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Prophylaxis and Treatment of Menstrual Migraine
Original Article Prophylaxis and Treatment of Menstrual Migraine ---
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Yvonne M. D’Arcy, MS, CRNP, CNS
ABSTRACT:
Migraine is a very disabling condition that can severely impair quality of life. Eighteen percent of women suffer from migraine headaches, and of those, approximately 60% have migraines near the time of their menstrual period. Migraine is generally undertreated, not only because some sufferers do not have access to proper care, but also because many fail to seek treatment because of misperceptions that nothing can be done for a condition from which generations of women have suffered. Research has shown that migraine is not a disorder of blood vessels, but rather a brain disorder characterized by inflammation. The goal of this paper is to explain practical approaches to managing menstrual migraine. Ó 2011 by the American Society for Pain Management Nursing
MIGRAINE HEADACHE
From Suburban Hospital–Johns Hopkins Medicine, Bethesda, Maryland. Address correspondence to Yvonne M. D’Arcy, MS, CRNP, CNS, Suburban Hospital–Johns Hopkins Medicine, Bethesda, Maryland, United States. E-mail: ydarcy@surburbanhospital. org Received April 8, 2010; Revised August 1, 2010; Accepted August 17, 2010. Publication of this article was supported by Endo Pharmaceuticals Inc. 1524-9042/$36.00 Ó 2011 by the American Society for Pain Management Nursing doi:10.1016/j.pmn.2010.11.002
Across the globe, migraine headaches affect approximately 10% of the adult population, with a lifetime prevalence of 14%; migraine affects 2 to 3 times as many women than men (Jensen & Stovner, 2008; Martin & Lipton, 2008; Stovner et al., 2007). According to the World Health Organization, for women, headache is considered the third most costly neurological disorder and the fifth most disabling disorder (Stovner et al., 2007). The burden of migraine includes $13.3 billion in indirect costs associated with reduced efficiency or lost time from work plus another $1 billion in expenditures associated with treatments and hospitalizations (Hu, Markson, Lipton, Stewart, & Berger, 1999; Jensen & Stovner, 2008). These numbers were derived from a 1994 study in the United States of adults aged 20 to 65 years; 80% of all the costs were incurred by women with migraines (Jensen & Stovner, 2008). Women are more often afflicted with migraines; the incidence of migraines in women is 15% to 25% compared with 6% to 8% in men (Pietrobon, 2005). Although migraine characteristics are unique to each individual, the typical nonmenstrually related migraine headache has a unilateral location with a severe pain intensity that is described as ‘ different than any other headache,’ and often as ‘ pounding,’ ‘ pulsing,’ or ‘ throbbing.’ Physical exertion is often either an aggravating cause of migraine or avoided while the patient is experiencing headache. Headaches are diagnosed worldwide based on the criteria established in the second edition of The International Classification of Headache Disorders (ICHD-II), published in 2004 (Diamond et al., 2007; Hutchinson & Silberstein, 2008; Silberstein & Hutchinson, 2008). The International Headache Society Criteria for migraines Pain Management Nursing, Vol 12, No 1 (March), 2011: pp S11-S16
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without aura are those headaches which cannot be attributed to another disorder, which last for 4 to 72 hours, are accompanied by nausea/vomiting or phonophobia/photophobia, and for which at least two of the following are true: unilateral in location, pulsating in quality, moderate to severe in pain intensity, and aggravated by physical activity (Headache Classification Subcommittee of the International Headache Society, 2004). The risk of developing migraines has been genetically linked, although the specific genes involved have not yet been established (the relevance of a few identified in a screen—genes encoding subunits of a calcium channel, a sodium potassium pump, and a sodium channel—are still being assessed) (Pietrobon, 2005; Stovner, 2008). In a study of 7,732 women younger than 55 years, the prevalence of migraine was found to be significantly increased in those with total body obesity (p ¼ .001), as well as in those with abdominal obesity (p < .001) compared with women with body mass indexes under 30 (Peterlin, Rosso, Rapoport, & Scher, 2010). Migraine has been connected to cardiovascular and metabolic ailments, such as stroke, hypertension, diabetes and obesity, as well as to neurological dysfunction, including fibromyalgia, low back pain, anxiety, and depression (Jensen & Stovner, 2008; Peterlin, Katsnelson, & Calhoun, 2009). Often, these comorbidities complicate the management of patients who are severely affected by migraine. In a survey of 1,032 women, headache chronicity, severe disability, and intense somatic symptoms were linked to comorbid depression (Tietjen et al., 2007). Furthermore, in a study of 1,413 patients with migraine (89% women), migraine was linked to cutaneous allodynia, particularly in those with other pain disorders and depression or anxiety (Tietjen et al., 2009). Meanwhile, the Head-HUNT questionnaire-based study found a higher prevalence of headache among the 43,782 individuals surveyed who also had gastrointestinal symptoms such as nausea, reflux, diarrhea, and constipation (Aamodt, Stovner, Hagen, & Zwart, 2008). A study of 297 participants found that severe sleep distubances were 5 times more likely among those who had migraines (odds ratio ¼ 5.4; 95% confidence interval, 2.0–15.5) (Ødeg ard et al., 2010). Perhaps not unexpectedly, migraine is associated with functional impairment, which affects both social and work daily activities (Brandes, 2009). Yet, despite the burdens associated with migraines, the condition remains undertreated; for example, in a study of 162,576 Americans, only 12.4% of those reporting migraines were currently taking preventative medications for the condition and only 38.7% had ever used migraine prophylaxis (Diamond et al., 2007).
