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Oral contraceptives in migraine Expert Rev. Neurother. 9(3), 381–393 (2009)
Gianni Allais†, Ilaria Castagnoli Gabellari, Cristina De Lorenzo, Ornella Mana and Chiara Benedetto † Author for correspondence Women’s Headache Center, Department of Gynecology and Obstetrics, University of Turin, Via Ventimiglia 3, I-10126 Turin, Italy
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Combined oral contraceptives are a safe and highly effective method of birth control, but they can also raise problems of clinical tolerability and/or safety in migraine patients. It is now commonly accepted that, in migraine with aura, the use of combined oral contraceptives is always contraindicated, and that their intake must also be suspended by patients suffering from migraine without aura if aura symptoms appear. The newest combined oral contraceptive formulations are generally well tolerated in migraine without aura, and the majority of migraine without aura sufferers do not show any problems with their use; nevertheless, the last International Classification of Headache Disorders identifies at least two entities evidently related to the use of combined oral contraceptives: exogenous hormone-induced headache and estrogen-withdrawal headache. As regards the safety, even if both migraine and combined oral contraceptive intake are associated with an increased risk of ischemic stroke, migraine without aura per se is not a contraindication for combined oral contraceptive use. Other risk factors (tobacco use, hypertension, hyperlipidemia, obesity and diabetes) must be carefully considered when prescribing combined oral contraceptives in migraine without aura patients, in particular in women aged over 35 years. Furthermore, the exclusion of a hereditary thrombophilia and of alterations of coagulative parameters should precede any decision of combined oral contraceptive prescription in migraine patients. Keywords : combined oral contraceptives • ischemic stroke • migraine • safety • thrombophilia • tolerability
For most women, combined oral contraceptives (COCs) are the preferred method of contra ception because of their ease of use and proven efficacy [1] . COCs also provide many noncontraceptive health benefits, such as menstrual cycle control, treatment of dysfunctional uterine bleeding, protection against several gynecologic and nongynecologic cancers, preservation of bone density and improvement of acne [2] . Since they are commonly associated with headache, however, physicians are frequently asked for advice regarding their interaction. In the specific case of migrainous women, physicians should always bear in mind the fact that COCs may raise two classes of problems: one regarding their tolerability, the other their safety. Both topics are reviewed in this paper. COC tolerability
It is commonly believed that COCs can initiate or aggravate headaches. Since migraine in particular has a higher prevalence during the fertile age, and the use of COCs is obviously more frequent at this time, it is often not clear whether headache existed prior to or was a consequence of using COCs in general population studies. Moreover, www.expert-reviews.com
10.1586/14737175.9.3.381
headache is one of the side-effects most frequently reported during the use of COCs, and a common cause of their discontinuation [3] . Many studies of migraine during COC administration are retrospective and lack a clear description and classification of the headaches observed. Other methodological biases include the duration of the observation period and the absence of a clear statement of the interval between the commencement of pill intake and the first occurrence of headache. Moreover, some studies are very old and deal with COCs containing 50 µg or more of ethinylestradiol (EE). Loder et al. reviewed the literature to assess the evidence of an association between COC use and new onset or worsening of headache [3] . Analysis of clinical trials including an active, untreated or placebo control group revealed only small and not always significant increases in headache activity during the early treatment stages. Regardless of its cause, headache associated with COCs tended to improve as their use continued [3] . In the specific case of women suffering from migraine without aura (MO), it is difficult to predict the course of headache when COCs are
© 2009 Expert Reviews Ltd
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Allais, Gabellari, De Lorenzo, Mana & Benedetto
started. Most migrainous women find that COCs use do not result in a substantial change in their headaches, though some report an exacerbation: nearly 25% of MO women in some epidemiological studies [4–7] . The International Classification of Headache Disorders, Second Edition (ICHD‑II) identifies at least two entities evidently related to the use of COCs [8] : exogenous hormone-induced headache (code 8.3.1) and estrogen-withdrawal headache (code 8.4.3), as well as a general headache as an acute adverse event attributed to medications used for other indications (code 8.1.10). Two of the diagnostic criteria for the former are of special interest: • Headache or migraine develops or markedly worsens within 3 months of commencing exogenous hormones; • Headache or migraine resolves or reverts to its previous pattern within 3 months after total discontinuation of exogenous hormones. ICHD‑II acknowledges that COCs may initiate or worsen migraine, while their suspension may arrest it or restore its previous state. Suspension of COCs when migraine starts with its use may be followed by immediate relief. In other cases, however, there is a delay of 6–12 months, and some patients report that migraine can continue on a long-term basis [9] . In COC users, migraine (presumably triggered by estrogen withdrawal) is more likely to occur during the pill-free week. In the ICHD‑II, this estrogen-withdrawal headache (code 8.4.3) is usually ‘a headache or migraine that develops within 5 days after cessation of estrogen use and resolves within 3 days (estrogen use must have lasted for at least 3 weeks prior to cessation)’ [8] . We have recently described the clinical features of this type of migraine [10] . Subgroups of women with an apparently greater risk of new onset or worsening of headache when on COCs use have been described, namely those with higher ages [3] and those with a personal or family history of migraine [3,9] . As to the influence of migraine subtypes, Cupini et al. found worsening (in both intensity and frequency) in 50% of migraine with aura (MA) patients and in 34.8% of MO patients on COCs. New onset of migraine was reported by 22.2% of MA patients and 16.2% of MO patients [6] . Granella et al. also noted that COC use worsened migraine in MA more frequently (MA 56.4%; MO 25.3%; odds ratio [OR]: 3.8; 95% confidence interval [CI]: 1.6–9.3) [11] . Also among MO, those previously suffering from menstrually related migraine or pure menstrual migraine constitute a subgroup at higher risk of worsening. Mueller, in fact, found a significant association between worsening of migraine during the use of COCs and a history of menstruation-associated headaches (83.8 vs 67.1%; p
