E. Anne MacGregor

Menstruation, sex hormones, and migraine

All women with migraine are susceptible to the effects of hormonal changes. For a minority with menstrual migraine, fluctuating hormones of the normal ovarian cycle are a specific trigger, particularly during perimenopause. The author proposes that the term menstrual migraine should be restricted to migraine attacks occurring on day 1 +/- 2 days of the menstrual cycle with freedom from migraine during the rest of the cycle. This definition is compatible with the mechanism of estrogen withdrawal. Other mechanisms such as prostaglandin release also may be important for some women. The changing hormonal environment at various stages of life provides further evidence of the role of estrogen in migraine. Treatments that stabilize hormone levels in the form of estrogen supplementation for menstrual migraine, elimination of the pill-free week, and adequate, stable levels of estrogen for HRT, all are associated with an improvement in migraine. The control of the menstrual cycle, however, is extremely complex, and until further studies are undertaken using strict criteria, the mechanism of migraine triggered by hormonal events remains uncertain.

Sex-Related Differences in Epidemiological and Clinic-Based Headache Studies

(Headache 2011;51:843‐859)

Sex differences in the epidemiology, clinical features, and pathophysiology of migraine

Migraine is two to three times more prevalent in women than men, and women report a longer attack duration, increased risk of headache recurrence, greater disability, and a longer period of time required to recover. Conditions recognised to be comorbid with migraine include asthma, anxiety, depression, and other chronic pain conditions, and these comorbidities add to the amount of disability in both sexes. Migraine-specifically migraine with aura-has been identified as a risk factor for vascular disorders, particularly in women, but because of the scarcity of data, the comparative risk in men has yet to be established. There is evidence implicating the role of female sex hormones as a major factor in determining migraine risk and characteristics, which accounts for sex differences, but there is also evidence to support underlying genetic variance. Although migraine is often recognised in women, it is underdiagnosed in men, resulting in suboptimal management and less participation of men in clinical trials.

Domperidone plus paracetamol in the treatment of migraine

This study was designed to evaluate the safety and efficacy of domperidone in combination with paracetamol in the treatment of migraine. Severity of headache, duration of migraine attack and overall efficacy of treatment were amongst the variables assessed in a randomized, double-blind, three-way cross-over comparison of 1 g paracetamol plus either domperidone 30 mg, domperidone 20 mg or placebo, taken at onset of headache. Forty-six patients attending the City of London Migraine Clinic completed the study. A significant difference was observed in the duration of the migraine attack: a median of 17.5 h with paracetamol alone was reduced to 12.0 h with the addition of domperidone 20 mg, and to 12.0 h with domperidone 30 mg. No significant adverse events were reported. A reduction in pain intensity and nausea was noted but this was not statistically significant. It was concluded that domperidone shortens the duration of a migraine attack and may help reduce headache and associated symptoms.

Headache in Pregnancy

Primary headaches are most common in women during their reproductive years and are affected by the hormonal fluctuations during pregnancy. Most headaches follow a benign course during pregnancy, although migraine is associated with increased risk of hypertensive disorders of pregnancy and stroke. Management of primary headaches during pregnancy is essentially similar to management in the nonpregnant state, with a few exceptions. This article reviews the epidemiology, prognosis, and management of primary headaches during pregnancy and lactation, and considers secondary headaches that are important to exclude.

Prevention and Treatment of Menstrual Migraine

Migraine is a prevalent headache disorder affecting three times more women than men during the reproductive years. Menstruation is a significant risk factor for migraine, with attacks most likely to occur on or between 2 days before the onset of menstruation and the first 3 days of bleeding. Although menstrual migraine has been recognized for many years, diagnostic criteria have only recently been published. These have enabled better comparison of the efficacy of drugs for this condition. Acute treatment, if effective, may be all that is necessary for control. Evidence of efficacy, with acceptable safety and tolerability, exists for sumatriptan 50 and 100 mg, mefenamic acid 500 mg, rizatriptan 10 mg and combination sumatriptan/naproxen 85 mg/500 mg. However, there is evidence that menstrual attacks are more severe, longer, less responsive to treatment, more likely to relapse and associated with greater disability than attacks at other times of the cycle. Prophylactic strategies can reduce the frequency and severity of attacks and acute treatment is more effective. Predictable menstrual attacks offer the opportunity for perimenstrual prophylaxis taken only during the time of increased migraine incidence. There is grade B evidence of efficacy for short-term prophylaxis with transcutaneous estradiol 1.5 mg, frovatriptan 2.5 mg twice daily and naratriptan 1 mg twice daily. Contraceptive strategies offer the opportunity for treating menstrual migraine in women who also require effective contraception.

Characteristics of menstrual vs nonmenstrual migraine: a post hoc, within-woman analysis of the usual-care phase of a nonrandomized menstrual migraine clinical trial.

Objective.— To compare, using a within‐woman analysis, the severity, duration, and relapse of menstrual vs nonmenstrual episodes of migraine during treatment with usual migraine therapy.

Mouth-dispersible aspirin in the treatment of migraine: a placebo-controlled study.

Objective.—To compare the efficacy of mouth‐dispersible aspirin 900 mg and placebo in the treatment of migraine.

Predicting menstrual migraine with a home-use fertility monitor

A home-use fertility monitor was used to time perimenstrual prophylaxis in 27 women with menstrual or menstrually related migraine. Cycle length variability was mostly caused by follicular phase variability; the postovulatory luteal phase was relatively constant. The monitor accurately identified ovulation in >90% of cycles, enabling prediction of menstruation and precise timing of perimenstrual prophylaxis. Ninety-seven percent of women found the monitor useful in predicting menstrual migraine attacks.

Randomized controlled trial of the CGRP receptor antagonist telcagepant for prevention of headache in women with perimenstrual migraine.

Aim The aim of this article is to evaluate the safety and efficacy of perimenstrual telcagepant, a CGRP receptor antagonist, for headache prophylaxis. Methods We conducted a randomized, double-blind, placebo-controlled, six-month trial in women with migraine for ≥3 months who experienced perimenstrual headaches. Women were randomized to telcagepant 140 mg or placebo (2:1 ratio) for seven consecutive days perimenstrually. Safety was assessed by adverse events and laboratory tests. The primary efficacy endpoint was mean monthly headache days in the subset of women reporting perimenstrual migraine (−2 days to +3 days of menses onset) and ≥5 moderate or severe migraines per month prior to entering the trial. Results Telcagepant was generally well tolerated: 66/2660 (2.5%) on telcagepant and 36/1326 (2.7%) on placebo discontinued because of a clinical adverse event. The percentages of patients with clinical adverse events, laboratory adverse events, or discontinuation because of a laboratory adverse event were also similar between treatments. Alanine aminotransferase elevations ≥3× normal occurred in 0.6% of women on telcagepant and 0.4% on placebo. Three women on telcagepant vs none on placebo had alanine aminotransferase elevations ≥8× normal. In the efficacy subset there was no significant effect of telcagepant (n = 887) vs placebo (n = 447) in mean monthly headache days (treatment difference −0.5 day (95% CI: −1.1, 0.1)). However, telcagepant was associated with a reduction in on-drug headache days (treatment difference −0.4 day (95% CI: –0.5, –0.2), nominal p < 0.001). Conclusions Telcagepant 140 mg taken perimenstrually for seven days was generally well tolerated, but was associated with transaminase elevations. Telcagepant did not reduce monthly headache frequency, but did reduce perimenstrual headaches.