European Journal of Obstetrics & Gynecology and Reproductive Biology 183 (2014) 178–182
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European Journal of Obstetrics & Gynecology and Reproductive Biology journal homepage: www.elsevier.com/locate/ejogrb
Progestin-only contraception compared with extended combined oral contraceptive in women with migraine without aura: a retrospective pilot study Matteo Morotti *, Valentino Remorgida, Pier Luigi Venturini, Simone Ferrero Department of Obstetrics and Gynecology, IRCCS Azienda Ospedaliera Universitaria San Martino—IST Istituto Nazionale per la Ricerca sul Cancro, Largo Rosanna Benzi 1, Genoa, Italy
A R T I C L E I N F O
A B S T R A C T
Article history: Received 28 May 2014 Received in revised form 8 October 2014 Accepted 22 October 2014
Objective: To evaluate the effect of a desogestrel progestogen-only pill (POP) compared to continuous combined oral contraception (COC) on migraine patterns in women with migraine without aura. Study design: A retrospective analysis of prospective headache charts from migrainous women who used the POP or COC in our clinic between July 2009 and July 2013. The quality and quantity of migraine attacks and use of medications were evaluated at three and six months. Health related quality of life was evaluated after 6 months’ treatment. Results: Fifty-three patients were evaluable for the analysis (22 in the COC group and 31 in the POP group). Six months’ POP treatment led to a statistical reduction in migraine days; headache days; pain intensity; number of days with severe pain and days with pain medication. The only statistical difference between the two groups was a reduction in the number of days with pain medication in the POP group compared to the COC group (p = 0.044). After 6 months’ treatment a quality of life improvement was seen only in the POP group, but no statistical differences were found when comparing the two groups. Conclusions: Our preliminary data confirm that POP therapy improves migraine patterns and quality of life after 6 months’ treatment in women with migraine without aura and it decreases the analgesic consumption with respect to an extended COC therapy. As POP represents a healthier opportunity, in terms of vascular risk, than combined contraception, its role in migrainous women deserves to be further investigated. ß 2014 Elsevier Ireland Ltd. All rights reserved.
Keywords: Combined oral contraceptive Desogestrel-only pill Headache Migraine without aura Pain Progestins
Introduction Migraine is a common neurological disorder, affecting about 18% of women in US and Europe, and it is more common during the reproductive years [1]. Women of reproductive age often request hormonal contraception for fertility purposes. In addition some of them can suffer gynecological conditions that are comorbid with migraine (such as endometriosis) that can be treated with combined hormonal contraception (CHC). This enhances the likelihood of CHC use in the migrainous population [2,3]. As hormonal fluctuations are thought to likely play a role in migraine pathophysiology, and estrogen withdrawal is probably one of the more important triggers, several studies have tried to optimize hormonal treatment in women with migraine without aura (MO)
* Corresponding author. Tel.: +39 010511525; fax: +39 010511525.. E-mail address: [email protected] (M. Morotti). http://dx.doi.org/10.1016/j.ejogrb.2014.10.029 0301-2115/ß 2014 Elsevier Ireland Ltd. All rights reserved.
who desire hormonal contraception [4–7]. The rationale of these studies was to eliminate or minimize premenstrual estrogen withdrawal and thus maintain steady estrogen levels [8]. Continuous strategies include CHC consumption in extended-cycle regimens, where the placebo week is eliminated for extended periods, often for 12 weeks or more. These strategies also include the use of a continuous vaginal-ring contraceptive or an estradiol patch or combined oral contraceptives (COCs) which contain ethinylestradiol and a synthetic progestin. Sulak et al. reported the efficacy of extended dosing with a 30-mg ethinylestradiol COC in reducing menstrual headache in a 6-month open-label trial [5]. For this reason extended contraception has been widely used in patients with MO desiring hormonal therapy. However, both migraine with aura and MO can increase vascular risk, especially the risk of stroke in younger women [9,10]. This risk may further increase when CHCs are used [11–13]. The cardiovascular risk of CHCs is mainly attributed to the estrogen component, which exerts a strong effect on the coagulation system [12,13].
