A.gregor, Prevention n Treatment of Menstrual Migraen

Prevention and Treatment ofMenstrual MigraineE. 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. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17991. Literature Search Strategy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18002. Acute Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1800

2.1 Efficacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18012.2 Safety and Tolerability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1806

3. Prophylaxis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18063.1 Perimenstrual (Short-Term/Intermittent Prevention) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1806

3.1.1 NSAIDs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18063.1.2 Triptans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18103.1.3 Estrogen . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18123.1.4 Magnesium. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18123.1.5 Vitamin E . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1812

3.2 Continuous Hormonal Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18133.2.1 Combined Hormonal Contraceptives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18133.2.2 Estradiol Implants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18133.2.3 Phytoestrogens. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18133.2.4 Gonadotrophin-Releasing Hormone Analogues. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1813

3.3 Continuous Nonhormonal Methods. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18133.3.1 Bromocriptine. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18133.3.2 Anti-Estrogens. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1815

3.4 Practical Recommendations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18154. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1815

Abstract Migraine is a prevalent headache disorder affecting three times morewomen than men during the reproductive years. Menstruation is a significantrisk factor for migraine, with attacks most likely to occur on or between2 days before the onset of menstruation and the first 3 days of bleeding.Although menstrual migraine has been recognized for many years, diagnosticcriteria have only recently been published. These have enabled better com-parison of the efficacy of drugs for this condition. Acute treatment, if effec-tive, may be all that is necessary for control. Evidence of efficacy, withacceptable safety and tolerability, exists for sumatriptan 50 and 100mg,mefenamic acid 500mg, rizatriptan 10mg and combination sumatriptan/naproxen 85mg/500mg. However, there is evidence that menstrual attacks

REVIEW ARTICLEDrugs 2010; 70 (14): 1799-1818

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ª 2010 Adis Data Information BV. All rights reserved.

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

Migraine is a prevalent disorder, affecting atleast 11–14% of the population.[1-3] Diagnosticfeatures accompanying headache include photo-phobia, nausea and limitation of usual daily ac-tivities (table I).[5] Four of every ten women andtwo of every ten men will experience migraine intheir lifetime, most before the age of 35 years.[6]

For both sexes, migraine prevalence is highest inthe peak reproductive years, although the pre-valence 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 womenbeing at age 25 – 8.6 years and 50 – 15.8 years.[1]

Menstruation is a significant risk factor formigraine.[7] In population- and clinic-based stu-dies, between 20% and 60% of women with mi-graine report an association between migraineand menstruation.[8-14] Attacks are most likely tooccur on or between 2 days before menstruationand the first 3 days of bleeding.[13,15-22] Menstrualattacks are almost invariably without aura, evenin women who have attacks with aura at othertimes of the cycle.[13,17,22,23] Based on these find-ings, the International Headache Society (IHS)Classification of Headache Disorders includesspecific definitions for pure menstrual migraineand menstrually related migraine (table II).[4]

For most women with menstrual attacks, mi-graine also occurs at other times of the month(‘menstrually related’ migraine).[4,13] Fewer than10% of women report migraine exclusively withmenstruation and at no other time of the month(‘pure’ menstrual migraine).[4,8,11-14]

Menstrual migraine is also associated with in-creased menstrual distress and disability.[24,25]

Attacks are more severe and disabling, last longer

and are less responsive to symptomatic med-ication than attacks at other times of the cy-cle.[10,14,19,26-30] Disability does not only affect theindividual but extends to affect family members,friends and work colleagues.[14]

The recognition of menstrual migraine as aclinical entity has resulted in specific clinical trialsassessing the efficacy, safety and tolerability ofacute and prophylactic treatments for this con-dition, which are discussed in this review. Pro-posed research criteria for menstrual migrainewere only issued in 2004.[4] The considerablevariability in definitions used for earlier studieslimits direct comparison of the results.[31]

1. Literature Search Strategy

Data for this review were identified by aMEDLINE search last conducted in July 2010using the search terms ‘estrogen’, ‘estradiol’, ‘men-struation’, ‘menstrual cycle’, ‘menstrual migraine’,‘menstrually related migraine’, ‘menstrually asso-ciatedmigraine’, ‘migraine’, ‘prevention’, ‘treatment’.No inclusion/exclusion criteria were specified. Pub-lications were scrutinized for relevancy to thisreview. In addition, references from the author’sown files, a hand-search of the journalsCephalalgiaand Headache, and peer-reviewed presentationsat international congresses were considered.

