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REVIEW ARTICLE

Drugs 2010; 70 (14): 1799-1818 0012-6667/10/0014-1799/$55.55/0

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Prevention and Treatment of Menstrual Migraine


E. Anne MacGregor1,2
1 The City of London Migraine Clinic, London, England 2 Centre for Neuroscience and Trauma, Blizard Institute of Cell and Molecular Science, Barts and the London School of Medicine and Dentistry, London, England

Contents
Abstract. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1. Literature Search Strategy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2. Acute Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1 Efficacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2 Safety and Tolerability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3. Prophylaxis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1 Perimenstrual (Short-Term/Intermittent Prevention) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.1 NSAIDs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.2 Triptans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.3 Estrogen . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.4 Magnesium. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.5 Vitamin E . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2 Continuous Hormonal Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.1 Combined Hormonal Contraceptives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.2 Estradiol Implants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.3 Phytoestrogens. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.4 Gonadotrophin-Releasing Hormone Analogues. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3 Continuous Nonhormonal Methods. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3.1 Bromocriptine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3.2 Anti-Estrogens. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4 Practical Recommendations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1799 1800 1800 1801 1806 1806 1806 1806 1810 1812 1812 1812 1813 1813 1813 1813 1813 1813 1813 1815 1815 1815

Abstract

Migraine is a prevalent headache disorder affecting three times more women than men during the reproductive years. Menstruation is a significant risk factor for migraine, with attacks most likely to occur on or between 2 days before the onset of menstruation and the first 3 days of bleeding. Although menstrual migraine has been recognized for many years, diagnostic criteria have only recently been published. These have enabled better comparison of the efficacy of drugs for this condition. Acute treatment, if effective, may be all that is necessary for control. Evidence of efficacy, with acceptable safety and tolerability, exists for sumatriptan 50 and 100 mg, mefenamic acid 500 mg, rizatriptan 10 mg and combination sumatriptan/ naproxen 85 mg/500 mg. However, there is evidence that menstrual attacks

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are more severe, longer, less responsive to treatment, more likely to relapse and associated with greater disability than attacks at other times of the cycle. Prophylactic strategies can reduce the frequency and severity of attacks and acute treatment is more effective. Predictable menstrual attacks offer the opportunity for perimenstrual prophylaxis taken only during the time of increased migraine incidence. There is grade B evidence of efficacy for shortterm prophylaxis with transcutaneous estradiol 1.5 mg, frovatriptan 2.5 mg twice daily and naratriptan 1 mg twice daily. Contraceptive strategies offer the opportunity for treating menstrual migraine in women who also require effective contraception.

Migraine is a prevalent disorder, affecting at least 1114% of the population.[1-3] Diagnostic features accompanying headache include photophobia, nausea and limitation of usual daily activities (table I).[5] Four of every ten women and two of every ten men will experience migraine in their lifetime, most before the age of 35 years.[6] For both sexes, migraine prevalence is highest in the peak reproductive years, although the prevalence is greater in women. By age 30 years, migraine is 3-fold higher in women than in men, the peak periods for migraine risk in women being at age 25 8.6 years and 50 15.8 years.[1] Menstruation is a significant risk factor for migraine.[7] In population- and clinic-based studies, between 20% and 60% of women with migraine report an association between migraine and menstruation.[8-14] Attacks are most likely to occur on or between 2 days before menstruation and the first 3 days of bleeding.[13,15-22] Menstrual attacks are almost invariably without aura, even in women who have attacks with aura at other times of the cycle.[13,17,22,23] Based on these findings, the International Headache Society (IHS) Classification of Headache Disorders includes specific definitions for pure menstrual migraine and menstrually related migraine (table II).[4] For most women with menstrual attacks, migraine also occurs at other times of the month (menstrually related migraine).[4,13] Fewer than 10% of women report migraine exclusively with menstruation and at no other time of the month (pure menstrual migraine).[4,8,11-14] Menstrual migraine is also associated with increased menstrual distress and disability.[24,25] Attacks are more severe and disabling, last longer
2010 Adis Data Information BV. All rights reserved.

and are less responsive to symptomatic medication than attacks at other times of the cycle.[10,14,19,26-30] Disability does not only affect the individual but extends to affect family members, friends and work colleagues.[14] The recognition of menstrual migraine as a clinical entity has resulted in specific clinical trials assessing the efficacy, safety and tolerability of acute and prophylactic treatments for this condition, which are discussed in this review. Proposed research criteria for menstrual migraine were only issued in 2004.[4] The considerable variability in definitions used for earlier studies limits direct comparison of the results.[31] 1. Literature Search Strategy Data for this review were identified by a MEDLINE search last conducted in July 2010 using the search terms estrogen, estradiol, menstruation, menstrual cycle, menstrual migraine, menstrually related migraine, menstrually associated migraine, migraine, prevention, treatment. No inclusion/exclusion criteria were specified. Publications were scrutinized for relevancy to this review. In addition, references from the authors own files, a hand-search of the journals Cephalalgia and Headache, and peer-reviewed presentations at international congresses were considered. 2. Acute Treatment No drugs are approved specifically for the acute treatment of menstrual migraine; however, since menstrual attacks, by definition, fulfil the IHS criteria for migraine, treatments licensed for
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Table I. Diagnostic criteria for migraine without aura (adapted from the Headache Classification Subcommittee of the International Headache Society[4]) A. B. C. At least five attacks fulfilling criteria BD Headache attacks lasting 472 hours (untreated or unsuccessfully treated) Headache has at least two of the following characteristics: 1. Unilateral location 2. Pulsating quality 3. Moderate or severe pain intensity 4. Aggravation by or causing avoidance of routine physical activity (e.g. walking or climbing stairs) D. During headache at least one of the following: 1. Nausea and/or vomiting 2. Photophobia and phonophobia E. Not attributed to another disorder

migraine are also indicated for the treatment of menstrual migraine.[4]


