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A crossover study comparing gabapentin and fluoxetine for the treatment of vasomotor symptoms among postmenopausal women
IJG-08400; No of Pages 4 International Journal of Gynecology and Obstetrics xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
International Journal of Gynecology and Obstetrics journal homepage: www.elsevier.com/locate/ijgo
CLINICAL ARTICLE
A crossover study comparing gabapentin and fluoxetine for the treatment of vasomotor symptoms among postmenopausal women Mojgan Rahmanian a, Arash Mohseni a, Raheb Ghorbani b,⁎ a b
Research Center of Abnormal Uterine Bleeding, Semnan University of Medical Sciences, Semnan, Iran Research Center for Social Determinants of Health, Department of Community Medicine, Faculty of Medicine, Semnan University of Medical Sciences, Semnan, Iran
a r t i c l e
i n f o
Article history: Received 29 November 2014 Received in revised form 31 March 2015 Accepted 18 June 2015 Keywords: Fluoxetine Gabapentin Hot flash Night sweats Vasomotor symptoms
a b s t r a c t Objective: To compare the effectiveness of fluoxetine and gabapentin for treatment of vasomotor symptoms (VMS) after the menopause. Methods: Between March 2011 and March 2012, a randomized crossover study was performed at a center in Semnan, Iran, among postmenopausal women aged 45–57 years with hot flashes (≥ 2 per day for previous 4 months) for which they had received no previous treatment. Participants were divided into two groups with consecutive numbers assigned in order of recruitment. In the first treatment round (4 weeks), group A received 20 mg/day fluoxetine and group B received 300 mg/day gabapentin. After a 2-week washout period, group A received gabapentin and group B received fluoxetine in a second round (4 weeks). Information about VMS was obtained with the Greene Climacteric Scale questionnaire. Participants and all investigators except one were masked to group assignment. Results: Data for 79 participants (39 in group A, 40 in group B) were analyzed. In both treatment rounds, gabapentin caused greater reductions in the severity of hot flashes than did fluoxetine (P b 0.001 for both). After the first round of treatment, those who had received gabapentin reported greater reductions in the severity of night sweats (P b 0.001). Conclusion: Gabapentin at a dose of 300 mg/day is more effective for treatment of VMS among postmenopausal women than is 20 mg/day fluoxetine. Iranian Registry of Clinical Trials: IRCT2014092711019N3. © 2015 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.
1. Introduction Menopause is the permanent cessation of a woman's menstrual cycle. Despite the increasing life expectancy worldwide, the average age at menopause has remained at approximately 51 years [1]. Considering that the average life expectancy of US women is 81 years [2], they are postmenopausal for more than one-third of their lives [1]. The main consequence of menopause is a reduced estrogen level [1], which in turn causes a wide range of symptoms. The most prevalent of these symptoms are vasomotor symptoms (VMS) [1,3,4], such as hot flashes and night sweats [4,5]. The underlying physiological mechanisms of hot flashes are not well understood. However, it is speculated that a central process initiates in the hypothalamus due to increased central body temperature, metabolism, and skin temperature, which leads to peripheral vasodilation and sweating in some women [1]. Over 65% of menopausal women report some type of VMS [3,4,6]. VMS usually diminish within the first year after the menopause; ⁎ Corresponding author at: Research Center for Social Determinants of Health, Department of Community Medicine, Faculty of Medicine, Semnan University of Medical Sciences, Semnan 35198–9951, Iran. Tel.: +98 23 33654367; fax: +98 23 33654209. E-mail addresses: [email protected], [email protected] (R. Ghorbani).
