Menstrual Migraine: How "Mini-Prophylaxis" Can Work for Your Patient

Migraine is an episodic, often debilitatingcondition that affects women moreoften than men. Twenty-eight millionAmericans suffer from migraineheadaches--and nearly 75% of theseare women.¹ Unlike other chronic painconditions, migraine has its peakprevalence during the years of greatestproductivity, when most women arejuggling family responsibilities andcareers.² Many women are particularlysusceptible to migraine attacks justbefore and during menses.Currently, there is no acceptedformal definition of "menstrual migraine."Headaches that occur in associationwith menses are still classifiedas migraine with or without aura. Proposeddefinitions are "menstrually associatedmigraine" (MAM) and "truemenstrual migraine."Here, I will provide a brief overviewof an array of treatment options--including lifestyle modifications,drug therapy, and "mini-prophylaxis"--that can markedly diminishthe frequency and severity of menstrualmigraine.WHAT IS MENSTRUALMIGRAINE?
True menstrual migraine is definedas a headache that develops exclusivelyduring the perimenstrual period(2 days before to 3 days aftermenses).³ It does not occur at anyother time of the month. By these criteria,approximately 7% to 14% of femalemigraineurs can be said to havetrue menstrual migraine.Menstrually associated migraine(MAM) also begins 2 days before to 3days after menses. Unlike true menstrualmigraine, however, MAM alsooccurs at other times of the month. Approximately60% of women migraineursfit this definition; most note more frequentmigraines during the perimenstrualperiod.⁴ These women have atleast double the probability of sufferinga migraine on the first 2 days of menstruationthan on days 6 through 28 oftheir cycle.Pathophysiology. A simple pathophysiologicmechanism underlyinghormonally associated migraines hasnot yet been discovered. While it is believedthat fluctuations of estro-gen levels--particularly precipitousdrops--trigger MAM, studies have so far involvedonly a few patients, and dataneed to be reconfirmed.In his classic studies, Sommerville^5,6concluded that it was the dropin levels of estrogen--not progesterone--that triggered MAM. He injectedpremenstrual women with progesterone;this delayed the onset ofmenstruation but did not alter predictableMAM. He then injected thesewomen with estrogen premenstrually,which delayed the usual drop in estrogenlevels. Menstruation occurred atthe usual time, but onset of MAM wasdelayed.Only 6 migraineurs were studiedin Sommerville's classic experiment,and his results have not been reproduced.Researchers have found no differencein the levels of reproductivehormones in women with and withoutmigraine. There is speculation, however,that responses to normal hormonalfluctuations in the CNS differ inwomen who have migraine. Changesin neurotransmitter concentrations,receptor number, and/or sensitivitiesmay be involved.Interestingly, nocturnal secretionof melatonin (which is synthesizedfrom serotonin) is decreased duringthe late luteal phase of the menstrualcycle. The clinical relevance of thisfinding is not yet known. Obviously,the mechanism of MAM is more complexthan a simple relationship toestrogen concentrations.NONDRUG THERAPY
A comprehensive approach totherapy needs to be considered for patientswith MAM. This involves:

• Patient education.
• Encouraging the patient to becomean active participant in her care(for example, by keeping a headachediary).
• Employing nonpharmacologic measures,either alone or in conjunctionwith drug therapy.

A headache diary is a vital tool intracking headache frequency; a reliablerecord can help you accuratelydetermine whether a consistent menstrualtrigger exists. Predictable headachesin association with regularmenses may help you develop aneffective treatment plan.Counsel your patient that migrainehas a neurobiologic basis. Lether know that there are many potentialtriggers for the disorder that are bestrecognized and--when possible--prevented,at least during times of greatestheadache frequency.Chronobiology is especially importantduring periods of headachevulnerability. Advise your patient thatconsistency in her daily activitiesmay reduce headache frequency. Forexample, encourage your patient toawake and eat at roughly the sametime every day; to maintain adequatehydration; to avoid particular food triggers;and to practice stress reductionmodalities, such as biofeedback orexercise.Unfortunately, some triggers(such as hormonal fluctuations) cannotalways be prevented. Patients mayfear that they are at the mercy of theirhormones. Reassure such women thathormonal fluctuations are only one ofmany potential headache triggers. Emphasizethe importance of identifyingand addressing controllable triggers,and reassure your patient that mosttherapies for nonhormonal headachesalso work quite well for MAM.

⁷

DRUG THERAPY

First-line therapy for women withMAM is the same as that for othertypes of migraines.

Triptans.

In a stratified approachto care, migraine-specific agents, suchas the triptans, are generally acceptedas first-line therapy for moderate to severelydisabling migraines.

⁸

Most agoniststhat affect serotonin 5-HT

_1B

and5-HT

_1D

receptor sites, including sumatriptan(tablet or injectable form),

⁹

zolmitriptan (tablet),

¹⁰

and rizatriptan(tablet),

¹¹

are significantly more effectivethan placebo.

Alternatives to triptans.

