (n = 63) or group 2 (n = 1586). Rates of headache response at 2 hours were similar in group 1 vs group 2 (odds ratio [OR] = 1.11 [95% confidence interval (CI).91, 1.36]; P =.2944). The rate of headache recurrence was significantly higher in group 1 vs group 2 (26.8% vs 18.6%; OR = 1.67 [95% CI 1.23, 2.26]; P <.1). The odds of achieving sustained nausea responses were significantly lower in group 1 than in group 2 (OR =.7 [95% CI.54,.92]; P =.97). There was no significant difference between group 1 and group 2 in the odds of achieving a sustained photo/phonophobia and functional response (OR =.96 [95% CI.77, 1.2]; P =.7269 and OR = 1.14 [95% CI.87, 1.5]; P =.3425, respectively). Adverse events were comparable between group 1 and group 2. Conclusions. Two-hour headache outcome measures were similar in women treated with eletriptan both within and outside of the defined menstrual time period (menses days 1 to +4). The main treatment differences between the 2 groups occurred 2-24 hours post-treatment, with higher recurrence rates and lower sustained response rates for nausea in the group treated during the menstrual time period. Key words: eletriptan, headache, migraine, menses, menstrual migraine, triptan Abbreviations: AE adverse event, CI confidence interval, ICHD International Classification of Headache Disorders, ICHD-3 beta International Classification of Headache Disorders Third Edition beta version, MRM menstrually related migraine, NMM non-menstrual migraine, OR odds ratio, PMM pure menstrual migraine (Headache 214;54: ) From Pfizer Inc., New York, NY, USA (R. Bhambri, Y. Abdulsattar, M. Almas, A. Chatterjee, and E. Ramos); Division of General Internal Medicine, University of Cincinnati, Cincinnati, OH, USA (V.T. Martin); Thomas Jefferson University, Philadelphia, PA, USA (S. Silberstein). Address all correspondence to E. Ramos, Pfizer Inc., 235 East 42nd Street, 235/13/Office 16, New York, NY 117, USA, elodie.ramos@pfizer.com This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. Accepted for publication September 17,

2 344 February 214 INTRODUCTION Acute migraine is an episodic headache disorder characterized by various combinations of neurological, gastrointestinal, and autonomic nervous system changes. 1 About 3 million people in the United States have migraines, 2 and the estimated 1-year prevalence in 24 was 17% in women and 6% in men. 3 Approximately 5-6% of women describe an association between migraine and menstruation. 4,5 These migraines are not usually associated with aura, although this may occur in some cases. 4,6 The International Classification of Headache Disorders Third Edition beta version (ICHD-3 beta) defines 3 distinct categories of migraine without aura: pure menstrual migraine (PMM), menstrually related migraine (MRM), and non-menstrual migraine (NMM). 7 PMM attacks occur exclusively from days 2 to +3 of menstruation in at least 2 out of 3 menstrual cycles and at no other times of the cycle. MRM attacks occur on days 2 to +3 of menstruation in at least 2 out of 3 menstrual cycles and additionally at other times of the cycle. NMM attacks have no menstrual relationship. These definitions remain in the appendix rather than the main body of the classification because of uncertainty by the International Headache Society as to whether they should be regarded as separate entities. Compared with migraine attacks not related to menses, migraine attacks associated with menstruation have higher recurrence rates, longer duration, are more resistant to treatment, and are associated with greater functional disability, regardless of whether they are defined using ICHD criteria for MRM and NMM 8,9 or other definitions. 4,1-12 Triptan therapy has been shown to be effective and well tolerated in the treatment of menstrual migraine Eletriptan is a selective 5- hydroxytryptamine 1B/1D receptor agonist that is indicated for the acute treatment of migraine with or without aura in adults. The efficacy of eletriptan in treating migraine attacks associated with menstruation vs those outside a defined menstrual period has not been evaluated. The objective of this analysis was to compare the efficacy of eletriptan in the treatment of migraine attacks occurring during a defined menstrual time period (menses days 1 to +4) with those occurring outside of this menstrual time period (all other days outside of menses days 1 to +4), based on outcomes relating to a single index migraine. The available patient information did not allow classification according to the ICHD-3 beta definitions of PMM, MRM, and NMM. METHODS Study Design and Procedures. This analysis was performed