Hormonal therapies for menstrual migraine

Menstrual-related migraine (MRM) affects the majority of female migraineurs, with menstrual-associated attacks reported to be more disabling, longer lasting, and less responsive to traditional treatments than nonmenstrual attacks. Emerging evidence suggests that minimizing or eliminating monthly declines in estrogen concentration may be effective in preventing MRM. This article gives a practical overview of current hormonal options, both contraceptive and noncontraceptive. Our intent is to help the reader better understand the differences in currently available formulations and how some of these agents may be utilized as hormonal preventives of MRM.     

Preventative treatment of menstrual migraine

More than 20 million US women suffer with migraine, two thirds of whom experience menstrually related migraine. Estrogen plays an important role in triggering migraine, and given the numerous hormonal fluctuations throughout a woman’s lifetime, there are many opportunities for a hormonal impact. Accurate diagnosis is key to initiating effective treatment, and when acute therapy fails, the unique predictability of menstrual migraine lends itself to preventative treatment.     

Platelet serotonin pathway in menstrual migraine

In order to understand the possible 5-hydroxytryptamine (5HT) anomalies in migraine, particularly in the period before the headache attack, we compared the levels of 5HT, its stable metabolite 5-hydroxyindoleacetic acid (5HIAA) and platelet monoaminoxidase (MAO) activity in patients with menstrual migraine with those of healthy female controls. In every subject, blood samples were drawn during both follicular and late luteal phases of the menstrual cycle. In controls, platelet 5HT levels remained stable, whereas 5HIAA levels and MAO activity were higher in the luteal than in the follicular phase, suggesting an increased catabolism of 5HT which occurs physiologically just before menses. In menstrual migraine 5HIAA levels and MAO activity showed similar changes with higher values in the luteal than in the follicular phase. The luteal phase values were significantly higher than those of controls. Also, and in contrast to controls, 5HT levels decreased in the luteal phase. These data suggest that 5HT availability is reduced in menstrual migraine, possibly due to an increased catabolism and/or to a reduced synthesis, and hence predisposes patients to migraine attacks.     

Adolescent issues in migraine: A focus on menstrual migraine

Migraine commonly affects adolescents, and menstrual migraine often begins in young girls. If undiagnosed or ineffectively treated, migraine can lead to disability, school absenteeism, emotional or social difficulties, and chronification of headache. Thus, recognizing and accurately diagnosing migraine and menstrual migraine, developing effective treatment strategies (both pharmacologic and nonpharmacologic), and educating both the adolescent and her parents are important in order to minimize the potential early disability of this disorder and limit the otherwise likely progression of migraine to a disabling disorder of adulthood.     

Rizatriptan efficacy in ICHD-II pure menstrual migraine and menstrually related migraine

Objective.— To examine the efficacy of rizatriptan for the treatment of pure menstrual migraine (PMM). Background.— In 2004, the International Headache Society proposed new research criteria for menstrual migraine (International Classification of Headache Disorders [ICHD‐II]). Two subtypes were defined: PMM, in which attacks occur exclusively with menstruation, and menstrually related migraine (MRM), in which attacks may also occur at other times of the cycle. Methods.— The 2 protocols (MM1 and MM2) were identical randomized, double‐blind studies. Adult patients with ICHD‐II menstrual migraine were assigned to either rizatriptan 10‐mg tablet or placebo (2:1). Patients were to treat a single menstrual migraine attack of moderate or severe pain intensity. This prospectively planned substudy pooled data from patients with a diagnosis of PMM from both studies. The primary substudy endpoint was 2‐hour pain relief. Efficacy data were summarized for patients with a diagnosis of MRM. Results.— Of 707 (MM1: 357, MM2: 350) patients treated in the study, 146 patients (MM1: 81, MM2: 65) had a diagnosis of PMM. The percentage of patients reporting 2‐hour pain relief was significantly greater for rizatriptan than for placebo for both PMM (73% vs 50%, P = .006) and MRM subgroups (71% vs 52%, P < .001). Most other efficacy endpoints favored rizatriptan compared with placebo in patients with either PMM or MRM. Conclusion.— Rizatriptan 10 mg was superior to placebo for the treatment of PMM, as measured by 2‐hour pain relief. Rizatriptan was also effective for the treatment of MRM and for relief of migraine‐associated symptoms for both headache subtypes.     