MENSTRUALLY RELATED MIGRAINE Of women who suffer from migraine, 35% to 54% have menstrually related migraines (Martin & Lipton, 2008). Migraine headaches that regularly occur during the time period 2 days prior to 3 days following the onset of menses are commonly referred to as menstrual migraines (Martin & Lipton, 2008). Menstrually related migraines may occur during the menstrual cycle, but can occur at other times of the month as well—e.g., during periods of intense stress—while pure menstrual migraines occur only during the menstrual cycle and at no other time (Headache Classification Subcommittee of the International Headache Society, 2004). The International Headache Society Criteria for menstrually related migraine are headaches without aura which occur on days 2 to þ3 of menstruation (menses onset is þ1) and in 2 out of 3 (66%) of yearly menstrual cycles (Headache Classification Subcommittee of the International Headache Society, 2004). Studies have indicated that menstrual migaines are longer in duration, more severe, more often associated with vomiting (4.7 times more), more resistant to treatment, more prone to relapse, and associated with more disability than are nonmenstrual migraines (Brandes, 2006; MacGregor, Victor, et al., 2010; Martin & Lipton, 2008). Photophobia, localized pain (e.g., ‘ a red-hot poker piercing the eye’’), and nausea are other common complaints linked to menstrually related migraine. A study of brushevoked cutaneous allodynia in women with headache found a greater sensitized surface area during the menstrual phase (p < .0001) (Bigal et al., 2008). Menstrually related migraine is likely triggered by the significant drop in circulating estrogen that occurs a few days before menses (Figure 1) (Martin & Lipton, 2008). Several observations support the causative influence of estrogen in the development of menstrual migraine (Peterlin et al., 2009). First, prepubescent boys and girls have a similar incidence of migraine (4%), but with maturity, the prevalence of migraines significantly increases to 18% in women and only 6% in men (Brandes, 2006). During the third trimester of pregnancy, when estrogen levels are the highest, menstrually related migraine is not observed; after delivery, however, when there is a sharp decline in estrogen levels, most women report the return of migraines (94%) (Brandes, 2006). Finally, with menopause, migraines are less prevalent (Brandes, 2006). Rather, postmenopausal migraine has been linked to daily alcohol use, previous use of oral contraceptives, current hormone therapy, younger age at onset of menopause, and current smoking status. Established migraine triggers include the common inducers— alcohol, caffeine, stress, sleep deprivation, strenuous
Prophylaxis and Treatment of Menstrual Migraine
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Relationship of Headache to Circulating Estrogen Pattern of Monthly Estrogen Fluctuations (Adapted From MacGregor et al, 1996)
Ovulation
Menses
Follicular phase
Luteal phase Frequency of Attacks (Adapted From Stewart et al, 2000)
12
Migraine with aura Migraine without aura Tension-type headache
Peak headache
10 8 6 4 2 0 -16
-12
-8
-4
0
4
8
12
16
Days of Menstrual Cycle
FIGURE 1. - The graph shows the relatively high occurrence of migraine during the perimenstrual time of 2 to þ3 of the cycle when estradiol hormone levels are low. In a population-based study, the frequency of migraine without aura and tension-type headache peaked within a few days of onset of menses. Interestingly, migraine with aura did not appear to have as strong a relationship to the hormonal fluctuations associated with onset of menses. Menstrual migraine appears to be triggered when serum levels fall below 45 to 50 pg/mL. (Martin & Lipton, 2008). Used with permission from John Wiley & Sons, Inc.
exercise, coughing, chewing, sunlight, weather shifts, interpersonal issues—as well as the less well-known nitroglycerine and carbon monoxide (Hutchinson & Silberstein, 2008; Robbins, Crystal, Grosberg, & Hutchinson, 2010; Silberstein, 2008). Oral contraceptives can exacerbate or ameliorate menstrual migraine as well (Hutchinson & Silberstein, 2008). Additionally, the overproduction of prostaglandins has been implicated in the pathogenesis of menstrual migraine, as these proinflammatory substances contribute to pain pathways and are found in elevated concentrations during menstrual migraine attacks (Mannix, 2008). Indeed, it is generally accepted that the pathophysiology of migraines includes the activation of the meningeal trigeminovascular afferent nerves, which leads to downstream activation of structures in the dorsal horn, as well as to the release of vasoactive neuropeptides, such as nitric oxide, substance P, and calcitonin gene-related peptide (CGRP), that in turn causes the release of proinflammatory mediators (Pietrobon, 2005). Also, migraine symptoms have been temporally linked to cortical spreading depression, in which a neural disturbance propagates across the cortex, initiated by a strong sustained neural
depolarization hallmarked by hyperemia (increased blood flow). This phenomenon was originally observed in animal models, but has been observed recently in humans using a magnetic resonance imaging (MRI) technique that measures blood oxygenation levels (BOLD fMRI). Cortical spreading depression produces substantial changes in extracellular fluid, including an increase in the concentration of prostaglandins as well as the upregulation of proinflammatory genes (Pietrobon, 2005). Similarly, research has also implicated neurogenic inflammation in the pathophysiology of fibromyalgia, a disease that also has the primary symptom of pain and that is comorbid with migraine (Tietjen et al., 2009; Torresani, Bellafiore, & De Panfilis, 2009). Some literature also proposes that women have an emotional response to pain, or that emotions can contribute to the genesis of pain. Certainly, increased stress levels do contribute to the development of menstrually related migraines; therefore, stress-reduction techniques can benefit these patients. In particular with menstrually related migraines, patients may find the recurring nature of the headaches distressing and have difficulty coping
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to the extent that the migraines interfere with their daily lives.