on pooled data from 5 double-blind, randomized, placebo-controlled trials that assessed the efficacy and safety of eletriptan for the acute treatment of migraine. All studies had a similar design, and utilized similar entry criteria and outcome measures. Initially, 44 completed Phase III and IV eletriptan studies were screened for suitability, and 11 doubleblind, placebo-controlled studies were identified for further evaluation (Fig. 1). Of these, 5 studies met the inclusion criteria for the current analysis: enrolled adult patients; and had recorded information on whether the single index migraine had started within Conflict of Interest: R.B., M.A.,Y.A., and E.R. are paid employees of Pfizer Inc.A.C. was an employee of Pfizer at the time this study was conducted and the manuscript was drafted. V.M. has received a grant from GSK; has acted as consultant for Nautilus Pharma,Allergan, and Zogenix; and has acted as a speaker for Allergan and Zogenix. S.S. is on the advisory panel of and receives honoraria from Allergan, Capnia, Iroko Pharmaceuticals, Lilly, MAP, Medtronic, Neuralieve, NINDS, NuPathe, Pfizer, and St. Jude Medical; serves as a consultant for and receives honoraria from Alderbio, Amgen, Electrocore, Opti-Nose, and Zogenix; employer receives research support from Allergan, BMS, Cumberland, ElectroCore, Lilly, Merck, Merz, Opti-Nose, St. Jude Medical, and Troy Healthcare. Financial Support: This analysis was designed, undertaken, and funded by Pfizer Inc. Clinical Trial Registration Number: Not applicable. *Former Pfizer.

3 Headache 345 All completed phase III and IV eletriptan studies (44 studies) All double-blind, placebo-controlled studies (11 studies) Menstrual information available (6 studies) - Open-label (16 studies) - Active-control (4 studies) - Dose-ranging (2 studies) - Safety/non-interventional (8 studies) - Difference in design or special population (3 studies) No menstrual information (5 studies) Adolescent data (1 study) Enrolled adult subjects (5 studies; 3217 subjects) Women (n = 2796) Menstruation data not available (n = 58) Excluded Menstruation data available (n = 2216) Included Group 1 (n = 63) Group 2 (n = 1586) Fig 1. Selection of controlled studies and subjects for inclusion in pooled analysis. Group 1 = women with migraine beginning during the menstrual time period (days 1 to +4); group 2 = women with migraine beginning outside of the menstrual time period. the time period of 1 day before and 4 days after the onset of menstrual flow (menses days 1 to +4) in women. This definition describes a 5-day time period as the first day of menstruation was considered day 1 (there was no day ). The individual patient menstruation information available did not allow classification according to the ICHD-3 beta definitions. The relationship between migraine and menses was determined by the patient s response to the question Did the migraine headache begin between 1 day before and 4 days after the onset of menstrual flow? The studies included in this analysis were conducted before the ICHD definitions of PMM, MRM, and NMM were published. The primary data from 3 of these studies have been published elsewhere In all studies, patients aged 18 years and over were enrolled if they expected to have at least 1 acute migraine attack (with or without aura) within the next 6 weeks. Diagnosis of migraine was made according to the International Headache Society criteria. The key exclusion criteria were: pregnant or breast-feeding women; patients with concomitant frequent (non-migraine) headache; atypical migraine attacks consistently failing to respond to therapy; migraine with prolonged aura; presence of coronary artery disease, significant arrhythmias, heart failure, uncontrolled hypertension, or abnormal electrocardiogram; clinically significant active systemic, renal, hepatic, gastrointestinal, neurological, endocrine, metabolic, or psychiatric disease; subjects taking any experimental drug within the past month or who had previously taken oral eletriptan; and alcohol or substance misuse, including analgesics and ergotamine. In all studies, patients kept diary records of migraine symptoms for assessment of efficacy outcomes. Headache severity was rated on a -3 scale ( = none, 1 = mild, 2 = moderate, and 3 = severe) and the degree of functional impairment was also rated on a 4-point scale (no impairment, mild, moderate, and severe to bed rest) both at 2 and 24 hours after administration of the medication. The presence or absence of associated symptoms such as nausea and photo/ phonophobia at 2 and 24 hours was also recorded. Headache response was defined as an improvement from moderate to severe headache at baseline to a mild headache or no pain at 2 hours postdose. Headache recurrence was defined as the return of