2. Acute Treatment

No drugs are approved specifically for theacute treatment of menstrual migraine; however,since menstrual attacks, by definition, fulfil theIHS criteria for migraine, treatments licensed for

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migraine are also indicated for the treatment ofmenstrual migraine.[4]

2.1 Efficacy

Data from randomized placebo-controlledtrials for the acute treatment of menstrual attacksof migraine are available for the nonprescriptioncombination of acetaminophen (paracetamol),aspirin and caffeine (AAC; Excedrin� Migraine,Bristol-Myers Squibb Company, NewYork, NY,USA); the NSAID mefenamic acid; five of theseven available triptans (almotriptan, naratrip-tan, rizatriptan, sumatriptan, zolmitriptan); anda sumatriptan/naproxen combination (table III).An evidence-based systematic review and meta-analysis concluded that, based on trial quality,evidence supported grade B recommendationsfor use of sumatriptan 50 and 100mg, mefenamicacid 500mg and rizatriptan 10mg for acutetreatment of menstrual migraine.[51] Trial qualityalso supports grade B recommendations (goodevidence of efficacy, benefits outweigh harms, im-proves important health outcomes) for the combi-nation of sumatriptan/naproxen 85mg/500mg.[48]

Abstract reports of efficacy are available foreletriptan and frovatriptan. With respect to ele-triptan, an abstract report of a post hoc analysisof six randomized controlled trials evaluatedefficacy in the acute treatment of migraine occur-ring between day -1 and day +4 of the menstrual

cycle.[52] Headache response at 2 hours after treat-ment was achieved in 64% of the eletriptan 40mggroup, 68% of the 80mg group and 26% of theplacebo group (p < 0.001 for both comparisons).

An abstract of a post hoc analysis of frova-triptan for acute treatment reported overall mi-graine relief within 24 hours in 82% of menstrualattacks and 87% of nonmenstrual attacks. Thetime to overall relief was a little longer in men-strual attacks (5.5 vs 3.6 hours).[53]

A post hoc subanalysis of an open-label, post-marketing surveillance study of acute treatmentwith frovatriptan rated prestudy medications asgood or very good for effectiveness by 20.3% and19.2% of the menstrual migraine and nonmen-strual migraine groups, respectively. In contrast,the effectiveness of frovatriptan was rated as verygood or good by 92.7% and 90.9% of women inthe menstrual migraine and nonmenstrual mi-graine groups, respectively.[54]

It is important to note that post hoc analyses ofefficacy comparing menstrual and nonmenstrualattacks are based on pooled data from migrainetrials, not within-woman analyses of trials under-taken specifically on menstrual migraine. Resultsfrom pooled data suggest no difference in efficacyof acute treatments for menstrual versus non-

Table I. Diagnostic criteria for migraine without aura (adapted from

the Headache Classification Subcommittee of the International

Headache Society[4])

A. At least five attacks fulfilling criteria B–D

B. Headache attacks lasting 4–72 hours (untreated or

unsuccessfully treated)

C. 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

Table II. Diagnostic criteria for pure menstrual migraine and men-

strually related migraine (adapted from the Headache Classification

Subcommittee of the International Headache Society [IHS][4])

Pure menstrual migraine without aura

A. Attacks, in a menstruating woman, fulfilling IHS criteria for

migraine without aura

B. 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

Menstrually related migraine without aura

A. Attacks, in a menstruating woman, fulfilling IHS criteria for

migraine without aura

B. 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

a The first day of menstruation is day 1 and the preceding day is

day -1; there is no day 0.

b For the purposes of this classification, menstruation is consid-

ered to be endometrial bleeding resulting from either the normal

menstrual cycle or from the withdrawal of exogenous progesto-

gens, as in the case of combined oral contraceptives and cyclical

hormone replacement therapy.