2.1 Efficacy

Data from randomized placebo-controlled trials for the acute treatment of menstrual attacks of migraine are available for the nonprescription combination of acetaminophen (paracetamol), aspirin and caffeine (AAC; Excedrin Migraine, Bristol-Myers Squibb Company, New York, NY, USA); the NSAID mefenamic acid; five of the seven available triptans (almotriptan, naratriptan, rizatriptan, sumatriptan, zolmitriptan); and a sumatriptan/naproxen combination (table III). An evidence-based systematic review and metaanalysis concluded that, based on trial quality, evidence supported grade B recommendations for use of sumatriptan 50 and 100 mg, mefenamic acid 500 mg and rizatriptan 10 mg for acute treatment of menstrual migraine.[51] Trial quality also supports grade B recommendations (good evidence of efficacy, benefits outweigh harms, improves important health outcomes) for the combination of sumatriptan/naproxen 85 mg/500 mg.[48] Abstract reports of efficacy are available for eletriptan and frovatriptan. With respect to eletriptan, an abstract report of a post hoc analysis of six randomized controlled trials evaluated efficacy in the acute treatment of migraine occurring between day -1 and day +4 of the menstrual
2010 Adis Data Information BV. All rights reserved.

cycle.[52] Headache response at 2 hours after treatment was achieved in 64% of the eletriptan 40 mg group, 68% of the 80 mg group and 26% of the placebo group (p < 0.001 for both comparisons). An abstract of a post hoc analysis of frovatriptan for acute treatment reported overall migraine relief within 24 hours in 82% of menstrual attacks and 87% of nonmenstrual attacks. The time to overall relief was a little longer in menstrual attacks (5.5 vs 3.6 hours).[53] A post hoc subanalysis of an open-label, postmarketing surveillance study of acute treatment with frovatriptan rated prestudy medications as good or very good for effectiveness by 20.3% and 19.2% of the menstrual migraine and nonmenstrual migraine 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 menstrual migraine and nonmenstrual migraine groups, respectively.[54] It is important to note that post hoc analyses of efficacy comparing menstrual and nonmenstrual attacks are based on pooled data from migraine trials, not within-woman analyses of trials undertaken specifically on menstrual migraine. Results from pooled data suggest no difference in efficacy of acute treatments for menstrual versus nonTable II. Diagnostic criteria for pure menstrual migraine and menstrually related migraine (adapted from the Headache Classification Subcommittee of the International Headache Society [IHS][4]) Pure menstrual migraine without aura A. B. Attacks, in a menstruating woman, fulfilling IHS criteria for migraine without aura Attacks occur exclusively on day 1 2 (i.e. days -2 to +3)a of menstruationb in at least two out of three menstrual cycles and at no other times of the cycle Attacks, in a menstruating woman, fulfilling IHS criteria for migraine without aura Attacks occur on day 1 2 (i.e. days -2 to +3)a of menstruationb in at least two out of three menstrual cycles and additionally at other times of the cycle The first day of menstruation is day 1 and the preceding day is day -1; there is no day 0. For the purposes of this classification, menstruation is considered to be endometrial bleeding resulting from either the normal menstrual cycle or from the withdrawal of exogenous progestogens, as in the case of combined oral contraceptives and cyclical hormone replacement therapy.

Menstrually related migraine without aura A. B.

a b

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Table III. Acute treatment of menstrual attacks of migraine Trial, year AAC Silberstein et al.,[32] 1999 Post hoc analysis of pooled data from three single-attack RCTs 185 menstrual attacks; 393 nonmenstrual attacks Acetaminophen (paracetamol) 500 mg, aspirin 500 mg, caffeine 130 mg vs placebo during moderate or severe pain Menstrual attacks: 2-h response: AAC 61% vs placebo 29% (p < 0.001) 2-h pain free: AAC 25% vs placebo 6% (p < 0.001) Nonmenstrual attacks: 2-h response: AAC 58% vs placebo 33% (p < 0.001) 2-h pain free: AAC 21% vs placebo 7% (p < 0.001) Trial design No.a Treatment Resultsb

Mefenamic acid Al-Waili,[33] 2000 Crossover 24 Mefenamic acid 500 mg vs placebo tid from onset of menstrual migraine until end of bleeding 2-h pain response: mefenamic acid 79.1% vs placebo 16.4% (p < 0.05)

Triptans Almotriptan Diamond et al.,[34] 2008 Post hoc analysis of parallel RCT 190 Almotriptan 12.5 mg vs placebo during mild, moderate or severe pain within 1 h of onset (placebo data not reported) Menstrual attacks: 2-h response: almotriptan 77.4% 2-h pain free: almotriptan 35.4% Sustained pain free: almotriptan 22.9% Nonmenstrual attacks: 2-h response: almotriptan 68.3% 2-h pain free: almotriptan 35.9% Sustained pain free: almotriptan 23.8% 2-h response: almotriptan 12.5 mg 67.9% vs zolmitriptan 2.5 mg 68.6% (p = 0.9) 2-h pain free: almotriptan 12.5 mg 44.9% vs zolmitriptan 2.5 mg 41.2% (p = 0.554) Sustained pain free: almotriptan 12.5 mg 29.3% vs zolmitriptan 2.5 mg 27.1% (p = 0.698)

Allais et al.,[35] 2006

Parallel RCT

255

Almotriptan 12.5 mg vs zolmitriptan 2.5 mg during moderate or severe pain

Frovatriptan Allais et al.,[36] 2008 Open-label 20 Frovatriptan 2.5 mg for migraine in the pill-free wk of combined oral contraceptives 2-h relief: frovatriptan 2.5 mg 55% 2-h pain free: frovatriptan 2.5 mg 10%

Naratriptan Massiou et al.,[37] 2005 Single-attack RCT 229 Naratriptan 2.5 mg vs placebo during mild, moderate or severe pain 2-h pain free: naratriptan 2.5 mg 43% vs placebo 25% (p = 0.004) 4-h pain free: naratriptan 2.5 mg 58% vs placebo 30% (p < 0.001) Continued next page

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Prevention and Treatment of Menstrual Migraine