4 346 February 214 headache to moderate or severe pain intensity within 22 hours of initial 2-hour headache response. Functional response was defined as an improvement in functional impairment from moderate or severe/bed rest to mild or no impairment at 2 and 24 hours. In all studies, medication was taken within 6 hours of onset of a moderate or severe migraine. For subjects who responded to the initial dose of study medication but whose headache subsequently returned, a second dose of study medication was permitted 2 hours after the initial dose. For subjects who did not respond to study medication, use of rescue medication was permitted 2 hours after initial dose of study medication. For all studies, the protocol was approved by Institutional Review Boards (Ethics Committees) at each site or country as appropriate and written informed consent was obtained from all subjects at the screening visit before study entry. Data Pooling and End Points. Individual patient data for all women enrolled in the 5 qualifying studies described above who had reported the required menstruation information were pooled for this analysis. For studies assessing multiple attacks, the first attack was used as the index attack.two groups were defined for this analysis: women with index migraine beginning during the defined menstrual (group 1) or nonmenstrual (group 2) time periods. The following traditional migraine headache end points were considered for this analysis: headache response at 2 hours, recurrence within 22 hours after initial 2-hour headache response, 2-hour absence of associated symptoms (nausea and photo/ phonophobia), and 2-hour functional response. In addition to the above traditional end points, the following more stringent end points were also explored: sustained nausea response, sustained photo/ phonophobia response, and sustained functional response. Sustained nausea response was defined as the subset of subjects who had nausea present at baseline that became absent 2 hours after the first dose of study medication and remained absent until 24 hours postdose, but did not take the second dose of study medication. Similarly, sustained photo/ phonophobia response was defined as the subset of subjects who had photo/phonophobia present at baseline that became absent 2 hours after the first dose of study medication and remained absent until 24 hours postdose, but did not take the second dose of study medication. Sustained functional response was defined as a change from moderate to severe functional impairment at baseline to no impairment or mild impairment 2 hours after the first dose, which was maintained until 24 hours postdose in the absence of a second dose. The frequency of adverse events (AEs) in groups 1 and 2 was also evaluated. The authors had full access to all the data from this analysis and take responsibility for the integrity of the data and the accuracy of the data analysis. Statistical Analyses. Statistical analyses were carried out using SAS Version 9 (SAS Institute, Cary, NC, USA) and were performed on the intentto-treat patient sample (defined as all patients who had a valid headache assessment at baseline and posttreatment). Logistic regression was used to assess the difference in efficacy between group 1 and group 2, and between eletriptan and placebo. The model included the response variables such as headache response at 2 hours and headache recurrence, and the covariates such as baseline headache severity, treatment dosage, and group. For sustained response assessment, the model included sustained response for each end point as the response variable, group as the main effect, and treatment dosage and protocol number as covariates; in the case of sustained functional response, the model also included severity of functional disability at baseline as a covariate. Logistic regression was also used to assess efficacy end points such as presence or absence of nausea and photo/phonophobia, and functional assessment and descriptive statistics are provided. AEs in groups 1 and 2 are also reported using descriptive statistics. RESULTS A total of 2796 women were pooled from the 5 randomized controlled trials (Fig. 1). Menstruation data were not available for 58 women in this population. Therefore, 2216 women were included in this analysis: 63 in group 1 and 1586 in group 2. Demographic and clinical characteristics for the subjects included in this analysis were generally similar in groups 1 and 2 (Table 1).