M. Morotti et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 183 (2014) 178–182
Interestingly, recent studies showed that 3-month desogestrel therapy (DSG, 75 mg/day) reduces the number of migraine attacks and improves health-related quality of life (HRQoL) in women suffering migraine with and without aura [14–16]. As progestinonly pill (POP) contraception is a safer alternative to COCs in term of cardiovascular risk and it is preferable in women with cerebrovascular diseases or risk factors for stroke [17] and we noticed frequent improvement in migraine patterns in daily clinical practice in many women treated with desogestrel, we retrospectively analyzed the headache diaries of women with MO who chose POP or continuous COC in our clinic over recent years. Materials and methods The study was performed at the Gynecology subunit of the Department of Obstetrics and Gynecology, San Martino Hospital, University of Genoa, where one of the authors (SF) runs an outpatient clinic for sexual health and contraception. From our electronic prospective database, we retrospectively reviewed all the patients with a diagnosis of MO who were prescribed the desogestrel-only pill or continuous COC from July 2009 to July 2013. The electronic database contains demographic and clinical records of all the patients who attend our clinic, and every dose of every medication administered, and also serves as a repository for laboratory data and other clinical outcome data for audit purposes (adverse effects of the treatment, acceptance of therapy, quality of life during treatment and general feedback). This database is always filled by the specialty registrars attending the clinic. Patients’ charts were subsequently identified by two authors (MM and SF) and then evaluated. Charts were included only for patients with a diagnosis of MO made by a neurologist according to the criteria of the International Headache Society [18] and with at least three monthly headache episodes reported in the pre-treatment period. The exclusion criteria were: previous hormonal therapies in the three months before the start of the therapy and use of other medications known to be effective in migraine prophylaxis (such as beta blockers, antidepressants and anticonvulsants). Patients were evaluated only if they had used one of the following therapies: continuous oral desogestrel 150 mcg and ethinylestradiol 20 mcg (Mercilon1; Schering, formerly NV Organon, Oss, The Netherlands; COC group) or oral desogestrel (75 mcg/day, Cerazette1; Schering-Plough, formerly NV Organon, Oss, The Netherlands; POP group). The treatment was always started on the first day of menstruation. The migrainous patients in our clinic keep headache diaries including information on quantity and quality of migraine patterns, the use of triptans and other pain medication. The following characteristics of migraine are recorded: number of attacks; number of days with severe pain; and intensity of pain (graded on a four point scale, where 0 = no pain; 1 = mild, does not impair daily activities;
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2 = moderate, may inhibit, but does not prohibit daily activities; 3 = severe, prohibits daily activities) [19]. The adverse effects of the two different treatments were extracted from the diaries, in particular the number of days in which the women experienced spotting or vaginal bleeding. Vaginal bleeding was defined as follows: spotting (scanty bleeding not requiring usual sanitary protection), breakthrough bleeding (light or moderate bleeding requiring sanitary protection) and metrorrhagia (more than normal menstruation). The validated language version of the Short Form–36 version 2 (SF36v2) questionnaire, which we routinely administer to all migrainous patients after 6 months’ therapy, was used to measure HRQoL [20]. Results are usually presented as summary measures: the physical health component score (PCS) is the summation of the first four indexes (bodily pain through overall general health), whereas the mental health component score (MCS) includes the last four indexes (from vitality to mental health). The summaries and eight domain scales are adjusted with scores ranging from 0 to 100 (maximum), with higher scores indicating higher levels of functioning or well-being. The University’s Institutional Review Board approved this retrospective database. Statistical analysis Demographic characteristics and symptom variations were compared using a two-sided t-test or the Mann–Whitney U-test according to data distribution and analysis of variance or Kruskal– Wallis test with Dunnett’s multiple comparisons test according to data distribution when comparing three or more categories. Categorical variables were compared by using the chi-squared test or McNemar’s test according to data distribution. p < 0.05 Was considered statistically significant. Data were analyzed using the PRISM software version 6 (GraphPad Software, La Jolla, CA, USA). Results Out of 74 patients treated during the study period, 53 were evaluable for the analysis (22 in the COC group and 31 in the POP group). Twenty-one patients were excluded because of: loss to follow-up (n = 4, two in both groups), incomplete diaries (n = 9; five using POP and four using COC) and withdrawal for adverse effects (n = 8; prolonged bleeding n = 4; three in the POP group and one in the COC group; increase of headache n = 4, two in both groups). The demographic characteristics and baseline data of the patients included and excluded in the study are presented in Table 1. No differences of the considered variables were seen between patients included in the study (Table 1). Interestingly, we found that 6 months’ POP treatment led to a significant reduction in migraine days (p < 0.001); headache days (p = 0.010); pain intensity (p = 0.002), number of days with severe pain (p < 0.001) and days with pain medication (p < 0.001). A