Prevention and Treatment of Menstrual Migraine 1801


Table III. Acute treatment of menstrual attacks of migraine

Trial, year Trial design No.a Treatment Resultsb

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)

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%

Allais et al.,[35] 2006 Parallel RCT 255 Almotriptan 12.5 mg vs zolmitriptan

2.5 mg during moderate or severe pain

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)

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)

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Table III. Contd


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)


2-h pain free: rizatriptan 10 mg 57.5% vs rizatriptan

5 mg 32.9% (p > 0.05)

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

Study 1:

2-h response: rizatriptan 10 mg 70% vs placebo 53%(p = 0.001)

Study 2:


Pooled data – ICHD pure menstrual migraine:


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)


2002

Post hoc analysis of open-

label extension study

95


1418 nonmenstrual

attacks

Rizatriptan 10 mg during moderate or

severe pain

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%


2000


data from two crossover

RCTs


393 nonmenstrual

attacks

Rizatriptan 5 mg vs rizatriptan 10 mg vs


pain

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

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Table III. Contd


5 mg 33% vs placebo 12% (p < 0.05)


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

Open-label 31 Sumatriptan 100 mg during moderate

or severe pain

2-h response: sumatriptan 70%2-h pain free: sumatriptan 41%

Dowson et al.,[29]

2005

Crossover RCT 93 Sumatriptan 100 mg vs placebo during


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)


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)

Landy et al.,[44]

2004; Nett et al.,[45]

2003

Two single-attack RCTs 752 Sumatriptan 50 mg vs sumatriptan

100 mg vs placebo during mild,

moderate and severe pain

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


Study 2:

2-h pain free: sumatriptan 50 mg 51% vs


Sustained pain free: sumatriptan 50 mg 30% vs


Facchinetti et al.,[46]

1995

Parallel RCT 179 Subcutaneous sumatriptan 6 mg vs


pain

Attack 1:

1-h response: sumatriptan 71% vs placebo 22%(p < 0.001)


2-h pain free: sumatriptan 55% vs placebo 14%

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Table III. Contd


Attack 2:



2-h pain free: sumatriptan 55% vs placebo 14%

Solbach and

Waymer,[47] 1993


data from two single-attack

RCTs

157 menstrual; 512

nonmenstrual attacks

Subcutaneous sumatriptan 6 mg vs


pain

Menstrual attacks:




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

Single-attack RCT 334 Zolmitriptan 2.5 mg vs placebo during


2-h response: zolmitriptan 2.5 mg 65.7% vs placebo

32.8% (p < 0.0001)

Allais et al.,[35] 2006 Post hoc analysis of parallel

RCT

255 Zolmitriptan 2.5 mg vs almotriptan

12.5 mg during moderate or severe

pain

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)

Loder et al.,[50]

2004

Parallel RCT 597 Zolmitriptan 1.25 mg (for mild pain),

2.5 mg (for moderate pain) or 5 mg (for

severe pain) vs placebo

2-h response: zolmitriptan 2.5 mg 48% vs placebo

27% (p < 0.0001)

a No. of patients unless specified.

b 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, re-sults from prospective clinical trials in womendiagnosed with menstrual migraine confirm theclinical impression that menstrual attacks do notrespond as well to acute treatment as nonmen-strual attacks.[29,55] This difference may be be-cause pooled data will include menstrual attacksoccurring by chance rather than by a confirmedassociation between migraine and menstruation.

2.2 Safety and Tolerability

The single-dose combination of AAC was welltolerated for both menstrual and nonmenstrualattacks. Nausea (menstrual attacks: AAC 10.3%,placebo 1.0%, p = 0.006; nonmenstrual: AAC3.8%, placebo 2.5%, nonsignificant), dizziness(menstrual attacks: AAC 1.1%, placebo 1.0%,nonsignificant; nonmenstrual: AAC 4.1%, place-bo 1.5%, p = 0.030) and nervousness (menstrualattacks: AAC 8.0%, placebo 0%, p= 0.004; non-menstrual: AAC 4.3%, placebo 0.7%, p = 0.001)were the most common adverse events.[32]

Treatment with the NSAID mefenamic acid500mg initiated at the onset of a menstrual attackand continued 8-hourly for the duration of men-struation resulted in no adverse effects reportedexcept for two patients who experienced mildepigastric pain with mefenamic acid but whocontinued the study.[33]

Triptans are also well tolerated for the acutetreatment of menstrual migraine, with adverseevents similar to those reported in other triptanclinical trials.[29,34-43,45-50,54]