5 Headache 347 Table 1. Demographic Characteristics by Group and Dose E2 (n = 57) E4 (n = 254) E8 (n = 175) Placebo (n = 144) E2 (n = 11) E4 (n = 669) E8 (n = 472) Placebo (n = 335) Age in years, mean (SD) 38.3 (7.6) 36.5 (7.6) 37. (8.5) 36.7 (8.6) 36.7 (8.3) 37.5 (1.) 38.2 (1.2) 38. (1.1) Duration of illness in years, mean (SD) 16.5 (1.6) 14.8 (9.3) 14. (9.4) 15.2 (9.) 15.2 (1.7) 15.4 (1.8) 16.9 (1.6) 15.5 (11.2) Migraine type, n (%) With aura 7 (12.3) 34 (13.4) 13 (7.4) 2 (13.9) 8 (7.3) 96 (14.3) 48 (1.2) 29 (8.7) Without aura 38 (66.7) 158 (62.2) 121 (69.1) 96 (66.7) 73 (66.4) 421 (62.9) 327 (69.3) 231 (69.) Mixed 12 (21.1) 62 (24.4) 41 (23.4) 28 (19.4) 29 (26.4) 152 (22.7) 97 (2.6) 75 (22.4) Number of migraines over past 3 months, mean (SD) 8.3 (5.7) 9. (8.) 6.9 (4.6) 7.4 (5.1) 8.3 (5.) 8.2 (5.6) 8.4 (6.4) 8.5 (4.9) Number of moderate/severe migraines over past 3 months, mean (SD) 7.7 (4.8) 8. (6.4) 6.1 (4.) 6.5 (3.9) 7.5 (4.1) 7.3 (5.2) 7.4 (5.2) 7.6 (4.4) Index headache severity, n (%) Mild 1 (<1.) 2 (<1.) 2 (<1.) Moderate 38 (66.7) 18 (7.9) 111 (63.4) 1 (69.4) 87 (79.1) 444 (66.5) 31 (63.8) 28 (62.1) Severe 19 (33.3) 74 (29.1) 64 (36.6) 44 (3.6) 23 (2.9) 223 (33.4) 169 (35.8) 125 (37.3) Baseline symptoms present, n (%) Nausea 4 (7.2) 162 (64.3) 113 (64.9) 86 (59.7) 71 (64.5) 428 (64.3) 3 (63.6) 216 (64.7) Vomiting 19 (7.5) 7 (4.) 3 (2.1) 1 (<1.) 38 (5.7) 33 (7.1) 27 (8.1) Photo/phonophobia 51 (89.5) 226 (89.3) 152 (87.4) 129 (89.6) 94 (85.5) 592 (88.6) 411 (87.1) 294 (87.8) Baseline functional disability, n (%) Normal (no disability) 2 (<1.) 3 (1.7) 3 (2.1) 4 (3.6) 9 (1.3) 8 (1.7) 3 (<1.) Mild impairment 9 (15.8) 4 (15.8) 28 (16.2) 28 (19.6) 2 (18.2) 97 (14.5) 68 (14.4) 56 (16.8) Moderate impairment 36 (63.2) 154 (6.9) 97 (56.1) 87 (6.8) 68 (61.8) 386 (57.8) 27 (57.3) 19 (56.9) Severe impairment 12 (21.1) 57 (22.5) 45 (26.) 25 (17.5) 18 (16.4) 176 (26.3) 125 (26.5) 85 (25.4) E2 = eletriptan 2 mg; E4 = eletriptan 4 mg; E8 = eletriptan 8 mg; group 1 = women with migraine beginning during the menstrual time period (menses days 1 to +4); group 2 = women with migraine beginning outside of the menstrual time period; SD = standard deviation.