MENSTRUAL MIGRAINE MANAGEMENT Managing menstrually related migraine involves three different approaches: aborting headache when possible by taking medication at the first onset of signs and symptoms of a headache, decreasing the occurrence of headache through prophylaxis, and application of treatment when a headache is occurring. The best currently available evidence on treating menstrually related migraine was presented in a 2008 systematic review of the literature published in the journal Neurology (Pringsheim, Davenport, & Dodick, 2008). Nineteen prospective, double-blind, randomized, controlled trials met the criteria to be included in the meta-analysis, yet provided only enough data for U.S. Preventive Services Task Force (USPSTF) grade B recommendations, at best, for prophylaxis and treatment. A grade of ‘‘B’’ indicates that the benefits of treatment outweigh the harms and are supported by at least fair evidence; hence, a strong recommendation for the routine provision of the treatment to an eligible patient is given. Acute Treatment For providing pain relief during the acute phase of migraine, the evidence-based treatment options that have a grade B recommendation include the triptans (5-HT1B/1D agonists) sumatriptan 50 mg or 100 mg and rizatriptan 10 mg, as well as mefenamic acid 500 mg taken three times per day (Pringsheim et al., 2008). Sumatriptan or rizatriptan should not be taken by women with cardiac disease, uncontrolled hypertension, or concomitant use of ergotamine or monoamine oxidase inhibitors (MAOIs). Because mefenamic acid is a nonsteroidal anti-inflammatory drug (NSAID), the analgesic should not be prescribed for patients with peptic ulcer disease, a history of gastrointestinal bleeding, or for those who have risk factors associated with cardiovascular disease. Also, one trial of fair quality and another of poor quality have provided evidence on the use of zolmitriptan 2.5 mg during the acute phase of migraine. These limited data have led to a grade C recommendation for the use of zolmitriptan, meaning that the the riskto-benefit balance is approximately equal at this time and therefore does not support a general endorsement for use (Pringsheim et al., 2008). The most common adverse effects of the medication are dizziness, paraesthesias, and fatigue. One poor-quality trial has provided insufficient evidence to support a recommendation for
using naratriptan 2.5 mg to treat acute migraine pain (Pringsheim et al., 2008). Prophylaxis Grade B recommendations for prophylaxis of migraine are perimenstrual treatment with percutaneous estradiol gel 1.5 mg, transdermal estradiol patch, frovatriptan 2.5 mg twice per day, or naratriptan 1 mg twice per day (Pringsheim et al., 2008). A reduction in the number of menstrually related or pure menstrual migraines was observed in trials of these therapies. Additonally, a 6-day regimen of frovatriptan was effective at reducing the incidence and severity of recalcitrant menstrual migraines (Brandes et al., 2009). Furthermore, a 2010 meta-analysis of safety data on patients with menstrual migraine concluded that frovatriptan is well tolerated as acute treatment (including 1,206 patients in randomized controlled trials and another 496 in 12-month open label trials) and for short-term preventative therapy (including data on 1,487 women) (MacGregor, Pawsey, Campbell, & Hu, 2010). Frovatriptan or naratriptan should not be taken by women with cardiovascular disease, uncontrolled hypertension, or who are already taking ergotamine or MAOIs, while percutaneous estradiol should not be prescribed for women with a history of breast cancer or who are currently taking hormonal contraception. Although nimesulide, magnesium, and phytoestrogens have also been studied for migraine prevention, no trials were of sufficiently high quality to support a recommendation for the use of these agents (Pringsheim et al., 2008). Naproxen has been shown to be effective for preventing migraine—potentially by hindering neurogenic inflammation; other oral NSAIDs have been studied in small trials, as well (Silberstein & Hutchinson, 2008). Oral NSAIDs are recommended by the European Federation of Neurological Societies (EFNS) task force 2009 guidelines for the acute treatment of migraine attacks (Evers et al., 2009). Alternatives Other options for treating menstrually related migraine include the ergot alkaloids, such as ergotamine tartrate and dihydroergotamine. Comparative trials, however, have indicated that triptans provide better efficacy than do ergot compounds (Evers et al., 2009). Also, ergot alkaloids can cause drug-overuse headaches even at low doses, as well as the adverse effects of nausea, vomiting, and paraesthesias (Evers et al., 2009). Although opioids are an established option for persistent noncancer pain (American Geriatrics Society Panel on the Pharmacological Management of Persistent Pain in Older Persons, 2009; Chou et al., 2009), these
Prophylaxis and Treatment of Menstrual Migraine
