Alice, a 26-year-old with no significant past medical history presents for severe migraines, which she’s had since she was 16 years old. She treats them with abortive NSAIDs or sumatriptan. However, over the last year she has been missing work once a month because of their severity. Her migraines predominantly occur during menstruation and do not have aura.
This is a common presentation for female migraineurs, of which, approximately 22% suffer from menstrual migraine specifically.1 Menstrual migraine is defined by the International Classification of Headache Disorders (ICHD3, beta version) as migraine without aura that occurs within days -2 and +3 of the menstrual period on at least 2 of 3 consecutive menstrual cycles (where menstruation onset is defined as day 1). Menstrual migraine is further subdivided into pure menstrual migraine or menstrual related migraine depending if migraine occur solely during menstruation or at other times of the cycle as well.
Clinically, this is an important entity for physicians to recognize because menstrual migraines are more severe, longer lasting, and more difficult to treat than traditional migraines.2 Overall the treatment approach to menstrual migraine depends on migraine frequency, refractoriness to abortive medications, and overall predictability of the menstrual cycle (Figure).
For infrequent migraines, abortive treatment is the mainstay of therapy. Studies specifically evaluating the efficacy of acute abortive treatment in menstrual migraine have primarily looked at triptans. Overall, rizatriptan has the best evidence for pain freedom at 2 hours (63% of patients pain free) followed by sumatriptan (61% of patients pain free), amlotriptan (48% of patients pain free), and zolmitriptan (28% to 48% of patients pain free).3 It should be noted that failure of one triptan does not indicate lack of efficacy for the entire drug class and additional trials of alternative triptans should be undertaken. In instances where triptans are not effective or contraindicated, second-line agents are typically NSAIDs—naproxen being favored.
Short-term prophylactic treatment
As with all migraineurs, keeping a headache diary is instrumental for achieving the best therapeutic outcomes. In the setting of menstrual migraine, a headache diary is crucial in determining the predictability of the menstrual cycle. For women with regular menstrual cycles and menstrual migraines that are refractory to abortive therapy, short-term prophylactic agents started a few days before the anticipated onset of menstruation has been shown to be effective at reducing the frequency and severity of menstrual migraine.
Of the agents studied, frovatriptan currently has the most evidence as a short-term prophylactic agent for menstrual migraine. One trial demonstrated that 57% of patients were migraine free over the course of 3 menstrual cycles.4 The most efficacious regimen was 2.5 mg twice daily, starting 2 days prior to the onset of menstruation, and continuing for a total of 6 days (Table). This regimen also allows for an additional 2.5 mg dose once daily for breakthrough headaches without exceeding the maximum recommended daily dose. Post hoc subgroup analysis showed efficacy even in women with pure menstrual migraine, and in select difficult-to-treat migraines where previous abortive treatments had failed.5,6 Based on this data, short-term prevention of menstrual migraine with frovatriptan was given an A rating by the American Headache Society and American Academy of Neurology for migraine prevention.
Different primary outcomes have made across-study comparison of triptans difficult. However, other triptans have also shown efficacy in short-term prophylactic treatment including: sumatriptan (52.4% of menstrual cycles migraine free), zolmitriptan ( 58.6% of patients had ≥ 50% reduction in migraine frequency), and naratriptan (50% for patients migraine free over 4 menstrual cycles).7-9 For patients who have a contraindication to triptans, short-term prophylaxis with magnesium, naproxen, or estrogen can be considered.3
Long-term prophylactic treatment
Ideally, a long-term daily prophylactic agent for women with frequent menstrual migraines who do not have predictable menstrual cycles would be helpful. Unfortunately, the data assessing the best long-term prophylactic agents for menstrual migraine is sparse and standard migraine prophylactic agents are currently the mainstay of therapy. There are, however, data that support the use of estrogen, which comes from the observation that menstrual migraines tend to occur during the hormone-free intervals for women on oral contraceptives pills (OCPs).10 Sulak and colleagues11 found that a 168-day extended OCP regimen reduced headache severity compared with a 28-day OCP cycle (21 days of estrogen plus progestin and 7 days of placebo). However, long-term safety data for this are limited and should be considered prior to extended OCP therapy. Going forward, additional data are needed to identify specific medications that work best for long-term prophylaxis in menstrual migraine.
Given the severity and treatment resistance of menstrual migraine, specific approaches have been developed that depend on migraine frequency, responsiveness to abortive agents, and overall predictability of the menstrual cycle. For infrequent migraines, abortive therapy is recommende and—rizatriptan has shown the best efficacy. For frequent migraines in the setting of a predictable menstrual cycle and poor response to abortive therapy, short-term perimenstrual prophylaxis with frovatriptan is recommended. For patients with unpredictable menstrual cycles and frequent migraines, short-term prophylaxis is not a viable option and data is sparse for the best long-term prophylactic agent. Currently, the best approach is iterative trials with standard migraine prophylactic therapies.
A common missed opportunity to improve the lives of our patients is not making the diagnosis of menstrual migraine. It is important to be vigilant in making the diagnosis of menstrual migraine given that it is relatively common, easily missed, and better managed if the diagnosis is clear. The key practice point is having all female migraine patients keep a headache diary with their menstrual cycle timing. This will increase diagnostic sensitivity for menstrual migraine and also stratify patients according to menstrual cycle predictability for correct management (Figure).
In Alice’s case, she has a predictable menstrual cycle with frequent migraines that are refractory to abortive therapy and would likely benefit from short-term peri-menstrual prophylactic therapy with frovatriptan. Although menstrual migraine is typically more severe than non-menstrual migraine, tailored management plans taking into account migraine characteristics can improve the quality of life of female migraineurs.
Dr Hullett is a Neurology Resident, University of California, San Francisco, Department of Neurology. Dr Maasumi is Attending Neurologist and Director of Outpatient Headache Infusion, UCSF Headache Center, UCSF Department of Neurology, University of California San Francisco Medical Center, San Francisco, CA.
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