6 348 February 214 (A) 4 Patients with recurrence (%) *P <.1 OR = 1.67 (95% CI 1.23, 2.26)* n = 339 n = 83 (B) 4 Patients with recurrence (%) Eletriptan 2 mg Eletriptan 4 mg Eletriptan 8 mg Placebo n = 26 n = 162 n = 116 n = 35 n = 46 n = 382 n = 32 n = 1 Fig 2. Headache recurrence within 22 hours of initial 2-hour headache response: (A) all patients and (B) by dose. Group 1 = women with migraine beginning during the menstrual time period (days 1 to +4); group 2 = women with migraine beginning outside of the menstrual time period. The number at the foot of each bar denotes the total number of patients assessed in that group. Eletriptan and placebo subjects pooled. Headache Response, Absence of Associated Symptoms, and Functional Response Rates at 2 Hours. The rates of headache response at 2 hours were similar in group 1 and group 2 (odds ratio [OR] = 1.11 [95% confidence interval (CI).91, 1.36]; P =.2944). In group 1 and group 2, headache response at 2 hours was significantly higher for each eletriptan dose vs placebo (all P <.5). Likewise, the proportion of patients in group 1 and group 2 without nausea (OR = 1.6 [95% CI.57, 1.98]; P =.8531; adjusted for treatment), without photo/phonophobia (OR = 1.12 [95% CI.92, 1.36]; P =.2712; adjusted for treatment), and with a functional response (OR =.99 [95% CI.8, 1.23]); P =.9513; adjusted for treatment) was similar in group 1 and group 2, with higher response rates for each eletriptan dose vs placebo (all P <.5). Headache Recurrence. Headache recurrence within 22 hours of initial 2-hour headache response of a migraine attack was significantly higher in group 1 than in group 2, as shown in Figure 2A. Headache recurrence rates were numerically lower for each eletriptan dose compared with placebo in group 1 and for eletriptan 4 mg and 8 mg compared with placebo in group 2 (Fig. 2B). The odds of headache recurrence were significantly greater in the placebo group compared with the eletriptan 4 mg and eletriptan 8 mg groups (OR = 1.83 [95% CI 1.18, 2.83]; P <.1 and OR = 1.98 [95% CI 1.25, 3.14]; P <.1, respectively). Sustained Response Rates for Nausea, Photo/ Phonophobia, and Function. The odds of achieving a sustained nausea response were significantly lower in group 1 than in group 2 (Fig. 3A). The odds of achieving a sustained nausea response were significantly lower for placebo vs the 4 mg and 8 mg eletriptan doses (OR =.35 [95% CI.24,.5]; P <.1 and OR =.37 [95% CI.25,.54]; P <.1, respectively). There were no significant differences between group 1 and group 2 in the odds of achieving sustained photo/phonophobia and functional responses (Fig. 3C and 3E). However, the odds of achieving a sustained photo/phonophobia response were significantly lower for placebo vs each eletriptan dose (OR =.48 [95% CI.29,.82]; P =.73 vs eletriptan 2 mg; OR =.26 [95% CI.19,.37]; P <.1 vs eletriptan 4 mg; and OR =.2 [95% CI.14,.29]; P <.1 vs eletriptan 8 mg). Likewise, sustained functional responses were significantly lower for placebo vs each eletriptan dose (OR =.27 [95% CI.13,.55]; P =.3 vs eletriptan 2 mg; OR =.2 [95% CI.12,.33]; P <.1 vs eletriptan 4 mg; and OR =.19 [95% CI.11,.31]; P <.1 vs eletriptan 8 mg). For all 3 parameters, sustained response rates were numerically higher for each eletriptan dose vs placebo in both group 1 and group 2 (Fig. 3B,D,F). Safety. Menstrual status did not appear to affect tolerability, with all 3 eletriptan doses well tolerated in both groups. The occurrence of AEs was compa-

7 Headache 349 (A) 4 OR =.7 (95% CI.54,.92)* (B) Eletriptan 2 mg Eletriptan 4 mg Eletriptan 8 mg Placebo Patients with sustained nausea response (%) *P < n = 395 n = 995 Patients with sustained nausea response (%) n = 4 n = 161 n = 11 n = 84 n = 7 n = 42 n = 294 n = 211 (C) Patients with sustained photo/phonophobia response (%) *P =.7269 OR =.96 (95% CI.77, 1.2)* n = 547 n = 1368 (D) Patients with sustained photo/phonophobia response (%) Eletriptan 2 mg Eletriptan 4 mg Eletriptan 8 mg Placebo n = 51 n = 221 n = 148 n = 127 n = 94 n = 582 n = 42 n = 29 (E) Patients with sustained functional response (%) *P =.3425 OR = 1.14 (95% CI.87, 1.5)* n = 59 n = 131 (F) Patients with sustained functional response (%) Eletriptan 2 mg Eletriptan 4 mg Eletriptan 8 mg Placebo n = 48 n = 21 n = 14 n = 111 n = 86 n = 557 n = 392 n = 275 Fig 3. Twenty-four-hour sustained response rates by group and dose: nausea in (A) all patients and (B) by dose; photo/ phonophobia in (C) all patients and (D) by dose; functional response in (E) all patients and (F) by dose. Group 1 = women with migraine beginning during the menstrual