analgesics have not undergone rigorous testing for migraine and are not considered first-line options for menstrually related migraine (Evers et al., 2009). Cooling pads or gels and combination medications of acetaminophen/aspirin/caffeine sold over the counter can be beneficial for migraines, as well (Silberstein, 2008). Ginger has a beneficial effect on migraines and also reduces nausea. Managing migraines can be facilitated by maintaining a headache diary to track the frequency and severity of symptoms and their onset in relation to menstrual cycles (Hutchinson & Silberstein, 2008). Also, home fertility monitors can be used to test for estrone-3-glucuronide and luteinizing hormone in an attempt to abort the development of headache. Knowledge of these hormone levels can be used to relatively accurately predict ovulation and, hence, the timing of menstruation (MacGregor, Frith, Ellis, & Aspinall, 2005). Then, estradiol gel can be applied vaginally during the perimenstrual period as menstrual migraine prophylaxis, thereby reducing the severity of the sharp decline in estrogen that occurs endogenously (Calhoun & Hutchinson, 2009). Behavioral techniques such as biofeedback can be particularly useful in educating patients to become aware of the onset of a migraine, while cognitive behavioral and relaxation techniques including imagery can be beneficial as well, especially for counteracting muscle tension and increasing blood flow (Silberstein, 2008). Acupuncture may also have a place in the treatment of menstrual migraine. A Cochrane review considered the high-quality trial evidence on acupuncture, including a trial that enrolled only women with menstrually related migraine, and concluded that the intervention has consistently demonstrated effectiveness as prophylaxis for migraines with few adverse effects (Linde et al., 2009). Lifestyle management, such as developing regular sleeping and eating habits, exercise, hydration, and trigger avoidance can be beneficial (Silberstein & Hutchinson, 2008). Stress management
REFERENCES
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can be useful for identifying stressors and intervening before a migraine develops. In addition, there is a pressing need for the development of new agents for the treatment and prophylaxis of menstrually related migraine because a substantial number of women do not find relief from the mainstay therapies, such as the triptans (Edvinsson & Linde, 2010). Telcagepant is the first of a new class of medications in development intended to block CGRP activity in the trigeminal and central nervous systems as an acute treatment for migraine (Edvinsson & Linde, 2010; Stovner, Tronvik, & Hagen, 2009). The role of CGRP in the pathogenesis of migraine has not been fully established, although it is found throughout the central and peripheral nervous systems. CGRP is thought to play a leading role in neurogenic inflammation and is known to cause vasodilation and mast cell degranulation. Notably, telcagepant does not cause vasoconstriction or have associated restrictions, as do the triptans (Edvinsson & Linde, 2010).
CONCLUSIONS Not only are migraines prevalent in women, they also cause a substantial burden. Menstrually related migraines, in particular, can be refractory to treatment and debilitating. Complicating the management of menstrual migraine are comorbidities, such as cardiovascular disease, depression, anxiety, and gastrointestinal conditions, that often require other pharmacotherapies. Symptoms such as nausea and vomiting—perhaps requiring treatment with an antiemetic—also contribute to the difficulty of managing migraines (Hutchinson & Silberstein, 2008). Still, based on the current evidence base, several preventative medications and acute treatments for menstrually related migraine can be recommended. Meanwhile, ongoing basic and clinical research will provide new approaches to management and a better evidence base for the current options.
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Martin, V. T., & Lipton, R. B. (2008). Epidemiology and biology of menstrual migraine. Headache, 48(Suppl 3), S124–S130. Ødeg ard, S. S., Engstrøm, M., Sand, T., Stovner, L. J., Zwart, J. A., & Hagen, K. (2010). Associations between sleep disturbance and primary headaches: The third NordTrøndelag Health Study. The Journal of Headache and Pain, 11(3), 197–206. Peterlin, B. L., Katsnelson, M. J., & Calhoun, A. H. (2009). The associations between migraine, unipolar psychiatric comorbidities, and stress-related disorders and the role of estrogen. Current Pain & Headache Reports, 13(5), 404– 412. Peterlin, B. L., Rosso, A. L., Rapoport, A. M., & Scher, A. I. (2010). Obesity and migraine: The effect of age, gender and adipose tissue distribution. Headache, 50(1), 52–62. Pietrobon, D. (2005). Migraine: New molecular mechanisms. Neuroscientist, 11(4), 373–386. Pringsheim, T., Davenport, W. J., & Dodick, D. (2008). Acute treatment and prevention of menstrually related migraine headache: Evidence-based review. Neurology, 70(17), 1555–1563. Robbins, M. S., Crystal, S. C., Grosberg, B. M., & Hutchinson, S. (2010). Teaching case: Menopausal migraine. Headache, 50(2), 338–341. Silberstein, S. D. (2008). Treatment recommendations for migraine. Nature Clinical Practice Neurology, 4(9), 482–489. Silberstein, S. D., & Hutchinson, S. L. (2008). Diagnosis and treatment of the menstrual migraine patient. Headache, 48(Suppl 3), S115–S123. Stovner, L. J. (2008). Headache: New concepts, models, and treatments. Lancet Neurology, 7(1), 11–12. Stovner, L. J., Hagen, K., Jensen, R., Katsarava, Z., Lipton, R., Scher, A.,. . . Zwart, J. A. (2007). The global burden of headache: A documentation of headache prevalence and disability worldwide. Cephalalgia, 27(3), 193-210. Stovner, L. J., Tronvik, E., & Hagen, K. (2009). New drugs for migraine. The Journal of Headache and Pain, 10(6), 395–406. Tietjen, G. E., Brandes, J. L., Digre, K. B., Baggaley, S., Martin, V., Recober, A.,. . . Khuder, S. A. (2007). High prevalence of somatic symptoms and depression in women with disabling chronic headache. Neurology, 68 (2), 134-140. Tietjen, G. E., Brandes, J. L., Peterlin, B. L., Eloff, A., Dafer, R. M., Stein, M. R.,. . . Khuder, S. A. (2009). Allodynia in migraine: Association with comorbid pain conditions. Headache, 49(9), 1333-1344. Torresani, C., Bellafiore, S., & De Panfilis, G. (2009). Chronic urticaria is usually associated with fibromyalgia syndrome. Acta Dermato-Venereologica, 89(4), 389–392.