Table 1 Demographic characteristics of patients included and excluded from the study. Patients included
Age (years; mean SD) BMI (kg/m2; mean SD) Smoking cigarettes (number of patients, %) Cigarettes per day (mean SD) Age of migraine onset (years; mean SD) Previous COC users (n; %) Family history of migraine (n, %) Systolic BP (mean SD) Dyastolic BP (mean SD)
p
COC (n = 22)
POP (n = 31)
29.4 3.3 21.1 2.0 6/22 (27.3%) 8.2 3.3 (n = 6) 19.1 3.2 12/22, (54.5%) 5/22 (22.7%) 122.3 8.9 76.6 3.5
30.3 2.9 21.3 2.1 10/31 (32.3%) 9.3 4.8 (n = 10) 20.1 4.4 19/31, (61.3%) 7/31 (22.6%) 124.4 6.9 76.5 5.8
0.285 0.701 0.697 0.618 0.401 0.784 0.999 0.288 0.921
Patients excluded COC (n = 9)
POP (n = 12)
28.9 4.1 21.2 2.3 2/9 (22.2%) 6.5 3.5 (n = 2) 19.9 5.4 4/12, (33.3%) 3/12 (25.0%) 121.8 6.2 76.1 4.4
30.1 3.1 22.3 1.8 4/12 (33.3%) 10.2 4.6 (n = 4) 19.1 4.3 6/12, (50.0%) 5/12 (41.7%) 123.6 8.8 78.7 7.2
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Table 2 Effect of COC or POP use on migraine patterns and pain medication at 3 and 6 months treatment. COC (n = 22) baseline
POP (n = 31) baseline
COC (n = 22) 3 months
POP (n = 31) 3 months
COC (n = 22) 6 months
POP (n = 31) 6 months
Migraine days (mean SD)
5.1 2.2
5.5 2.6 p = 0.534
4.6 2.4 p = 0.454
4.1 2.2 p = 0.284
Headache days (mean SD)
3.1 0.9
3.6 1.5 p = 0.121
2.7 1.8 p = 0.274
Headache intensity/month# (mean SD)
13.8 4.6
14.4 5.4 p = 0.725
12.3 4.7 p = 0.446
Days with headache score 3 (mean SD)
4.6 1.7
4.9 1.9 p = 0.106
4.2 1.7 p = 0.345
Pain medication (mean SD)
5.3 1.7
6.1 1.4 p = 0.083
4.5 1.5 p = 0.145
Triptan use (mean SD)
11.3 3.6
11.4 5.0 p = 0.914
10.5 3.4 p = 0.518
Number of days with bleeding (mean SD)
NA
NA
2.8 0.1
4.2 1.6 p = 0.012 p = 0.414 3.1 1.1 p = 0.222 p = 0.131 11.7 4.9 p = 0.063 p = 0.683 3.7 1.5 p = 0.011 p = 0.798 4.9 1.1 p = 0.001 p = 0.339 9.8 4.5 p = 0.307 p = 0.604 4.6 0.2 p < 0.001
3.5 1.2 p < 0.001 p = 0.218 2.7 1.1 p = 0.010 p = 0.309 10.3 2.4 p = 0.002 p = 0.193 3.3 1.4 p < 0.001 p = 0.631 3.5 1.4 p < 0.001 p = 0.044 9.3 4.7 p = 0.134 p = 0.717 5.1 0.4 p < 0.001
2.4 1.9 p = 0.029 11.8 2.4 p = 0.278 3.5 1.1 p = 0.192 4.2 1.3 p = 0.037 9.7 3.6 p = 0.195 3.2 0.3
In the first row subdomains values at 3 and 6-month follow-up were compared with baseline values with ANOVA test. In the second row comparison between POP and COC group at same months follow-up with unpaired Student t-test. Number of bleeding days were compared between group COC and POP at 3 and 6 months with unpaired t-test, respectively. # Headache intensity was calculated as the 90-day sum of headache severities rated from a four-point scale. For the monthly headache severity, we divided this sum by three.
similar improvement trend was also observed in the continuous COC group (Table 2), but a statistical reduction was seen only in the number of headache days and in days with pain medication (p = 0.029 and p = 0.037, respectively). When we compared the two groups, we found that after 6 months’ therapy, the only statistical difference was a reduction in the number of days with pain medication in the POP group compared to the COC group (p = 0.044) (Table 2). Interestingly, the number of days with use of triptans did not significantly decrease in both groups at three and six months’ follow-up (Table 2). Regarding the quality of life, the baseline values of PCS and MCS were similar for both groups (44.90 4.55 and 43.63 3.96, p = 0.283; and 49.44 6.86 and 49.26 6.85; p = 0.826, for the COC and POP groups, respectively). After 6 months’ treatment a statistical improvement in both components was observed in the POP group (p < 0.001 for both PCS and MCS), while we noticed a trend in overall better PCS and MCS in the COC group but without reaching statistical significance (p = 0.127 and p = 0.478 for PCS and MCS, respectively). In the same way, we found a trend towards a better HRQoL in the POP group with respect to the COC group after 6 months’ treatment but without any statistical differences (p = 0.153 and p = 0.191 for PCS and MCS, respectively, Fig. 1). Interestingly we found four patients with an increase in the number of migraine days (12.9%, 4/31) in the POP group and two patients in the COC group (9.1%, 2/22). More common adverse effects reported were acne 3.2% (1 patient in both groups, 4.5% and 3.2% in the COC and POP groups, respectively), nausea in (2/22, 9.1% in the COC group and 1/31, 3.2% in the POP group), breast pain (2/31, 6.4% in the POP group) and weight gain (1/22, 4.5% and 2/31, 6.4% in the COC and POP groups, respectively). The number of days with bleeding was higher in the POP group compared to the continuous COC group at 6-months’ treatment (5.1 0.4 and 3.2 0.3, p = 0.001).
desogestrel only-pill in the treatment of women with migraine without aura (MO). In this parallel retrospective cohort analysis we confirmed that both treatments are effective in women with MO and the usage of an estrogen-free pill contraceptive resulted in a slightly significant reduction in number of days with medication compared with an extended COC treatment. Decreasing the estrogen withdrawal was the aim of several studies that tried to optimize the hormonal treatment in women with MO. The use of a cyclic versus an extended progestin/ethinyl estradiol patch, the use of a 168-day extended COC regimen or the use of 24 + 4 days COC instead of a 21 + 7 days formulation seemed to reduce the total incidence of headache days compared with a 21/ 7-day regimen [4–7]. The good results obtained in these studies (decrease in migraine pattern when extended cycles were tested) led to the use of this formulation in this population. As shown by two recent epidemiologic studies, however, the risk of deep venous thrombosis and thrombotic stroke is two to six-fold
Comments To our knowledge this is the first study comparing the use of an established therapy (extended hormonal contraception) to a
Fig. 1. Changes in health-related quality of life at baseline and after 6 months of extended COC or POP.
