Targeted treatment strategies for menstrual migraine

Professor of Clinical Medicine,University of Cincinnati College of Medicine, Cincinnati, Ohio

Epidemiologic evidence suggests that migraine headache is modulated by female ovarian hormones. Migraine headache is 3 times more common in women than men, occurring in 18.2% of women and 6.5% of men.¹ The prevalence significantly increases during the peak reproductive years of women (aged 20-50 years), which represents a period of cyclic fluctuations in ovarian hormones as a result of the female menstrual cycle. Reproductive life events such as menarche, pregnancy, and menopause can alter the frequency and disability of preexisting migraine attacks or may lead to the new onset of migraine in some women.^2-6 Therefore, changes in ovarian hormones encountered during the female menstrual cycle as well as during reproductive life events influence the clinical course of migraine headache.

The perimenstrual time has been found to be a time of particular vulnerability to migraine headache. Two past population-based studies reported that attacks of migraine without aura were 1.66 to 2.04 times more likely to occur during the first 2 to 3 days after the onset of menstruation when compared with all other days of the menstrual cycle.^7,8 Interestingly, the incidence of attacks of migraine with aura did not increase during the perimenstrual time period. MacGregor et al demonstrated that the relative risk for migraine was 1.7 during the 2 days before menstruation and 2.5 for the first 3 days after the onset of menstruation in a subspecialty-based study.⁹ Authors have referred to attacks of migraine without aura that consistently occur during the perimenstrual time period as menstrual migraine.

 

Definition of Menstrual Migraine

The International Headache Society has subcategorized menstrual migraine into pure menstrual migraine and menstrually related migraine in the appendix of their diagnostic criteria for migraine and other headache disorders.¹⁰ Both represent attacks of migraine without aura that occur during the 5-day perimenstrual period, 2 days before to 3 days after onset of menstruation, for at least 2 out of 3 cycles (TABLE 1). Attacks occur both within and outside the perimenstrual time period in women with menstrually related migraine whereas they occur exclusively within the perimenstrual time period in those with pure menstrual migraine. Interestingly, women with menstrually related migraine can experience attacks of migraine either with or without aura outside the menstrual period.¹⁰

Diagnostic Criteria for Menstrual Migraine

 

Epidemiology

Migraine headache commonly begins during the teenage years with the onset of menarche in female migraineurs. Stewart et al reported that the peak incidence of migraine was 12 to 13 years of age for migraine with aura and 14 to 17 years of age in migraine without aura.² The prevalence of migraine in the general population is 5% to 10% in adolescent girls, 20% to 25% in menstruating women aged 30 to 50 years, and less than 10% in postmenopausal women.¹ Menstrual migraine occurs in 3% of the general population but increases in those with migraine headache.¹¹ In fact, 35% to 55% of patients with migraine have menstrually related migraine and 7% to 19% have pure menstrual migraine.^5,12-17 These data would suggest that migraine headache is modulated by the cyclic changes in ovarian hormones encountered during the female menstrual cycle.

Recent evidence also supports the widely held belief that menstrual migraine headaches are more severe, of longer duration, and are less responsive to both acute and preventive treatment than migraines occurring at other times of the menstrual cycle. Granella et al reported that attacks of menstrual migraine were more disabling, less responsive to treatment, and of longer duration than nonmenstrual migraine.¹⁸ Martin et al found that attacks of migraine during the perimenstrual time were more severe, disabling, and required a greater amount of abortive medication than those occurring during nonmenstrual times.¹⁹ Associated symptoms such as nausea and vomiting may be more common during attacks of menstrual migraine than other types of migraine.⁹

 

Estrogen Levels and the Pathophysiology of Menstrual Migraine

Although the exact pathophysiology of menstrual migraine is not currently known, the importance of estrogen was established more than 3 decades ago by Somerville.^20,21 He demonstrated that declining levels of estradiol during the late luteal phase of the menstrual cycle were responsible for the development of menstrual migraine; a decline in the progesterone level did not affect the onset of menstrual migraine.²² Further evidence supporting the importance of a declining estrogen level includes the predictable onset of migraine during the placebo week of oral contraceptives and the return of migraine headaches during the postpartum period when estrogen levels fall abruptly after pregnancy. These latter are referred to as postpartum headaches.^23,24 Postmenopausal women with a history of menstrual migraine developed severe migraine following injection of depo-estradiol cyprionate correlating with a decline in estrogen level, whereas women without a history of menstrual migraine did not.²⁵ Therefore, “estrogen withdrawal” during the perimenstrual time appears to represent the primary mechanism through which menstrual migraine is triggered.

