migraine management during menstruation relationship...

Migraine ManagementDuring Menstruationand Menopause

E. Anne MacGregor, MBBS, MD, FFSRH, MICR

ABSTRACTPurpose of Review:Migraine is most prevalent in women during their reproductiveyears. An understanding of the effects of menstruation and menopause on migrainecan enable neurologists to provide targeted and appropriate medical and hormonalstrategies, enabling their patients to achieve better control of migraine and reduceddisability. This article reviews the effects of hormonal events on migraine and summa-rizes the evidence-based options available for management.Recent Findings: Estrogen ‘‘withdrawal’’ during the late luteal phase of the naturalmenstrual cycle and the hormone-free interval of combined hormonal contraceptiveshas long been implicated in the pathophysiology ofmenstrual migraine. However,morerecent research suggests that other independent mechanisms may be relevant. Pros-taglandin inhibitors used for management of dysmenorrhea are effective for associatedmenstrual migraine, suggesting a common pathophysiology. The interplay between sero-tonin and estrogen also deserves further research.Summary: Menstrual and perimenopausal migraine can bemanaged effectively usinga variety of strategies, the choice of which depends on the efficacy of acute treatment,predictability and regularity of menstruation, use of contraception, and presence ofmenstrual disorders or perimenopausal vasomotor symptoms.

Continuum (Minneap Minn) 2015;21(4):990–1003.

INTRODUCTIONUp until puberty, migraine affects bothsexes equally. Followingpuberty,migraineis more prevalent in women, in whommigraine attacks are also more frequent,longer lasting, more severe, and morelikely to relapse.1

Themost likely reason for the increasedprevalence of migraine in women com-pared to men following puberty is theeffect of female sex hormones. Puberty,which begins in girls around 10 to 11 yearsof age, is initiated by increasing levels ofsex steroids resulting from a complexhypothalamic-pituitary-ovarian feedbacksystem. The first menstrual period typi-cally starts around 12 to 13 years of age,followed by marked fluctuations in hor-

mone levels for another 2 to 3 years untilpuberty is complete and menstruationbecomes regular. At the other end of thereproductive spectrum, menopause ismarked by the last menstrual periodaround 51 years of age. Menopause ispreceded by several years of fluctuatinghormones typically associated with irreg-ular periods with the addition of vaso-motor symptoms. Followingmenopause,lower levels of hormones continue tofluctuate for another 4 to 5 years.

Both adolescence and perimenopause(the years immediately preceding andfollowingmenopause) are associatedwithincreased risk of migraine, evidenced bya bimodal prevalence distribution.2 Theincidence of migraine with aura peaks

Address correspondence toDr E. Anne MacGregor, BartsSexual Health Centre,St Bartholomew’s Hospital,London EC1A 7BE,United Kingdom,[email protected].

Relationship Disclosure:

Dr MacGregor has served as aconsultant for the MenariniGroup and received personalcompensation for speakingengagements from BayerHealthCare AG. Dr MacGregorreceives royalties fromOxford University Press.

Unlabeled Use ofProducts/InvestigationalUse Disclosure:Dr MacGregor discusses theunlabeled/investigational offrovatriptan, naratriptan, andzolmitriptan for perimenstrualmigraine prophylaxis.

* 2015, American Academyof Neurology.

990 www.ContinuumJournal.com August 2015

Review Article

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

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during early puberty, whereas the inci-dence of migraine without aura peaksduring late puberty (Figure 3-13). By30 years of age, migraine is 3 timesmoreprevalent in women than in men.4

EFFECTS OF MENSTRUATIONON MIGRAINEMenstruation is a significant risk factorfor migraine without aura but not mi-graine with aura. In population- andclinic-based studies, between 20% and60% of women with migraine report anassociation with menstruation.5Y7

The incidence of migraine withoutaura is greatest during 5 days of the men-strual cycle, beginning 2 days beforemen-struation and continuing through the first3 days of bleeding.8Y10 In both womenwith natural cycles andwomen using com-bined hormonal contraceptives, at leasta twofold increased risk ofmigraine existson the first 3 days of bleeding comparedto all other days of the cycle.9,11

Most women with menstrual exacer-bation ofmigraine have additional attacksof migraine with or without aura at othertimes of the cycle (menstrually relatedmigraine). Fewer than 10% of women re-port migraine exclusively with menstru-ation and at no other time of the month(‘‘pure’’menstrualmigraine) (Table 3-1).12