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Yvonne M. D’Arcy, MS, CRNP, CNS
ABSTRACT:
Migraine is a very disabling condition that can severely impair quality of life. Eighteen percent of women suffer from migraine headaches, and of those, approximately 60% have migraines near the time of their menstrual period. Migraine is generally undertreated, not only because some sufferers do not have access to proper care, but also because many fail to seek treatment because of misperceptions that nothing can be done for a condition from which generations of women have suffered. Research has shown that migraine is not a disorder of blood vessels, but rather a brain disorder characterized by inflammation. The goal of this paper is to explain practical approaches to managing menstrual migraine. Ó 2011 by the American Society for Pain Management Nursing
MIGRAINE HEADACHE
From Suburban Hospital–Johns Hopkins Medicine, Bethesda, Maryland. Address correspondence to Yvonne M. D’Arcy, MS, CRNP, CNS, Suburban Hospital–Johns Hopkins Medicine, Bethesda, Maryland, United States. E-mail: ydarcy@surburbanhospital. org Received April 8, 2010; Revised August 1, 2010; Accepted August 17, 2010. Publication of this article was supported by Endo Pharmaceuticals Inc. 1524-9042/$36.00 Ó 2011 by the American Society for Pain Management Nursing doi:10.1016/j.pmn.2010.11.002
Across the globe, migraine headaches affect approximately 10% of the adult population, with a lifetime prevalence of 14%; migraine affects 2 to 3 times as many women than men (Jensen & Stovner, 2008; Martin & Lipton, 2008; Stovner et al., 2007). According to the World Health Organization, for women, headache is considered the third most costly neurological disorder and the fifth most disabling disorder (Stovner et al., 2007). The burden of migraine includes $13.3 billion in indirect costs associated with reduced efficiency or lost time from work plus another $1 billion in expenditures associated with treatments and hospitalizations (Hu, Markson, Lipton, Stewart, & Berger, 1999; Jensen & Stovner, 2008). These numbers were derived from a 1994 study in the United States of adults aged 20 to 65 years; 80% of all the costs were incurred by women with migraines (Jensen & Stovner, 2008). Women are more often afflicted with migraines; the incidence of migraines in women is 15% to 25% compared with 6% to 8% in men (Pietrobon, 2005). Although migraine characteristics are unique to each individual, the typical nonmenstrually related migraine headache has a unilateral location with a severe pain intensity that is described as ‘ different than any other headache,’ and often as ‘ pounding,’ ‘ pulsing,’ or ‘ throbbing.’ Physical exertion is often either an aggravating cause of migraine or avoided while the patient is experiencing headache. Headaches are diagnosed worldwide based on the criteria established in the second edition of The International Classification of Headache Disorders (ICHD-II), published in 2004 (Diamond et al., 2007; Hutchinson & Silberstein, 2008; Silberstein & Hutchinson, 2008). The International Headache Society Criteria for migraines Pain Management Nursing, Vol 12, No 1 (March), 2011: pp S11-S16
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without aura are those headaches which cannot be attributed to another disorder, which last for 4 to 72 hours, are accompanied by nausea/vomiting or phonophobia/photophobia, and for which at least two of the following are true: unilateral in location, pulsating in quality, moderate to severe in pain intensity, and aggravated by physical activity (Headache Classification Subcommittee of the International Headache Society, 2004). The risk of developing migraines has been genetically linked, although the specific genes involved have not yet been established (the relevance of a few identified in a screen—genes encoding subunits of a calcium channel, a sodium potassium pump, and a sodium channel—are still being assessed) (Pietrobon, 2005; Stovner, 2008). In a study of 7,732 women younger than 55 years, the prevalence of migraine was found to be significantly increased in those with total body obesity (p ¼ .001), as well as in those with abdominal obesity (p < .001) compared with women with body mass indexes under 30 (Peterlin, Rosso, Rapoport, & Scher, 2010). Migraine has been connected to cardiovascular and metabolic ailments, such as stroke, hypertension, diabetes and obesity, as well as to neurological dysfunction, including fibromyalgia, low back pain, anxiety, and depression (Jensen & Stovner, 2008; Peterlin, Katsnelson, & Calhoun, 2009). Often, these comorbidities complicate the management of patients who are severely affected by migraine. In a survey of 1,032 women, headache chronicity, severe disability, and intense somatic symptoms were linked to comorbid depression (Tietjen et al., 2007). Furthermore, in a study of 1,413 patients with migraine (89% women), migraine was linked to cutaneous allodynia, particularly in those with other pain disorders and depression or anxiety (Tietjen et al., 2009). Meanwhile, the Head-HUNT questionnaire-based study found a higher prevalence of headache among the 43,782 individuals surveyed who also had gastrointestinal symptoms such as nausea, reflux, diarrhea, and constipation (Aamodt, Stovner, Hagen, & Zwart, 2008). A study of 297 participants found that severe sleep distubances were 5 times more likely among those who had migraines (odds ratio ¼ 5.4; 95% confidence interval, 2.0–15.5) (Ødeg ard et al., 2010). Perhaps not unexpectedly, migraine is associated with functional impairment, which affects both social and work daily activities (Brandes, 2009). Yet, despite the burdens associated with migraines, the condition remains undertreated; for example, in a study of 162,576 Americans, only 12.4% of those reporting migraines were currently taking preventative medications for the condition and only 38.7% had ever used migraine prophylaxis (Diamond et al., 2007).
