Menstrual Migraine Research Articles

An Analysis of Migraine Triggers in a Clinic‐Based Population

Many migraineurs report attack "triggers," but relatively few published data exist regarding the relative prevalences of individual triggers, variations related to gender, duration of migraine or migraine subtype, or the existence of any regional variations in the prevalences and distributions of triggers. We sought to determine the prevalence and types of migraine triggers in our clinic population, to determine what influence gender, migraine subtype, or duration of migraine might have on the prevalences and types of triggers reported and to compare our findings with data derived from surveys we previously had conducted involving 2 clinic-based populations and 1 general population sample from other regions of the USA. We evaluated 200 consecutive new migraine patients referred to our clinic. All patients specifically were queried as to whether they had noted any of 7 specific factors to serve consistently as migraine attack triggers and additionally were surveyed as to whether they might have "other" triggers not listed on the intake questionnaire. Among the other data collected and analyzed were age, gender, age at time of migraine onset, and migraine subtype (ie, episodic vs chronic). Actively cycling females who reported menses as a trigger were questioned as to whether their menstrual migraine (MM) attacks differed from their non-menstrual migraines and, if so, how they differed. One hundred and eighty-two patients (91%) reported at least 1 migraine trigger, and 165 (82.5%) reported multiple triggers. The most common trigger reported (59%) was "emotional stress," followed by "too much or little sleep" (53.5%), "odors" (46.5%), and "missing meals" (39%). Females or subjects of either gender with chronic migraine were no more likely than males or subjects with episodic migraine to report triggers or multiple triggers. Similarly, longer exposure to migraine did not correlate with a higher likelihood of reporting a trigger or multiple triggers. Fifty-three (62%) of 85 actively cycling females reported menses as a trigger, and of the 51 with menstrually related migraine, 34 (67%) reported their MM to be more severe, more refractory to symptomatic therapy or of longer duration than their non-menstrual attacks; 13 (24.5%) of the 53 women with apparent MM reported their MM to be at least occasionally manifested as status migrainosus. The prevalence and type of triggers reported by this predominantly white female population were similar to those reported by clinic-based populations in San Diego, California and Mobile, Alabama, and in a population-based sample of Hispanics in San Diego County. A large majority of migraineurs report migraine attack triggers, and the triggers most commonly reported include emotional stress, a disrupted sleep pattern, and various odors. These findings do not appear to vary according to geographic region or race/ethnicity. Among the triggers, MM appears inclined to provoke headache that is more severe, less amenable to treatment, or longer in duration than headaches that occur at other times during the cycle.

Management of Menstrual Migraine: A Review of Current Abortive and Prophylactic Therapies

After menarche, women have an increased prevalence of migraine compared to men. There is significant variability in the frequency and severity of migraine throughout the menstrual cycle. Women report migraines occur more frequently during menses, and that those are more severe than other migraines. This creates a unique challenge of effectively treating menstrually related and pure menstrual migraines. As with treatment of other migraines, both abortive and prophylactic treatment regimens are used. Triptans demonstrate efficacy in the abortive management of menstrually related and pure menstrual migraines. For migraines that occur primarily during menses or that are particularly resistant to other therapies, intermittent prophylactic therapies can be used. Naproxen and estrogens have been studied for this use. More recently, triptans have been examined and have shown efficacy for intermittent prophylaxis of menstrual migraine.

Genetics of Menstrual Migraine: The Epidemiological Evidence

Approximately one of every three to five women with migraine without aura experience migraine attacks in relation to menstruation. The International Classification of Headache Disorders, 2nd Edition provides appendix diagnoses for pure and menstrually related migraine without aura that need further validation. Probands with menstrual migraine might have more affected relatives than probands with nonmenstrual migraine. However, precise epidemiological, family, and twin data still are lacking.