Table III. Contd Trial, year Rizatriptan Martin et al.,[38] 2008 Post hoc analysis of pooled data from two single-attack RCTs 94 Rizatriptan 10 mg vs placebo during mild pain Menstrual attacks: 2-h pain free: rizatriptan 10 mg 63.5% vs placebo 29% (p = 0.002) Nonmenstrual attacks: 2-h pain free: rizatriptan 10 mg 57.5% vs rizatriptan 5 mg 32.9% (p > 0.05) Study 1: 2-h response: rizatriptan 10 mg 70% vs placebo 53% (p = 0.001) Study 2: 2-h response: rizatriptan 10 mg 73% vs placebo 50% (p = 0.001) Pooled data ICHD pure menstrual migraine: 2-h response: rizatriptan 10 mg 73% vs placebo 50% (p = 0.006) 2-h pain free: rizatriptan 10 mg 42% vs placebo 12% (p-value not assessed) Sustained pain free: rizatriptan 10 mg 23% vs placebo 10% (p-value not assessed) Pooled data ICHD menstrually related migraine: 2-h response: rizatriptan 10 mg 71% vs placebo 52% (p < 0.001) 2-h pain free: rizatriptan 10 mg 36% vs placebo 19% (p-value not assessed) Sustained pain free: rizatriptan 10 mg 24% vs placebo 14% (p-value not assessed) Menstrual attacks (ICHD timing): 2-h response: rizatriptan 10 mg 78% 2-h pain free: rizatriptan 10 mg 48% Sustained pain free: rizatriptan 10 mg 32% Nonmenstrual attacks: 2-h response: rizatriptan 10 mg 78% 2-h pain free: rizatriptan 10 mg 52% Sustained pain free: rizatriptan 10 mg 37% Menstrual attacks: 2-h response: rizatriptan 10 mg 68% vs rizatriptan 5 mg 70% vs placebo 44% (p < 0.05) 2-h pain free: rizatriptan 10 mg 42% vs rizatriptan Continued next page Trial design No.a Treatment Resultsb

Nett et al.,[39] 2008; Mannix et al.,[40] 2007

Two single-attack RCTs of ICHD menstrual migraine

707

Rizatriptan 10 mg vs placebo during moderate or severe pain

Silberstein et al.,[41] 2002

Post hoc analysis of openlabel extension study

95 421 menstrual attacks; 1418 nonmenstrual attacks

Rizatriptan 10 mg during moderate or severe pain

Silberstein et al.,[42] 2000

Post hoc analysis of pooled data from two crossover RCTs

335 menstrual attacks; 393 nonmenstrual attacks

Rizatriptan 5 mg vs rizatriptan 10 mg vs placebo during moderate or severe pain

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Table III. Contd Trial, year Trial design No.a Treatment Resultsb 5 mg 33% vs placebo 12% (p < 0.05) Nonmenstrual attacks: 2-h response: rizatriptan 10 mg 69% vs rizatriptan 5 mg 66% (p > 0.05) 2-h pain free: rizatriptan 10 mg 37% vs rizatriptan 5 mg 31% (p > 0.05) Sumatriptan Schreiber and Cady,[43] 2007 Dowson et al.,[29] 2005 Open-label 31 Sumatriptan 100 mg during moderate or severe pain Sumatriptan 100 mg vs placebo during moderate or severe pain 2-h response: sumatriptan 70% 2-h pain free: sumatriptan 41% Menstrual attacks: 4-h response: sumatriptan 100 mg 67% vs placebo 33% (p = 0.0072) 4-h pain free: sumatriptan 100 mg 49% vs placebo 10% (p = 0.0001) Nonmenstrual attacks: 4-h response: sumatriptan 100 mg 79% vs placebo 31% (p < 0.0001) 4-h pain free: sumatriptan 100 mg 60% vs placebo 9% (p < 0.0001) Study 1: 2-h pain free: sumatriptan 50 mg 51% vs sumatriptan 100 mg 58% vs placebo 22% (p < 0.001) Sustained pain free: sumatriptan 50 mg 30% vs sumatriptan 100 mg 35% vs placebo 8% (p < 0.001) Study 2: 2-h pain free: sumatriptan 50 mg 51% vs sumatriptan 100 mg 61% vs placebo 29% (p < 0.001) Sustained pain free: sumatriptan 50 mg 30% vs sumatriptan 100 mg 31% vs placebo 14% (p < 0.001) Attack 1: 1-h response: sumatriptan 71% vs placebo 22% (p < 0.001) 2-h response: sumatriptan 73% vs placebo 31% (p < 0.001) 2-h pain free: sumatriptan 55% vs placebo 14% Continued next page

Crossover RCT

93

Landy et al.,[44] 2004; Nett et al.,[45] 2003

Two single-attack RCTs

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Sumatriptan 50 mg vs sumatriptan 100 mg vs placebo during mild, moderate and severe pain

Facchinetti et al.,[46] 1995

Parallel RCT

179

Subcutaneous sumatriptan 6 mg vs placebo during moderate or severe pain

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Prevention and Treatment of Menstrual Migraine

Table III. Contd Trial, year Trial design No.a Treatment Resultsb Attack 2: 1-h response: sumatriptan 70% vs placebo 24% (p < 0.001) 2-h response: sumatriptan 81% vs placebo 29% (p < 0.001) 2-h pain free: sumatriptan 55% vs placebo 14% Solbach and Waymer,[47] 1993 Post hoc analysis of pooled data from two single-attack RCTs 157 menstrual; 512 nonmenstrual attacks Subcutaneous sumatriptan 6 mg vs placebo during moderate or severe pain Menstrual attacks: 1-h response: sumatriptan 80% vs placebo 19% (p < 0.001) Nonmenstrual attacks: 1-h response: sumatriptan 70% vs placebo 20% (p < 0.001)

Sumatriptan/naproxen Mannix et al.,[48] 2009 Two single-attack RCTs 621 Sumatriptan 85 mg, naproxen 500 mg vs placebo during mild pain Study 1: 2-h pain free: sumatriptan/naproxen 42% vs placebo 23% (p < 0.001) Pain free through 48 h: sumatriptan/naproxen 26% vs placebo 17% (p = 0.04) Study 2: 2-h pain free: sumatriptan/naproxen 52% vs placebo 22% (p < 0.001) Pain free through 48 h: sumatriptan/naproxen 28% vs placebo 8% (p < 0.001)

Zolmitriptan Tuchman et al.,[49] 2006 Allais et al.,[35] 2006 Single-attack RCT 334 Zolmitriptan 2.5 mg vs placebo during moderate or severe pain Zolmitriptan 2.5 mg vs almotriptan 12.5 mg during moderate or severe pain 2-h response: zolmitriptan 2.5 mg 65.7% vs placebo 32.8% (p < 0.0001) 2-h response: zolmitriptan 2.5 mg 68.6% vs almotriptan 12.5 mg 67.9% (p = 0.9) 2-h pain free: zolmitriptan 2.5 mg 41.2% vs almotriptan 12.5 mg 44.9% (p = 0.554) Sustained pain free: zolmitriptan 2.5 mg 27.1% vs almotriptan 12.5 mg 29.3% (p = 0.698) 2-h response: zolmitriptan 2.5 mg 48% vs placebo 27% (p < 0.0001)

Post hoc analysis of parallel RCT

255

Loder et al.,[50] 2004 a b

Parallel RCT

597

Zolmitriptan 1.25 mg (for mild pain), 2.5 mg (for moderate pain) or 5 mg (for severe pain) vs placebo

No. of patients unless specified. Percentage of patients unless specified.