For patientswith moderate to severe MAM,the ergots and ergot derivative, dihydroergotamine(in tablet, sublingual,suppository, injectable, or nasal formulations),can be effective.

¹²

Unfortunately,ergots may cause nausea, andmigraineurs may require additionalanti-emetics with these medications.NSAIDs may be used as a firstlineabortive therapy for women withmildly to moderately disabling MAM.

¹³

These agents are especially appealingin this setting because they also haveantiprostaglandin effects (the hormoneis believed to play a role inMAM and dysmenorrhea).Combination analgesics that containacetaminophen, aspirin, and caffeinealso offer effective pain relief forpatients with MAM.

¹⁴

In addition, anal-gesics, such as butalbital combinationsor opioids, may be prescribed whenother abortives are contraindicated orineffective. Keep in mind that overuseof these agents may lead to reboundheadaches or habituation--especiallyin patients with a history of substanceabuse, frequent headaches, or comorbidanxiety.Generally, abortive medicationsshould not be used more than 2 daysper week. However, this rule may beextended for patients with prolongedmigraines that occur exclusively duringmenses and at no other time of themonth. In this setting, the risk of reboundheadaches is acceptably low,even when analgesics are used for 4 or5 consecutive days.Be sure to assess headache frequencyand disability throughout themonth, not just during menses. Forwomen with frequent headaches, considerstandard preventive agents, suchas β-blockers, calcium channel block-ers, NSAIDs, antidepressants, anticonvulsants,or antiserotonin agents (ie,methysergide). For women who havesevere headaches during menses, it isreasonable to increase drug dosagestemporarily during the period ofgreatest headache vulnerability.

HORMONALMANIPULATION

This approach is usually reservedfor MAM that is refractory to standardabortive and preventive measures.

^3,4,15,16

Results are still unpredictable,and theoretical benefits areunproven in well-controlled studies.Cyclic fluctuations in estrogen--asoccur with menstruation, during theweek of placebo tablets in oral contraceptiveusers, and with cyclic hormonereplacement therapy during postmenopausalyears--may unpredictablyworsen migraines.

¹⁵

Stable low estrogenlevels during menopause or stablehigh levels during the last 2trimesters of pregnancy often diminishthe frequency of migraines. Therefore(at least in theory), migraineurs can behelped if their estrogen levels are stabilized,particularly if headaches havea hormonal trigger.How to stabilize estrogen levels?There are several approaches:

• For women already using oral contraceptivesthat contain monophasicestrogen and progesterone, considercontinuous hormonal therapy.¹⁷ Havethe patient skip the placebo week ofpills and start on the next pack asweek 4.This regimen is usually followedfor 9 weeks to 12 weeks. It allows thepatient to menstruate only 3 or 4 timesa year, thereby reducing the frequencyof MAM. Some women may still getunpredictable breakthrough spottingand headaches.
• Another approach is to add estrogensupplementation over the week of menstruationor during the placebo week ofpills (days 22 to 28) for the patient whois already taking an oral contraceptive.Estrogen supplementation has beenfound to decrease headache frequencyand severity. Supplementation may includea low-dose (20 μg of estradiol)oral contraceptive; a 0.625- to 1.25-mgconjugated equine estrogen pill¹⁸; percutaneousestradiol gel¹⁹; or a transdermalestradiol 0.075- to 0.1-mg patchused on days 22 through 28 of a 28-daymenstrual cycle.²⁰Start with low doses of estrogenand increase as needed.¹⁸ Use hormonesat bedtime to avoid a nadir ofdrug level coincident with the hours ofmost common onset of migraine (ie, inthe early morning from 4 AM to 9 AM).Benefits of oral contraceptive use includeregular cycling of menses (andperhaps at least predictable MAM), reliefof dysmenorrhea, decreased bloodloss with menses, reliable contraception,and decreased risk of ovarian cancer.Potential risks of hormonal manipulationamong migraineurs are stillcontroversial.^21,22 At issue is whetherthere is:
• Potential increased risk of ischemicstroke among female migraineursyounger than 45 years.
• A possible additive risk of ischemicstroke with oral contraceptive use.

Most studies that demonstratedincreased relative risk involved womentaking oral contraceptives in dosagesrarely used today. Many experts believethat the risk of stroke is minimalfor women taking low-dose oral contraceptiveswho have no other risk factors,such as smoking or prolongedmigraine aura.

ALTERNATIVETHERAPIES

One study found that magnesiumtherapy could help reduce the frequencyof MAM.

²³

The 20 women inthe study were given placebo or oralmagnesium pyrrolidone carboxylicacid in 3 divided doses totaling 360mg/d on days 15 of the menstrualcycle to day of onset of menses for2 months. The findings suggest thatmagnesium supplementation mayoffer effective migraine prophylaxis--and that a low migraine thresholdcould be related to a magnesiumdeficiency.Other alternative therapies foundeffective for migraines in general, suchas feverfew and riboflavin, have notbeen specifically studied in MAM.