3. Prophylaxis

The goals of prophylactic strategies are to re-duce attack frequency, severity and duration,improve responsiveness to treatment of acute at-tacks, and improve function and reduce disabil-ity.[56] A number of different treatment strategieshave been studied for the prevention of menstrualmigraine in randomized placebo-controlled trialsand open-label studies. An evidence-based sys-tematic review and meta-analysis concluded that,based on trial quality, evidence supported gradeB recommendations for use of transcutaneous

estradiol 1.5mg, frovatriptan 2.5mg twice dailyand naratriptan 1mg twice daily for prophylactictreatment of menstrual migraine.[51] Prophylaxisis particularly suited to those women who haveinadequate relief from the usual forms of acutetherapy or who are troubled by headache recur-rence and require multiple doses of acute mi-graine medications. Since no investigations canidentify the most effective prophylactic for eachindividual, an empirical approach is necessary,considering also the need for contraception andco-morbid menstrual problems. It must be notedthat none of the perimenstrual or continuous stra-tegies reviewed is licensed for prevention of men-strual migraine. Prescribers should ensure that theyfollow their organization’s policy on the use ofmedicines outside of the terms of the product licence.

3.1 Perimenstrual (Short-Term/IntermittentPrevention)

Women who have regular periods and apredictable relationship betweenmigraine andmen-struation can be treated with short-term preven-tive therapy during the perimenstrual period,typically starting treatment a few days beforeexpected onset of menstruation or the anticipatedmenstrual attack (table IV). Women with men-strual irregularity can use a home-use fertilitymonitor to predict menstruation.[80] Short-termprevention strategies have the advantage thattreatment is only used at the time of need, thusavoiding continuous exposure to active drug andthe potential for adverse events associated withdaily prophylaxis.[81]

3.1.1 NSAIDs

Open-label studies using perimenstrual naprox-en 500–550mg once daily suggest efficacy of thisapproach for menstrual migraine.[57,59] Ran-domized studies using naproxen 550mg twicedaily perimenstrually have confirmed efficacywith good tolerability.[60,61] Sances et al.[60] notedthat 25% of women taking naproxen reportedmild or moderate nausea and epigastric distressbut all continued treatment.

Rofecoxib was not associated with gastro-intestinal symptoms in an open-label study.[63]

1806 MacGregor


Table IV. Perimenstrual prophylaxis

Trial, year No. of

pts

Dose Treatment cycles, timing and trial design Results

NSAIDs

Naproxen

Guidotti et al.,[57]

2007;

North American

Menopause

Society,[58] 2010

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

Allais et al.,[59] 2007 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 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 Baseline untreated two cycles followed by three treated

cycles

Days -7 days to +6

RCT

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

Szekely et al.,[61]

1989

22 550 mg PO bid Baseline untreated two cycles followed by four treated

cycles

Treatment started 8 days after ovulatory temperature

rise (day -2/-3) to day +8

RCT

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)

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


2009

179 2.5 mg PO bid

2.5 mg PO od

Three cycles


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

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Table IV. Contd

Trial, year No. of

pts


Brandes et al.,[66]

2009

410 2.5 mg PO bid

2.5 mg PO od

Three cycles


Duration 6 days

Parallel RCT

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)


2007

14 2.5 mg PO od Baseline untreated cycle followed by one treated cycle


Duration 6 days

Open-label


2.5 (p = 0.049 vs estradiol or naproxen)


2004

546 2.5 mg PO bid

2.5 mg PO od

Three cycles


Duration 6 days

Crossover RCT

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

1 mg PO bid Four cycles


Duration 6 days

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)

Moschiano et al.,[68]

2005

59 1 mg PO bid Baseline untreated three cycles followed by three

treated cycles

Days -2 to +4

Open-label

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

Newman et al.,[69]

2001

206 1 mg PO bid

2.5 mg PO bid

Four cycles

Days -2 to +3

Parallel RCT

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

2–3 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

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Table IV. Contd

Trial, year No. of

pts


Estrogens (estradiol)


2007

10 0.025 mg

transdermal

patch

Baseline untreated cycle followed by one treated cycle


Duration 6 days

Open-label


3.0

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


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


Duration 7 days

Crossover RCT

Days of moderate to severe migraine during treatment:

estradiol 47 vs placebo 86 (p < 0.001)

de Lignieres et al.,[77]

1986

18 1.5 mg gel Three cycles


Duration 7 days

Crossover RCT

Migraine in 30.8% estradiol treated cycles vs 96.3% with placebo

(p < 0.01)

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However, the drug has since been withdrawnbecause of cardiovascular safety concerns withlong-term use of high dosages. Limited data froma single randomized placebo-controlled trial sug-gest nimesulide may be an effective alternative.[62]