AAC = acetaminophen (paracetamol), aspirin plus caffeine; ICHD = International Headache Society Classification of Headache Disorders; RCTs = randomized controlled trials; tid = three times daily.

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menstrual attacks.[32,34,35,38,42,47] In contrast, results from prospective clinical trials in women diagnosed with menstrual migraine confirm the clinical impression that menstrual attacks do not respond as well to acute treatment as nonmenstrual attacks.[29,55] This difference may be because pooled data will include menstrual attacks occurring by chance rather than by a confirmed association between migraine and menstruation.
2.2 Safety and Tolerability

The single-dose combination of AAC was well tolerated for both menstrual and nonmenstrual attacks. Nausea (menstrual attacks: AAC 10.3%, placebo 1.0%, p = 0.006; nonmenstrual: AAC 3.8%, placebo 2.5%, nonsignificant), dizziness (menstrual attacks: AAC 1.1%, placebo 1.0%, nonsignificant; nonmenstrual: AAC 4.1%, placebo 1.5%, p = 0.030) and nervousness (menstrual attacks: AAC 8.0%, placebo 0%, p = 0.004; nonmenstrual: AAC 4.3%, placebo 0.7%, p = 0.001) were the most common adverse events.[32] Treatment with the NSAID mefenamic acid 500 mg initiated at the onset of a menstrual attack and continued 8-hourly for the duration of menstruation resulted in no adverse effects reported except for two patients who experienced mild epigastric pain with mefenamic acid but who continued the study.[33] Triptans are also well tolerated for the acute treatment of menstrual migraine, with adverse events similar to those reported in other triptan clinical trials.[29,34-43,45-50,54] 3. Prophylaxis The goals of prophylactic strategies are to reduce attack frequency, severity and duration, improve responsiveness to treatment of acute attacks, and improve function and reduce disability.[56] A number of different treatment strategies have been studied for the prevention of menstrual migraine in randomized placebo-controlled trials and open-label studies. An evidence-based systematic review and meta-analysis concluded that, based on trial quality, evidence supported grade B recommendations for use of transcutaneous
2010 Adis Data Information BV. All rights reserved.

estradiol 1.5 mg, frovatriptan 2.5 mg twice daily and naratriptan 1 mg twice daily for prophylactic treatment of menstrual migraine.[51] Prophylaxis is particularly suited to those women who have inadequate relief from the usual forms of acute therapy or who are troubled by headache recurrence and require multiple doses of acute migraine medications. Since no investigations can identify the most effective prophylactic for each individual, an empirical approach is necessary, considering also the need for contraception and co-morbid menstrual problems. It must be noted that none of the perimenstrual or continuous strategies reviewed is licensed for prevention of menstrual migraine. Prescribers should ensure that they follow their organizations policy on the use of medicines outside of the terms of the product licence.
3.1 Perimenstrual (Short-Term/Intermittent Prevention)

Women who have regular periods and a predictable relationship between migraine and menstruation can be treated with short-term preventive therapy during the perimenstrual period, typically starting treatment a few days before expected onset of menstruation or the anticipated menstrual attack (table IV). Women with menstrual irregularity can use a home-use fertility monitor to predict menstruation.[80] Short-term prevention strategies have the advantage that treatment is only used at the time of need, thus avoiding continuous exposure to active drug and the potential for adverse events associated with daily prophylaxis.[81]
3.1.1 NSAIDs

Open-label studies using perimenstrual naproxen 500550 mg once daily suggest efficacy of this approach for menstrual migraine.[57,59] Randomized studies using naproxen 550 mg twice daily perimenstrually have confirmed efficacy with good tolerability.[60,61] Sances et al.[60] noted that 25% of women taking naproxen reported mild or moderate nausea and epigastric distress but all continued treatment. Rofecoxib was not associated with gastrointestinal symptoms in an open-label study.[63]
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Table IV. Perimenstrual prophylaxis Trial, year NSAIDs Naproxen Guidotti et al.,[57] 2007; North American Menopause Society,[58] 2010 Allais et al.,[59] 2007 14 500 mg PO od Baseline untreated cycle followed by one treated cycle 2 days before anticipated menstrual migraine Duration 6 days Open-label Median score of headache severity: baseline 4.3; during treatment 3.9 No. of pts Dose Treatment cycles, timing and trial design Results

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Prevention and Treatment of Menstrual Migraine

20

550 mg PO od

Baseline untreated cycle followed by three treated cycles on days -7 to +7, then three treated cycles on days -5 to +5 Open-label Baseline untreated two cycles followed by three treated cycles Days -7 days to +6 RCT Baseline untreated two cycles followed by four treated cycles Treatment started 8 days after ovulatory temperature rise (day -2/-3) to day +8 RCT

Baseline no. of attacks: 1.7 0.11 End of month 3: 1.2 0.10 (p < 0.001) End of month 6: 1.1 0.07 (p < 0.0001)

Sances et al.,[60] 1990

35

550 mg PO bid

No significant difference in Pain Total Index [no. of attacks + (duration severity)] 16.7% patients in first treatment month with naproxen and 33% in second and third month reported absence of migraine vs 0% placebo Frequency reduced with both naproxen and placebo. Reduction in frequency by naproxen greater than placebo (p = 0.02) Reduction in HI >44%: naproxen 68% vs placebo 36% (p = 0.03)