Clinical Trials Report: Sumatriptan–Naproxen Combination for Symptomatic Treatment of Comorbid Dysmenorrhea and Migraine

Dysmenorrhea and headache are common menstrual disorders, affecting millions of women worldwide. Both of these conditions are associated with significant disability resulting in work or school absenteeism and substantially impaired quality of life. Migraine is a recurrent headache disorder estimated to affect at least 15% of the population, and is defined as episodic headaches lasting 4 to 72 h, accompanied by photophobia, phonophobia, nausea and vomiting, and restricted activity [1]. The condition is more prevalent in women than in men, with 4 of every 10 women experiencing migraine in their lifetime, most before the age of 35 years [2]. In population-based studies, around 50% of women with migraine report an association between migraine and menstruation [3]. The peak incidence of migraine during the menstrual cycle is on or between 2 days before the onset of menstrual flow and the first 3 days of bleeding [4]. The term menstrual migraine is used to describe attacks that regularly occur at this time [1]. Primary dysmenorrhea is the occurrence of painful menstrual cramps of uterine origin in the absence of pathology. The exact prevalence is unclear, although it is probable that most women experience dysmenorrhea at some time during their reproductive years. Cramps usually develop within hours of the start of menstruation and peak during the first 48 to 72 h of the cycle, when the flow becomes heaviest. Naproxen is an NSAID. NSAIDs are non-narcotic analgesics recommended as first-line treatment for primary dysmenorrhea, relieving symptoms in up to 70% of women [5]. Naproxen also is effective for the management of moderate to severe migraine, reducing headache intensity, rendering patients pain-free at 2 h, and improving migraineassociated symptoms [6]. Sumatriptan was the first triptan to be developed of seven triptans currently available, with established efficacy for symptomatic treatment of migraine [7]. The sumatriptan–naproxen sodium combination (sumatriptan, 85 mg, formulated with RT Technology, and naproxen sodium, 500 mg, in a single-tablet formulation [Treximet; GlaxoSmithKline, Research Triangle Park, NC]) is a more recent advance for symptomatic treatment of migraine and has been shown to be more effective in restoring normal function following treatment than either sumatriptan or naproxen sodium alone [8]. Prostaglandins have been implicated in the pathophysiology of both menstrual migraine and dysmenorrhea, E. A. MacGregor The City of London Migraine Clinic, 22 Charterhouse Square, London EC1M 6DX, UK

Report of a randomised trial of acupuncture as prophylaxis for menstrual migraine

Report of a randomised trial of acupuncture as prophylaxis for menstrual migraine

Catamenial migraine: epidemiology, pathogenesis, diagnosis, clinical features

Based on a review of the literature, the authors consider the pathogenesis, diagnosis, epidemiology, and clinical features of catamenial migraine. The view that catamenial migraine attacks are severest receives more and more support. The criteria that may be used to predict a severer course of catamenial migraine attacks in a specific patient are to be further defined.

Chronotypes in menstrual migraine: a case–control study

Migraine attacks have a seasonal, menstrual and circadian periodicity, suggesting a role of chronobiological mechanisms probably related to a hypothalamic involvement. The aim of the study was to evaluate the chronotypes in patients with menstrual migraine, a migraine sub-type with a cyclical recurrence compared to normal female. Ninety-three patients with ICHD-II diagnosis of pure menstrual migraine and menstrually-related migraine were recruited and compared to 85 age-matched healthy women. The Italian version of Morningness-Eveningness Questionnaire was administered to identify circadian preference of our participants. No differences were found regarding the distribution of chronotypes in patients with menstrual migraine and healthy controls. The study did not confirm the presence of a morning and evening preference among migraineurs as previously reported.

Changes in Salivary Prostaglandin Levels During Menstrual Migraine With Associated Dysmenorrhea