however, in some women these symptoms last for over 30 years [7]. VMS can interfere with a woman’s work and activities of daily living [2], negatively affecting the quality of her life [6]. Estrogen-replacement therapy is the most effective treatment for VMS among postmenopausal women [1]. It is also the only common method of treatment approved by the US Food and Drug Administration [1,3,5]. Estrogen has been used as a hormonal supplement for treatment of menopausal symptoms for over 60 years [8]. However, recent studies have revealed multiple adverse effects of prolonged estrogen therapy, including cardiovascular events and cancers [5,9], and therefore many women are reluctant to use such treatment. Additionally, estrogen therapy is contraindicated for the treatment of VMS among women with estrogensensitive tumors, chronic liver dysfunction, acute thrombosis (with or without embolism), and vascular diseases of visual nervous system [6]. Other hormones, and non-hormonal and non-medical treatments have been considered for VMS among postmenopausal women. Gabapentin is an antiseizure medication that reduces VMS [10,11]. Fluoxetine has also been reported to reduce the symptoms of hot flashes when used for treatment of depression [12]. Although it is not clear how fluoxetine works, it is assumed to work centrally through changes in dopamine, serotonin, or norepinephrine pathways, rather than through changes in hormonal (e.g. estrogen, progesterone, or androgen) pathways [13].
http://dx.doi.org/10.1016/j.ijgo.2015.04.042 0020-7292/© 2015 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.
Please cite this article as: Rahmanian M, et al, A crossover study comparing gabapentin and fluoxetine for the treatment of vasomotor symptoms among postmenopausal women, Int J Gynecol Obstet (2015), http://dx.doi.org/10.1016/j.ijgo.2015.04.042
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M. Rahmanian et al. / International Journal of Gynecology and Obstetrics xxx (2015) xxx–xxx
However, previous studies conducted to examine the effectiveness of these drugs for treatment of VMS among postmenopausal women have used varying doses of fluoxetine (10–40 mg/day [14–17]) and gabapentin (100–2700 mg/day [18–20]). Furthermore, the effectiveness of gabapentin and fluoxetine and their adverse effects do not seem to have been directly compared. Therefore, the purpose of the present study was to compare the effectiveness of fluoxetine (20 mg/day) and gabapentin (300 mg/day) in reducing VMS among postmenopausal women. The adverse effects were also monitored and compared. 2. Methods Women aged 45–57 years who visited the Amir-al-Momenin University Hospital in Semnan, Iran, between March 21, 2011, and March 19, 2012, complaining of hot flashes were enrolled in a randomized crossover study. Women were eligible when their last menstrual cycle was at least 1 year previously, they reported at least two hot flashes per day for the previous 4 months, and they had not previously received any treatment for hot flashes. Women taking multivitamins, blood thinners (e.g. warfarin), or other antidepressants were excluded, as were those undergoing chemotherapy. Women with thyroid disorders, hemophilia, autoimmune disorders, diabetes, hypertension, or rheumatic heart disease were also excluded. All participants were informed about the experimental procedure and the potential adverse effects of the medications used in the study before signing a consent form. All procedures were approved by the Office of Research Ethics of Semnan Medical Science University. Each participant was assigned a number in order of recruitment. Participants with an odd number formed group A, and those with an even number formed group B. Both groups received two rounds of treatment (4 weeks each) with a 2-week washout period in between. In the first round of treatment, group A received 20 mg/day fluoxetine (Abidi Pharmaceutical Company, Tehran, Iran) while group B received 300 mg/day gabapentin (Razak Pharmaceutical Company, Tehran, Iran). In the second round of treatment, group A received 300 mg/day gabapentin while group B received 20 mg/day fluoxetine. Participants were masked to group assignment throughout the study; all drugs were provided in unlabeled containers. Among the investigators, only one (M.R.) was not masked to group assignment. Participants were asked to complete items 19 and 20 of the Greene Climacteric Scale questionnaire (vasomotor symptoms) [21] before the first round of treatment, on completion of the first round, and on completion of the second round. Items 19 and 20 relate to hot flashes and sweating at night, which are the symptoms of interest in the present study. The severity of these symptoms was rated by participants using a four-point rating scale. The instructions were: “Please indicate the extent to which you are bothered at the moment by each of these symptoms by placing a tick in the appropriate box.” They could answer “Not at all,” “A little,” “Quite a bit,” and “Extremely.” A trained research assistant (A.M.), masked to group assignment, helped the participants to fill out the questionnaire. The instructions were given in Farsi and an example was provided to ensure participants understood the instructions correctly. Before each round of treatment, participants were provided with a list of potential adverse effects of gabapentin and fluoxetine (e.g. tremor, loss of appetite, sleepiness, dizziness, headache, fatigue, gastrointestinal disturbances, dry mouth and ataxia). Participants were given a diary and asked to record whether they experienced any of these adverse effects during the course of the study, when they occurred, and for how long. They were also instructed to contact the primary researcher (M.R.) if they experienced any severe adverse effect, and the plan was to discontinue the medication in such cases. The checklists and the diaries were collected at the end of each round of treatment. Additionally, participants’ age, years since menopause, weight, height, and body mass index (BMI; calculated as weight in kilograms divided by the square of height in meters) were recorded.