MENSTRUALLY RELATED MIGRAINE Of women who suffer from migraine, 35% to 54% have menstrually related migraines (Martin & Lipton, 2008). Migraine headaches that regularly occur during the time period 2 days prior to 3 days following the onset of menses are commonly referred to as menstrual migraines (Martin & Lipton, 2008). Menstrually related migraines may occur during the menstrual cycle, but can occur at other times of the month as well—e.g., during periods of intense stress—while pure menstrual migraines occur only during the menstrual cycle and at no other time (Headache Classification Subcommittee of the International Headache Society, 2004). The International Headache Society Criteria for menstrually related migraine are headaches without aura which occur on days 2 to þ3 of menstruation (menses onset is þ1) and in 2 out of 3 (66%) of yearly menstrual cycles (Headache Classification Subcommittee of the International Headache Society, 2004). Studies have indicated that menstrual migaines are longer in duration, more severe, more often associated with vomiting (4.7 times more), more resistant to treatment, more prone to relapse, and associated with more disability than are nonmenstrual migraines (Brandes, 2006; MacGregor, Victor, et al., 2010; Martin & Lipton, 2008). Photophobia, localized pain (e.g., ‘ a red-hot poker piercing the eye’’), and nausea are other common complaints linked to menstrually related migraine. A study of brushevoked cutaneous allodynia in women with headache found a greater sensitized surface area during the menstrual phase (p < .0001) (Bigal et al., 2008). Menstrually related migraine is likely triggered by the significant drop in circulating estrogen that occurs a few days before menses (Figure 1) (Martin & Lipton, 2008). Several observations support the causative influence of estrogen in the development of menstrual migraine (Peterlin et al., 2009). First, prepubescent boys and girls have a similar incidence of migraine (4%), but with maturity, the prevalence of migraines significantly increases to 18% in women and only 6% in men (Brandes, 2006). During the third trimester of pregnancy, when estrogen levels are the highest, menstrually related migraine is not observed; after delivery, however, when there is a sharp decline in estrogen levels, most women report the return of migraines (94%) (Brandes, 2006). Finally, with menopause, migraines are less prevalent (Brandes, 2006). Rather, postmenopausal migraine has been linked to daily alcohol use, previous use of oral contraceptives, current hormone therapy, younger age at onset of menopause, and current smoking status. Established migraine triggers include the common inducers— alcohol, caffeine, stress, sleep deprivation, strenuous
Prophylaxis and Treatment of Menstrual Migraine
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Relationship of Headache to Circulating Estrogen Pattern of Monthly Estrogen Fluctuations (Adapted From MacGregor et al, 1996)
Ovulation
Menses
Follicular phase
Luteal phase Frequency of Attacks (Adapted From Stewart et al, 2000)
12
Migraine with aura Migraine without aura Tension-type headache
Peak headache
10 8 6 4 2 0 -16
-12
-8
-4
0
4
8
12
16
Days of Menstrual Cycle
FIGURE 1. - The graph shows the relatively high occurrence of migraine during the perimenstrual time of 2 to þ3 of the cycle when estradiol hormone levels are low. In a population-based study, the frequency of migraine without aura and tension-type headache peaked within a few days of onset of menses. Interestingly, migraine with aura did not appear to have as strong a relationship to the hormonal fluctuations associated with onset of menses. Menstrual migraine appears to be triggered when serum levels fall below 45 to 50 pg/mL. (Martin & Lipton, 2008). Used with permission from John Wiley & Sons, Inc.