To measure prostaglandin levels in the saliva of individuals during menstrual migraine associated with dysmenorrhea (MMaD) and in response to treatment with a single tablet combination of sumatriptan succinate and naproxen sodium. Prostaglandins are thought to play a role in MMaD as elevated serum prostaglandin levels have been reported during attacks of menstrual migraine and are increased in the menstrual fluid of women with dysmenorrhea. While triptans are the primary line of migraine treatment, nonsteriodal anti-inflammatory drugs are the most commonly prescribed therapy for dysmenorrhea symptoms. Data from recent clinical studies have provided evidence that treatment with a single tablet combination of sumatriptan and naproxen sodium is an effective abortive therapy for attacks of MMaD. Women diagnosed with MMaD were treated with a sumatriptan succinate and naproxen sodium single tablet combination or placebo at time of migraine attack. Saliva samples were collected at time of attack as well as 2 and 4 hours after treatment. PGD(2), PGE(2), PGF(2), PGI(2), and TXA(2) levels were determined by enzyme-linked immunosorbent assay. Elevated levels of PGD(2), PGF(2), and TXA(2) at 2 and 4 hours and PGE(2) at 4 hours were found in saliva obtained from placebo subjects when compared with onset of attack levels. However, in subjects treated with a single tablet combination of sumatriptan and naproxen sodium, the levels of PGD(2), PGF(2), and PGE(2) were not elevated at either time point while TXA(2) levels were still elevated at 4 hours. Data from this pilot study provide evidence that saliva levels of several prostaglandins increase during attacks of MMaD and that treatment with a single tablet combination of sumatriptan and naproxen sodium prevents elevation of prostaglandin levels.

Perimenstrual Eletripan Prevents Menstrual Migraine: An Open‐Label Study

To prospectively evaluate the efficacy of perimenstrual prophylaxis with eletriptan to reduce headaches in women identified with menstrual migraine (MM). Female migraineurs self-reporting a substantial relationship between migraine and menses were evaluated with 3 consecutive months of daily headache recording diaries. A relationship between menses and migraine was evaluated using International Classification of Headache Disorders (ICHD-II) criteria and a probability model called Probability MM. Women prospectively diagnosed with ICHD-II MM were treated for 3 consecutive months with perimenstrual eletriptan 20 mg 3 times daily starting 2 days prior to the expected onset of menstruation and continued for a total of 6 days. Headache activity was compared during the 3 months of recording prior to eletriptan therapy and 3 months with eletriptan perimenstrual prevention therapy. Three months of pretreatment prospective diaries were completed by 126 women. ICHD-II menstrually related migraine was diagnosed in 74%, with pure MM in 7%. Among those women diagnosed with ICHD-II MM, 61 completed at least 1 treatment month. Overall change in headache activity was a 46% decrease. The mean percentage of treated menses without migraine occurring during the 6 days of treatment was 71%. The percentage of subjects with 1, 2, and 3 migraine-free menstrual periods (no migraines occurring 2 days before menses through the first 3 days of menstruation) with eletriptan, respectively, were 14%, 19%, and 53%. Among those subjects who remained headache-free during the 6 days of eletriptan treatment, migraine occurred during the 3 days immediately after discontinuing eletriptan for 9%. Perimenstrual eletriptan was generally tolerated and no abnormalities were identified on the 6(th) day of treatment using either blood pressure recording or electrocardiogram. Among patients with prospectively identified MM, eletriptan 20 mg 3 times daily effectively reduced MM. A significant reduction in headache activity occurred for 53% of patients.

A Prospective Comparison Between ICHD‐II and Probability Menstrual Migraine Diagnostic Criteria

To prospectively evaluate the diagnosis of menstrual migraine (MM) by comparing 2 diagnostic systems. Female migraineurs self-reporting a substantial relationship between migraine and menses were evaluated with 3 consecutive months of daily headache recording diaries. A relationship between menses and migraine was evaluated using International Classification of Headache Disorders (ICHD-II) criteria and a probability model called Probability MM. Three months of pretreatment prospective diaries were completed by 126 women. ICHD-II menstrually related migraine was diagnosed in 73.8% with pure MM in 7.1%. ICHD-II and Probability diagnoses agreed for all cases of ICHD-II non-MM and pure MM, with disagreement among women diagnosed with ICHD-II menstrually related migraine, only half of whom were identified as having a relationship with menses greater than chance alone using the Probability model. Interestingly, 20% of those women self-reporting a substantial relationship between migraine and menses were not prospectively diagnosed with MM using either diagnostic system. Differences in menstrual vs nonmenstrual headaches were greater when using the Probability model. Prospective headache diaries are needed to diagnose MM. A probability-based method, which considers the chance occurrence of headaches during the menstrual cycle, identifies fewer women as having menstrually related migraine compared with the diary-based methods recommended by the current ICHD-II candidate criteria.