time period (days 1 to +4); group 2 = women with migraine beginning outside of the menstrual time period. The number at the foot of each bar denotes the total number of patients assessed in that group. Eletriptan and placebo subjects pooled. rable between groups 1 and 2; the proportion of patients with any AEs were group 1: eletriptan 2 mg 29.8%, 4 mg 4.2%, 8 mg 47.4%, and placebo 42.4%; and group 2: eletriptan 2 mg 39.1%, 4 mg 42.6%, 8 mg 55.7%, and placebo 38.8%. There was a similar dose response effect in both groups, with a modest increase in the rate of any AEs with increasing eletriptan dose. The most common treatmentemergent AEs were asthenia, chest pain, dry mouth, nausea, vomiting, dizziness, hypertonia, and somnolence. Serious AEs were experienced by 5 patients: 1 in group 1 eletriptan 2 mg dose, 3 in group 2 eletriptan 4 mg dose, and 1 in group 2 placebo. The proportion of patients discontinuing due to AEs in

8 35 February 214 the eletriptan 2 mg, 4 mg, 8 mg, and placebo groups were group 1: 5.3%, 1.6%, 3.4%, and 2.1%, respectively; and group 2:.9%,.6%, 2.8%, and 1.5%, respectively. Dose was reduced or temporarily discontinued because of an AE in 2 patients in group 2 eletriptan 8 mg dose and 2 patients in group 2 placebo. DISCUSSION In this pooled analysis of data from 5 doubleblind, randomized, placebo-controlled trials, the efficacy of eletriptan in treating moderate or severe migraine in women was similar for migraines beginning during menstrual and non-menstrual time periods, as assessed by headache response, absence of nausea and photo/phonophobia, and functional response at 2 hours after administration of the study medication. The main differences between the 2 groups occurred within clinical end points that were measured 2-24 hours postdose. The odds of headache recurrence were 67% higher during the defined menstrual vs non-menstrual time period, and the odds of achieving a sustained nausea response were 3% lower during the menstrual time period. This suggests that migraines occurring during the menstrual time period have a longer duration and are more likely to be associated with a lower rate of sustained nausea response. In women receiving treatment during menstrual time periods, eletriptan was significantly more effective than placebo on all outcome measures. At 2 hours, headache response rates and the proportions of patients without associated symptoms and with a functional response were significantly higher for each eletriptan dose vs placebo during menses. The odds of headache recurrence were significantly higher for placebo vs eletriptan 4 mg and 8 mg, and the odds of a sustained nausea response were significantly lower for placebo vs these 2 eletriptan doses during menses. Furthermore, the odds of sustained photo/ phonophobia and functional responses were significantly lower for placebo compared with all 3 eletriptan doses assessed. Although women receiving eletriptan 8 mg were included in this analysis, the maximum recommended single dose in the product label is 4 mg in the United States. 31 It is interesting that sustained response rates for nausea were lower during menstrual time periods while those related to photo/phonophobia and function did not differ between the 2 groups. This apparent discrepancy might be explained in several different ways. First, certain outcome measures such as sustained response rates for nausea may be more dependent than others upon the hormonal changes encountered during menstrual time periods. Second, outcome measures may differ in their responsiveness to abortive medications. Third, non-hormonal factors may be more important for certain outcome measures such as functional response. For example, a recent study found that comorbid medical and psychiatric disorders accounted for 65% of the migrainerelated disability experienced by persons with migraine. 32 This is the first assessment of eletriptan efficacy in the acute treatment of migraine attacks occurring during menstruation and one of the largest analyses assessing this patient population. In this analysis, menses-associated migraine was defined using the criteria of a single index migraine beginning during menses days 1 to +4 and was compared with migraine occurring outside of menses days 1 to +4. This definition was used based on patient-level data available from the randomized studies included in this analysis. It could not be confirmed whether migraines also ended within the defined menstrual time period, and information was not available in order to determine PMM and MRM according to the ICHD-3 beta definitions. Previous