NSAIDs have the additional benefit of treat-ing associated dysmenorrhoea.[82]

3.1.2 Triptans

Trials of frovatriptan, naratriptan, suma-triptan and zolmitriptan for perimenstrual pro-phylaxis have suggested efficacy, although directcomparison of the results is limited by the dif-ferent endpoints used (table V).[57,64-71] Althoughthe definitions of menstrual migraine appearto be similar, only one trial required review ofdocumented diary data as confirmation for inclu-sion.[66] Diary evidence should be a prerequisitegiven that a patient-reported history of a men-strual association can be unreliable.[9,29] Womenwho have migraine attacks occurring at the timeofmenstruationmay not havemenstrual migraine(the latter definition reserved for women whoexperience regular and predictable menstrual at-tacks rather than a chance association). This dif-ference is clinically relevant, as the latter groupmay be more responsive to perimenstrual pro-phylaxis. Only two studies required confirmationof menstrual migraine as a specific diagnosis.[66,68]

Perimenstrual triptan prophylaxis is well tol-erated and the incidence and type of adverseevents reported is consistent with those reportedin trials of acute treatment. The high completionrates in the clinical trials are notable. However,there is potential concern that treatment maydefer attacks or result in ‘rebound’ migraine fol-lowing treatment. This has been noted with nara-triptan, with the percentage of patients reportingmigraine during the immediate post-treatmentperiod being higher in those treated with nara-triptan than in patients receiving placebo.[67]

Increased migraine post-treatment has been re-ported not to occur following perimenstrualfrovatriptan.[66]

Specific analyses of safety and tolerability havebeen undertaken on long-term trials of frovatriptanand naratriptan. During treatment of up to 12 peri-menstrual periods over a 12- to 15-month period,T

ab

leIV

.C

ontd

Trial,

year

No.of

pts

Dose

Tre

atm

entcycle

s,

tim

ing

and

tria

ldesig

nR

esults

Mag

nesiu

m

Facchin

ett

ietal.,[7

8]

1991

20

360

mg

PO

od

Baselin

eoftw

ountr

eate

dcycle

sfo

llow

ed

by

two

treate

dcycle

s(t

hen

two

open-labelcycle

s)

Day

+15

today

+1a

ofnextcycle

Para

llelR

CT

Pain

Tota

lIndex

decre

ased

inboth

treate

dand

pla

cebo

gro

ups

(NS

)

Menstr

ualD

istr

ess

Questionnaire

decre

ased

intr

eate

dgro

up

vs

pla

cebo

(p<

0.0

1)

Vit

am

inE

Zia

eie

tal.,[7

9]2009

67

400

IUT

wo

pla

cebo

cycle

sfo

llow

ed

one

untr

eate

dth

en

two

treate

dcycle

s

Days

-2to

+3C

rossover

RC

T

Media

nP

ain

Severity

(IQ

R)/d

ay:vitam

inE

1(1

-2)

vs

pla

cebo

2

(2-3

)[p

<0.0

01]

Media

nF

unctionalD

isabili

ty(I

QR

)/day:v

itam

inE

1(1

-2)vs

pla

cebo

2(2

-3)

[p<

0.0

01]

Mean

–S

Dib

upro

fen

consum

ption

dose

(mg):

vitam

inE

219

–195

vs

pla

cebo

388

–220

(p<

0.0

01)

Mean

–S

Ddura

tion

ofpain

(hours

):vitam

inE

6.4

–4.8

vs

pla

cebo

8.9

–6.1

(p<

0.0

01)

aD

ay

+1=

firs

tday

ofble

edin

g.

bid

=tw

ice

daily

;H

I=H

eadache

Index;IQ

R=

inte

rquart

ilera

nge;IU

=in

tern

ationalunits;N

S=

notsig

nific

ant;

od

=once

daily

;P

O=

ora

l;p

ts=

patients

;R

CT

=ra

ndom

ized

contr

olle

d

tria

l;R

R=

rela

tive

risk;S

D=

sta

ndard

devia

tion;S

EM

=sta

ndard

err

or

ofth

em

ean;ti

d=

thre

etim

es

daily

.