M. Morotti et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 183 (2014) 178–182
more elevated in CHC users compared to non-users, while interestingly no increased risk was found for POP users [12,13]. Surprisingly, although progestins have a lower cardiovascular risk compared to CHC, only a few studies have evaluated these compounds in this high-risk population of patients with MO [21–24] and the use of progestins has not been consistent over time, probably due to the fact that these compounds cause more adverse effects (such as weight gain, mastalgia and irregular menstrual bleeding) than CHCs and that they might be less tolerated by the patients [25]. Over the last two years, renewed interest has been focused on the use of progestins (desogestrel-only pill) in migrainous women. Three pilot studies found that three months’ administration of POP in women with migraine with and without aura had a beneficial effect on the number of migraine attacks, duration of aura and several neurological symptoms as well as an improvement in HRQoL [14–16]. In our retrospective revision of clinical charts, we found that both treatments (continuous hormonal contraception and desogestrel only-pill) are effective in controlling migraine features in women with MO and that the administration of progestin-only contraception led to a significant reduction in the number of days with medication compared to a continuous COC treatment. Convincingly, we found similar results in term of migraine pattern improvements after 3 months’ POP treatment as previously shown by Merki-Feld et al. [15,16] (Table 2) and we confirmed a similar percentage of women experiencing an increase in migraine days under POP treatment (12.9% of women in our study compared to 13.1% shown by Merki-Field et al.) [15]. We also demonstrated that POP therapy improves HRQoL (but with another questionnaire) at 6 months’ treatment, suggesting that even a longer progestin treatment is beneficial and well tolerated in this migrainous subpopulation (Table 2; Fig. 1). We did not, however, find any differences in term of HRQoL changes when comparing the two groups. The small number of the patients and the retrospective nature of the studies might be cause of this result, as a modest trend in favor of better improvements in POP group was seen (Fig. 1). We confirmed that both treatments are effective in controlling migraine patterns: furthermore, we found that the women under POP treatment have a reduced number of days with pain medication compared to continuous CHC treatment (Table 2). We believe that this is an important clinical concern, as often these patients undergo analgesic overuse that might led to clinical consequences and limitation of their quality of life [26]. Thus, as suggested by Nappi et al., we believe that the reduction of pain medication intake during progestin-only contraception is an interesting finding that needs to be further investigated [26]. However, as described by Merki-Feld et al. [15] the use of triptans was not significant modified under the treatment: this may also be due to the low number of triptans users in our study. Strengths of this retrospective analysis include a neurologic expert diagnosis according to accepted diagnostic criteria and the use of a COC including the same progestin used in the POP (desogestrel). However, several weaknesses are present. First, all retrospective studies have selection or information biases. Although the charts were retrospectively reviewed by a prospective file, the patients decided to choose their medications after counseling that might have led to a supposed better perception of one drug respect to the other. Twenty-one patients could not be included in the analysis and therefore these results might not be representative for all women with MO, but only for a subpopulation that tolerated and then continued the treatments. The women were not extensively evaluated for other comorbidities, such as endometriosis, that are common in this subpopulation and this might have led to other confounding biases [27,28]. Finally, the follow-up is short and this
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poses the question of whether the progestins might be tolerated for longer treatment. Recent studies have highlighted new perspectives on the use of progestin in migrainous women [14–16]. The potential role of these compounds and in particular of a desogestrel only pill in migraine pathophysiology is complex. In terms of estrogen withdrawal, the POP with its continuous administration is able to inhibit ovulation. The formulation dosage allows the ovary to synthesize stable amounts of estrogens, which are relevant for wellbeing and bone density, but avoiding an estrogen peak, although some fluctuations may still occur [29,30]. Female reproductive hormones have been associated with neuronal excitability where estrogen acts as an inducer and progesterone as a depressor [31]. Progestins are known to antagonize estrogen actions in the brain by lowering estrogen receptor expression [32,33] and they can also directly act on the electrical trigeminal ganglion modulation by a direct agonism on GABA receptors [34]. Furthermore, CHCs can stimulate the production of vasodilative markers, including 5-hydroxyindole acetic acid, a relevant player in migraine attacks, and this effect is probably attributed to the estrogenic component [35,36]. In conclusion, our preliminary retrospective data indicate that both therapies (POP and extended COC) improve migraine patterns after 6 months’ treatment in a population of women with MO. POP therapy, however, seems to determine a slightly decreased analgesic consumption with respect to women using extended COC therapy. Indeed, as it represents a healthier opportunity, in terms of vascular risk, than CHC contraception, the role of desogestrel-only contraception in migrainous women deserves to be further investigated in prospective randomized clinical trials. Conflict of interest statement None. Condensation Desogestrel-only pills have a beneficial effect on migraine patterns and reduce analgesic consumption compared to standard continuous combined contraception in women with migraine without aura. Acknowledgement We acknowledge Rosa Boracchia for her precious recommendations. References [1] Lj S, Hagen K, Jensen R, et al. The global burden of headache: a documentation of headache prevalence and disability worldwide. Cephalalgia 2007;27: 193–210. [2] Calhoun AH, Hutchinson S. Hormonal therapies for menstrual migraine. Curr Pain Headache Rep 2009;13:381–5. [3] Calhoun A. Combined hormonal contraceptives: is it time to reassess their role in migraine? Headache 2012;52:648–60. [4] LaGuardia KD, Fisher AC, Bainbridge JD, et al. Suppression of estrogen-withdrawal headache with extended transdermal contraception. Fertil Steril 2005;83:1875–7. [5] Sulak P, Willis S, Kuehl T, Coffee A, Clark J. Headaches and oral contraceptives: impact of eliminating the standard 7-day placebo interval. Headache 2007;47:27–37. [6] De Leo V, Scolaro V, Musacchio MC, Di Sabatino A, Morgante G, Cianci A. Combined oral contraceptives in women with menstrual migraine without aura. Fertil Steril 2011;96:917–20. [7] Calhoun A, Ford S, Pruitt A. The impact of extended-cycle vaginal ring contraception on migraine aura: a retrospective case series. Headache 2012;52: 1246–53. [8] Harris M, Kaneshiro B. An evidence-based approach to hormonal contraception and headaches. Contraception 2009;80:417–21.