Characteristics of Menstrual vs Nonmenstrual Migraine: A Post Hoc, Within‐Woman Analysis of the Usual‐Care Phase of a Nonrandomized Menstrual Migraine Clinical Trial

To compare, using a within-woman analysis, the severity, duration, and relapse of menstrual vs nonmenstrual episodes of migraine during treatment with usual migraine therapy. Studies comparing the clinical characteristics of menstrual and nonmenstrual migraine attacks have yielded conflicting results, contributing to disagreement regarding whether menstrual migraine attacks are clinically more problematic than nonmenstrual migraine attacks. Post hoc within-woman analysis of the usual-care phase (month 1) of a 2-month, multicenter, prospective, open-label study at 21 US medical practices (predominantly primary care). Participants were women > or =18 years of age with regular predictable menstrual cycles (28 +/- 4 days) who self-reported a > or =1-year history of migraine attacks occurring between days -2 and +3 (menses onset = day +1) and > or =8 such attacks within the previous 12 cycles. Migraine treatment episodes were categorized as menstrual (occurring on days -2 to +3 of menses) or nonmenstrual (occurring on days +4 to -3 of menses). Pain severity, functional impairment, duration, relapse in 24 hours, and use of rescue medication were compared. Sources of variability (within- or between-patient) were determined using mathematical modeling. The http://www.clinicaltrial.gov code for trial is NCT00904098. Women (n = 153; intent to treat) reported 212 menstrual (59.2%) and 146 nonmenstrual (40.8%) migraine treatment episodes. Compared with nonmenstrual treatment episodes, menstrual episodes were more likely to cause impairment (unadjusted odds ratio, 1.65, 95% CI, 1.05-2.60; P = .03), were longer (unadjusted hazard ratio 1.68; 95% CI, 1.31-2.16; P < .001), and were more likely to relapse within 24 hours (unadjusted odds ratio, 2.66; 95% CI, 1.25-5.68; P = .01). Within-patient effects accounted for only 18-33% of the total variance in these outcomes. Post hoc, within-woman analysis of migraine treatment episodes categorized based on International Headache Society criteria showed that menstrual treatment episodes were more impairing, longer lasting, and more likely to relapse than nonmenstrual treatment episodes in this selected population of women with frequent menstrual migraine. The current analysis indicates that most of the variability in these outcomes is due to differences between headache types and not within-patient differences for a given type of headache, suggesting that menstrual episodes are potentially treatable. These findings underscore the differences between menstrual and nonmenstrual episodes of migraine and the need to offer effective migraine treatment to women.

Safety and tolerability of frovatriptan in the acute treatment of migraine and prevention of menstrual migraine: Results of a new analysis of data from five previously published studies

