FEATURE

Update on Menstrual Migraine

Stewart J. Tepper, MD; Jennifer S. Kriegler, MD

Menstrual migraine tends to be more severe, debilitating, and resistant to treatment than nonmenstrual migraine. On the other hand, its predictability raises the possibility of prevention, which can reduce these problems.
igraine headache is a common, disabling problem that is chronically underdiagnosed. The International Classification of Headache Disorders definition is detailed in Table 1.1 Moreover, it is estimated that 60% of menstruating women have migraine in association with the menstrual cycle at times ie, menstrually related migraine (MRM; Table 2).1 Fewer women (7% to 14%) have migraine only in association with the menstrual cycle ie, pure menstrual migraine (PMM; Table 2).2 Both MRM and PMM have been reported to be more severe and more difficult to treat than nonmenstrual migraine (NMM).3

EPIDEMIOLOGY

M
DIAGNOSIS

Migraine headache is 3 times more likely to occur in women Migraine is more than men.4 This is thought to common in prepube due in part to an association with female reproductive hor- bertal boys than mones. This effect is particu- girls, but this changes larly strong at menarche, when at menarche, when approximately 33% of young migraine becomes girls begin to have migraines; other times include menstrua- more prevalent in tion, pregnancy/lactation, peri- girls due to uctumenopause, and menopause. ating estrogen At these times, the fluctuations in female hormone levels levels. may affect the neurochemical milieu of the brain, making it more susceptible to migraine. Migraine is more common in prepubertal boys than girls, but this changes dramatically at menarche, when migraine becomes more prevalent in girls due to uctuating estrogen levels. During the reproductive years, the prevalence of migraine in women increases to 25%

FOCUSPOINT

Menstrual migraine (MM), which includes both MRM and PMM, may easily be diagnosed during a routine physician visit if the patient complains of headache associated with her menses. The Menstrual Migraine Assessment Tool (MMAT) is a brief screening tool that allows for quick diagnosis of MM (Figure 1). Its 3 questions cover the essentials: menstrual relationship, severity, and photophobia.2 If an association with the menstrual cycle remains unclear, the patient can keep a daily diary detailing both headaches and menstruation for a few months to establish a pattern.
Stewart J. Tepper, MD, and Jennifer S. Kriegler, MD, are both at the Center for Headache and Pain, Neurological Institute, Cleveland Clinic, Cleveland, OH.

TABLE 1. Diagnostic Criteria for Migraine Without Aura1

A. At least 5 attacks, 1 fullling criteria BD B. Headache attacks lasting 472 hours (untreated or unsuccessfully treated) C. Headache has at least 2 of the following characteristics: Unilateral location Pulsating quality Moderate or severe pain intensity Aggravation by or causing avoidance of routine physical activity (eg, walking or climbing stairs) D. During headache, at least 1 of the following: Nausea and/or vomiting Photophobia and phonophobia E. Not attributed to another disorder

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Update on Menstrual Migraine

TABLE 2. Definitions of Menstrual Migraine1

Pure menstrual migraine without aura (PMM) Meet criteria for migraine (Table 1) and attacks occur exclusively on days -2 to +3 of menstruation in at least 2/3 of menstrual cycles and at no other times.

Menstrually related Meet criteria for migraine (Table 1) and attacks migraine without occur on days -2 to +3 of menstruation in at least aura (MRM) 2/3 of menstrual cycles and additionally at other times during the month.

to 30% compared with 6% to 8% in men. Pregnancy is usually associated with an improvement in Menstrual migraine (especially after the migraine is second trimester), probably due generally more to relatively stable estrogen levels. Perimenopause, which can severe than nonbegin as early as age 40, with its menstrual migraine, irregular menstrual cycles may although the differagain cause a dramatic increase in migraine. Women who ences may be undergo natural menopause subtle. usually show improvement in migraine postmenopausally; however, women who undergo surgical menopause more often experience worsening of their migraines.5,6 Multiple epidemiologic studies have demonstrated a higher frequency of migraines around the time of menses (Figure 2).