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European Journal of Obstetrics & Gynecology and Reproductive Biology journal homepage: www.elsevier.com/locate/ejogrb
Progestin-only contraception compared with extended combined oral contraceptive in women with migraine without aura: a retrospective pilot study Matteo Morotti *, Valentino Remorgida, Pier Luigi Venturini, Simone Ferrero Department of Obstetrics and Gynecology, IRCCS Azienda Ospedaliera Universitaria San Martino—IST Istituto Nazionale per la Ricerca sul Cancro, Largo Rosanna Benzi 1, Genoa, Italy
A R T I C L E I N F O
A B S T R A C T
Article history: Received 28 May 2014 Received in revised form 8 October 2014 Accepted 22 October 2014
Objective: To evaluate the effect of a desogestrel progestogen-only pill (POP) compared to continuous combined oral contraception (COC) on migraine patterns in women with migraine without aura. Study design: A retrospective analysis of prospective headache charts from migrainous women who used the POP or COC in our clinic between July 2009 and July 2013. The quality and quantity of migraine attacks and use of medications were evaluated at three and six months. Health related quality of life was evaluated after 6 months’ treatment. Results: Fifty-three patients were evaluable for the analysis (22 in the COC group and 31 in the POP group). Six months’ POP treatment led to a statistical reduction in migraine days; headache days; pain intensity; number of days with severe pain and days with pain medication. The only statistical difference between the two groups was a reduction in the number of days with pain medication in the POP group compared to the COC group (p = 0.044). After 6 months’ treatment a quality of life improvement was seen only in the POP group, but no statistical differences were found when comparing the two groups. Conclusions: Our preliminary data confirm that POP therapy improves migraine patterns and quality of life after 6 months’ treatment in women with migraine without aura and it decreases the analgesic consumption with respect to an extended COC therapy. As POP represents a healthier opportunity, in terms of vascular risk, than combined contraception, its role in migrainous women deserves to be further investigated. ß 2014 Elsevier Ireland Ltd. All rights reserved.
Keywords: Combined oral contraceptive Desogestrel-only pill Headache Migraine without aura Pain Progestins
Introduction Migraine is a common neurological disorder, affecting about 18% of women in US and Europe, and it is more common during the reproductive years [1]. Women of reproductive age often request hormonal contraception for fertility purposes. In addition some of them can suffer gynecological conditions that are comorbid with migraine (such as endometriosis) that can be treated with combined hormonal contraception (CHC). This enhances the likelihood of CHC use in the migrainous population [2,3]. As hormonal fluctuations are thought to likely play a role in migraine pathophysiology, and estrogen withdrawal is probably one of the more important triggers, several studies have tried to optimize hormonal treatment in women with migraine without aura (MO)
* Corresponding author. Tel.: +39 010511525; fax: +39 010511525.. E-mail address: [email protected] (M. Morotti). http://dx.doi.org/10.1016/j.ejogrb.2014.10.029 0301-2115/ß 2014 Elsevier Ireland Ltd. All rights reserved.
who desire hormonal contraception [4–7]. The rationale of these studies was to eliminate or minimize premenstrual estrogen withdrawal and thus maintain steady estrogen levels [8]. Continuous strategies include CHC consumption in extended-cycle regimens, where the placebo week is eliminated for extended periods, often for 12 weeks or more. These strategies also include the use of a continuous vaginal-ring contraceptive or an estradiol patch or combined oral contraceptives (COCs) which contain ethinylestradiol and a synthetic progestin. Sulak et al. reported the efficacy of extended dosing with a 30-mg ethinylestradiol COC in reducing menstrual headache in a 6-month open-label trial [5]. For this reason extended contraception has been widely used in patients with MO desiring hormonal therapy. However, both migraine with aura and MO can increase vascular risk, especially the risk of stroke in younger women [9,10]. This risk may further increase when CHCs are used [11–13]. The cardiovascular risk of CHCs is mainly attributed to the estrogen component, which exerts a strong effect on the coagulation system [12,13].