Triptans are a recommended first-line treatment for moderate to severe migraine. Using clinical trial data, we evaluated the safety and tolerability of frovatriptan as acute treatment (AT) and as short-term preventive (STP) therapy for menstrual migraine (MM). Data from 2 Phase III AT trials (AT1: randomized, placebo controlled, 1 attack; AT2: 12-months, noncomparative, open label) and 3 Phase IIIb STP trials in MM (MMP1 and MMP2: randomized, placebo controlled, double blind, 3 perimenstrual periods; MMP3: open label, noncomparative, 12 perimenstrual periods) were analyzed. In AT1, patients treated each attack with frovatriptan 2.5 mg, sumatriptan 100 mg, or placebo. In AT2, they used frovatriptan 2.5 mg. In MMP1 and MMP2, women administered frovatriptan 2.5 mg for 6 days during the perimenstrual period, taking a loading dose of 2 or 4 tablets on day 1, followed by once-daily or BID frovatriptan 2.5 mg, respectively; in MMP3, they used BID frovatriptan 2.5 mg. In AT1, which was previously published in part, group differences in adverse events (AEs) were analyzed using the Fisher exact test, and response rates were compared using logistic regression. Post hoc analyses of sustained pain-free status with no AEs (SNAE) and sustained pain response with no AEs (SPRNAE) were performed using a 2-sample test for equality of proportions without continuity correction. For AT2 and the STP studies, data were summarized using descriptive statistics. Results of individual safety analyses for the STP studies were previously reported; the present report includes new results from a pooled analysis of MMP1 and MMP2 and a new analysis of MMP3 in which AEs were coded using Medical Dictionary for Regulatory Activities version 8.0. AT1 included 1206 patients in the safety group; AT2 included 496. In the STP studies, safety data were collected for 1487 women. In AT1 and AT2, 85.6% and 88.3%, respectively, of enrolled patients were women. Overall, AEs were generally mild to moderate (AT studies: 82.3%-90.0%; STP studies: 78.9%89.5%). In AT1, 27.3% (131/480) of frovatriptan patients, 33.4% (161/482) of sumatriptan patients, and 14.8% (36/244) of placebo patients experienced an AE considered possibly or probably related to treatment (P < 0.001 for either drug vs placebo).There were no significant differences between frovatriptan and sumatriptan in SNAE at 4 to 24 hours or in SPRNAE at 2 to 24 hours or at 4 to 24 hours. In randomized, controlled STP trials for MM, AEs were reported by 57.8% (166/287, BID) and 63.4% (210/331, once daily) of frovatriptan users versus 62.8% (216/344) of placebo recipients. There were no consistent differences in AEs reported by patients with potential cardiovascular risk or in AEs related to the use of estrogencontaining contraceptives (ECCs). In randomized controlled trials and 12-month open-label studies, frovatriptan was well tolerated in these women during AT and STP therapy for MM. Subgroup analyses provide preliminary evidence of tolerability in women using ECCs and in women with comorbidities that do not contraindicate triptan use but may be suggestive of cardiovascular risk.

Menstrual and nonmenstrual migraines differ in women with menstrually-related migraine

We compared migraine features and acute therapy response in menstrually-related migraines (MRMs) and non-menstrually-related migraines (NMRMs). Women with frequent, disabling migraines were prospectively diagnosed with MRM according to the International Classification of Headache Disorders (ICHD-II; N = 107) criteria using a daily electronic headache dairy. Participants received individualized acute therapy while free of prophylactic migraine medications. Repeated measures logistic regression revealed MRMs were longer (23.4 vs. 16.1 hours, odds ratio [OR] = 1.01, confidence interval [CI] 1.01, 1.02) and more likely associated with disability (85.6% vs. 75.6%, OR = 1.82, CI 1.27, 2.58) than NMRMs. MRMs were also less responsive to acute therapy (two-hour pain-free response = 6.7% vs. 13.4%, OR = .45, CI .26, .80) and reoccurred more frequently within 24 hours after a four-hour pain-free response (36.0% vs. 19.6%, OR = 2.12, CI 1.27, 3.53) than NMRMs. These results support the proposed ICHD-II classification of MRMs and suggest that MRMs may require a treatment approach different from that for NMRMs.

Self-reported menstrual migraine in the general population

A number of women with migraine experience increased incidence of attacks during the perimenstrual period. The Appendix of the International Classification of Headache Disorders (ICHD II) describes two types of migraine without aura related to menstruation: pure menstrual migraine (PMM) and menstrually related migraine (MRM). The phrase “menstrual migraine” is often used to cover both PMM and MRM. Although menstrual migraine is well recognized, further scientific evidence is needed before these definitions can be formally included in the ICHD III. The aim of the present study was to investigate the prevalence of PMM and MRM in the general population in Norway. The survey included 15,000 women, 30–44 years old, residing in the eastern part of Norway. They received a postal questionnaire containing six questions about migraine, headache frequency and the relation of migraine and menstruation. The study included 11,123 women. The questionnaire response rate was 77%. The prevalence of self-reported migraine was 34.8%. Of the migraineurs, 21% reported migraine related to menstruation in at least two of three menstrual cycles, of which 7.7% were considered to have PMM and 13.2% MRM. This corresponds to the prevalence of PMM and MRM in the general population of 2.7 and 4.6%, respectively. Thus, self-reported menstrual migraine among women aged 30–44 years appears to be common in the general population in Norway.