Szekely et al.,[61] 1989

22

550 mg PO bid

Nimesulide Giacovazzo et al.,[62] 1993 30 100 mg PO tid Two cycles First day of menstrual migraine Duration 10 days Parallel RCT Pain intensity and duration reduced during treatment with nimesulide vs placebo (p = 0.0001)

Rofecoxib Von Seggern et al.,[63] 2004 14 25 mg or 50 mg PO od Baseline untreated cycle followed by two treated cycles Days -5 to +5 Mean migraine frequency decreased from 5.6 to 2.6 migraines per menstrual cycle (p = 0.005) 57% reported 50% reduction in headache frequency

Triptans Frovatriptan Silberstein et al.,[64] 2009 179 2.5 mg PO bid 2.5 mg PO od Three cycles 2 days before anticipated menstrual migraine Duration 6 days Post hoc subgroup analysis of Silberstein et al.[65] Migraine incidence 37.7% during bid treatment, 51.3% during od treatment (p = 0.002), 67.1% with placebo

Continued next page

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Table IV. Contd Trial, year Brandes et al.,[66] 2009 No. of pts 410 Dose 2.5 mg PO bid 2.5 mg PO od Treatment cycles, timing and trial design Three cycles 2 days before anticipated menstrual migraine Duration 6 days Parallel RCT Baseline untreated cycle followed by one treated cycle 2 days before anticipated menstrual migraine Duration 6 days Open-label Three cycles 2 days before anticipated menstrual migraine Duration 6 days Crossover RCT Results 0.92 headache-free treatment periods during bid treatment, 0.69 during od treatment, 0.42 with placebo (p < 0.001 and p < 0.02 vs placebo)

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1808

Guidotti et al.,[57] 2007

14

2.5 mg PO od

Median score of headache severity: baseline 4.6; during treatment 2.5 (p = 0.049 vs estradiol or naproxen)

Silberstein et al.,[65] 2004

546

2.5 mg PO bid 2.5 mg PO od

Migraine incidence 41% during bid treatment, 52% during od treatment, 67% with placebo (p < 0.0001 vs placebo)

Naratriptan Mannix et al.,[67] 2007 Study 1: 287 Study 2: 346 59 1 mg PO bid Four cycles 3 days before anticipated menstrual migraine Duration 6 days Parallel RCT Baseline untreated three cycles followed by three treated cycles Days -2 to +4 Open-label Four cycles Days -2 to +3 Parallel RCT Study 1: mean 40% of treatment periods without migraine per patient with naratriptan vs 27% with placebo (p < 0.05) Study 2: mean 37% of treatment periods without migraine per patient with naratriptan vs 24% with placebo (p < 0.05) Baseline no. of attacks: 3.5 1.4 per 3 months End of month 3: 1.6 1.3 per 3 months 61.4% reported 50% reduction in mean no. of attacks

Moschiano et al.,[68] 2005

1 mg PO bid

Newman et al.,[69] 2001

206

1 mg PO bid 2.5 mg PO bid

50% headache-free treatment periods per patient with 1 mg bid vs 25% with placebo (p = 0.003) Mean no. of migraines 2.0 with 1 mg bid vs 4.0 with placebo (p < 0.05) No significant difference with 2.5 mg bid

Sumatriptan Newman et al.,[70] 1998 20 25 mg PO tid Baseline untreated two cycles followed by up to 14 treated cycles 23 days before anticipated menstrual migraine Duration 5 days Open-label 52.4% treated cycles with no headache 42% treated cycles with 50% reduction in severity of pain

Zolmitriptan Tuchman et al.,[71] 2008 244 2.5 mg PO bid 2.5 mg PO tid Three cycles Days -2 to +5 Parallel RCT 58.6% reported 50% reduction in migraine with 2.5 mg tid vs 54.7% with 2.5 mg tid and 37.8% with placebo (p = 0.0007 and p = 0.002) vs placebo Continued next page

MacGregor

Table IV. Contd Trial, year Estrogens (estradiol) Guidotti et al.,[57] 2007 10 0.025 mg transdermal patch Baseline untreated cycle followed by one treated cycle 2 days before anticipated menstrual migraine Duration 6 days Open-label Median score of headache severity: baseline 4.2; during treatment 3.0 No. of pts Dose Treatment cycles, timing and trial design Results

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Prevention and Treatment of Menstrual Migraine

MacGregor et al.,[72] 2006

35

1.5 mg gel

Baseline untreated three cycles followed by six treated cycles Treatment started 9 days after luteinizing hormone surge (day -5/-6) to day +2 Crossover RCT

22% reduction in migraine days during estradiol treated cycles vs placebo RR 0.78, 95% CI 0.62, 0.99 (p = 0.04)

Pradalier et al.,[73] 1994

24

0.025 mg or 0.1 mg transdermal patch

Baseline untreated cycle followed by two treated cycles Days -4 to +4 Open-label

Presence of menstrual migraine in baseline cycle 22/24. In second treated cycle: estradiol 0.025 mg 11/12; estradiol 0.1 mg 6/12

Smits et al.,[74] 1994

20

0.5 mg patch

Three cycles Days -2 to +6 Crossover RCT

No significant difference in percentage of treatment periods with migraine

Pfaffenrath,[75] 1993

41

0.5 mg patch

Baseline of two untreated cycles followed by four treated cycles 2 days before anticipated menstrual migraine Duration not stated Crossover RCT

No significant difference in reduction in headache duration, intensity and impairment

Dennerstein et al.,[76] 1988

18

1.5 mg gel

Baseline of two untreated cycles followed by four treated cycles 2 days before anticipated menstrual migraine Duration 7 days Crossover RCT

Days of moderate to severe migraine during treatment: estradiol 47 vs placebo 86 (p < 0.001)

`res et al.,[77] de Lignie 1986

18

1.5 mg gel

Three cycles 2 days before anticipated menstrual migraine Duration 7 days Crossover RCT

Migraine in 30.8% estradiol treated cycles vs 96.3% with placebo (p < 0.01)

Continued next page

1809

1810

MacGregor

bid = twice daily; HI = Headache Index; IQR = interquartile range; IU = international units; NS = not significant; od = once daily; PO = oral; pts = patients; RCT = randomized controlled trial; RR = relative risk; SD = standard deviation; SEM = standard error of the mean; tid = three times daily.