Self-reported menstrual migraine in the general population

A number of women with migraine experience increased incidence of attacks during the perimenstrual period. The Appendix of the International Classification of Headache Disorders (ICHD II) describes two types of migraine without aura related to menstruation: pure menstrual migraine (PMM) and menstrually related migraine (MRM). The phrase “menstrual migraine” is often used to cover both PMM and MRM. Although menstrual migraine is well recognized, further scientific evidence is needed before these definitions can be formally included in the ICHD III. The aim of the present study was to investigate the prevalence of PMM and MRM in the general population in Norway. The survey included 15,000 women, 30–44 years old, residing in the eastern part of Norway. They received a postal questionnaire containing six questions about migraine, headache frequency and the relation of migraine and menstruation. The study included 11,123 women. The questionnaire response rate was 77%. The prevalence of self-reported migraine was 34.8%. Of the migraineurs, 21% reported migraine related to menstruation in at least two of three menstrual cycles, of which 7.7% were considered to have PMM and 13.2% MRM. This corresponds to the prevalence of PMM and MRM in the general population of 2.7 and 4.6%, respectively. Thus, self-reported menstrual migraine among women aged 30–44 years appears to be common in the general population in Norway.     

Current topics and controversies in menstrual migraine

As menstrual-related migraine (MRM) has been reported to be longer, more disabling, less responsive to acute therapy, and more prone to recurrence than nonmenstrual migraine attacks, effective preventive strategies are key to their management. Some combined hormonal contraceptives have been suggested as specific preventives for MRM. This article takes a closer look at some of these products, including concerns surrounding them, non-contraceptive benefits, and their potential role as preventive agents for MRM.     

Short-term frovatriptan for the prevention of difficult-to-treat menstrual migraine attacks

The efficacy of a 6-day regimen of frovatriptan for menstrual migraine (MM; attacks starting on day −2 to +3 of menses) prevention in women with difficult-to-treat MM was assessed. Women with a documented inadequate response to triptans for acute MM treatment were included in this placebo-controlled, parallel-group trial. Women were randomized to double-blind treatment for three perimenstrual periods (PMPs) with either frovatriptan 2.5 mg (q.d. or b.i.d.) or placebo initiated 2 days before anticipated MM. The efficacy analysis included 410 women with 85% completing three double-blind PMPs. The mean number of headache-free PMPs was 0.92 with frovatriptan b.i.d., 0.69 with frovatriptan q.d. and 0.42 with placebo [ P  < 0.001 (b.i.d.) and P  < 0.02 (q.d.) vs. placebo]. When migraine occurred, severity was reduced with frovatriptan q.d. ( P  < 0.001) and b.i.d. ( P  < 0.001) vs. placebo. Both frovatriptan regimens were well tolerated. In women with difficult-to-treat MM, a 6-day regimen of frovatriptan significantly reduced MM incidence and severity.     

New Theories in the pathogenesis of menstrual migraine

Hormonal and nonhormonal factors play a role in the pathophysiology of menstrual migraine, but estrogen withdrawal appears to be the most potent of these factors. It is postulated that estrogen withdrawal directly enhances excitability of trigeminal afferents, modulates the synthesis of neuropeptides, activates/deactivates specific neurotransmitter systems, and influences the function of microglia. These changes could activate and/or sensitize the trigeminal system and increase the likelihood of migraine headache during perimenstrual time periods. Three new theories are advanced in this article to explain the pathophysiology of menstrual migraine. Only through an understanding of the mechanisms involved in menstrual migraine can we gain insight into the management of this severe and debilitating form of migraine headache.     

Altered trigeminal system excitability in menstrual migraine patients

To evaluate brainstem excitability in menstrual migraine (MM) patients and compare the electrophysiological parameters of the trigeminocervical reflex (TCR) during the perimenstrual (headache period) and follicular (headache-free) periods with those in healthy controls. Thirty-one patients with MM and 22 volunteer age- and sex-matched healthy women were included in the study. The TCR was studied bilaterally with stimulation of the supraorbital branch of the trigeminal nerve during the perimenstrual period and follicular phase. The electrophysiological parameters of the TCR were compared between MM patients and controls. In controls, there was no statistically significant difference in the mean reflex latencies recorded during the perimenstrual and follicular phases (P > 0.05). In MM patients, the mean reflex latencies recorded during the perimenstrual (headache period) and follicular phase (headache-free) periods were significantly different from each other and from those in controls. The latencies of MM patients during the follicular (headache-free) period were significantly longer than those of controls. Brainstem excitability differed significantly between the perimenstrual (headache period) and follicular phase (headache-free) periods in MM. Furthermore, trigeminal excitability in MM patients was significantly different from that in healthy controls in both phases of the menstrual period.     