Perimenstrual headache: Migraine without aura or premenstrual syndrome symptom?

Definition of menstrual migraine as a specific clinical entity or, maybe, migraine headache with menstrually related occurring, still remains unresolved question. The aim of this study was to investigate if perimenstrual headache in our patients fulfills diagnostic the International Classification of Headache Disorders (ICHD) criteria for migraine without aura or represents a different type of headache which is the symptom of premenstrual syndrome (PMS). The study included 50 women with headache in perimenstrual period in at least two out of three menstrual cycles, during the last year or longer. Two questionnaires, a questionnaire for headache and a questionnaire for PMS, were used. The majority of all the examined women, 29 of them, had migraine and PMS and 9 women had migraine without PMS. Headache in 38 (76.0%) patients fulfilled diagnostic criteria for menstrual migraine, (26 and 12 women had pure menstrual migraine and menstrually related migraine respectively). Intensity of PMS was not different in a groups of women with different types of headache (p = 0.184): a total number of PMS symptoms was 8.2 +/- 4.6 in the group with pure menstrual migraine, 10.8 +/- 3.9 in the group with menstrually related migraine and 10.8 +/- 6.3 in the group with non-migraine headache. This study shows that headache, occurring in perimenstrual period, is not always migraine, but could fulfill criteria for tension-type headache, as well. Specific characteristics of perimenstrual headache, which could distinguish it as a symptom of PMS, were not found. Expected relation in time of headache onset and menarche was not confirmed.

Short-Term Frovatriptan for the Prevention of Difficult-To-Treat Menstrual Migraine Attacks

The efficacy of a 6-day regimen of frovatriptan for menstrual migraine (MM; attacks starting on day -2 to +3 of menses) prevention in women with difficult-to-treat MM was assessed. Women with a documented inadequate response to triptans for acute MM treatment were included in this placebo-controlled, parallel-group trial. Women were randomized to double-blind treatment for three perimenstrual periods (PMPs) with either frovatriptan 2.5 mg (q.d. or b.i.d.) or placebo initiated 2 days before anticipated MM. The efficacy analysis included 410 women with 85% completing three double-blind PMPs. The mean number of headache-free PMPs was 0.92 with frovatriptan b.i.d., 0.69 with frovatriptan q.d. and 0.42 with placebo [P < 0.001 (b.i.d.) and P < 0.02 (q.d.) vs. placebo]. When migraine occurred, severity was reduced with frovatriptan q.d. (P < 0.001) and b.i.d. (P < 0.001) vs. placebo. Both frovatriptan regimens were well tolerated. In women with difficult-to-treat MM, a 6-day regimen of frovatriptan significantly reduced MM incidence and severity.

Scheduled Short‐Term Prevention With Frovatriptan for Migraine Occurring Exclusively in Association With Menstruation

This post hoc subgroup analysis evaluated scheduled short-term preventive frovatriptan therapy for women with migraine occurring exclusively in association with menstruation (occurring day -2 to +3; day 1 = menses start, no migraines outside this window). A previously published randomized, double-blind, placebo-controlled 3-way crossover trial assessed the efficacy and safety of a scheduled 6-day preventive regimen with frovatriptan for the treatment of menstrual migraine; the study population included women experiencing both menstrual and non-menstrual migraine and women experiencing only menstrual migraine. Women received each treatment (placebo, frovatriptan 2.5 mg once daily, and frovatriptan 2.5 mg twice daily) once over 3 perimenstrual periods in randomized sequence. For this subset analysis, screening questions were used to identify women with migraine occurring exclusively in association with menstruation. Efficacy was evaluated by occurrence and severity of migraine, functional impairment, and rescue medication use. Adverse events and tolerability were also assessed. Among 179 patients, the mean age (SD) was 37.3 (7.7) years and mean menstrual migraine history was 10.6 (8.7) years. Significantly fewer women experienced menstrual migraine during treatment with frovatriptan twice daily (37.7%, P < .001) or once daily (51.3%, P = .002) than during treatment with placebo (67.1%); a significant dose response was noted (P = .01, twice daily vs once daily). Significant treatment differences were also found for several secondary endpoints, but the data from this post hoc analysis must be interpreted with caution. Frovatriptan was well tolerated and most adverse events were mild or moderate and similar to those reported with the acute treatment of migraine with frovatriptan; the most common adverse events were nausea, dizziness, and headache. Scheduled short-term preventive frovatriptan therapy effectively reduced the occurrence of menstrual migraine in women with attacks occurring exclusively in association with menstruation.