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Interestingly, recent studies showed that 3-month desogestrel therapy (DSG, 75 mg/day) reduces the number of migraine attacks and improves health-related quality of life (HRQoL) in women suffering migraine with and without aura [14–16]. As progestinonly pill (POP) contraception is a safer alternative to COCs in term of cardiovascular risk and it is preferable in women with cerebrovascular diseases or risk factors for stroke [17] and we noticed frequent improvement in migraine patterns in daily clinical practice in many women treated with desogestrel, we retrospectively analyzed the headache diaries of women with MO who chose POP or continuous COC in our clinic over recent years. Materials and methods The study was performed at the Gynecology subunit of the Department of Obstetrics and Gynecology, San Martino Hospital, University of Genoa, where one of the authors (SF) runs an outpatient clinic for sexual health and contraception. From our electronic prospective database, we retrospectively reviewed all the patients with a diagnosis of MO who were prescribed the desogestrel-only pill or continuous COC from July 2009 to July 2013. The electronic database contains demographic and clinical records of all the patients who attend our clinic, and every dose of every medication administered, and also serves as a repository for laboratory data and other clinical outcome data for audit purposes (adverse effects of the treatment, acceptance of therapy, quality of life during treatment and general feedback). This database is always filled by the specialty registrars attending the clinic. Patients’ charts were subsequently identified by two authors (MM and SF) and then evaluated. Charts were included only for patients with a diagnosis of MO made by a neurologist according to the criteria of the International Headache Society [18] and with at least three monthly headache episodes reported in the pre-treatment period. The exclusion criteria were: previous hormonal therapies in the three months before the start of the therapy and use of other medications known to be effective in migraine prophylaxis (such as beta blockers, antidepressants and anticonvulsants). Patients were evaluated only if they had used one of the following therapies: continuous oral desogestrel 150 mcg and ethinylestradiol 20 mcg (Mercilon1; Schering, formerly NV Organon, Oss, The Netherlands; COC group) or oral desogestrel (75 mcg/day, Cerazette1; Schering-Plough, formerly NV Organon, Oss, The Netherlands; POP group). The treatment was always started on the first day of menstruation. The migrainous patients in our clinic keep headache diaries including information on quantity and quality of migraine patterns, the use of triptans and other pain medication. The following characteristics of migraine are recorded: number of attacks; number of days with severe pain; and intensity of pain (graded on a four point scale, where 0 = no pain; 1 = mild, does not impair daily activities;
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2 = moderate, may inhibit, but does not prohibit daily activities; 3 = severe, prohibits daily activities) [19]. The adverse effects of the two different treatments were extracted from the diaries, in particular the number of days in which the women experienced spotting or vaginal bleeding. Vaginal bleeding was defined as follows: spotting (scanty bleeding not requiring usual sanitary protection), breakthrough bleeding (light or moderate bleeding requiring sanitary protection) and metrorrhagia (more than normal menstruation). The validated language version of the Short Form–36 version 2 (SF36v2) questionnaire, which we routinely administer to all migrainous patients after 6 months’ therapy, was used to measure HRQoL [20]. Results are usually presented as summary measures: the physical health component score (PCS) is the summation of the first four indexes (bodily pain through overall general health), whereas the mental health component score (MCS) includes the last four indexes (from vitality to mental health). The summaries and eight domain scales are adjusted with scores ranging from 0 to 100 (maximum), with higher scores indicating higher levels of functioning or well-being. The University’s Institutional Review Board approved this retrospective database. Statistical analysis Demographic characteristics and symptom variations were compared using a two-sided t-test or the Mann–Whitney U-test according to data distribution and analysis of variance or Kruskal– Wallis test with Dunnett’s multiple comparisons test according to data distribution when comparing three or more categories. Categorical variables were compared by using the chi-squared test or McNemar’s test according to data distribution. p < 0.05 Was considered statistically significant. Data were analyzed using the PRISM software version 6 (GraphPad Software, La Jolla, CA, USA). Results Out of 74 patients treated during the study period, 53 were evaluable for the analysis (22 in the COC group and 31 in the POP group). Twenty-one patients were excluded because of: loss to follow-up (n = 4, two in both groups), incomplete diaries (n = 9; five using POP and four using COC) and withdrawal for adverse effects (n = 8; prolonged bleeding n = 4; three in the POP group and one in the COC group; increase of headache n = 4, two in both groups). The demographic characteristics and baseline data of the patients included and excluded in the study are presented in Table 1. No differences of the considered variables were seen between patients included in the study (Table 1). Interestingly, we found that 6 months’ POP treatment led to a significant reduction in migraine days (p < 0.001); headache days (p = 0.010); pain intensity (p = 0.002), number of days with severe pain (p < 0.001) and days with pain medication (p < 0.001). A