The precise mechanisms through which estrogen withdrawal triggers menstrual migraine are unknown, but several theories have been advanced. First, animal studies suggest that declining levels of estrogen can sensitize second-order neurons of the trigeminal nerve, which may increase firing rates within these neurons.²⁶ Second, estrogen withdrawal may enhance excitatory tonus (eg, glutamatergic) and/or reduce inhibitory tonus (eg, serotonergic, opiatergic, and GABAtergic systems) within neurotransmitter systems of the trigeminal system or modulatory brainstem nucleii.²⁷ Third, estrogen withdrawal could decrease serum magnesium levels, which could lead to enhanced neuronal excitability.^28,29

Estrogen may not be the whole story, however, as serum prostaglandin levels have been shown to increase during menstrual migraine. Because some prostaglandins are potent mediators of hyperalgesia, their role in menstrual migraine seems plausible.³⁰

 

Clinical Criteria for Diagnosis

A careful, focused history and physical examination is essential to first establish a diagnosis of migraine without aura and then to classify it as menstrual migraine. The diagnostic criteria for migraine without aura as defined by the International Headache Society are listed in TABLE 1.¹⁰ Migraine without aura requires the presence of 2 of 4 clinical characteristics (eg, unilateral, moderate-to-severe pain, worse with exertion, and throbbing quality) and 1 of 2 associated symptoms (eg, nausea or vomiting, or both phonophobia and photophobia). While several features help to differentiate migraine from tension-type headache, the presence of nausea, photophobia, and disability are sensitive and specific indicators of migraine (TABLE 2).³¹

Lipton et al found that the presence of any 2 of the above 3 variables had a sensitivity of 81% and specificity of 75% for the diagnosis of migraine headache in a primary care setting.³² Another study found that the presence of nausea alone had a sensitivity of 81%, specificity of 83%, and positive predictive value greater than 80% for the diagnosis of migraine headaches for patients presenting with a complaint of headache.³³

Once a diagnosis of migraine headache is established, menstrual migraine can be confirmed by noting the temporal relationship between attacks of migraine and the perimenstrual time period. This can be accomplished best by asking the patient to record the timing of her migraine attacks and menses on a calendar or diary. Samples of headache diaries are available from the American Headache Society (www.achenet.org/resources/diary.php) and the National Headache Foundation (www.headaches.org/professional/educationresources/PDF/headache_diary.pdf)

Differentiating Migraine From Tension-Type Headache

Feature	Tension-Type	Migraine
Mild-to-moderate pain		—
Moderate-to-severe pain	—
Intense, pounding, throbbing, and/or disabling pain	—
Distracting but not disabling		—
Worsens with motion	—
Steady ache		—
One side of head	—
Both sides of head
Nausea/vomiting	—
Sensitivity to light and/or sounds	—
Aura before headache onset	—

 

Assessment of Migraine Disability

During the patient work-up, it may be helpful to use a disability assessment tool to determine the effect of menstrual migraine on the patient. The benefit of this approach is that it provides a baseline disability assessment, which can be used to assess the success or failure of abortive and/or preventive therapies when repeated at a later date. To identify the effect, the Migraine Disability Assessment (MIDAS) questionnaire or the Headache Impact Test™ can be used.

MIDAS is a brief, self-administered questionnaire designed to quantify headache-related disability over a 3-month period (www.migraine-disability.net/About_Midas/default.asp).³⁴ The MIDAS score has been shown to have moderately high test-retest reliability among headache sufferers and correlates well with clinical judgment regarding the need for medical care. It also exhibits good correlation with a detailed headache diary.