retrospective analyses have assessed the efficacy of triptans for the treatment of migraine associated with menstruation. However, the definitions of migraine associated with menstruation vary in those reports, making comparison with our findings difficult. Nonetheless, the results of those reports are generally consistent with our findings in that there were no differences in triptan efficacy in treating migraine associated with menstruation with outcome measures recorded 2 hours after triptan administration. A retrospective analysis of data from 2 large, randomized trials indicated that rizatriptan 1 mg showed similar efficacy in treating a single migraine attack associated with menses (occurring ±3 days from menses onset)

9 Headache 351 and migraine outside of this window. Pain relief at 2 hours was achieved in 68% vs 69% of patients, respectively. 26 Both trials in that analysis were double-masked, placebo-controlled, incomplete block, 2-period, crossover trials in which patients were instructed to take medication when they developed a moderate/severe migraine that was not resolving spontaneously. Treatment of migraine may be more effective if medication is taken early when the pain is mild However, early intervention trials have found no differences in 2-hour outcomes according to menstrual status. In a post-hoc analysis of data from an early intervention trial of almotriptan 12.5 mg, similar responses were seen in menses-associated migraine (defined as migraine occurring ±2 days from first day of menstrual flow) and migraine outside of this window, with 2-hour pain relief rates of 77.4% vs 68.3%, respectively (defined as a decrease in baseline pain intensity from severe or moderate to mild or no pain). 27 Furthermore, the pain free at 2 hours response rates were also similar, and there were no differences in migraine-associated symptoms and functional disability. 27 In that double-blind, randomized, placebocontrolled trial, patients were instructed to take study medication within 1 hour of onset of any level of headache pain typical of their usual migraine for 3 consecutive migraines. Furthermore, a prospective subgroup analysis of 2 trials found no difference in the proportion of patients achieving pain-free status at 2 hours with rizatriptan for MRM compared with non-mrm, as defined by ICHD-second edition criteria. 25 Both trials were randomized, placebocontrolled, double-blind, early intervention trials in which rizatriptan 1 mg or placebo was taken within 1 hour of migraine onset while pain was mild. Our findings support the existing evidence of a higher rate of recurrence in migraine occurring during menstrual time periods. In a headache diary study, Granella et al reported a significantly higher mean number of recurrences per attack in migraine starting 2 days before the onset of bleeding (.8 ±.8; P =.2) and in migraine starting in the first 2 days of menstruation (.9 ±.9; P =.1) vs migraine starting outside of menses days 2 to +7 (.5 ±.9). 11 Another study also found higher recurrence rates in those attacks that were menstrually related than in those that were non-menstrually related (36.% vs 19.6%). 8 In contrast, in the retrospective analysis of rizatriptan trials by Silberstein et al described above, recurrence rates were similar in women with a menstruationassociated attack (occurring ±3 days from onset of menses) and those with a non-menses-related attack in the 1 mg dose group, although the authors noted that the sample sizes for recurrence estimates were relatively small. 26 The higher recurrence rates noted for attacks treated during perimenstrual time periods can likely be explained by the fact that menstrually related attacks have a longer duration than nonmenstrually related attacks. Pinkerman and colleagues reported a duration of 23.4 hours for menstrually related attacks and 16.1 hours for nonmenstrually related attacks. 8 We speculate that the longer duration may occur as a result of the persistence of hormonal triggers that may span several days during the menstrual time period. There is strong evidence that estrogen plays a key role in menstrual migraine. 4 The decline in serum estrogen levels that occurs during the perimenstrual time period has been shown to be associated with an increased probability of migraine attacks, 36 and supplementation of estrogen during perimenstrual periods can prevent migraine attacks. 