Table 1 Demographic characteristics of patients included and excluded from the study. Patients included
Age (years; mean SD) BMI (kg/m2; mean SD) Smoking cigarettes (number of patients, %) Cigarettes per day (mean SD) Age of migraine onset (years; mean SD) Previous COC users (n; %) Family history of migraine (n, %) Systolic BP (mean SD) Dyastolic BP (mean SD)
p
COC (n = 22)
POP (n = 31)
29.4 3.3 21.1 2.0 6/22 (27.3%) 8.2 3.3 (n = 6) 19.1 3.2 12/22, (54.5%) 5/22 (22.7%) 122.3 8.9 76.6 3.5
30.3 2.9 21.3 2.1 10/31 (32.3%) 9.3 4.8 (n = 10) 20.1 4.4 19/31, (61.3%) 7/31 (22.6%) 124.4 6.9 76.5 5.8
0.285 0.701 0.697 0.618 0.401 0.784 0.999 0.288 0.921
Patients excluded COC (n = 9)
POP (n = 12)
28.9 4.1 21.2 2.3 2/9 (22.2%) 6.5 3.5 (n = 2) 19.9 5.4 4/12, (33.3%) 3/12 (25.0%) 121.8 6.2 76.1 4.4
30.1 3.1 22.3 1.8 4/12 (33.3%) 10.2 4.6 (n = 4) 19.1 4.3 6/12, (50.0%) 5/12 (41.7%) 123.6 8.8 78.7 7.2
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Table 2 Effect of COC or POP use on migraine patterns and pain medication at 3 and 6 months treatment. COC (n = 22) baseline
POP (n = 31) baseline
COC (n = 22) 3 months
POP (n = 31) 3 months
COC (n = 22) 6 months
POP (n = 31) 6 months
Migraine days (mean SD)
5.1 2.2
5.5 2.6 p = 0.534
4.6 2.4 p = 0.454
4.1 2.2 p = 0.284
Headache days (mean SD)
3.1 0.9
3.6 1.5 p = 0.121
2.7 1.8 p = 0.274
Headache intensity/month# (mean SD)
13.8 4.6
14.4 5.4 p = 0.725
12.3 4.7 p = 0.446
Days with headache score 3 (mean SD)
4.6 1.7
4.9 1.9 p = 0.106
4.2 1.7 p = 0.345
Pain medication (mean SD)
5.3 1.7
6.1 1.4 p = 0.083
4.5 1.5 p = 0.145
Triptan use (mean SD)
11.3 3.6
11.4 5.0 p = 0.914
10.5 3.4 p = 0.518
Number of days with bleeding (mean SD)
NA
NA
2.8 0.1
4.2 1.6 p = 0.012 p = 0.414 3.1 1.1 p = 0.222 p = 0.131 11.7 4.9 p = 0.063 p = 0.683 3.7 1.5 p = 0.011 p = 0.798 4.9 1.1 p = 0.001 p = 0.339 9.8 4.5 p = 0.307 p = 0.604 4.6 0.2 p < 0.001
3.5 1.2 p < 0.001 p = 0.218 2.7 1.1 p = 0.010 p = 0.309 10.3 2.4 p = 0.002 p = 0.193 3.3 1.4 p < 0.001 p = 0.631 3.5 1.4 p < 0.001 p = 0.044 9.3 4.7 p = 0.134 p = 0.717 5.1 0.4 p < 0.001
2.4 1.9 p = 0.029 11.8 2.4 p = 0.278 3.5 1.1 p = 0.192 4.2 1.3 p = 0.037 9.7 3.6 p = 0.195 3.2 0.3
In the first row subdomains values at 3 and 6-month follow-up were compared with baseline values with ANOVA test. In the second row comparison between POP and COC group at same months follow-up with unpaired Student t-test. Number of bleeding days were compared between group COC and POP at 3 and 6 months with unpaired t-test, respectively. # Headache intensity was calculated as the 90-day sum of headache severities rated from a four-point scale. For the monthly headache severity, we divided this sum by three.
similar improvement trend was also observed in the continuous COC group (Table 2), but a statistical reduction was seen only in the number of headache days and in days with pain medication (p = 0.029 and p = 0.037, respectively). When we compared the two groups, we found that after 6 months’ therapy, the only statistical difference was a reduction in the number of days with pain medication in the POP group compared to the COC group (p = 0.044) (Table 2). Interestingly, the number of days with use of triptans did not significantly decrease in both groups at three and six months’ follow-up (Table 2). Regarding the quality of life, the baseline values of PCS and MCS were similar for both groups (44.90 4.55 and 43.63 3.96, p = 0.283; and 49.44 6.86 and 49.26 6.85; p = 0.826, for the COC and POP groups, respectively). After 6 months’ treatment a statistical improvement in both components was observed in the POP group (p < 0.001 for both PCS and MCS), while we noticed a trend in overall better PCS and MCS in the COC group but without reaching statistical significance (p = 0.127 and p = 0.478 for PCS and MCS, respectively). In the same way, we found a trend towards a better HRQoL in the POP group with respect to the COC group after 6 months’ treatment but without any statistical differences (p = 0.153 and p = 0.191 for PCS and MCS, respectively, Fig. 1). Interestingly we found four patients with an increase in the number of migraine days (12.9%, 4/31) in the POP group and two patients in the COC group (9.1%, 2/22). More common adverse effects reported were acne 3.2% (1 patient in both groups, 4.5% and 3.2% in the COC and POP groups, respectively), nausea in (2/22, 9.1% in the COC group and 1/31, 3.2% in the POP group), breast pain (2/31, 6.4% in the POP group) and weight gain (1/22, 4.5% and 2/31, 6.4% in the COC and POP groups, respectively). The number of days with bleeding was higher in the POP group compared to the continuous COC group at 6-months’ treatment (5.1 0.4 and 3.2 0.3, p = 0.001).
desogestrel only-pill in the treatment of women with migraine without aura (MO). In this parallel retrospective cohort analysis we confirmed that both treatments are effective in women with MO and the usage of an estrogen-free pill contraceptive resulted in a slightly significant reduction in number of days with medication compared with an extended COC treatment. Decreasing the estrogen withdrawal was the aim of several studies that tried to optimize the hormonal treatment in women with MO. The use of a cyclic versus an extended progestin/ethinyl estradiol patch, the use of a 168-day extended COC regimen or the use of 24 + 4 days COC instead of a 21 + 7 days formulation seemed to reduce the total incidence of headache days compared with a 21/ 7-day regimen [4–7]. The good results obtained in these studies (decrease in migraine pattern when extended cycles were tested) led to the use of this formulation in this population. As shown by two recent epidemiologic studies, however, the risk of deep venous thrombosis and thrombotic stroke is two to six-fold
Comments To our knowledge this is the first study comparing the use of an established therapy (extended hormonal contraception) to a
Fig. 1. Changes in health-related quality of life at baseline and after 6 months of extended COC or POP.