FOCUSPOINT

blood vessels, all of which may in turn inuence the migraine process. High estrogen levels increase the number of progesterone receptors and serotonin-2 (5-HT2) receptors while decreasing the number of 5-HT1 receptors. By contrast, withdrawal of estrogen increases trigeminal mechanoreceptor receptive elds, contributing to the risk of migraine. Estrogen withdrawal is also accompanied by a drop in central opioid concentrations, a rise in dopamine receptor hypersensitivity, and enhanced cerebral vasoreactivity to 5-HT. Estradiol directly dilates small-diameter cerebral blood vessels, which, in conjunction with raising prostaglandin levels through endometrial shedding during menstruation, further heightens the risk of migraine.

CLINICAL CHARACTERISTICS
Menstrual migraine is not associated with aura, even in women who experience aura in NMM episodes. Menstrual migraine is generally more severe than NMM, although the differences may be subtle. Pain intensity tends to be higher in menstrual versus nonmenstrual migraine.7 Headache duration is also longer in MM, with increased nausea, irritability, fatigue, disability, and loss of productivity as well.6-8 Some (but not all) studies describe reduced response to acute treatment in MM compared with NMM.8-10

ACUTE TREATMENT BIOLOGY

Estrogen has a number of effects on the central nervous system. As a potent neuromodulator, it affects neurons, glia, and cerebral The goal of acute treatment for MM would be a one and done responseie, the patient takes a single dose of medication and is pain-free within 2 hours, with no recurrence or further

QUESTION 1

Do you have headaches that are related to your period (ie, occur between 2 days before the onset of your period, until the third day of your period) most months? When my headaches are related to my period, they eventually become severe. When my headaches are related to my period, light bothers me more than when I dont have a headache.

Answer: yes/no

QUESTION 2 QUESTION 3

Answer: yes/no Answer: yes/no Sensitivity 0.94 Specicity 0.74

With yes to question 1 and at least 1 other yes With yes to question 1 and at least 1 other yes FIGURE 1. Menstrual Migraine Assessment Tool (MMAT)2

Reprinted with permission from Wiley-Blackwell. Tepper SJ, Zatochill M, Szeto M, Sheftell F, Tepper DE, Bigal M. Development of a simple menstrual migraine screening tool for obstetric and gynecology clinics: the Menstrual Migraine Assessment Tool. Headache. 2008;48(10):14191425.

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TEPPER and KRIEGLER

dosing; this is termed a sustained pain-free response. Acute treatment of migraine may be either nonspecic or migraine-specic. Nonspecic medications include: NSAIDs Aspirin (ASA) Acetaminophen (APAP) ASA or APAP with caffeine (AAC) Neuroleptics -Aminobutyric acid (GABA) agonists, eg, baclofen Antihistamines Mild vasoconstrictor/sedative/APAP mixtures (eg, isometheptene/dichloralphenazone/ APAP) Barbiturate mixtures (eg, butalbital/AAC with either ASA or APAP) Opioids Caution should be used when prescribing barbiturate mixtures or opioids; using these medications as little as 5 days per month can lead to medication overuse, additional headaches, chronic daily headache, or rebound headache.11 In addition, nonspecic treatments have not been subjected to randomized controlled trials (RCTs)for MM.12,13

Dalton, 1973 (42) MacGregor et al, 1990 (1) Johannes et al, 1995 (43) Stewart et al, 2000 (29) Our study

-7 -6 -5 -4 -3 -2 -1 1 2 3 4 5 6 7 Day of menstrual cycle FIGURE 2. Prevalence of Menstrual Migraine7

Reprinted with permission from Wiley-Blackwell. Granella F, Sances G, Allais G, et al. Characteristics of menstrual and nonmenstrual attacks in women with menstrually related migraine referred to headache centres. Cephalalgia. 2004;24(9):707716.

Specic migraine treatments comprise triptans or ergots. The choice of specic or nonspecic acute treatment should be based on the frequency and impact of the migraines; women with moderate to severe disability should use triptans as rst-line therapy in the absence of vascular contraindications.14 Triptans are highly effective for MM, optimally administered early in the attack without temporizing or

Coding for Update on Menstrual Migraine

The ICD-9 diagnosis code for migraine is covered under code 346. However, you are required to add a 5th-digit subclassification when using code 346. 346 Migraine

Philip N. Eskew Jr, MD

This means that for any of the diagnoses listed under 346.4, you should code it as 346.40 unless the patient has intractable or status migraine symptoms. The office visit codes may be based on time when diagnosing and treating patients with menstrual migraines. You should document any history obtained and reviewed, any physical examination performed, and any medical decisionmaking steps (tests ordered and/or prescriptions written) you have taken. However, you may spend the entire visit reviewing the patients headache diary or counseling the patient on prevention and treatment procedures. Documentation is the key point when justifying which level of service you are billing. You should document the actual time when more than 50% of your visit time was spent in counseling. Also, document what you discussed and how you spent that counseling time. Philip N. Eskew Jr, MD, is past member, CPT Editorial Panel; past member, CPT Advisory Committee; past chair, ACOG Coding and Nomenclature Committee; and instructor, CPT Coding and Documentation courses and seminars.