The Headache Impact Test™ is a 1- to 2-minute questionnaire that measures the effect of headaches on a person’s ability to function on the job, at home, at school, and in social situations (www.headachetest.com).³⁵

 

Treatment Goals

The goals of menstrual migraine treatment, which are the same as those for migraine, are generally to reduce the morbidity and other consequences of menstrual migraine (TABLE 3).³⁶ To achieve these goals, nonpharmacologic and pharmacologic treatments are needed. Although these treatments are similar for migraine and menstrual migraine, the addition of short-term preventive therapies may be necessary for menstrual migraine to achieve a satisfactory treatment response.

Goals of Menstrual Migraine Treatment

 

Nonpharmacologic Treatments

Nonpharmacologic treatments include the identification and avoidance of triggers, many of which are the same as the triggers for nonmenstrual migraine (TABLE 4).³⁷ In some cases, a trigger may be important during menses, yet be insufficient to trigger a migraine at another time of the menstrual cycle. The headache diary can be very helpful in identifying triggers. Other nonpharmacologic treatments include maintaining regular routines for eating, sleeping, and exercise, as well as good hydration.³⁸ The use of biofeedback and relaxation techniques may be helpful for patients in whom stress is a trigger.

Nonmenstrual Triggers

 

Acute Treatments for All Migraineurs

All patients with menstrual migraine will need some type of acute therapy to treat their attacks, including attacks that may occur while the patient is using preventive therapy. The management goals of acute menstrual migraine are shown in TABLE 5.^36,39 It must be emphasized that the goal of significant symptom relief and a return in the ability to function within 2 hours of initiating treatment is achievable in most patients, particularly if the abortive medication is administered within 1 hour after the onset of the attack.

Early use of abortive therapy is advised prior to the development of cutaneous allodynia of the ipsilateral forehead, which can occur within 20 minutes to 2 hours after the onset of pain. Cutaneous allodynia refers to a non-painful stimulus to the skin being perceived as painful and implies sensitization of second-order neurons of the trigeminal nucleus caudalis. Once second-order trigeminal neurons become sensitized, migraine becomes much more refractory to treatment.⁴⁰ Other benefits of early acute treatment include fewer headache recurrences, decreased disability, and reduced exposure to potential adverse events, largely as a result of a reduced need for rescue medication.⁴¹

Acute therapy should be individualized with consideration for associated symptoms, comorbidities, previous treatments, and the patient’s response and side effect profile.

The United States Headache Consortium recommends a non-oral route of administration for a patient with significant nausea and vomiting.³⁶ Additionally, a non-oral route should be used when the headache intensity rapidly escalates because intranasal and subcutaneous routes of administration are faster than oral routes. Women of child-bearing potential should be strongly advised to use adequate birth control measures because many of the drugs are contraindicated during pregnancy.

Goals of Acute Migraine Therapy

Triptans: Effective for Acute Migraine

The triptans are agonists of serotonin 1B/1D receptors and represent some of the most commonly prescribed medications for the acute treatment of migraine. Most of the triptans provide pain relief of 60% to 70% and freedom from pain of 30% to 40% at 2 hours after administration when treating moderate to severe attacks of migraine.⁴² Results at 2 hours can be improved to 45% to 65% freedom from pain by treating early after onset when the pain is mild.^43-47

The triptans share similar efficacy in the treatment of menstrual and nonmenstrual attacks.⁴⁸ Eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan, and zolmitriptan have been studied in moderate-to-severe attacks of menstrual migraine and were found to be significantly superior to placebo as acute therapies for migraine.^48-53 Oral sumatriptan has been studied in the treatment of menstrual migraine when the pain was mild, wherein it demonstrated 2-hour pain-free results of 50% to 65% (FIGURE 1).⁵⁴ Almotriptan, 12.5 mg, has been compared with zolmitriptan, 2.5 mg, for the acute treatment of menstrual migraine.⁵⁵ Pain-relief 2 hours after dosing was achieved in 68% of almotriptan-treated patients and 69% of zolmitriptan-treated patients, while 45% and 41%, respectively, were pain free. Recurrence within 24 hours occurred in 33% and 35% of patients, respectively.

Although many available triptans share similar efficacy, switching to a different triptan is reasonable should an adequate trial of 1 triptan be unsuccessful. Before concluding failure with any given triptan, it should be used on 3 attacks. In addition, it must be verified that the patient initiated treatment early after the onset of the migraine attack (before allodynia was established), that the initial dosage was adequate, and that the route of administration was appropriate to the pattern of attack.