Hormones, menstrual distress, and migraine across the phases of the menstrual cycle

OBJECTIVE: The primary objectives of the present study were to (1) contrast reproductive hormone levels and ratings of menstrual distress of female migraineurs with those of a control group in each menstrual cycle phase, (2) examine correlations between hormone levels and migraine frequency, severity, and migraine-related disability, and (3) examine correlations between menstrual distress and migraine frequency, severity, and migraine-related disability. A secondary objective was to evaluate the validity of a migraine disability measure modified to reflect 7-day recall. BACKGROUND: Further controlled, prospective study is needed regarding the temporal relationships between reproductive hormones at each stage of the menstrual cycle and fluctuations in migraine activity across the cycle. METHODS: Twenty-three women (17 with migraine, 6 control participants) completed laboratory hormone assays and measures of menstrual distress and disability at each phase of one menstrual cycle, and monitored their headache activity daily during the same cycle. Results.-The migraine group evidenced lower premenstrual luteinizing hormone and more menstrual distress symptoms at each phase of the menstrual cycle. Hormones were associated with migraine activity and disability within cycle phases, and across phases in a time-lagged manner. Menstrual distress was associated with ovulatory phase migraine activity and with migraine-related disability across the menstrual cycle. A retrospective 7-day migraine disability measure appeared to be a consistently valid index. CONCLUSIONS: Both reproductive hormones and menstrually related distress appear to predict migraine activity and disability. These associations were evident not only for perimenstrual migraine, but also for migraine at each phase of the menstrual cycle.     

Contraceptive-induced amenorrhoea leads to reduced migraine frequency in women with menstrual migraine without aura

Background

Menstrual migraine without aura (MM) affects approximately 20% of female migraineurs in the general population. The aim of the present study was to investigate the influence of contraception on the attacks of migraine without aura (MO) in women with MM.

Findings

141 women from the general population with a history of MM according to the International Classification of Headache Disorders II (ICHD II) were interviewed by a headache specialist. Of 49 women with a history of MM currently using hormonal contraception, 23 reported amenorrhoea. Significantly more women with amenorrhoea reported no MO- days during the preceding month compared to women without amenorrhoea (OR 16.1; 95% confidence interval (CI) 1.8-140.4; P = 0.003). A reduction of MO-frequency was more often reported in women with than without amenorrhoea (OR 3.5; 95% CI 1.1-11.4; P = 0.04).

Conclusion

Amenorrhoea leads to a reduction of MO-frequency in women with MM using hormonal contraceptives. Future prospective studies on MM should focus on contraceptive methods that achieve amenorrhoea.     

Botox therapy for refractory chronic migraine

Chronic migraine is unfortunately both common and often resistant to treatment even with prophylactic medications known to be effective in populations with episodic migraine. We undertook an open-label study to evaluate the safety and utility of botulinum toxin type A injection therapy for patients with chronic migraine who previously had failed to respond to at least three prophylactic medications.     

The association of menstrual migraine with the premenstrual syndrome

To investigate the comorbidity of premenstrual syndrome (PMS) and menstrual migraine, the Menstrual Distress Questionnaire (MDQ) was prospectively administered for two consecutive menstrual cycles to 22 patients with menstrual migraine, 12 cases with migraine without aura and 15 patients with PMS. MDQ scores varied throughout the menstrual cycle in each patient group, the wider changes being shown by patients with PMS. Fourteen menstrual migraine patients and 4 migraine without aura patients achieved diagnostic criteria for PMS over two menstrual cycles. In these patients MDQ scores did not differ from PMS sufferers at any stage of the menstrual cycle. The premenstrual increase of each cluster of PMS symptoms was identical in menstrual migraine and PMS subjects with the exception of negative affect. We suggest that PMS symptoms should be taken into account in the IHS diagnostic criteria for menstrual migraine.