The following 5th-digit subclassification is for use with category 346: 0 without mention of intractable migraine without mention of status migrainosus 1 with intractable migraine, so stated, without mention of status migrainosus 2 without mention of intractable migraine with status migrainosus 3 with intractable migraine, so stated, with status migrainosus 346.4 Menstrual migraine Menstrual headache Menstrually related migraine Premenstrual headache Premenstrual migraine Pure menstrual migraine

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TABLE 3. Trials of Oral Triptans for Acute Treatment of Menstrual Migraine13

Triptan (dose) Naratriptan (2.5 mg)10 Rizatriptan* (10 mg) 4 Study Design Cycle Days Relative to Onset Initiation of of Menses Treatment Result of Primary Endpoint

Randomized, double-blind, 2 to + 4 parallel group, singleepisode; N = 229 Retrospective analysis; N = 335 enrolled in 1 of 2 RCTs 3 to +3

Mild headache; Signicantly increased within 1 h of number of patients headache start pain-free at 4 h Moderate to severe headache Statistically similar effects in menstrual and nonmenstrual migraine; signicantly more patients were pain-free at 4 h postdose compared with placebo

Sumatriptan (100 mg or 50 mg)8 Zolmitriptan (1.25 to 5 mg, depending on baseline headache intensity)9

Randomized, double-blind, 2 to +4 placebo-controlled; N = 349 Randomized, double-blind, 3 to +5 parallel group; N = 579

Mild headache Signicantly more patients were pain-free at 2 h with either dose compared with placebo Mild, moderate, 2-h pain-free response was or severe achieved in signicantly more headache migraine attacks compared with placebo

*Primary endpoint not applicable for retrospective analysis. N = number; RCT = randomized controlled trial. Reprinted with permission from Wiley-Blackwell. Tepper SJ. Tailoring management strategies for the patient with menstrual migraine: focus on prevention and treatment. Headache. 2006;46(CME Suppl 2):S61S68.

using nonspecic medications rst. The RCTs on triptans for MM are summarized in Table 3.

PREVENTION
Acute treatments for MM are often associated with partial relief and recurrence. These

Infrequent
Yes No

Acute (abortive) therapy

Long duration/ Poorly responsive to acute therapy Predictable?

Yes No

Consider short-term prevention stategies

Consider long-term prevention stategies

FIGURE 3. Treatment Algorithm for Menstrual Migraine13

Reprinted with permission from Wiley-Blackwell. Tepper SJ. Tailoring management strategies for the patient with menstrual migraine: focus on prevention and treatment. Headache. 2006;46 (CME Suppl 2):S61S68.

issues can be addressed by administering the acute treatment as early as possible in an attack; prescribing triptans or ergots with lower recurrence rates (eg, naratriptan, dihydroergotamine [DHE]) versus those with higher recurrence rates (eg, sumatriptan, zolmitriptan, rizatriptan); or adding an NSAID to triptan therapy (eg, sumatriptan plus naproxen). However, the partial benefits of the acute treatments, the predictability of MM, and the continued impact of migraine all lead many patients to request preventive regimens. Daily preventive treatments for MM are generally the same as those for NMM, and the best evidence supports the use of tricyclic antidepressants (eg, amitriptyline), beta-blockers (eg, propranolol), or antiseizure drugs (eg, topiramate, divalproex).15 Because of the potential risk for polycystic ovary syndrome and teratogenicity, divalproex should be avoided for migraine prevention in women of childbearing age.16 Studies are under way on the effectiveness and safety of using continuous daily oral contraceptive therapy or parenteral hormonal contraception for MM prevention.
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Short-Term Prevention
The predictability of MM raises the clinical possibility of prevention administered only during the time of greatest vulnerabilityie, short-term prevention. Figure 3 provides an algorithm for use in deciding between daily and short-term prevention. There are few RCTs addressing nontriptan short-term prevention of MM. However, RCTs on magnesium (360 mg/d) and naproxen (550 mg twice daily) beginning at ovulation and maintained through menstruation have shown some efcacy.17,18 The use of hormonal treatment to blunt the menstrual fall in estrogen levels and prevent or reduce MM has been considered. However, the best RCT on this approach found that estradiol gel, initiated 10 days after the rst day of peak fertility and continued daily through day +2 of menses, resulted in a 40% increase in migraine in the 5 days following treatment.19 Multiple triptans have been studied for short-term prevention of MM in both randomized and open-label trials. All have shown efcacy when administered daily beginning a few days prior to ow and maintained for 5 or 6 days. Frovatriptan was also studied prospectively over 1 year in this paradigm to

