Menstrually-Related Migraine Treatments
Many researchers have established a link between estrogen and progesterone — the female sex hormones — and migraine.1-5 Migraine occurs more frequently in adult women (18%) than in men (6%),2,6 and develops most frequently in the second decade, with the peak incidence occurring with adolescence.1,4 Menstrually-related migraine (MM) begins at menarche in 33% of affected women, occurring mainly at the time of menses in many migrainous women and exclusively with menses — true menstrual migraine (TMM) — in some.1 Its frequency has been reported to be as high as 60% to 70%; retrospective analysis suggests that its prevalence ranges from 26% to 60% in headache clinic patients, although the prevalence appears to be lower in non-headache clinic patients.7
Menstrual migraine can be associated with other somatic complaints arising before and often persisting into menses, such as nausea, backache, breast tenderness and cramps, and, like these symptoms, appears to be the result of falling sex hormone levels.5,6,8 Indeed, MM appears to occur at the time of greatest fluctuation in estrogen levels. In addition, premenstrual migraine (PMM), defined as attacks occurring 2 to 7 days before the onset of menses, can be associated with premenstrual syndrome (PMS), which is distinct from the physical symptoms of the perimenstrual period and is probably not directly driven by declining progesterone levels.9 Migraine occurring during (rather than prior to) menstruation is usually not associated with PMS. One group of researchers10 has defined “true menstrual migraine” (TMM) as attacks that occur regularly on or between days -2 to +3 of the menstrual cycle and at no other time, and MM as attacks that occur at any time during the cycle with an increased frequency during menstruation. It now appears that migraine attacks occur more frequently with menstruation but are not longer in duration or clinically significantly more severe.11
Treating Menstrually-Related Migraine
Effective migraine treatment depends upon making an accurate diagnosis, teaching the patient to identify and avoid headache triggers and developing a treatment plan that reduces the impact of migraine on the individual patient, targeting the most disturbing symptoms. The use of a headache calendar will help establish a relationship between headache and the menstrual cycle and establish if headaches are menstrually triggered migraine (MM) or TMM. Women who have headache throughout their menstrual cycle should be treated with reassurance, education, and pharmacologic intervention.
There are two pharmacologic approaches to treatment. Acute (abortive) therapy is used to decrease the duration and intensity of an individual attack and the associated symptoms such as nausea and vomiting.12,13 Preventive (prophylactic) treatment is used to decrease attack frequency and severity and should be considered when there are three or more attacks a month that are prolonged and unresponsive to abortive measures, or when abortive measures are contraindicated or produce significant side effects.
The Rationale for the Use of Triptans in Menstrually-Related Migraine
The class of medications known as triptans are considered especially useful in MM because they can be used for both acute and preventive treatment. These agents are selective 5-HT1 agonists with activity at the 5-HT1D, 5-HT1B, and/or 5-HT1F receptor sites. In particular, zolmitriptan (Zomig®), sumatriptan (Imitrex®) and rizatriptan (Maxalt®) are as effective for menstrually associated migraine14 as for migraine not associated with menses (non-MM) and, in addition, control the nausea and vomiting associated with attacks.15,16
The efficacy of zolmitriptan has been evaluated in three placebo-controlled (2.5 or 5mg) clinical trials involving almost 1000 women. Approximately 28% of the women had MM and 14% had migraines while using oral contraceptives (OCs). The response rates for women with and without menses (vs. placebo) is presented in Figure 1.
Zolmitriptan induced a similar two-hour headache response in the OC group17 (those using oral contraceptives; see Figure 2).
The 2.5mg data from those three placebo-controlled trials were included in an analysis of prospectively recorded data from the zolmitriptan clinical trial program.18 Also included were data from two multiple-attack comparative trials with sumatriptan and two long-term open studies; all used zolmitriptan 2.5 or 5mg, and data were combined where both dosages were used. A total of 4,345 menstruating patients were included in the analysis. Zolmitriptan 2.5mg was significantly more effective than placebo in the treatment of moderate to severe MM; two-hour headache response rates were 60% with zolmitriptan vs. 39% with placebo (p=0.0008). In the active comparator trials, zolmitriptan produced a two-hour headache response in 68% of MM attacks and 65% of non-MM attacks. In the two long-term studies, the two-hour response rates were 80% and 83% in MM vs. 81% and 82% in non-MM. Furthermore, within individual patients, response rates were similar in both types of attacks, irrespective of the percentage of attacks treated during menses.
A more recent study involving 579 women suggests that zolmitriptan exhibits efficacy as early as 30 minutes in MM.19 This study differs from others in that treatment was intensity based, with mild migraine headaches treated with one half of a zolmitriptan 2.5-mg tablet, moderate headache with 2.5mg, and severe headache with 5mg (two 2.5-mg tablets), or corresponding placebos. Additionally, patients were required to have MM in two of three prior menstrual cycles. Treatment with zolimitriptan was more effective than placebo in achieving early headache response for all MM as well as a subset excluding mild attacks (see Figure 3).
Decrease in VAS (visual analog scale) of 50% or greater in headache response over a two hour period is presented in figure 4 with response seen as early as 30 minutes.
In a retrospective analysis of data from two randomized, double-blind, placebo-controlled, parallel-group trials, 80% of women who treated MM with sumatriptan injection (6mg) reported headache relief one hour post-dose (p14 Sumatriptan injection 6mg was also effective in the acute treatment of MM in a prospective, double-blind, placebo-controlled, parallel-group, two-attack study.20 Across the two attacks, 70% to 71% of patients treating MM with sumatriptan reported headache relief one hour post-dose, versus 22% to 24% of placebo-treated patients. Additionally, sumatriptan tablets (100mg) were effective in the acute treatment of MM in a prospective, double-blind, placebo-controlled, cross-over study in women with a history of MM. Figure 5 presents comparison of headache relief for MM and non-MM using sumatriptan 100 mg tablets.