1810 MacGregor


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)

Definition of MM Primary outcome measure

Frovatriptan

Silberstein

et al.,[64]

2009

Post hoc

subgroup

analysis

2.5 mg PO bid

2.5 mg PO od

(double dose

on day 1)

3 2 days before

anticipated

MM

6 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

Brandes

et al.,[66]

2009

Parallel 2.5 mg PO bid

2.5 mg PO od

(double dose

on day 1)

3 2 days before

anticipated

MM


+3 (inclusive)a in at least two out of three

menstrual cycles

No. of headache-free PMPs out of three

treated PMPs

Guidotti

et al.,[57]

2007

Open-

label

2.5 mg PO od

(double dose

on day 1)

1 baseline

1 treated

2 days before

anticipated

MM


+3 (inclusive)a in at least two out of three

menstrual cycles

Percentage of patients with MM

Score of headache intensity or severity

from day -2 to day +3*

Silberstein

et al.,[65]

2004

Crossover 2.5 mg PO bid

2.5 mg PO od

(double dose

on day 1)

3 2 days before

anticipated

MM


+4 (inclusive)a

Incidence of MM during the treated PMP

Naratriptan

Mannix

et al.,[67]

2007

Parallel 1 mg PO bid 4 3 days before

anticipated

MM


+4 (inclusive)a

Mean percentage of treated PMPs

without migraine per patient.

Moschiano

et al.,[68]

2005

Open-

label

1 mg PO bid 3 baseline

3 treated

2 days before

anticipated

menstruation


+3 (inclusive)a and at no other time

Mean no. of MM over three treated

cycles vs three baseline cycles

Newman

et al.,[69]

2001

Parallel 1 mg PO bid

2.5 mg PO bid

4 2 days before

anticipated

menstruation


+4 (inclusive)a

No. of MMs that occurred over four

PMPs

Sumatriptan

Newman

et al.,[70]

1998

Open-

label

25 mg PO tid 2 baseline

£14 treated

2–3 days

before

anticipated

MM

5 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

Zolmitriptan

Tuchman

et al.,[71]

2008

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

Proportion of patients with ‡50%reduction in frequency of MM (per

menstrual period) vs baseline

a Day +1 = first day of bleeding.

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

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adverse events with frovatriptan were generallymild or moderate in severity and were similar tothose observed with acute use of triptans.[83] Re-sults of subgroup analyses of women whose medi-cal histories included co-morbidities that mightsuggest increased cardiovascular risk, but werenot themselves contraindications to frovatriptan,provide preliminary evidence of the safety of fro-vatriptan in this population.[84]

Patients completing 6–12 months of perimen-strual prophylaxis with naratriptan noted that nospecific adverse event considered to be at leastpossibly related to study medication occurredin more than 2% of patients. No serious drug-related adverse events were reported and no pa-tient experienced clinically relevant drug-relatedchanges in 12-lead ECGs, vital signs or clinicallaboratory tests.[85]

3.1.3 Estrogen

The rationale for perimenstrual estrogen sup-plementation is based on evidence that the nat-ural decline in estrogen in the late luteal phase ofthe menstrual cycle, just prior to menstruation, isassociated with an increased risk of migraine.[86]

Somerville[87] showed that migraine could bepostponed by maintaining high plasma estradiollevels with an intramuscular injection of long-acting estradiol valerate in oil; migraine subse-quently occurred when the plasma estradiol fell.Somerville[88] further attempted to control estro-gen fluctuations with oral estrogens and estrogenimplants. Both of these routes of delivery failed toprovide stable plasma estradiol levels and so, notsurprisingly, were of no benefit to migraine.[88]

This supports the hypothesis that prolonged es-trogen exposure is necessary for ‘withdrawal’ totrigger migraine.

Several trials have confirmed the efficacy oftranscutaneous estradiol for menstrual migraineprophylaxis.[72-77] The effective dose is a 100 mgpatch or estradiol gel 1.5mg, which produce ser-um estradiol levels of 75 pg/mL. Lower doses of25 and 50 mg estradiol are not effective.[57,73-75]

Estradiol is well tolerated but post-treatmentmigraine can occur. Somerville[87] noted that es-tradiol treatment delayed migraine by between 3and 9 days in all six women studied. de Lignieres

et al.[77] reported that 1 of 20 women had mi-graine 3 days after stopping estradiol treatment.MacGregor et al.[72] found an increase in mi-graine occurrence in the 5 days immediately fol-lowing estradiol use compared with placebo(relative risk 1.40; 95% CI 1.03, 1.92; p= 0.03).Possible reasons for this post-treatment migrainemay be that the dose of estradiol was inadequate,the duration of treatment was too short or per-haps that exogenous estrogen prevents the nor-mal secretion of endogenous estrogen. Menstrualirregularity can occur, probably due to suppres-sion of endogenous estrogen during treatment.[72]