The term menstrual migraine is oftenused to encompass both conditions. Afew women report exacerbation of mi-graine following ovulation, but no evi-dence supports this association.13

In women with menstrually relatedmigraine, menstrual attacks are moresevere and disabling, last longer, and areless responsive to symptomatic medica-tion compared to attacks at other timesof the cycle (Figure 3-2).14Y16

EFFECTS OF MENOPAUSEON MIGRAINEAlthough perimenopause is a time ofincreased risk of migraine, postmen-

opause sometimes brings respite formigraine without aura. Improvement isassociated with increasing time sincemenopause.17,18 Surgical menopause,with or without oophorectomy, is typi-cally associated with initial worseningof migraine compared to natural meno-pause.19 Migraine with aura appears tobe unaffected by menopause.18

DIAGNOSING MENSTRUALMIGRAINEDiagnosis of menstrual migraine is basedon the history, examination, and diaryanalysis, with investigations only indicatedto exclude secondary headache. Diariesrecording migraine and menstruation,kept over aminimumof three completemenstrual cycles, can confirm attacks ofmigraine without aura starting on daysY2 to +3 of menstruation in at least twoof three consecutive menstrual cycles(Table 3-1).12 Relying solely on the pa-tient history is unreliable, with both un-derestimation and overestimation ofmenstrual migraine.13 It is important toensure that attacks with menstruationare a true association rather than chanceassociation, somenstrual migraine shouldnot be diagnosed in women with fre-quent migraine. Several proposals for

KEY POINTS

h The most likely reasonfor the increasedprevalence of migrainein women compared tomen following pubertyis the effect of femalesex hormones.

h The menstrual period isa significant risk factorfor migraine withoutaura but not migrainewith aura.

h The incidence ofmigraine without aura isgreatest during 5 daysof the menstrual cycle,beginning 2 days beforemenstruation andcontinuing through thefirst 3 days of bleeding.

h Menstrual migraineattacks are more severeand disabling, lastlonger, and are lessresponsive to symptomaticmedication comparedto attacks at other timesof the cycle.

FIGURE 3-1 Incidence of migraine in puberty and adolescence.

Adaptedwith permission fromStewartWF, et al, Am J Epidemiol.3B 1991 Oxford

University Press. aje.oxfordjournals.org/content/134/10/1111.short.

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statistical confirmation of the associa-tion have been published.13,20,21

As well as confirming the associationbetween migraine and menstruation,simple diaries can assess menstrual regu-

larity and duration and likely menopausestatus. Premenopausal women typicallyhave regular menstrual cycles rang-ing from 21 to 35 days with a mean of28 days, with menstruation ranging from

KEY POINT

h As well as confirming theassociation betweenmigraineandmenstruation,simple diaries can assessmenstrual regularityand duration and likelymenopause status.

FIGURE 3-2 Risk of migraine features in menstrual versus nonmenstrual attacks in womenwith menstrually related migraine.

Rx = prescription.

Data from Pinkerman B, Holroyd K, Cephalalgia.15

cep.sagepub.com/content/30/10/1187.short.

TABLE 3-1 ICHD Diagnostic Criteria for Menstrual Migrainea

b Pure Menstrual Migraine Without Aura

A. Attacks in a menstruating womanb fulfilling criteria for migraine withoutaura and criterion B below.

B. Documented and prospectively recorded evidence over at least threeconsecutive cycles has confirmed that attacks occur exclusively onday 1 T 2 (ie, days Y2 to +3)c of menstruation in at least two out of threemenstrual cycles and at no other times of the cycle.

b Menstrually Related Migraine Without Aura

A. Attacks in a menstruating womanb fulfilling criteria for migraine withoutaura and criterion B below.

B. Documented and prospectively recorded evidence over at least threeconsecutive cycles has confirmed that attacks occur on day 1 T 2 (ie, days Y2to +3)c of menstruation in at least two out of three menstrualcycles, and additionally at other times of the cycle.

ICHD = International Classification of Headache Disorders.a Reprinted with permission from Headache Classification Committee of the International HeadacheSociety (IHS), Cephalalgia.12 B 2013 International Headache Society. www.ihs-classification.org/_downloads/mixed/International-Headache-Classification-III-ICHD-III-2013-Beta.pdf.

b For the purposes of International Classification of Headache Disorders, Third Edition, beta version(ICHD-3 beta), menstruation is considered to be endometrial bleeding resulting from either thenormal menstrual cycle or from the withdrawal of exogenous progestogens, as in the use of com-bined oral contraceptives or cyclical hormone replacement therapy.

c The first day of menstruation is day 1 and the preceding day is day Y1; there is no day 0.