All triptans are available in an oral formulation. Almotriptan, eletriptan, rizatriptan, sumatriptan, and zolmitriptan quickly reach peak concentrations in the blood and, therefore, have a faster onset of action. Frovatriptan and naratriptan have the longest elimination half-lives, which makes them a good choice for patients whose migraine attacks are of long duration, such as can occur in menstrual migraine. Rizatriptan and zolmitriptan are also available as orally disintegrating tablets, and sumatriptan and zolmitriptan as a nasal spray. Sumatriptan is available as a subcutaneous injection with the STATdose Pen^® and has the fastest onset of action.

Although they are the most effective agents for acute treatment of migraine, triptans are not appropriate for all patients with migraine. The cardiovascular safety profile of triptans was thoroughly investigated by the Triptan Cardiovascular Safety Expert Panel. Their conclusion was that the cardiovascular risk-benefit profile of triptans favors their use in the absence of contraindications.⁵⁶ However, because of vasoactive effects on coronary arteries, they are contraindicated for patients with ischemic heart disease or uncontrolled hypertension, or patients who are at high risk of heart disease.

Triptans also should not be used in patients with 2 sub-types of migraine with aura, basilar and hemiplegic, for theoretical reasons of increasing vasoconstriction of cerebral arteries. They should be used cautiously in persons older than 60 years because of the increased risk of asymptomatic coronary artery disease in this group.

Other Drugs in Acute Migraine Treatment

Numerous other medications have been used for the acute management of migraine. Although most are analgesics and not specific for migraine, they occasionally prove beneficial for patients who do not respond to triptans or in whom the triptans are contraindicated. The United States Headache Consortium has determined that the combination of isometheptene, acetaminophen, and dichlorphenazone (Midrin), though not as effective as the triptans, may be useful in treating mild-to-moderate migraine.

Other classes of drugs shown to be effective include nonsteroidal anti-inflammatory drugs (NSAIDs), combination analgesics, opioids, and metoclopramide.³⁹ These drugs are rarely used as monotherapy, but are instead used in combination with a triptan when monotherapy with a triptan does not result in rapid, consistent, and complete relief of migraine. It is especially important to monitor the frequency of opioid use and other combination analgesics to ensure that the patient is not taking the medication more than twice a week or otherwise escalating the dose, potentially placing the patient at risk for medication-overuse headache. For this same reason, butalbital-containing medication is best avoided, or at the very least, limited to no more than twice a week.

Opioids have been used for a long time in the acute management of migraine in the emergency department. A major barrier to their use is the potential for aberrant medication-related behavior among patients who may be predisposed to addictive disorders. Their use is best limited to patients who cannot tolerate or have a contraindication to the use of migraine-specific medications such as the triptans and ergots. Opioids can also be used in small quantities as rescue or back-up medications in the event that the primary abortive medication fails. Appropriate steps must be taken when these agents are prescribed, such as limiting the quantity, not providing refills, and monitoring the frequency of use. Among the opioids, butorphanol nasal spray is convenient and has shown efficacy in the abortive treatment of migraine.⁵⁷

Ergotamine remains available for oral and rectal use. Oral ergotamine with and without caffeine has been used for decades as an effective abortive therapy for migraine. Dihydroergotamine is available in the United States as a nasal spray and for intramuscular and intravenous administration. Nausea is a frequent side effect of treatment with ergot alkaloids, often requiring the administration of an antiemetic.

Combination analgesics represent the only nontriptan abortive therapies to be specifically studied in attacks of menstrual migraine. Silberstein et al reported that the combination of aspirin, acetaminophen, and caffeine significantly reduced pain severity and associated symptoms during attacks of menstrual migraine.⁵⁸ Since this study excluded patients who experienced severe disability with their migraines, these results may be more applicable to patients with attacks of mild-to-moderate severity/disability.

 

Preventive Treatment

Patients with attacks of menstrual migraine in which acute treatment has not been adequate are candidates for preventive treatment. Other indications for prevention include headaches that last more than 2 days or those that frequently recur despite acute treatment.¹² There are 2 approaches for the prophylaxis of menstrual migraine: short-term and continuous daily preventive therapies. The decision to use intermittent short-term or continuous preventive therapy depends on patient preference, the frequency of nonmenstrual migraine, and the regularity of menstrual periods (FIGURE 2). Sometimes both therapies may need to be administered concomitantly because continuous daily therapies may not always be effective for menstrual migraine.

