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Clinical Aspects of Perimenstrual Headache
Allais G, Gabellari IC, Mana O, Benedetto C.
Posted: November 2007  
Current Headache Reports: Vol. 6, October 2007;146-150


Most women with migraine describe an association between their headache and the perimenstrual period (PMP). Menstrual migraine (MM) is either pure, if attacks exclusively appear in the PMP, or menstrually related, if attacks always occur during (but are not confined to) the PMP. Menstrual attacks are generally longer, more severe, more disabling, less drug-responsive, and more likely to recur than are nonmenstrual attacks. Acute treatments include ergot derivatives, NSAIDs, cyclooxygenase-2 inhibitors (COXIBs), analgesics, and antiemetic agents. However, triptans, which have been widely demonstrated to have effectiveness in MM treatment, are usually preferred. In nonresponders, short-term perimenstrual prophylaxis with NSAIDs, COXIBs, triptans, or regotamine derivatives can be considered. If this approach fails, hormone manipulation, mainly perimenstrual application of percutaneous estradiol gel or extended oral contraceptive courses, can be tried. Magnesium and phytoestrogens may be a valid alternative for patients who prefer a "natural" approach.

CLINICAL FEATURES
More than 50% of women with migraine report an association between their headache and menstruation, whereas only 7% to 10% suffer from PMM.

The major trigger of migraine attacks is probably the premenstrual decrease of estrogen levels after exposure to high levels for several days. This may cause an abnormal biohumoral and molecular reaction that would partially explain the clinical features and perhaps the different response to abortive and prophylactic treatment that can occur between menstrual and nonmenstrual attacks.

Several clinical, population-based studies have shown that menstrual attacks are almost always without aura, even if this is present at other times of the cycle.

They are generally long and may exceed the upper limit of 72 hours proposed for migraine without aura in the IHS classification. In addition, they are more severe, accompanied by very substantial vegetative phenomena, and are more disabling than nonmenstrual attacks. Moreover, they are less drug-responsive and more likely to recur.

However, this greater severity may reflect findings drawn from women treated in specialty clinics rather than from those treated by primary care physicians.

ACUTE TREATMENT
Acute treatments typically recommended for MM are the same as those for non-MM (NMM). Triptans are usually preferred, but also ergot derivatives, NSAIDs, COXIBs, various analgesics, and antiemetic agents, alone or in combination, cn be used.

PROPHYLACTIC TREATMENT
Women whose MM does not fully respond to abortive medications may be ideal candidates for prophylaxis designed to reduce the frequency, duration, and intensity of their attacks, and also to render them more susceptible to acute treatment. Both short-term prophylaxis around the perimenstrual window and a perimenstrual increase in the dose of preventive agents used throughout the month have been advocated. Only the first approach is considered here.

SHORT-TERM PROPHYLAXIS
Because of their regular and predictable nature, perimenstrual attacks are excellent candidates for prophylaxis covering the PMP. Candidates need to have regular cycles and a comprehensive headache diary. Several options can be attempted, to fit in with a patientís wishes, menstrual regularity, need for contraception, timing of the attacks in relation to bleeding, and presence of dysmenorrheal. Many medications commonly used for acute treatment can also be used for short-term prophylaxis: NSAIDs, COXIBs, ergot derivatives, and triptans. In addition, some hormone treatments are effective for short-term prophylaxis. In any case, a regimen should be used for at least three cycles to allow assessment of its real efficacy.

NATURAL PRODUCTS
Two studies have assessed the effects of phytoestrogens in the prevention on MM. Patients were continuously treated with a placebo or with a daily combination of 60 mg. soy isoflavones, 100 mg. dong quai, and 50 mg. black cohosh. Average MM frequency was significantly reduced, compared with the placebo group. In the second study, a small group of PMM sufferers received perimenstrual prophylaxis with 56 mg. genisteine and 20 mg. daidzein per day. The average number of days with migraine decreased significantly after 3 months.

Magnesium pyrrolidone carboxylic acid (360 mg./day orally) was evaluated in a double-blind, placebo-controlled study. It was started on the 15th day of the cycle and continued until the next menses. This regimen reduced the intensity and the duration of MM, and also improved premenstrual complaints.

CONCLUSIONS
A daily diary card for at least three cycles is an essential aid for effective diagnosis and collection of information about the length and regularity of the cycle, because women with regular and irregular cycles may sometimes be treated in different ways.

The first step is always specific and effective treatment of the acute attack. Triptans, usually the drugs of first choice, are tailored in the light of their pharmacologic properties and effectiveness. Acute treatment should begin as soon as possible after the onset of an attack to optimize the patientís response. When attacks are particularly severe from the start, NSAIDs and triptans (e.g. sumatriptan and naproxen) can be combined. In women with irregular cycles, correct acute treatment is the only easy form of management, coupled, if necessary, with standard continuous prophylaxis. Continuous use of oral contraceptives (without the monthly break) should be considered for very carefully selected nonresponders. A perimenstrual short-term prophylaxis is recommended for women with regular cycles who do not respond to acute treatment; prostaglandin inhibitors (NSAIDs, COXIBs) are usually the first choice, because of their manageability and effectiveness against other menstrual complaints. If this approach fails or is not tolerated, a short-term prophylaxis with (preferable long-life) triptans or with ergotamine derivatives can be started. In this case, however, NSAIDs should be prescribed to treat breakthrough headaches, because the concomitant use of triptans and ergotamine derivatives is contraindicated. If this attempt also fails, hormone manipulations can be considered. The use of percutaneous estradiol gel seems the best approach, because it secures the most stable blood steroid levels. However, a rebound migraine may occur immediately after the cessation of any type of short-term prophylaxis.

If the preliminary trials are confirmed, phytoestrogens will provide a good form of "mild" hormone manipulation to prevent MM. Patients with particularly intense premenstrual complaints, including migraine, could also try magnesium supplementation.

If MM also regains refractory to standard continuous prophlaxis (e.g. Ŗ-blockers, calcium antagonists, antiepileptic drugs), major hormonal manipulation with danazol, Tamoxifen, or GnRH agonists can be considered after consultation with a gynecologist or an endrocrinologist, provided due account is taken of the substantial adverse events this approach may provoke.