exercise, coughing, chewing, sunlight, weather shifts, interpersonal issues—as well as the less well-known nitroglycerine and carbon monoxide (Hutchinson & Silberstein, 2008; Robbins, Crystal, Grosberg, & Hutchinson, 2010; Silberstein, 2008). Oral contraceptives can exacerbate or ameliorate menstrual migraine as well (Hutchinson & Silberstein, 2008). Additionally, the overproduction of prostaglandins has been implicated in the pathogenesis of menstrual migraine, as these proinflammatory substances contribute to pain pathways and are found in elevated concentrations during menstrual migraine attacks (Mannix, 2008). Indeed, it is generally accepted that the pathophysiology of migraines includes the activation of the meningeal trigeminovascular afferent nerves, which leads to downstream activation of structures in the dorsal horn, as well as to the release of vasoactive neuropeptides, such as nitric oxide, substance P, and calcitonin gene-related peptide (CGRP), that in turn causes the release of proinflammatory mediators (Pietrobon, 2005). Also, migraine symptoms have been temporally linked to cortical spreading depression, in which a neural disturbance propagates across the cortex, initiated by a strong sustained neural
depolarization hallmarked by hyperemia (increased blood flow). This phenomenon was originally observed in animal models, but has been observed recently in humans using a magnetic resonance imaging (MRI) technique that measures blood oxygenation levels (BOLD fMRI). Cortical spreading depression produces substantial changes in extracellular fluid, including an increase in the concentration of prostaglandins as well as the upregulation of proinflammatory genes (Pietrobon, 2005). Similarly, research has also implicated neurogenic inflammation in the pathophysiology of fibromyalgia, a disease that also has the primary symptom of pain and that is comorbid with migraine (Tietjen et al., 2009; Torresani, Bellafiore, & De Panfilis, 2009). Some literature also proposes that women have an emotional response to pain, or that emotions can contribute to the genesis of pain. Certainly, increased stress levels do contribute to the development of menstrually related migraines; therefore, stress-reduction techniques can benefit these patients. In particular with menstrually related migraines, patients may find the recurring nature of the headaches distressing and have difficulty coping
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to the extent that the migraines interfere with their daily lives.
MENSTRUAL MIGRAINE MANAGEMENT Managing menstrually related migraine involves three different approaches: aborting headache when possible by taking medication at the first onset of signs and symptoms of a headache, decreasing the occurrence of headache through prophylaxis, and application of treatment when a headache is occurring. The best currently available evidence on treating menstrually related migraine was presented in a 2008 systematic review of the literature published in the journal Neurology (Pringsheim, Davenport, & Dodick, 2008). Nineteen prospective, double-blind, randomized, controlled trials met the criteria to be included in the meta-analysis, yet provided only enough data for U.S. Preventive Services Task Force (USPSTF) grade B recommendations, at best, for prophylaxis and treatment. A grade of ‘‘B’’ indicates that the benefits of treatment outweigh the harms and are supported by at least fair evidence; hence, a strong recommendation for the routine provision of the treatment to an eligible patient is given. Acute Treatment For providing pain relief during the acute phase of migraine, the evidence-based treatment options that have a grade B recommendation include the triptans (5-HT1B/1D agonists) sumatriptan 50 mg or 100 mg and rizatriptan 10 mg, as well as mefenamic acid 500 mg taken three times per day (Pringsheim et al., 2008). Sumatriptan or rizatriptan should not be taken by women with cardiac disease, uncontrolled hypertension, or concomitant use of ergotamine or monoamine oxidase inhibitors (MAOIs). Because mefenamic acid is a nonsteroidal anti-inflammatory drug (NSAID), the analgesic should not be prescribed for patients with peptic ulcer disease, a history of gastrointestinal bleeding, or for those who have risk factors associated with cardiovascular disease. Also, one trial of fair quality and another of poor quality have provided evidence on the use of zolmitriptan 2.5 mg during the acute phase of migraine. These limited data have led to a grade C recommendation for the use of zolmitriptan, meaning that the the riskto-benefit balance is approximately equal at this time and therefore does not support a general endorsement for use (Pringsheim et al., 2008). The most common adverse effects of the medication are dizziness, paraesthesias, and fatigue. One poor-quality trial has provided insufficient evidence to support a recommendation for
using naratriptan 2.5 mg to treat acute migraine pain (Pringsheim et al., 2008). Prophylaxis Grade B recommendations for prophylaxis of migraine are perimenstrual treatment with percutaneous estradiol gel 1.5 mg, transdermal estradiol patch, frovatriptan 2.5 mg twice per day, or naratriptan 1 mg twice per day (Pringsheim et al., 2008). A reduction in the number of menstrually related or pure menstrual migraines was observed in trials of these therapies. Additonally, a 6-day regimen of frovatriptan was effective at reducing the incidence and severity of recalcitrant menstrual migraines (Brandes et al., 2009). Furthermore, a 2010 meta-analysis of safety data on patients with menstrual migraine concluded that frovatriptan is well tolerated as acute treatment (including 1,206 patients in randomized controlled trials and another 496 in 12-month open label trials) and for short-term preventative therapy (including data on 1,487 women) (MacGregor, Pawsey, Campbell, & Hu, 2010). Frovatriptan or naratriptan should not be taken by women with cardiovascular disease, uncontrolled hypertension, or who are already taking ergotamine or MAOIs, while percutaneous