Menstruation and Menopause


http://cep.sagepub.com/content/30/10/1187.short

http://www.ihs-classification.org/_downloads/mixed/International-Headache-Classification-III-ICHD-III-2013-Beta.pdf

http://www.ihs-classification.org/_downloads/mixed/International-Headache-Classification-III-ICHD-III-2013-Beta.pdf

2 to 8 days, typically lasting 4 to 6 days(Figure 3-3). During perimenopause,cycles become irregular and unpredict-able (Figure 3-4).

PATHOPHYSIOLOGYMuch research has focused on the asso-ciation between changes in menstrualcycle hormones and risk ofmigraine. Thetiming of menstrual attacks of migraineis consistent with the natural fall in estro-gen during the late luteal phase of themenstrual cycle (Figure 3-5). This estro-gen ‘‘withdrawal’’ trigger is independentof ovulation, as it can trigger migraineduring the hormone-free interval of com-bined hormonal contraceptives. It is alsoindependent of menstruation and thepresence or absence of progestin, as mi-graine can be triggered following an es-trogen challenge in women who havehad hysterectomies.22

It is unlikely that estrogen withdrawalis the sole trigger formenstrual migraine.The observation that menstrual migrainecan be associated with dysmenorrhea,both of which respond to nonsteroidalanti-inflammatory drugs (NSAIDs), im-plicates prostaglandins in the pathophys-iology.23 During the luteal phase of themenstrual cycle, uterine prostaglandinlevels increase threefold, with a furtherincrease during the first 48 hours ofmenstruation, mirroring the timing ofincreased migraine risk.

MANAGEMENT OF MENSTRUALMIGRAINEThe choice of strategy for managementof menstrual migraine depends on theefficacy of acute treatment, predictabilityand regularity of menstruation, use of orneed for contraception, and presence of

FIGURE 3-3 Example of a menstrual migraine diary from a 34-year-old premenopausal woman.

0 = period; 0 = spotting; X = migraine; / = headache.



menstrual disorders or perimenopausalvasomotor symptoms (Figure 3-624).

Acute TreatmentAll treatments licensed for migraine canbe used for acute treatment of menstrualmigraine. A number of drugs have shownefficacy in randomized controlled trials(Table 3-2). These are largely post hocanalyses of acute treatment comparingmenstrual and nonmenstrual attacks inwomenwhohavenot received adiagnosisof menstrual migraine. Hence, the true ef-ficacy in women withmenstrual migraineis unclear. Because of the long duration ofmenstrual attacks, repeated relapse canbe a problem, as illustrated in Case 3-1A.

ProphylaxisWomen with frequent migraine through-out their cycle, with or withoutmenstrualexacerbation, are most likely to benefitfrom standard prophylactic strategies. If

prophylaxis reduces the frequency andseverity of nonmenstrual attacks but notmenstrual attacks, then perimenstrualprophylaxis is indicated.

Perimenstrual prophylaxis.Womenwith regular cycles and menstrual exac-erbation of migraine may benefit fromshort-term perimenstrual prophylaxis,targeted to the time of increased risk(Table 3-3). For perimenstrual prophy-laxis, the method of administration isdifferent from the label, so the drugmust be prescribed off-label.

Nonsteroidal anti-inflammatory drugs.NSAIDs may be particularly effective forwomen with dysmenorrhea and men-strual migraine in whom prostaglandinrelease may be a significant trigger.Level B evidence (one class I or twoclass IItrials) exists for naproxen 550mg 2 timesa day taken for 7 to 14 days starting dur-ing the week before expected onset of

KEY POINTS

h The choice of strategyfor management ofmenstrual migrainedepends on the efficacyof acute treatment,predictability andregularity of menstruation,use of or need forcontraception, andpresenceof menstrual disordersor perimenopausalvasomotor symptoms.

h Women with regularcycles and menstrualexacerbation ofmigraine may benefitfrom short-termperimenstrual prophylaxis,targeted to the time ofincreased risk.

FIGURE 3-4 Example of a menstrual migraine diary from a 49-year-old perimenopausal woman.