Pain Total Index decreased in both treated and placebo groups (NS) Menstrual Distress Questionnaire decreased in treated group vs placebo (p < 0.01)

Median Pain Severity (IQR)/day: vitamin E 1 (1-2) vs placebo 2 (2-3) [p < 0.001] Median Functional Disability (IQR)/day: vitamin E 1 (1-2) vs placebo 2 (2-3) [p < 0.001] Mean SD ibuprofen consumption dose (mg): vitamin E 219 195 vs placebo 388 220 (p < 0.001) Mean SD duration of pain (hours): vitamin E 6.4 4.8 vs placebo 8.9 6.1 (p < 0.001)

However, the drug has since been withdrawn because of cardiovascular safety concerns with long-term use of high dosages. Limited data from a single randomized placebo-controlled trial suggest nimesulide may be an effective alternative.[62] NSAIDs have the additional benefit of treating associated dysmenorrhoea.[82]
3.1.2 Triptans

Trials of frovatriptan, naratriptan, sumatriptan and zolmitriptan for perimenstrual prophylaxis have suggested efficacy, although direct comparison of the results is limited by the different endpoints used (table V).[57,64-71] Although the definitions of menstrual migraine appear to be similar, only one trial required review of documented diary data as confirmation for inclusion.[66] Diary evidence should be a prerequisite given that a patient-reported history of a menstrual association can be unreliable.[9,29] Women who have migraine attacks occurring at the time of menstruation may not have menstrual migraine (the latter definition reserved for women who experience regular and predictable menstrual attacks rather than a chance association). This difference is clinically relevant, as the latter group may be more responsive to perimenstrual prophylaxis. Only two studies required confirmation of menstrual migraine as a specific diagnosis.[66,68] Perimenstrual triptan prophylaxis is well tolerated and the incidence and type of adverse events reported is consistent with those reported in trials of acute treatment. The high completion rates in the clinical trials are notable. However, there is potential concern that treatment may defer attacks or result in rebound migraine following treatment. This has been noted with naratriptan, with the percentage of patients reporting migraine during the immediate post-treatment period being higher in those treated with naratriptan than in patients receiving placebo.[67] Increased migraine post-treatment has been reported not to occur following perimenstrual frovatriptan.[66] Specific analyses of safety and tolerability have been undertaken on long-term trials of frovatriptan and naratriptan. During treatment of up to 12 perimenstrual periods over a 12- to 15-month period,
Drugs 2010; 70 (14)

Results

Baseline of two untreated cycles followed by two treated cycles (then two open-label cycles) Day +15 to day +1a of next cycle Parallel RCT

360 mg PO od

Dose

400 IU

Two placebo cycles followed one untreated then two treated cycles Days -2 to +3 Crossover RCT

Treatment cycles, timing and trial design

Facchinetti et al.,[78] 1991

Table IV. Contd

Magnesium

Trial, year

Ziaei et al.,[79] 2009

Vitamin E

2010 Adis Data Information BV. All rights reserved.

Day +1 = first day of bleeding.

No. of pts

20

67

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Prevention and Treatment of Menstrual Migraine

Table V. Differences between triptan trials for perimenstrual migraine prophylaxis (PMP) Trial, year Design Dose No. of cycles Timing of treatment Duration of PMP treatment (days) 6 Definition of MM Primary outcome measure

Frovatriptan Silberstein et al.,[64] 2009 Brandes et al.,[66] 2009 Guidotti et al.,[57] 2007 Silberstein et al.,[65] 2004 Naratriptan Mannix et al.,[67] 2007 Moschiano et al.,[68] 2005 Newman et al.,[69] 2001 Post hoc subgroup analysis Parallel 2.5 mg PO bid 2.5 mg PO od (double dose on day 1) 2.5 mg PO bid 2.5 mg PO od (double dose on day 1) 2.5 mg PO od (double dose on day 1) 2.5 mg PO bid 2.5 mg PO od (double dose on day 1) 1 mg PO bid 3 2 days before anticipated MM 2 days before anticipated MM 2 days before anticipated MM 2 days before anticipated MM Migraine starting between day -2 to day +3 (inclusive)a and at no other time Percentage of patients who experienced MM attacks during each of the three different treatment periods No. of headache-free PMPs out of three treated PMPs

Migraine starting between day -2 to day +3 (inclusive)a in at least two out of three menstrual cycles Migraine starting between day -2 to day +3 (inclusive)a in at least two out of three menstrual cycles Migraine starting between day -2 to day +4 (inclusive)a

Openlabel Crossover

1 baseline 1 treated 3

Percentage of patients with MM Score of headache intensity or severity from day -2 to day +3* Incidence of MM during the treated PMP

Parallel

3 days before anticipated MM 2 days before anticipated menstruation 2 days before anticipated menstruation 23 days before anticipated MM

Migraine starting between day -2 to day +4 (inclusive)a Migraine starting between day -2 to day +3 (inclusive)a and at no other time Migraine starting between day -2 to day +4 (inclusive)a

Mean percentage of treated PMPs without migraine per patient. Mean no. of MM over three treated cycles vs three baseline cycles No. of MMs that occurred over four PMPs

Openlabel Parallel

1 mg PO bid

3 baseline 3 treated 4

1 mg PO bid 2.5 mg PO bid

Sumatriptan Newman Openet al.,[70] label 1998

25 mg PO tid

2 baseline 14 treated

Association of migraine headache with each menstrual cycle at a predictable time relative to the onset of flow

Proportion of treated cycles with no headache Proportion of treated cycles with 50% reduction in the severity of MM vs baseline Proportion of patients with 50% reduction in frequency of MM (per menstrual period) vs baseline

Zolmitriptan Tuchman et al.,[71] 2008 a Parallel 2.5 mg PO bid 2.5 mg PO tid 3 2 days before anticipated menstruation 7 Migraine starting between day -2 through to the end of menses, and at no other time

Day +1 = first day of bleeding.

1811

bid = twice daily; MM = menstrual migraine; od = once daily; PO = orally; tid = three times daily.