There is no evidence that estradiol supplementsincrease the risks of cancer or thrombosis inpremenopausal women.[89]

Menstrual migraine also occurs in relation tothe hormone-free interval of combined hormonalcontraceptives.[90] Since estrogen withdrawal isalso the most likely mechanism of attacks, sup-plementing estrogen during this time should beeffective. A study using estradiol 0.05mg patchesduring this time suggested that this dose is sub-optimal for prophylaxis, although post-trialtreatment with 0.1mg doses was effective.[91]

3.1.4 Magnesium

Magnesium prolidone carboxylic acid 360mgdecreased the duration and intensity of pre-menstrually occurring migraine in a placebo-controlled, double-blind study of 24 women withpremenstrual syndrome and migraine.[92] Thisstudy was principally aimed at identifying the ef-fect of magnesium on a number of premenstrualproblems, not just headache. The generalizabilityof the results to women whose menstrual head-aches do not occur in association with other pre-menstrual symptoms is unclear. Diarrhoea wasreported by one woman during treatment withmagnesium.

3.1.5 Vitamin E

Vitamin E is an antiprostaglandin agent. Atrial of vitamin E 400 IU given perimenstrually ina crossover study of two menstrual cycles showedlimited effect as a prophylactic, although head-ache pain and associated symptoms were reduced

1812 MacGregor


compared with placebo.[79] Tolerability was notreported.

3.2 Continuous Hormonal Methods

Continuous hormonal methods are partic-ularly useful if cycles are irregular or when awoman also requires contraception (table VI).International guidelines for safe prescribing areavailable. In particular, contraceptive doses ofsynthetic estrogens should not be used by womenwho also have migraine with aura because of thesynergistic increased risk of ischaemic stroke.[100]

3.2.1 Combined Hormonal Contraceptives

In a small open-label study, 11 women withmenstrual migraine were treated with a 28-daycycle of an ethinylestradiol 0.02mg oral con-traceptive for 21 days followed by conjugatedequine estrogen 0.9mg daily for 7 days. Allwomen achieved at least a 50% reduction innumber of headache days per cycle (mean 77.9%reduction).[93]

Continuous use of combined hormonal con-traceptives is an alternative safe and effectivemethod of eliminating menstrual symptoms. Thisregimen is well tolerated, although unscheduledbleeding is a common reason for withdrawalfrom clinical trials in the first 6 months of treat-ment. Continued use induces amenorrhoea in80–100% of women by 10–12 months of treat-ment.[101] Despite its potential benefit for man-agement of menstrual migraine, no clinical trialdata are available for women with menstrualmigraine during ovulatory cycles. For womenwho experiencemigraine during the 7-day hormone-free interval of standard regimens, data from anopen-label study suggest that continuous use ofcombined hormonal contraceptives is effective.[102]

To date, larger trials have only assessed head-aches in the hormone-free interval and not spe-cifically migraine. A trial of 102 women takingdrospirenone 3mg and ethinylestradiol 0.03mgcontinuously showed that, compared with theusual 21/7-day regimen of combined hormonalcontraceptives, an 168-day extended placebo-freeregimen led to a decrease in headache severityalong with improvement in work productivity

and involvement in activities.[103] Similarly, anextended 84-day regimen of a transdermal contra-ceptive reduced the total incidence of mean head-ache days compared with a 21/7-day regimen.[104]

3.2.2 Estradiol Implants

In an open-label study, estradiol implants giv-en in doses large enough to suppress ovulationand produce constant plasma estrogen levelsachieved a 96% response rate in 24 women withmenstrual migraine treated for up to 5 years, with46% of women becoming completely headachefree.[94] Treatment was well tolerated.

3.2.3 Phytoestrogens

An open-label and a randomized placebo-controlled trial suggest efficacy and tolerability ofdaily phytoestrogens.[95,96] Phytoestrogens haveestrogenic effects in some tissues, without stimula-tion of the endometrium. Theoretically, this con-fers greater long-term safety than with estradioltreatment, although this has yet to be established.