0 = period; 0 = spotting; X = migraine without aura; A = migraine with aura.




menstruation. (Refer to Appendix Cfor the American Academy of Neurol-ogy [AAN] classification of evidence forthe rating of a therapeutic study andAppendix D for the classification ofrecommendations.) Although a poten-tial risk exists for the development ofmedication-overuse headache, NSAIDsappear to protect against chronificationof migraine.26 Women at risk of gastro-intestinal bleeding should avoid NSAIDs,and gastroduodenal protection shouldbe consideredwhenever NSAIDs are pre-scribed. Some women develop hyperten-sion as a consequence of fluid retentionand edema, which resolves followingcessation of treatment.

Triptans. Level A evidence (two ormore class I trials) exists for the efficacyof frovatriptan for the short-term pre-

vention of menstrual migraine.27 (Referto Appendix A for a summary of theAAN’s evidence-based guideline for cli-nicians.) Treatment is taken for 6 days,starting 2 days before the expectedonset of menstrual migraine. A loadingdose of 5 mg 2 times a day is taken onthe first day, followed by 2.5 mg 2 timesa day on days 2 to 6. The risk of post-treatment migraine is not increased.28

Level B evidence exists for naratriptanand zolmitriptan.27 Naratriptan 1 mg2 times a day is taken for 6 days, starting3 days before the expected onset ofmen-strual migraine. An increased risk ofmigraine exists immediately followingtreatment. Zolmitriptan 2.5 mg 2 timesa day or 3 times a day is taken for 7 days,starting 2 days before the expected onsetofmenstruation. The risk of posttreatment

KEY POINT

h Women at risk ofgastrointestinalbleeding shouldavoid nonsteroidalanti-inflammatorydrugs, andgastroduodenalprotection should beconsidered whenevernonsteroidalanti-inflammatory drugsare prescribed.

FIGURE 3-5 Inverse relationship between migraine incidence and estrogen levels.

1: Falling estrogen associated with high migraine incidence2: Rising estrogen associated with low migraine incidence

E1G = estrone-3-glucuronide; PdG = pregnanediol-3-glucuronide.

Adapted with permission from MacGregor EA, et al, Neurology.10 B 2006 American Academy of Neurology. www.neurology.org/content/67/12/2154.short.



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FIGURE 3-6 Algorithm for management of menstrual migraine.

CHC = combined hormonal contraceptive; GnRH = gonadotrophin-releasinghormone; HFI = hormone-free interval; HRT = hormone replacement therapy;

LNG-IUS = levonorgestrel-releasing intrauterine system; NSAID = nonsteroidal anti-inflammatory drug;POP = progestin-only pill; Rx = prescription.

Adapted with permission from MacGregor EA, J Fam Plann Reprod Health Care.24

B 2007 Faculty of Sexual & ReproductiveHealthcare of the Royal College of Obstetricians & Gynaecologists. jfprhc.bmj.com/content/33/1.toc.




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migraine following zolmitriptan has notbeen assessed.

Perimenstrual prophylaxis with trip-tans is well tolerated with adverse eventssimilar to those reported in acute treat-ment trials.

Estrogen supplements. Level C evi-dence (one class II trial) exists for estra-diol gel 1.5 mg daily used for 7 daysstarting between 2 and 5 days before ex-pected onset of menstruation.27 Thismaintains luteal phase estradiol levels,preventing the natural late luteal phasedrop in estrogen that can trigger estro-gen withdrawal migraine. It is importantthat women using this strategy are men-struating regularly and natural proges-terone following ovulation providesendometrial protection. Treatment iswell tolerated but can be followed by

an increase in migraine.29 Clinical expe-rience suggests that this is less likely tooccur if treatment is continued to day+7of the cycle, although this can result inmenstrual irregularity.

Continuous hormonal options. Theaims of continuous hormonal treatmentsare to suppress ovarian activity andmain-tain a stable hormonal milieu.

Contraceptives. Forwomenwithmen-strual migraine who also need contra-ception, several contraceptive strategiesmay also benefit migraine, as illustratedinCase 3-1B. In the absence of migraineaura, combined hormonal contraceptiveshave additional noncontraceptive ben-efits, including reduced risk of endo-metrial and ovarian cancer.30 Estrogenwithdrawal during the hormone-free in-terval can trigger migraine but can be

KEY POINT

h Perimenstrual prophylaxiswith triptans is welltolerated with adverseevents similar to thosereported in acutetreatment trials.