1812

MacGregor

adverse events with frovatriptan were generally mild or moderate in severity and were similar to those observed with acute use of triptans.[83] Results of subgroup analyses of women whose medical histories included co-morbidities that might suggest increased cardiovascular risk, but were not themselves contraindications to frovatriptan, provide preliminary evidence of the safety of frovatriptan in this population.[84] Patients completing 612 months of perimenstrual prophylaxis with naratriptan noted that no specific adverse event considered to be at least possibly related to study medication occurred in more than 2% of patients. No serious drugrelated adverse events were reported and no patient experienced clinically relevant drug-related changes in 12-lead ECGs, vital signs or clinical laboratory tests.[85]
3.1.3 Estrogen

The rationale for perimenstrual estrogen supplementation is based on evidence that the natural decline in estrogen in the late luteal phase of the menstrual cycle, just prior to menstruation, is associated with an increased risk of migraine.[86] Somerville[87] showed that migraine could be postponed by maintaining high plasma estradiol levels with an intramuscular injection of longacting estradiol valerate in oil; migraine subsequently occurred when the plasma estradiol fell. Somerville[88] further attempted to control estrogen fluctuations with oral estrogens and estrogen implants. Both of these routes of delivery failed to provide stable plasma estradiol levels and so, not surprisingly, were of no benefit to migraine.[88] This supports the hypothesis that prolonged estrogen exposure is necessary for withdrawal to trigger migraine. Several trials have confirmed the efficacy of transcutaneous estradiol for menstrual migraine prophylaxis.[72-77] The effective dose is a 100 mg patch or estradiol gel 1.5 mg, which produce serum estradiol levels of 75 pg/mL. Lower doses of 25 and 50 mg estradiol are not effective.[57,73-75] Estradiol is well tolerated but post-treatment migraine can occur. Somerville[87] noted that estradiol treatment delayed migraine by between 3 ` res and 9 days in all six women studied. de Lignie
2010 Adis Data Information BV. All rights reserved.

et al.[77] reported that 1 of 20 women had migraine 3 days after stopping estradiol treatment. MacGregor et al.[72] found an increase in migraine occurrence in the 5 days immediately following estradiol use compared with placebo (relative risk 1.40; 95% CI 1.03, 1.92; p = 0.03). Possible reasons for this post-treatment migraine may be that the dose of estradiol was inadequate, the duration of treatment was too short or perhaps that exogenous estrogen prevents the normal secretion of endogenous estrogen. Menstrual irregularity can occur, probably due to suppression of endogenous estrogen during treatment.[72] There is no evidence that estradiol supplements increase the risks of cancer or thrombosis in premenopausal women.[89] Menstrual migraine also occurs in relation to the hormone-free interval of combined hormonal contraceptives.[90] Since estrogen withdrawal is also the most likely mechanism of attacks, supplementing estrogen during this time should be effective. A study using estradiol 0.05 mg patches during this time suggested that this dose is suboptimal for prophylaxis, although post-trial treatment with 0.1 mg doses was effective.[91]
3.1.4 Magnesium

Magnesium prolidone carboxylic acid 360 mg decreased the duration and intensity of premenstrually occurring migraine in a placebocontrolled, double-blind study of 24 women with premenstrual syndrome and migraine.[92] This study was principally aimed at identifying the effect of magnesium on a number of premenstrual problems, not just headache. The generalizability of the results to women whose menstrual headaches do not occur in association with other premenstrual symptoms is unclear. Diarrhoea was reported by one woman during treatment with magnesium.
3.1.5 Vitamin E

Vitamin E is an antiprostaglandin agent. A trial of vitamin E 400 IU given perimenstrually in a crossover study of two menstrual cycles showed limited effect as a prophylactic, although headache pain and associated symptoms were reduced
Drugs 2010; 70 (14)

Prevention and Treatment of Menstrual Migraine

1813

compared with placebo.[79] Tolerability was not reported.


3.2 Continuous Hormonal Methods

and involvement in activities.[103] Similarly, an extended 84-day regimen of a transdermal contraceptive reduced the total incidence of mean headache days compared with a 21/7-day regimen.[104]
3.2.2 Estradiol Implants

Continuous hormonal methods are particularly useful if cycles are irregular or when a woman also requires contraception (table VI). International guidelines for safe prescribing are available. In particular, contraceptive doses of synthetic estrogens should not be used by women who also have migraine with aura because of the synergistic increased risk of ischaemic stroke.[100]
3.2.1 Combined Hormonal Contraceptives

In an open-label study, estradiol implants given in doses large enough to suppress ovulation and produce constant plasma estrogen levels achieved a 96% response rate in 24 women with menstrual migraine treated for up to 5 years, with 46% of women becoming completely headache free.[94] Treatment was well tolerated.
3.2.3 Phytoestrogens

In a small open-label study, 11 women with menstrual migraine were treated with a 28-day cycle of an ethinylestradiol 0.02 mg oral contraceptive for 21 days followed by conjugated equine estrogen 0.9 mg daily for 7 days. All women achieved at least a 50% reduction in number of headache days per cycle (mean 77.9% reduction).[93] Continuous use of combined hormonal contraceptives is an alternative safe and effective method of eliminating menstrual symptoms. This regimen is well tolerated, although unscheduled bleeding is a common reason for withdrawal from clinical trials in the first 6 months of treatment. Continued use induces amenorrhoea in 80100% of women by 1012 months of treatment.[101] Despite its potential benefit for management of menstrual migraine, no clinical trial data are available for women with menstrual migraine during ovulatory cycles. For women who experience migraine during the 7-day hormonefree interval of standard regimens, data from an open-label study suggest that continuous use of combined hormonal contraceptives is effective.[102] To date, larger trials have only assessed headaches in the hormone-free interval and not specifically migraine. A trial of 102 women taking drospirenone 3 mg and ethinylestradiol 0.03 mg continuously showed that, compared with the usual 21/7-day regimen of combined hormonal contraceptives, an 168-day extended placebo-free regimen led to a decrease in headache severity along with improvement in work productivity
2010 Adis Data Information BV. All rights reserved.