Short-Term Prevention

Short-term prevention is appropriate for women with a predictable menstrual migraine and regular menstrual periods each month. Short-term prevention is generally started a few days before the anticipated onset of menstrual migraine and continued for 4 to 10 days. The duration of treatment varies depending on the preventive agent used (TABLE 6).¹²

Short-Term Preventive Treatments for Menstrual Migraine

Triptans

Several trials have investigated frovatriptan, naratriptan, and sumatriptan for short-term prevention of menstrual migraine. The first was a pilot study of 20 patients treated with 5 days of sumatriptan, 25 mg 3 times daily, beginning 2 to 3 days before anticipated migraine onset.⁵⁹ Headache was absent in 52% of treated attacks and was reduced in severity in another 42%. These results led to trials involving triptans with a longer elimination half-life.

Women with menstrual migraine were randomized to receive treatment for 3 perimenstrual periods with frovatriptan, 2.5 mg once daily, frovatriptan, 2.5 mg twice daily, or placebo starting 2 days before the anticipated start of menstrual migraine and continuing for 6 days.⁶⁰ A loading dose of 10 mg was used on the first day in the 2.5-mg twice daily group and a 5-mg loading dose was used for the 2.5-mg once daily group. Both groups of frovatriptan were superior to placebo in reducing the incidence and severity of menstrual migraine (FIGURE 3).⁶⁰

Naratriptan has been investigated in several trials, including a double-blind, placebo-controlled, parallel-group trial.⁶¹ Patients received naratriptan, 1 mg or 2.5 mg, or placebo twice daily starting 2 days prior to anticipated menses and continuing for 5 days. Patients were treated over 4 menstrual cycles. Efficacy was measured as having 50% or fewer menstrual periods with migraine: by this measure, naratriptan, 1 mg, was statistically superior to either placebo or naratriptan, 2.5 mg (FIGURE 4).

Nonsteroidal Anti-Inflammatory Drugs

The NSAIDs naproxen sodium and mefenamic acid have been investigated with variable results. Naproxen, 550 mg twice daily, for 7 days before and 6 days after menstruation has been shown to reduce the number but not the severity of perimenstrual headaches.⁶² Another trial found no difference in headache severity or duration between placebo and naproxen, 550 mg twice daily, starting 8 days after ovulation and ending 8 days after the start of menses.⁶³ Because of variable response among the NSAIDs, a lack of response to one type of NSAID does not rule out the possibility of a response to an alternate NSAID.³⁸

Ergotamine Derivatives

To date there have been no randomized controlled trials of ergots for the short-term prevention of menstrual migraine. One case series of 40 patients treated with ergonovine, 0.2 mg 4 times daily, taken 1 day before to 1 day after menstruation, found that 60% had less severe attacks, 15% had less frequent attacks, and 35% had no improvement after 3 months of treatment.⁶⁴

Magnesium

Another nonhormonal option that has been investigated is magnesium supplementation. Facchinetti et al enrolled 20 patients with menstrual migraine in a double-blind, placebo-controlled trial.⁶⁵ Patients received magnesium, 360 mg daily, or placebo beginning on the fifteenth day of the cycle and continuing until the next menses for 2 months. Magnesium supplementation continued for an additional 2 months in an open-label design. The patients who received magnesium had a significant reduction in pain scores, number of days with headache, and perimenstrual complaints.

Hormonal Therapies

Hormonal agents can be use preventively as an attempt to counteract or prevent the luteal phase drop in estrogen. A variety of hormonal regimens have been investigated. Percutaneous estradiol gel patches have been investigated in 2 small, double-blind, placebo-controlled trials.^65,66 Patients in both trials received estradiol, 1.5 mg daily, or placebo started 2 days prior to menses and continued for 7 days. In one trial, 31% of the estradiol group and 96% of the placebo group reported menstrual migraine,⁶⁶ while the other reported a reduction in the frequency of menstrual migraine and consumption of analgesic medications in the estradiol group.⁶⁷

Results with the transdermal estradiol patch have been less beneficial. Three studies have found no difference between the estradiol patch, 50 mcg, and placebo in preventing menstrual migraine.^12,68,69 However, when administered at a dose of 100 mcg, a 50% reduction in the incidence rate of menstrual migraine has been reported.¹² These studies could indicate that higher dosages of transdermal estradiol are needed to prevent menstrual migraine.