TABLE 3-2 Acute Treatment of Menstrual Attacks of Migraine

Drug Route DoseMaximumDaily Dose

Acetaminophen 250 mg,aspirin 250 mg,caffeine 65 mg

Oral 2 caplets 8 caplets

Mefenamic acid Oral 250Y500 mg 1500 mg

Triptans

Almotriptan Oral 6.25Y12.5 mg 25 mg

Eletriptan Oral 20Y40 mg 80 mg

Frovatriptan Oral 2.5 mg 7.5 mg

Naratriptan Oral 1Y2.5 mg 5 mg

Rizatriptan Oral 5Y10 mga 30 mg

Sumatriptan Oral 25Y100 mg 200 mg

Subcutaneous 6 mg 12 mg

Intranasal 5Y20 mg 40 mg

Sumatriptan 85 mg,naproxen 500 mg

Oral 1 tablet 2 tablets

Zolmitriptan Oral 2.5 mg 10 mg

Intranasal 5 mg 10 mga In patients taking propranolol, initial dose of rizatriptan is 5 mg and maximum daily dose is 15 mg.



Case 3-1AA 34-year-old woman presented for treatment of migraine that occurred around the start of hermenstrual period, although she usually had two additional attacks each month. Nonmenstrual attackslasted the better part of a day, but menstrual attacks continued for several days.

She said shewokewith nasal congestion, which developed into a unilateral headache. The headachewasstabbing and thumping in character and associated with nausea and sensitivity to light and sound.She was disabled by the menstrual headaches, as she was unable to continue her usual daily activitieswithout treatment. She took acetaminophen 1 g, which usually helped nonmenstrual attacks buthad little effect on menstrual attacks, even when she repeated the dose.

She had not lost time fromwork, as her part-time status enabled her to plan work around her monthlycycle. However, the monthly headaches were a source of friction between the patient and her husband ashe often had to leave work early to pick the children up from school. When she did not have a headache,she felt well, with no other medical concerns.

Hermenstrual periodswere regular, every 27 to 29 days, lasting 5 days. The first couple of days, her flowwassometimes heavy with dysmenorrhea. Migraine usually started on the second or third day of menstruation.

Comment. Most women who present with menstrual or menstrually related migraine have a historyof migraine unrelated to menstruation for many years previous. Diary cards are essential, not just toconfirm the diagnosis, but also to assess response to treatment and document changes in pattern(Figure 3-3). This patient was not using effective symptomatic treatment for migraine and should beprescribed a nonsteroidal anti-inflammatory drug either with or without an oral triptan. For patients whoexperience repeated relapse, frovatriptan is an appropriate option based on its longer half-life andlonger duration of action.25

This patient should be encouraged to treat attacks as early as possible, which results in a higher, earlier,and sustained pain-free response; prevents progression to moderate/severe headache; and reduces painburden and functional disability.

If attacks are not effectively controlled with symptomatic treatment alone, prophylaxis is indicated.

TABLE 3-3 Short-Term Prophylaxis of Menstrual Migraine

Drug Treatment Regimen

Nonsteroidalanti-inflammatory drugs

Naproxen 550 mg orally 2 times/d taken for 7Y14 days starting during the week beforeonset of menstruation

Triptans

Frovatriptan 5 mg orally 2 times/d on day Y2 of menstruation; 2.5 mg orally 2 times/d ondays Y1 to +4 (total of 6 days)

Naratriptan 1 mg orally 2 times/d starting 3 days before expected migraine taken for 6 days(total of 6 days)

Zolmitriptan 2.5 mg orally 2 to 3 times/d on days Y2 to +5 of menstruation (total of 7 days)

Estradiol 1.5 mg (1.5 g gel) transdermally daily starting between days Y5 and Y2 ofmenstruation for 7 days (total of 7 days)




prevented with estrogen supplementsduring this time, such as 10 mcg oralethinyl estradiol, 0.9mg oral conjugatedequine estrogens, 100 mcg estradiolpatches, or 2 g estradiol gel.31 Womenusing estrogen supplements during thehormone-free interval of combined hor-monal contraceptives have endometrialprotection from the combined hormonalcontraceptive progestogen. However, asimpler strategy is to reduce the num-ber of withdrawal bleeds to four peryear with extended-cycle 84/7 regimensor to none by continuous combined hor-monal contraceptive use.31 These strate-gies are well tolerated; unscheduledbleedingwith continuous combined hor-monal contraceptives is common in theearly cycles of treatment but usually re-solves with time. Advising women to‘‘break with the bleed’’ (ie, stop com-bined hormonal contraceptives for 3 daysif troublesome bleeding lasts for morethan 3 days) can increase the likelihoodof continuingwith this strategy. By 10 to12 months of continuous use, 80% to100% of women are amenorrheic.32