An open-label and a randomized placebocontrolled trial suggest efficacy and tolerability of daily phytoestrogens.[95,96] Phytoestrogens have estrogenic effects in some tissues, without stimulation of the endometrium. Theoretically, this confers greater long-term safety than with estradiol treatment, although this has yet to be established.
3.2.4 Gonadotrophin-Releasing Hormone Analogues

Although effective, adverse effects of estrogen deficiency, e.g. hot flushes, restrict the use of gonadotrophin-releasing hormone analogues.[105] The hormones are also associated with a marked reduction in bone density and should not usually be used for longer than 6 months without regular monitoring and bone densitometry. Add-back continuous combined estrogen and progestogen treatment can be given to counter these difficulties.[97]
3.3 Continuous Nonhormonal Methods

There is limited evidence of efficacy of nonhormonal drugs used for menstrual migraine prevention (table VI).
3.3.1 Bromocriptine

Bromocriptine, a dopamine agonist, inhibits gonadotrophin-releasing hormone and luteinizing hormone. Its use can result in reduced peak luteal estradiol levels and consequent reduced premenstrual estrogen withdrawal. Two studies have suggested efficacy of bromocriptine in migraine, although larger double-blind placebo-controlled
Drugs 2010; 70 (14)

Table VI. Continuous menstrual migraine prophylaxis Trial, year Estrogens Ethinylestradiol, conjugated equine estrogen Calhoun,[93] 2004 11 Ethinylestradiol 0.02 mg for 21 days Conjugated equine estrogen 0.9 mg for 7 days PO Two consecutive 28-day cycles Open-label 77.9% reduction in number of headache days per cycle No. of pts Dose Treatment cycles, timing and trial design Results
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1814

Estradiol Magos et al.,[94] 1983 24 Estradiol 50100 mg SC Mean 2.5 years (range 0.55) Open-label 83% patients became completely or almost completely headache free

Phytoestrogens Ferrante et al.,[95] 2004 11 Genisteine 56 mg and diadzeine 20 mg PO od Baseline of three untreated cycles followed by three treated cycles Open-label Reduction in number of days of headache Baseline: 5.7 days per month End of month 3: 2.2 days per month (p < 0.005)

Burke et al.,[96] 2002

49

Soy isoflavones 60 mg, dong quai 100 mg and black cohosh 50 mg PO od

24 weeks Daily Parallel RCT

Average frequency of menstrual attacks during weeks 924 (mean SEM) Phytoestrogen 4.7 1.8 vs placebo 10.3 2.4 (p < 0.01)

GnRH analogue Murray and Muse,[97] 1997 5 Leuprolide acetate (leuprorelin) 3.75 mg IM monthly. Additional estradiol 0.1 mg transdermal patch and medroxyprogesterone acetate 2.5 mg PO daily from treatment month 5 Baseline of 2 untreated months followed by 10 treated months Open-label Headache scores per month mean SEM: Control months 15.3 2.4 GnRH analogue treatment months 4.0 1.5 GnRH analogue and add-back treatment months 3.1 0.7

Bromocriptine Herzog,[98] 1997 21 2.5 mg tid One treated year compared with prior untreated year Open-label 72% overall reduction in migraine frequency (p < 0.01)

Hockaday et al.,[99] 1976

1 mg tid at 4-day intervals

15 menstrual cycles Open-label

One migraine attack occurred in 12 treated cycles

MacGregor

GnRH = gonadotrophin-releasing hormone; IM = intramuscular; od = once daily; PO = oral; pts = patients; RCT = randomized controlled trial; SC = subcutaneous; SEM = standard error of the mean; tid = three times daily.

Prevention and Treatment of Menstrual Migraine

1815

studies are necessary before it can be recommended.[98,99] Although generally well tolerated, adverse events related to treatment included light-headedness or nausea.
3.3.2 Anti-Estrogens

There is some limited evidence of efficacy for danazol and tamoxifen, but symptoms of estrogen deficiency such as hot flushes, menstrual irregularity, fatigue and joint pains, restrict their use.[106-110]
3.4 Practical Recommendations

The majority of women with menstrual migraine only need to optimize symptomatic treatment. Factors that enhance the likelihood of successful treatment for other nonmenstrual attacks apply equally to menstrual attacks. These include use of an appropriate medication, use of appropriate treatment of associated symptoms (e.g. nausea or vomiting), use of an adequate dose of the medication, and use of the medication at a mild stage of the attack, rather than waiting until the attack is moderate to severe.[45] If this is insufficient for effective control, perimenstrual prophylaxis is usually considered in addition to symptomatic medication. Choice of prophylaxis depends on the regularity of the menstrual cycle, timing of the attack in relation to bleeding, presence of dysmenorrhoea and/or menorrhagia, and the need for contraception. Any prophylactic strategy should be tried for 3 months before considering an alternative option. Diary cards should be used to keep contemporaneous records of the outcomes. If migraine remains refractory despite trials of several different strategies given in an adequate dose for an adequate duration, reconsider the diagnosis. In particular, medication overuse, when triptans are used more often than 10 days a month, is an often overlooked cause of refractory headache. 4. Conclusions Women experiencing pure menstrual or menstrually related migraine can be informed that there is evidence of efficacy for a number of acute medications to control the symptoms of men 2010 Adis Data Information BV. All rights reserved.

strual attacks. In particular, grade B evidence exists for sumatriptan 50 and 100 mg, mefenamic acid 500 mg, rizatriptan 10 mg and combination sumatriptan/naproxen 85 mg/500 mg. Although other acute treatments may be as effective, there is no clinical trial evidence to confirm or refute their efficacy. The choice of acute treatment should be based on clinical indication and patient preference. With respect to prophylaxis, there are a number of contraceptive and noncontraceptive options available, the choice of which will depend on individual patient need and preference. Of the noncontraceptive option available, there is grade B evidence of efficacy for short-term prophylaxis with transcutaneous estradiol 1.5 mg, frovatriptan 2.5 mg twice daily and naratriptan 1 mg twice daily. Acknowledgements
Anne MacGregor has acted as a paid consultant to and/or her department has received research funding from Addex, Allergan, AstraZeneca, BTG, Endo Pharmaceuticals, GlaxoSmithKline, Menarini, Merck, Pozen and Unipath. She received no financial support for the preparation of this review.

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Correspondence: Professor Anne MacGregor, The City of London Migraine Clinic, 22 Charterhouse Square, London EC1M 6DX, UK. E-mail: anne.macgregor@migraineclinic.org.uk

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