monitor safety. The FDA has not approved the use of triptans for short-term prevention, but the effect appears to be class-wide (Table 4).

FOCUSPOINT
Selection of a triptan as rstline treatment is indicated in women with moderate to severe attacks and in the absence of vascular contraindications.

CONCLUSION

Menstrual migraine occurs from days 2 to +3 of the cycle, and it can be longer, more severe, more debilitating, and more difficult to treat than NMM. Selection of a triptan as rst-line treatment is indicated in women with moderate to severe attacks and in the absence of vascular contraindications. Daily prevention is used for women in whom triptans are contraindicated or produce recurrence or partial response. Predictable MM occurrence with respect to menses also allows for the possibility of short-term prevention using magnesium, naproxen, or a triptan beginning a few days before ow and maintained throughout. Hormonal short-term prevention appears to only delay attacks, but daily hormonal prevention is still being studied.

TABLE 4. Trials of Short-Term Menstrual Migraine Prevention13

Triptan Frovatriptan Study Design 3-way crossover design; N = 546 Dose Regimen vs Pbo Frovatriptan, 2.5 mg qd or bid; double dose on rst day of Rx; start 2 days before expected onset of MM; use for 6 days Outcome Incidence of MM: pbo = 67%, frovatriptan, 2.5 qd = 52%, frovatriptan, 2.5 bid = 41% (P <.0001 vs pbo for both active treatment arms) Incidence of pain-free perimenstrual period: Only 1 mg bid was statistically signicant vs pbo in reducing MM; naratriptan, 1 mg bid = 50% (P <.003); pbo = 25% 50% reduction in MM: zolmitriptan, 2.5 mg tid = 58.6%, zolmitriptan, 2.5 bid = 54.7%, pbo = 37.8% (P = .0007 and P = .002, respectively)

Naratriptan

Parallel design, N = 206

Naratriptan, 1 mg or 2.5 mg bid; start 2 days before expected onset of menses; use for 5 days

Zolmitriptan

Parallel design, N = 244

Zolmitriptan, 2.5 mg bid or tid; start 2 days before expected onset of menses; use for 7 days

Pbo = placebo; N = number; qd = once per day; bid = 2 times per day; Rx = prescription; MM = menstrual migraine; tid = 3 times per day. Reprinted with permission from Wiley-Blackwell. Tepper SJ. Tailoring management strategies for the patient with menstrual migraine: focus on prevention and treatment. Headache. 2006;46(CME Suppl 2):S61S68.

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Stewart J. Tepper, MD, received grants and research support in 2008 and 2009 from Advanced Technology Innovations, Endo Pharmaceuticals, GlaxoSmithKline, MAP Pharmaceuticals, Merck & Co, NanoMaterials Technology, and St Jude; served as a consultant in 2008 and 2009 for Coherex Medical, Endo Pharmaceuticals, GlaxoSmithKline, MAP Pharmaceuticals, Merck & Co, and NanoMaterials Technology; and was a member of the speakers bureau in 2008 and 2009 for GlaxoSmithKline, Merck & Co, NanoMaterials Technology, and Valeant Pharmaceuticals International. Jennifer S. Kriegler, MD, was a member of the speakers bureau in 2007 and 2008 for Endo Pharmaceuticals, GlaxoSmithKline, Merck & Co, and Pzer.

8.

9.

10.

11.

12.

13.

14.

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