Combined hormonal contraceptivesare associated with a twofold increasedrisk of stroke. Hence, women using themfor contraception are screened for thepresence of cardiovascular risk factorsbefore prescription.33 Although migrainewithout aura is not a significant risk forischemic stroke, migraine with aura isassociated with a twofold increased risk.On this basis, combined hormonal con-traceptives can safely be used by womenwith migraine without aura, unless theyhave significant cardiovascular risk fac-tors that would in themselves contra-indicate use. In contrast, neurologistsidentifying women with migraine withaura who are using combined hormonalcontraceptives should work with theprescribers to ensure that combined hor-monal contraceptives are being pre-scribed in accordance with currentguidance. While the absolute risk ofstroke in women with migraine withaura who use combined hormonal con-traceptives is very low, the impact of astroke is so devastating that cliniciansshould consider the use of progestin-only,

KEY POINT

h Estrogen withdrawalduring thehormone-free interval ofcombined hormonalcontraceptives can beprevented by continuoususe of the combinedhormonal contraceptive.

Case 3-1BThe patient returned for follow-up and reported that taking a triptan/nonsteroidalanti-inflammatory drug (NSAID) combination early had enabled her tocontrol hermenstrualmigraineandalsogaveher some relief fromdysmenorrhea.She asked if anything further could be done to prevent rather than treatthese symptoms. The doctor advised that she could take naproxen 550 mg2 times a day starting a couple of days before the expected onset ofmenstruationuntil day +7 as perimenstrual prophylaxis of menstrual migraine, whichwould also treat her dysmenorrhea. If she developed migraine, she couldcontinue to treat the symptomswith a triptan. The doctor also noted that thepatient used a copper intrauterine device for contraception. The doctorsuggested that she discuss alternative contraceptive methods with herobstetrician-gynecologist.

Comment. It is important to consider the effect that contraceptivemethodsmay have on menstrual migraine mechanisms. Copper intrauterine devices areassociated with dysmenorrhea, menorrhagia, and increased prostaglandinrelease. These effects can respond to perimenstrual NSAIDs, which inhibitprostaglandin release.However, switching to the levonorgestrel intrauterinedeviceor continuous combined hormonal contraception might be more appropriate.



intrauterine, or barrier contraceptives inthis setting.

Few data exist on progestogen-onlymethods and migraine, although someevidence exists thatmethods that achieveamenorrhea can benefit migraine.31 Ofinterest to the pathophysiology of mi-graine is the suggested benefit reportedby women using the levonorgestrel intra-uterine system, which achieves amenor-rhea by a local endometrial effect in theabsence of ovarian suppression.34

Gonadotrophin-releasing hormoneanalogues. Gonadotrophin-releasinghor-mone analogues have been reported aseffective for treatment of resistant men-

strual migraine. They cause a reversible‘‘medical’’ menopause at the hypothalamic-pituitary level, resulting in cessation ofovarian activity. Add-back hormone re-placement therapy is usually necessaryto treat vasomotor side effects and pre-vent loss of bone density.35

Surgical options. Since hysterectomywith or without oophorectomy increasesrisk of migraine, surgery is not generallyan option for management ofmenstrualmigraine. However, if a hysterectomy isindicated for gynecologic reasons, theeffect on migraine can be reduced byimmediate use of continuous transdermalestrogen replacement therapy.36

Case 3-2A 49-year-old woman presented for evaluation of migraine with aura that occurred every 2 to 3 months.These attacks were stereotypical, with fortification spectra lasting 20 to 30 minutes followed by aunilateral severe headache associated with photophobia and nausea. The headaches lasted for a day,and she had to leave work and go to bed. The attack generally resolved with sleep, although she still felttired and drained the following day. Her doctor had prescribed a triptan, which she took as soon as theaura started. She had not found this any more effective than her previous treatment with ibuprofen.

On further questioning, she reported she also had disabling ‘‘sinus’’ headaches with her periods,which she used to be able to manage, as her periods were predictable and she could plan around them.However, her periods had become more frequent and irregular, so she could no longer predict whentheywere likely to occur. These headaches lasted 1 to 4 days. She used a decongestant, which was sometimeseffective if taken early. Even then, it only took the edge off the pain. She was unable to go to work whenthe pain was severe. When asked about nasal discharge, she said she did not have a purulent dischargeaccompanying the headaches and was afebrile. She had no ‘‘sinus’’ symptoms between attacks.

Her periods usually lasted 5 days and were not otherwise troublesome. She reported that she hadnight sweats and hot flashes during the week before her period.