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more elevated in CHC users compared to non-users, while interestingly no increased risk was found for POP users [12,13]. Surprisingly, although progestins have a lower cardiovascular risk compared to CHC, only a few studies have evaluated these compounds in this high-risk population of patients with MO [21–24] and the use of progestins has not been consistent over time, probably due to the fact that these compounds cause more adverse effects (such as weight gain, mastalgia and irregular menstrual bleeding) than CHCs and that they might be less tolerated by the patients [25]. Over the last two years, renewed interest has been focused on the use of progestins (desogestrel-only pill) in migrainous women. Three pilot studies found that three months’ administration of POP in women with migraine with and without aura had a beneficial effect on the number of migraine attacks, duration of aura and several neurological symptoms as well as an improvement in HRQoL [14–16]. In our retrospective revision of clinical charts, we found that both treatments (continuous hormonal contraception and desogestrel only-pill) are effective in controlling migraine features in women with MO and that the administration of progestin-only contraception led to a significant reduction in the number of days with medication compared to a continuous COC treatment. Convincingly, we found similar results in term of migraine pattern improvements after 3 months’ POP treatment as previously shown by Merki-Feld et al. [15,16] (Table 2) and we confirmed a similar percentage of women experiencing an increase in migraine days under POP treatment (12.9% of women in our study compared to 13.1% shown by Merki-Field et al.) [15]. We also demonstrated that POP therapy improves HRQoL (but with another questionnaire) at 6 months’ treatment, suggesting that even a longer progestin treatment is beneficial and well tolerated in this migrainous subpopulation (Table 2; Fig. 1). We did not, however, find any differences in term of HRQoL changes when comparing the two groups. The small number of the patients and the retrospective nature of the studies might be cause of this result, as a modest trend in favor of better improvements in POP group was seen (Fig. 1). We confirmed that both treatments are effective in controlling migraine patterns: furthermore, we found that the women under POP treatment have a reduced number of days with pain medication compared to continuous CHC treatment (Table 2). We believe that this is an important clinical concern, as often these patients undergo analgesic overuse that might led to clinical consequences and limitation of their quality of life [26]. Thus, as suggested by Nappi et al., we believe that the reduction of pain medication intake during progestin-only contraception is an interesting finding that needs to be further investigated [26]. However, as described by Merki-Feld et al. [15] the use of triptans was not significant modified under the treatment: this may also be due to the low number of triptans users in our study. Strengths of this retrospective analysis include a neurologic expert diagnosis according to accepted diagnostic criteria and the use of a COC including the same progestin used in the POP (desogestrel). However, several weaknesses are present. First, all retrospective studies have selection or information biases. Although the charts were retrospectively reviewed by a prospective file, the patients decided to choose their medications after counseling that might have led to a supposed better perception of one drug respect to the other. Twenty-one patients could not be included in the analysis and therefore these results might not be representative for all women with MO, but only for a subpopulation that tolerated and then continued the treatments. The women were not extensively evaluated for other comorbidities, such as endometriosis, that are common in this subpopulation and this might have led to other confounding biases [27,28]. Finally, the follow-up is short and this
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poses the question of whether the progestins might be tolerated for longer treatment. Recent studies have highlighted new perspectives on the use of progestin in migrainous women [14–16]. The potential role of these compounds and in particular of a desogestrel only pill in migraine pathophysiology is complex. In terms of estrogen withdrawal, the POP with its continuous administration is able to inhibit ovulation. The formulation dosage allows the ovary to synthesize stable amounts of estrogens, which are relevant for wellbeing and bone density, but avoiding an estrogen peak, although some fluctuations may still occur [29,30]. Female reproductive hormones have been associated with neuronal excitability where estrogen acts as an inducer and progesterone as a depressor [31]. Progestins are known to antagonize estrogen actions in the brain by lowering estrogen receptor expression [32,33] and they can also directly act on the electrical trigeminal ganglion modulation by a direct agonism on GABA receptors [34]. Furthermore, CHCs can stimulate the production of vasodilative markers, including 5-hydroxyindole acetic acid, a relevant player in migraine attacks, and this effect is probably attributed to the estrogenic component [35,36]. In conclusion, our preliminary retrospective data indicate that both therapies (POP and extended COC) improve migraine patterns after 6 months’ treatment in a population of women with MO. POP therapy, however, seems to determine a slightly decreased analgesic consumption with respect to women using extended COC therapy. Indeed, as it represents a healthier opportunity, in terms of vascular risk, than CHC contraception, the role of desogestrel-only contraception in migrainous women deserves to be further investigated in prospective randomized clinical trials. Conflict of interest statement None. Condensation Desogestrel-only pills have a beneficial effect on migraine patterns and reduce analgesic consumption compared to standard continuous combined contraception in women with migraine without aura. Acknowledgement We acknowledge Rosa Boracchia for her precious recommendations. References [1] Lj S, Hagen K, Jensen R, et al. The global burden of headache: a documentation of headache prevalence and disability worldwide. Cephalalgia 2007;27: 193–210. [2] Calhoun AH, Hutchinson S. Hormonal therapies for menstrual migraine. Curr Pain Headache Rep 2009;13:381–5. [3] Calhoun A. Combined hormonal contraceptives: is it time to reassess their role in migraine? Headache 2012;52:648–60. [4] LaGuardia KD, Fisher AC, Bainbridge JD, et al. Suppression of estrogen-withdrawal headache with extended transdermal contraception. Fertil Steril 2005;83:1875–7. [5] Sulak P, Willis S, Kuehl T, Coffee A, Clark J. Headaches and oral contraceptives: impact of eliminating the standard 7-day placebo interval. Headache 2007;47:27–37. [6] De Leo V, Scolaro V, Musacchio MC, Di Sabatino A, Morgante G, Cianci A. Combined oral contraceptives in women with menstrual migraine without aura. Fertil Steril 2011;96:917–20. [7] Calhoun A, Ford S, Pruitt A. The impact of extended-cycle vaginal ring contraception on migraine aura: a retrospective case series. Headache 2012;52: 1246–53. [8] Harris M, Kaneshiro B. An evidence-based approach to hormonal contraception and headaches. Contraception 2009;80:417–21.
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