3.2.4 Gonadotrophin-Releasing HormoneAnalogues

Although effective, adverse effects of estrogendeficiency, e.g. hot flushes, restrict the use ofgonadotrophin-releasing hormone analogues.[105]

The hormones are also associated with a markedreduction in bone density and should not usuallybe used for longer than 6 months without regularmonitoring and bone densitometry. ‘Add-back’continuous combined estrogen and progestogentreatment can be given to counter these difficul-ties.[97]

3.3 Continuous Nonhormonal Methods

There is limited evidence of efficacy of non-hormonal drugs used for menstrual migraineprevention (table VI).

3.3.1 Bromocriptine

Bromocriptine, a dopamine agonist, inhibitsgonadotrophin-releasing hormone and luteiniz-ing hormone. Its use can result in reduced peakluteal estradiol levels and consequent reducedpremenstrual estrogenwithdrawal. Two studies havesuggested efficacy of bromocriptine in migraine,although larger double-blind placebo-controlled



Table VI. Continuous menstrual migraine prophylaxis

Trial, year No. of

pts


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

Estradiol

Magos et al.,[94]

1983

24 Estradiol 50–100 mg SC Mean 2.5 years (range 0.5–5)

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 9–24 (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

7 1 mg tid at 4-day intervals 15 menstrual cycles

Open-label

One migraine attack occurred in 12 treated cycles

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.

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studies are necessary before it can be recom-mended.[98,99] Although generally well tolerated,adverse events related to treatment includedlight-headedness or nausea.

3.3.2 Anti-Estrogens

There is some limited evidence of efficacy fordanazol and tamoxifen, but symptoms of estrogendeficiency such as hot flushes, menstrual irregular-ity, fatigue and joint pains, restrict their use.[106-110]

3.4 Practical Recommendations

The majority of women with menstrual mi-graine only need to optimize symptomatic treat-ment. Factors that enhance the likelihood ofsuccessful treatment for other nonmenstrual at-tacks apply equally to menstrual attacks. Theseinclude use of an appropriate medication, use ofappropriate treatment of associated symptoms(e.g. nausea or vomiting), use of an adequate doseof the medication, and use of the medication at amild stage of the attack, rather than waiting untilthe attack is moderate to severe.[45] If this isinsufficient for effective control, perimenstrualprophylaxis is usually considered in addition tosymptomatic medication.

Choice of prophylaxis depends on the reg-ularity of the menstrual cycle, timing of the attackin relation to bleeding, presence of dysmenor-rhoea and/or menorrhagia, and the need for con-traception. Any prophylactic strategy should betried for 3 months before considering an alter-native option. Diary cards should be used to keepcontemporaneous records of the outcomes. Ifmigraine remains refractory despite trials of sev-eral different strategies given in an adequate dosefor an adequate duration, reconsider the diag-nosis. In particular, medication overuse, whentriptans are used more often than 10 days amonth, is an often overlooked cause of refractoryheadache.

4. Conclusions

Women experiencing pure menstrual or men-strually related migraine can be informed thatthere is evidence of efficacy for a number of acutemedications to control the symptoms of men-

strual attacks. In particular, grade B evidenceexists for sumatriptan 50 and 100mg, mefenamicacid 500mg, rizatriptan 10mg and combinationsumatriptan/naproxen 85mg/500mg. Althoughother acute treatments may be as effective, thereis no clinical trial evidence to confirm or refutetheir efficacy. The choice of acute treatmentshould be based on clinical indication and patientpreference. With respect to prophylaxis, there area number of contraceptive and noncontraceptiveoptions available, the choice of which will dependon individual patient need and preference. Of thenoncontraceptive option available, there is gradeB evidence of efficacy for short-term prophylaxiswith transcutaneous estradiol 1.5mg, frovatri-ptan 2.5mg twice daily and naratriptan 1mgtwice daily.

Acknowledgements

Anne MacGregor has acted as a paid consultant to and/orher department has received research funding from Addex,Allergan, AstraZeneca, BTG, Endo Pharmaceuticals, Glaxo-SmithKline, Menarini, Merck, Pozen and Unipath. She re-ceived no financial support for the preparation of this review.

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Correspondence: Professor Anne MacGregor, The City ofLondon Migraine Clinic, 22 Charterhouse Square, LondonEC1M 6DX, UK.E-mail: [email protected]

1818 MacGregor


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