Comment. Migraine without aura is often not recognized as migraine, particularly by people whoalso have migraine with aura and consider the aura to be more typical of migraine. Neither is ituncommon formigrainewithout aura to bemisdiagnosed as sinus headache. In a study of 2991 patientswith a history of self-described or physician-diagnosed ‘‘sinus’’ headache, 2396 (80%) fulfilled InternationalHeadache Society criteria for migraine with or without aura.37 The diagnosis may be confused by additionalsymptoms that may occur during migraine but are typically associated with sinusitis, such as sinus pressure,sinus pain, and nasal congestion. This confirms the importance of taking a careful history.

The first step in managing this patient was to confirm the diagnosis of menstrual migraine andencourage her to use the triptan for these attacks. For management of migraine with aura, she wasadvised to delay taking the triptan until the onset of headache. Given the frequency of her migraines,standard migraine prophylaxis should be considered. Perimenstrual prophylaxis is not indicated becauseof menstrual irregularity. Although the patient had vasomotor symptoms, these only occurredpremenstrually. If they become troublesome, shemight consider hormone replacement therapy. In contrastto combined hormonal contraceptives, physiologic doses of natural estrogen used for hormonereplacement are not contraindicated in the presence of migraine aura.




PERIMENOPAUSEPerimenopausemarks a timeof increasedrisk of migraine and the additionalcomplication of irregular periods, whichprohibits perimenstrual prophylaxis, asillustrated in Case 3-2. Troublesomevasomotor symptoms may also warrantspecific treatment, most usually with hor-mone replacement therapy. Oral estro-gen can exacerbate migraine so nonoralroutes are preferred, administered con-tinuously toensure stablehormone levels.36

Endometrial protection with progestin isnecessary for women who have not hada hysterectomy, and continuous deliveryis better tolerated than cyclical administra-tion.38 However, continuous progestinis only licensed for use postmenopause,with the exception of the levonorgestrelintrauterine system.This has the advantageof also being licensed for contraceptionand delivers progestin directly to the en-dometrium with low systemic absorption.

For women in whom estrogen is con-traindicated, paroxetine 7.5 mg at bed-time is the only nonhormonal therapyapproved by the US Food and DrugAdministration (FDA) for the treatmentof vasomotor symptoms. Level A evidencefrom some randomized controlled trialssupports the efficacy of gabapentin forcontrol of vasomotor symptoms, al-though there is only Level U evidencefor migraine prophylaxis (inadequateor conflicting data to support or refutemedication use).11,34

CONCLUSIONMenstrual exacerbation of migraine iscommon, particularly during perimeno-pause. If symptomatic treatment alone isnot sufficient to manage the condition,perimenstrual prophylaxis can be of-fered. Contraceptive strategies may beappropriate for women also needingcontraception. Women with trouble-some vasomotor symptoms andmigrainemay benefit from hormone replace-ment therapy.

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12. Headache Classification Committee of theInternational Headache Society (IHS). TheInternational Classification of HeadacheDisorders, 3rd edition (beta version).Cephalalgia 2013;33(9):629Y808.doi:10.1177/0333102413485658.

KEY POINTS

h Perimenopause marksa time of increased riskof migraine and theadditional complicationof irregular periods,which prohibitsperimenstrual prophylaxis.

h Women with migrainetolerate nonoral deliveryof estrogen better thanoral, and it shouldbe administeredcontinuously to ensurestable hormone levels.



13. MacGregor EA. Classification of perimenstrualheadache: clinical relevance. Curr PainHeadache Rep 2012;16(5):452Y460.doi:10.1007/s11916-012-0282-y.

14. MacGregor EA, Victor TW, Hu X, et al.Characteristics of menstrual vs nonmenstrualmigraine: a post hoc, within-woman analysisof the usual-care phase of a nonrandomizedmenstrual migraine clinical trial. Headache2010;50(4):528Y538. doi:10.1111/j.1526-4610.2010.01625.x.

15. Pinkerman B, Holroyd K. Menstrual andnonmenstrual migraines differ in womenwith menstrually-related migraine.Cephalalgia 2010;30(10):1187Y1194.doi:10.1177/0333102409359315.

16. Vetvik KG, Benth JS, MacGregor EA, et al.Menstrual versus non-menstrual attacks ofmigraine without aura in women with andwithoutmenstrual migraine [published onlineahead of print March 9, 2015]. Cephalalgia.doi:10.1177/0333102415575723.