Safety and Tolerability of Short‐Term Preventive Frovatriptan: A Combined Analysis

To assess the safety and tolerability profile of the 5-HT(1B/1D) agonist frovatriptan (Frova(R), Endo Pharmaceuticals Inc., Chadds Ford, PA, USA) when used as a 6-day regimen for the short-term prevention of menstrual migraine scheduled over multiple perimenstrual periods. Two randomized controlled trials have established the efficacy of a 6-day regimen of frovatriptan for reducing the incidence and severity of menstrual migraine over 1 to 3 perimenstrual periods; long-term data are needed to further assess the safety and tolerability profile of this regimen. Two multinational trials were included in the analysis: Study 1 was a randomized, placebo-controlled double-blind parallel trial (3 perimenstrual periods treated) with an open-label extension (3 additional perimenstrual periods treated), and Study 2 was a long-term (12 perimenstrual periods treated over 12-15 months) open-label study. Enrolled women experienced menstrual migraine defined as predictable migraine attacks that started -2 days to +3 (Study 1) or +4 (Study 2) days relative to the first day of menses and that occurred in at least 2 out of 3 menstrual cycles. Frovatriptan or placebo was given 2 days before anticipated menstrual migraine and continued for 6 days. Adverse events, serious adverse events, vital signs, cardiovascular events, electrocardiograms, and laboratory parameters were assessed and recorded periodically and summarized using descriptive statistics. Adverse event data from Study 1 and Study 2 were compared using event rates. The demographic characteristics of the 2 study populations were similar: the mean age was approximately 38 years, > or =94% of participants were white, and 85% reported menstrual migraine began on days -2 to +1 of the menstrual cycle. The mean reported history of menstrual migraine was approximately 11 years. A large percentage of the respective safety populations completed each study or study period: 87% (362/416) and 88% (273/309) completed the double-blind period and open-label periods of Study 1, respectively, and 59% (308/525) completed treatment of 12 perimenstrual periods in Study 2. Major reasons for discontinuation in Study 1 included adverse events (5%, double-blind period) and "other" (10% double-blind period and 5% open-label period). In Study 2, major reasons for discontinuation included patient request (17.3%) and adverse event (10.2%). The most common treatment emergent adverse events in the double-blind period of Study 1 (placebo vs frovatriptan twice daily) were upper respiratory infection (9% vs 9%), nausea (6% vs 8%), dizziness (7% vs 7%), fatigue (4% vs 7%), dysmenorrhea (3% vs 7%), influenza (3% vs 6%), neck pain (4% vs 6%), and migraine (4% vs 4%). With the exception of migraine (which was reported using a different method in each study), prevalence rates for Studies 1 and 2 were numerically similar. The most frequently reported cardiovascular adverse events during double-blind treatment (placebo vs frovatriptan twice daily) were chest discomfort (2% and 3%), chest pain (2% and 2%), and hypertension (0 and 2%). The corresponding adverse event rates in Study 2 were 2% (chest pain), 3% (chest discomfort), and 3% (hypertension). In both studies, most adverse events were of mild or moderate intensity and their incidence numerically declined with each perimenstrual period/cycle, as did the incidence of menstrual migraine. The observed rate of intercurrent migraine in Study 2 over 12 perimenstrual periods was 1.5 per month, compared with 1.7 at baseline. There was no observable increase in the first occurrence of migraine in the 5 days following the perimenstrual period, indicating a lack of rebound headache. During treatment of up to 12 perimenstrual periods over a 12- to 15-month period, the safety and tolerability of frovatriptan for short-term prevention of menstrual migraine was similar to that observed with acute use of triptans. Adverse events were generally mild or moderate in severity, there was no evidence of an increased risk of cardiovascular adverse events relative to acute treatment, and rebound headache was not evident. A short-term regimen with frovatriptan presents a safe and viable treatment option for preventing predictable migraine such as menstrual migraine.