Oral contraceptive use is generally considered safe for women with migraine without aura who have no cardiovascular risk factors.⁷⁰ The use of an oral contraceptive is intended to minimize the fluctuation in estrogen levels throughout the menstrual cycle or to reduce the number of menstrual cycles, depending on the type of oral contraceptive prescribed.³⁸ However, migraines may worsen, remain stable, improve, or occur for the first time when oral contraceptive therapy is started.

Short-term estrogen preparations administered during the placebo week of oral contraceptives have shown benefit. Conjugated equine estrogens, 0.9 mg, were administered during the placebo week to 11 women with menstrual migraine who were taking an oral contraceptive containing ethinyl estradiol, 20 mcg, on days 1 to 21.⁷¹ All 11 patients achieved at least a 50% reduction in the number of headache days per cycle.

While estrogen administration may be beneficial as preventive therapy for some women with menstrual migraine, the risks associated with estrogen also must be considered. These risks include stroke⁷² and venous thromboembolism,⁷³ but probably not breast cancer⁷⁴ or coronary heart disease.⁷⁵

 

Continuous Prevention

For women with menstrual migraine refractory to short-term prevention treatment or with irregular menstrual periods, continuous prevention is indicated. Continuous prevention with standard preventative agents such as β-blockers, calcium channel blockers, tricyclic antidepressants, and anticonvulsants is generally ineffective for attacks of menstrual migraine.^12,76 The continuous use of the ergot derivative bromocriptine 3 times daily has been shown to reduce the frequency of migraine by 72% in an open-label trial of 24 women.⁷⁷ An alternative, albeit less effective, option is for patients receiving continuous prevention to increase the dosage of the preventative during the perimenstrual time period in an attempt to boost efficacy.

The use of continuous hormonal therapies such as estradiol implants, gonadotropin releasing-hormone agonists, danazol, and phytoestrogens are supported with limited data, but because of their side effects are recommended for only refractory, extremely debilitating migraines.¹² Another potential regimen to prevent menstrual migraine is extended-regimen oral contraceptives. These are monophasic oral contraceptives administered continuously for 3 months followed by a placebo week. Such regimens, which minimize declines in ethinyl estradiol, should theoretically decrease the incidence of menstrual migraine, but studies of their efficacy in menstrual migraine are lacking. One study, however, has reported that the incidence of “headache complaints” was less in the extended dosage oral contraceptive group compared with placebo (9.7% vs 17.3%, respectively).⁷⁸

Prevention Follow-Up

Preventive therapy should, of course, be evaluated on a regular basis, generally within 6 to 8 weeks following initiation. The frequency and severity of headaches and their associated symptoms should be determined, preferably by reviewing the patient’s headache diary. In addition, the patient should be specifically questioned about side effects, their impact, and how they are managed. Laboratory testing should be conducted as indicated by the specific drugs. In addition to the use of acute therapies, the patient also should be questioned regarding emergency department and other outpatient visits for acute therapy.

 

Summary

Menstrual migraine occurs in slightly more than half of women with migraine. A major goal of acute treatment is to provide complete pain relief within 2 hours. Options for acute management are those generally used for migraine and include triptans, NSAIDs, ergotamine, opioids, and metoclopramide. When abortive medications are not completely effective, preventative treatments can be used to prevent migraine from occurring and to reduce headache disability. For women with a regular menstrual cycle and predictable occurrence of migraine, short-term prevention is generally very effective. Treatment is initiated a few days prior to menses and continued for several days, depending on the drug used. Options include triptans, naproxen sodium, ergotamine derivatives, magnesium, and hormonal therapies. Long-term continuous prevention may be helpful for women with frequent attacks throughout the menstrual cycle, irregular menstrual periods, and/or women who do not achieve an adequate response to short-term prevention.

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