The discrepancy is likely explained by the strong relative contraindication, in the United States, to the use of OCs in smokers older than 35 years (the smoking prevalence in most of the European case series was more than 50%), as well as the more prevalent use of high-dose OCs in the international studies. High-dose pills were implicated in the majority of stroke cases in the World Health Organization (WHO) study, but were used by only 0.7% of cases and controls in the pooled U.S. studies.23 Nevertheless, both ACOG and WHO concluded that the risk of OC use usually outweighs the benefit in women older than 35 years whose migraines are complicated by focal neurologic deficits.
Extended-cycle OCs may offer a lengthy reprieve. Regimens that forego monthly withdrawal bleeds and provide extended administration of active pills can afford migraineurs a lengthy reprieve from MM.29 Breakthrough bleeding is the most common side effect but tends to decrease over time. It is preferable for the patient to take the pill at bedtime to avoid a drug nadir during susceptible stages of sleep, which may be associated with migraine generation. It also is prudent to avoid concomitant administration of drugs that might increase the rate of hepatic metabolism of estrogen (e.g., a high dosage of topiramate) and lead to a more rapid decline in concentration.
When using an extended-cycle regimen that allows for periodic withdrawal bleeds, give the patient supplemental estrogen during the withdrawal week if the decline in ethinyl estradiol (EE) exceeds 10 μg, a threshold that appears to elicit MM in susceptible women.21,22 For example, with an extended-cycle regimen that contains 30 μg of EE, it may be necessary to add 20 μg of estrogen during the placebo week to prevent MM, whereas an extended-cycle regimen that contains 20 μg EE, declining to 10 μg during the 13th week, would be adequate as packaged.
21/7 hormonal OCs may require supplemental estrogen to prevent MM. The late luteal-phase decline in estradiol concentration during the natural menstrual cycle is equivalent to the decline experienced with the transition to inert pills in 20- to 25-μg EE formulations. Therefore, these regimens confer the same risk of MM as the woman’s natural cycle. Products that contain incrementally higher dosages of EE (30, 35, and 50 μg) confer an increasingly greater risk of MM. Supplementation of estrogen during the placebo week may prevent MM by limiting the decline in estrogen.
In a small, open-label study, women took an OC containing 20 μg EE at bedtime on days 1 to 21 of the cycle, followed by 0.9 mg of conjugated equine estrogens (CEE) on days 22 to 28. All patients reported a reduction in migraine frequency of at least 50%, with a mean reduction of 78%.30
Parenteral options can be created utilizing a transdermal 20-μg EE/norelgestromin patch or a 15-μg EE/etonogestrel vaginal ring. With the first approach, I recommend adding a 0.1-mg EE patch during the withdrawal week to prevent MM. With the latter, a 0.075-mg EE patch may be used during the week following ring removal.31
Consider a menstrually targeted estrogen supplement. Some women who have contraindications to use of an OC may still be candidates for targeted strategies using lower dosages of supplemental estrogen rather than a combination OC. Among the options is perimenstrual administration of an estradiol patch or gel.32 One study found a 0.1-mg estrogen patch (worn 7 days and applied just before the expected onset of menses) to be effective, but lower dosages (0.025 to 0.05 mg EE) were not.33 Daily application of 1.5 mg estradiol gel for 7 days, beginning before the onset of MM, was also effective in preventing MM.34-36
With targeted strategies, timing is critical; if estrogen is begun too early, the incidence of migraine may rise after cessation.36
GnRH agonists may benefit women who have isolated MM. Administration of gonadotropin-releasing hormone (GnRH) agonists has been shown to ease MM, but the baseline frequency of headaches appears to be an important variable in the success of these agents.37-39 Leuprolide acetate markedly diminished MM in women who seldom experienced headaches other than their menstrual attacks.37 It did not benefit women who experienced migraine in the setting of chronic headache (≥15 days/month), probably because chronic migraine is influenced by other variables, such as nonrestorative sleep and overuse of medication.15,38,40
No evidence that progestin-only contraceptives are effective. Although these agents have been proposed for treatment of migraine, evidence of their benefit is lacking. It is my opinion that, more often than not, they exacerbate migraine.