17. Freeman EW, Sammel MD, Lin H, et al.Symptoms in the menopausal transition:hormone and behavioral correlates. ObstetGynecol 2008;111(1):127Y136. doi:10.1097/01.AOG.0000295867.06184.b1.

18. Mattsson P. Hormonal factors in migraine:a population-based study of womenaged 40 to 74 years. Headache 2003;43(1):27Y35. doi: 10.1046/j.1526-4610.2003.03005.x.

19. Wang SJ, Fuh JL, Lu SR, et al. Migraineprevalence during menopausal transition.Headache 2003;43(5):470Y478. doi:10.1046/j.1526-4610.2003.03092.x.

20. Marcus DA, Bernstein CD, Sullivan EA,Rudy TE. A prospective comparisonbetween ICHD-II and probability menstrualmigraine diagnostic criteria. Headache 2010;50(4):539Y550. doi:10.1111/j.1526-4610.2010.01627.x.

21. Barra M, Dahl FA, Vetvik KG. Statisticaltesting of association between menstruationand migraine. Headache 2015;55(2):229Y240.doi:10.1111/head.12457.

22. MacGregor EA. Oestrogen and attacks ofmigraine with and without aura. LancetNeurol 2004;3(6):354Y361. doi:10.1016/S1474-4422(04)00768-9.

23. Mannix LK. Menstrual-related pain conditions:dysmenorrhea and migraine. J WomensHealth (Larchmt) 2008;17(5):879Y891.doi:10.1089/jwh.2007.0440.

24. MacGregor EA. Menstrual migraine: a clinicalreview. J Fam Plann Reprod Health Care2007;33(1):36Y47.

25. Brandes JL, Poole AC, Kallela M, et al. Short-termfrovatriptan for the prevention of difficult-to-treat

menstrual migraine attacks. Cephalalgia2009;29(11):1133Y1148. doi: 10.1111/j.1468-2982.2009.01840.x.

26. Bigal ME, Serrano D, Buse D, et al.Acute migraine medications and evolutionfrom episodic to chronic migraine:a longitudinal population-based study.Headache 2008;48(8):1157Y1168.doi:10.1111/j.1526-4610.2008.01217.x.

27. Silberstein SD, Holland S, Freitag F, et al.Evidence-based guideline update:pharmacologic treatment for episodicmigraine prevention in adults: report of theQuality Standards Subcommittee of theAmerican Academy of Neurology and theAmerican Headache Society. Neurology2012;78(17):1337Y1345. doi:10.1212/WNL.0b013e3182535d20.

28. Brandes JL, Poole A, Kallela M, et al.Short-term frovatriptan for the prevention ofdifficult-to-treat menstrual migraine attacks.Cephalalgia 2009;29(11):1133Y1148.doi:10.1111/j.1468-2982.2009.01840.x.

29. MacGregor EA, FrithA, Ellis J, et al. Preventionof menstrual attacks of migraine: adouble-blind placebo-controlled crossoverstudy. Neurology 2006;67(12):2159Y2163.doi:10.1212/01.wnl.0000249114.52802.55.

30. ACOG practice bulletin no. 110:noncontraceptive uses of hormonalcontraceptives. Obstet Gynecol 2010;115(1):206Y218. doi:10.1097/AOG.0b013e3181cb50b5.

31. MacGregor EA. Contraception and headache.Headache 2013;53(2):247Y276. doi:10.1111/head.12035.

32. Archer DF. Menstrual-cycle-related symptoms:a review of the rationale for continuoususe of oral contraceptives. Contraception2006;74(5):359Y366. doi:10.1016/j.contraception.2006.06.003.

33. Centers for Disease Control andPrevention. United States medical eligibilitycriteria (US MEC) for contraceptive use,2010. www.cdc.gov/reproductivehealth/unintendedpregnancy/usmec.htm.Updated October 6, 2014. AccessedJune 18, 2015.

34. Vetvik KG, MacGregor EA, Lundqvist C,Russell MB. Contraceptive-inducedamenorrhoea leads to reduced migrainefrequency in women with menstrualmigraine without aura. J Headache Pain2014;15:30. doi:10.1186/1129-2377-15-30.

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http://www.cdc.gov/reproductivehealth/unintendedpregnancy/usmec.htm

http://www.cdc.gov/reproductivehealth/unintendedpregnancy/usmec.htm

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Arch Intern Med 2004;164(16):1769Y1772.doi:10.1001/archinte.164.16.1769.

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