37,38 In addition to estrogen withdrawal, other factors may be involved in precipitating menses-associated migraine, including low serum progesterone, release of prostaglandins from the endometrium during the menstrual cycle, and low serum magnesium, all of which may activate or sensitize the trigeminal nervous system to increase susceptibility to migraine and associated symptoms during the perimenstrual period. 39 The main limitation of this study is that the definitions of migraine associated with menstruation and migraine not related to menses differ from the ICHD-3 beta definitions of PMM, MRM, and NMM. Individual patient menstruation information was limited in the studies included in this pooled analysis and did not allow for classification according to the ICHD-3 beta definitions. Our grouping was based only on the index migraine, whereas ICHD-3 beta PMM and MRM definitions are based on information from at least 3 menstrual cycles. It is therefore pos-

10 352 February 214 sible that women included in this analysis may have experienced an attack that coincidentally occurred within the defined menstrual window. Some patients with PMM according to ICHD-3 beta may not have been included in group 1 as we did not have information on menses day 2, although this number is likely to be very small. Furthermore, we were not able to differentiate ICHD-3 beta PMM from MRM for this investigation. Additionally, this was a post-hoc data analysis and therefore subject to all of the limitations inherent in such analyses; prospective clinical trials would be helpful in further clarifying the natural history and treatment response of migraine related to menses as defined using the ICHD-3 beta definitions. However, in the absence of prospective trials, this analysis provides useful information on the efficacy of eletriptan in migraine beginning during menstruation. Its strengths are the large sample size and the homogeneity of the studies included, which had very similar designs, patient populations, and efficacy measures. In conclusion, the results of this pooled analysis indicate that eletriptan has similar efficacy and tolerability in the acute treatment of migraine occurring during menstrual and non-menstrual time periods when evaluating outcome measures 2 hours after administration of the medication. However, migraine was more likely to recur 2-24 hours postdose, and treatment was less likely to provide sustained relief from nausea during the menstrual time period. These findings support past research demonstrating that attacks of menstrual migraine are more refractory to acute therapy than attacks treated during nonmenstrual time periods. Acknowledgment: Medical writing support was provided by Helen Varley, PhD, CMPP, at Engage Scientific Solutions, Horsham, UK, and was funded by Pfizer Inc. STATEMENT OF AUTHORSHIP Category 1 (a) Conception and Design Vincent T. Martin, Mary Almas, and Anjan Chatterjee (b) Acquisition of Data Mary Almas (c) Analysis and Interpretation of Data Rahul Bhambri, Vincent T. Martin, Younos Abdulsattar, Stephen Silberstein, Mary Almas, Anjan Chatterjee, and Elodie Ramos Category 2 (a) Drafting the Manuscript Rahul Bhambri, Younos Abdulsattar, Mary Almas, and Elodie Ramos (b) Revising It for Intellectual Content Vincent T. Martin, Stephen Silberstein, and Anjan Chatterjee Category 3 (a) Final Approval of the Completed Manuscript Rahul Bhambri, Vincent T. Martin, Younos Abdulsattar, Stephen Silberstein, Mary Almas, Anjan Chatterjee, and Elodie Ramos REFERENCES 1. Silberstein SD. Migraine. Lancet. 24;363: Lipton RB, Stewart WF, Diamond S, Diamond ML, Reed M. Prevalence and burden of migraine in the United States: Data from the American Migraine Study II. Headache. 21;41: Lipton RB, Bigal ME, Diamond M, Freitag F, Reed ML, Stewart WF. Migraine prevalence, disease burden, and the need for preventive therapy. Neurology. 27;68: Brandes JL. The influence of estrogen on migraine: A systematic review. JAMA. 26;295: MacGregor EA. Menstrual migraine: Therapeutic approaches. Ther Adv Neurol Disord. 29;2: Allais G, Benedetto C. Update on menstrual migraine: From clinical aspects to therapeutical strategies. Neurol Sci. 24;25(Suppl. 3):S229-S Headache Classification Committee of the International Headache Society. The International Classification of Headache Disorders, 3rd edition (beta version). Cephalalgia. 213;33: Pinkerman B, Holroyd K. Menstrual and nonmenstrual migraines differ in women with menstruallyrelated migraine. Cephalalgia. 21;3: MacGregor EA, Victor TW, Hu X, et al. Characteristics of menstrual vs nonmenstrual migraine: A post hoc, within-woman analysis of the usual-care phase of a nonrandomized menstrual migraine clinical trial. Headache. 21;5:

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