Frovatriptan for Acute Treatment of Migraine Associated with Menstruation: Results from an Open-Label Postmarketing Surveillance Study

To examine the effectiveness and tolerability of acute treatment with frovatriptan in women experiencing menstrual migraine (MM) vs. female migraineurs with non-MM. This was an open-label postmarketing surveillance study (n = 7107) conducted in Germany to assess acute treatment with frovatriptan in one to three migraine attacks. This retrospective subanalysis evaluated acute frovatriptan treatment in women who experienced >or=1 MM attack vs. those women with non-MM attacks. Effectiveness and tolerability were graded using a 4-point scale (1 = very good, 2 = good, 3 = satisfactory, 4 = poor). Demographics were similar in MM (n = 1931) and non-MM patients (n = 2080), except that mean age (38.3 vs 45.3 years, respectively) and number of migraine attacks per month were less in the MM group than in the non-MM group (both p < 0.001). Although 98% of women reported that their previous migraines were moderate or severe, only one third in each treatment group previously used triptans. Prestudy medications were rated as good or very good for effectiveness by 20.3% and 19.2% of the MM and non-MM groups, respectively. In contrast, the effectiveness of frovatriptan was rated as very good or good by 92.7% and 90.9% of women in the MM and non-MM groups, respectively. Forty-three percent and 96% of all women rated their previous medication and frovatriptan, respectively, as having good or very good tolerability. Among women rating their previous medication as poor or satisfactory, most (94%) rated frovatriptan as very good or good. Acute frovatriptan treatment improved patient ratings of treatment effectiveness and tolerability in women with migraine associated with menses.

Combination Treatment for Menstrual Migraine and Dysmenorrhea Using Sumatriptan–Naproxen

To evaluate the efficacy and tolerability of sumatriptan-naproxen during the mild pain phase of a single menstrual migraine attack associated with dysmenorrhea. Two replicate randomized, multicenter, double-blind, placebo-controlled, trials of adults with menstrual migraine and dysmenorrhea were conducted. Participants treated their menstrual migraine attack during the mild pain phase (within 1 hour of onset) with sumatriptan 85 mg and naproxen sodium 500 mg in a single fixed-dose formulation (sumatriptan-naproxen) or placebo. The primary endpoint was 2-hour pain-free response. Sumatriptan-naproxen was statistically superior to placebo in both studies (n=311, Study 1; n=310, Study 2) for 2-hour and, 2- to 24-hour sustained pain-free response, use of headache and menstrual rescue medications, and several nonpain menstrual symptom categories. Two-hour pain-free rates were Study 1, 42% compared with 23%, and Study 2, 52% compared with 22%, P<.001. Two- to 24-hour sustained pain-free rates were Study 1, 29% compared with 18%, P=.022; Study 2, 38% compared with 10%, P<.001. Headache and menstrual medication rates were Study 1, 37% compared with 53%, P=.005; Study 2, 31% compared with 69%, P<.001. Women treated with sumatriptan-naproxen continued to be pain free through 48 hours compared with placebo: Study 1, 26% compared with 17%, P=.040; Study 2, 28% compared with 8%, P<.001. No serious adverse events were reported in either study; nausea and dizziness were the most frequently reported adverse events. Sumatriptan-naproxen provided an effective pain-free response at 2 hours, which was maintained up to 48 hours in menstrual migraineurs with dysmenorrhea. Sumatriptan-naproxen was well-tolerated and resulted in decreased rescue medication use and relief of nonpainful menstrual symptoms. ClinicalTrials.gov, www.clinicaltrials.gov, NCT00329459 and NCT00329355 I.