estradiol should not be prescribed for women with a history of breast cancer or who are currently taking hormonal contraception. Although nimesulide, magnesium, and phytoestrogens have also been studied for migraine prevention, no trials were of sufficiently high quality to support a recommendation for the use of these agents (Pringsheim et al., 2008). Naproxen has been shown to be effective for preventing migraine—potentially by hindering neurogenic inflammation; other oral NSAIDs have been studied in small trials, as well (Silberstein & Hutchinson, 2008). Oral NSAIDs are recommended by the European Federation of Neurological Societies (EFNS) task force 2009 guidelines for the acute treatment of migraine attacks (Evers et al., 2009). Alternatives Other options for treating menstrually related migraine include the ergot alkaloids, such as ergotamine tartrate and dihydroergotamine. Comparative trials, however, have indicated that triptans provide better efficacy than do ergot compounds (Evers et al., 2009). Also, ergot alkaloids can cause drug-overuse headaches even at low doses, as well as the adverse effects of nausea, vomiting, and paraesthesias (Evers et al., 2009). Although opioids are an established option for persistent noncancer pain (American Geriatrics Society Panel on the Pharmacological Management of Persistent Pain in Older Persons, 2009; Chou et al., 2009), these
Prophylaxis and Treatment of Menstrual Migraine
analgesics have not undergone rigorous testing for migraine and are not considered first-line options for menstrually related migraine (Evers et al., 2009). Cooling pads or gels and combination medications of acetaminophen/aspirin/caffeine sold over the counter can be beneficial for migraines, as well (Silberstein, 2008). Ginger has a beneficial effect on migraines and also reduces nausea. Managing migraines can be facilitated by maintaining a headache diary to track the frequency and severity of symptoms and their onset in relation to menstrual cycles (Hutchinson & Silberstein, 2008). Also, home fertility monitors can be used to test for estrone-3-glucuronide and luteinizing hormone in an attempt to abort the development of headache. Knowledge of these hormone levels can be used to relatively accurately predict ovulation and, hence, the timing of menstruation (MacGregor, Frith, Ellis, & Aspinall, 2005). Then, estradiol gel can be applied vaginally during the perimenstrual period as menstrual migraine prophylaxis, thereby reducing the severity of the sharp decline in estrogen that occurs endogenously (Calhoun & Hutchinson, 2009). Behavioral techniques such as biofeedback can be particularly useful in educating patients to become aware of the onset of a migraine, while cognitive behavioral and relaxation techniques including imagery can be beneficial as well, especially for counteracting muscle tension and increasing blood flow (Silberstein, 2008). Acupuncture may also have a place in the treatment of menstrual migraine. A Cochrane review considered the high-quality trial evidence on acupuncture, including a trial that enrolled only women with menstrually related migraine, and concluded that the intervention has consistently demonstrated effectiveness as prophylaxis for migraines with few adverse effects (Linde et al., 2009). Lifestyle management, such as developing regular sleeping and eating habits, exercise, hydration, and trigger avoidance can be beneficial (Silberstein & Hutchinson, 2008). Stress management
REFERENCES
Aamodt, A. H., Stovner, L. J., Hagen, K., & Zwart, J. A. (2008). Comorbidity of headache and gastrointestinal complaints. The Head-HUNT Study. Cephalalgia, 28(2), 144–151. American Geriatrics Society Panel on the Pharmacological Management of Persistent Pain in Older Persons (2009). Pharmacological management of persistent pain in older persons. Journal of the American Geriatrics Society, 57(8), 1331–1346. Bigal, M. E., Ashina, S., Burstein, R., Reed, M. L., Buse, D., Serrano, D.,. . . AMPP Group. (2008). Prevalence and characteristics of allodynia in headache sufferers: A population study. Neurology, 70(17), 1525-1533.
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can be useful for identifying stressors and intervening before a migraine develops. In addition, there is a pressing need for the development of new agents for the treatment and prophylaxis of menstrually related migraine because a substantial number of women do not find relief from the mainstay therapies, such as the triptans (Edvinsson & Linde, 2010). Telcagepant is the first of a new class of medications in development intended to block CGRP activity in the trigeminal and central nervous systems as an acute treatment for migraine (Edvinsson & Linde, 2010; Stovner, Tronvik, & Hagen, 2009). The role of CGRP in the pathogenesis of migraine has not been fully established, although it is found throughout the central and peripheral nervous systems. CGRP is thought to play a leading role in neurogenic inflammation and is known to cause vasodilation and mast cell degranulation. Notably, telcagepant does not cause vasoconstriction or have associated restrictions, as do the triptans (Edvinsson & Linde, 2010).
CONCLUSIONS Not only are migraines prevalent in women, they also cause a substantial burden. Menstrually related migraines, in particular, can be refractory to treatment and debilitating. Complicating the management of menstrual migraine are comorbidities, such as cardiovascular disease, depression, anxiety, and gastrointestinal conditions, that often require other pharmacotherapies. Symptoms such as nausea and vomiting—perhaps requiring treatment with an antiemetic—also contribute to the difficulty of managing migraines (Hutchinson & Silberstein, 2008). Still, based on the current evidence base, several preventative medications and acute treatments for menstrually related migraine can be recommended. Meanwhile, ongoing basic and clinical research will provide new approaches to management and a better evidence base for the current options.
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