Statistical analyses were performed using the Kolmogorov–Smirnov test, t test, Mann–Whitney test, paired t test, and Wilcoxon test. SPSS version 18.0 (SPSS Inc, Chicago, IL, USA) was used for statistical analyses. P b 0.05 was considered statistically significant. 3. Results A total of 80 women were enrolled (Fig. 1). One participant assigned to group A failed to comply with the instructions regarding use of the medications; her data were excluded from the analysis. Therefore, data from 79 participants—39 in group A and 40 in group B—were used for the analysis. None of the participants had severe adverse effects that led to discontinuation of their treatment. There was no significant difference between the two groups in age, BMI, mean age at menopause, and time since menopause (Table 1). Before the first round of treatment, there was no significant difference between the two groups in the severity of hot flashes (P = 0.210) or night sweats (P = 0.816) (Table 2). Both fluoxetine and gabapentin significantly reduced the severity of hot flashes for both groups: compared with baseline measures, fluoxetine reduced the severity of hot flashes in group A by 23% (P = 0.011) and in group B by 20% (P b 0.001), and gabapentin reduced the severity of hot flashes in group A by 55% (P b 0.001) and in group B by 68% (P b 0.001). At the end of the first round of treatment, group B (who had received gabapentin) had a lower score for the severity of hot flashes than did group A (who had received fluoxetine; P b 0.001) (Table 2). At the end of the second round of treatment, group A (who had then received gabapentin) reported significantly less severe hot flashes than did group B (who had then received fluoxetine; P b 0.001) (Table 2). Both drugs significantly reduced the severity of night sweats for both groups: compared with baseline measures, fluoxetine reduced the severity of night sweats in group A by 18% (P = 0.001) and in group B by 41% (P b 0.001); and gabapentin reduced the severity of night sweats in group A by 56% (P b 0.001) and in group B by 62% (P b 0.001). At the end of the first round of treatment, group B (who had received gabapentin) had a significantly lower score for the severity of night sweats than did group A (who had received fluoxetine; P b 0.001) (Table 2). However, the scores for the severity of night sweats did not differ significantly at the end of the second round of treatment (P = 0.071) (Table 2). Adverse effects were rare for both groups. Tremors were the only adverse effects reported while patients were taking gabapentin, and only 4 (5%) participants (two from each group) were affected. Lack of appetite was the only adverse effect reported for fluoxetine, and only 3 (4%) participants (one from group A and two from group B) were affected. 4. Discussion In the present study, both fluoxetine and gabapentin reduced the severity of VMS among postmenopausal women. However, participants who received 300 mg/day gabapentin had a greater reduction in their VMS than did those who received 20 mg/day fluoxetine. Gabapentin has been previously shown to effectively reduce hot flashes when compared with placebo. In a clinical experiment, Butt et al. [11] showed that 300 mg gabapentin three times per day (i.e. 900 mg/day) for 4 weeks significantly reduced the frequency of hot flashes. Similarly, Saati et al. [19] showed that 300 mg gabapentin three times per day for 3 months decreased the severity, frequency, and duration of hot flashes in menopausal women. In a systematic review of seven randomized controlled trials, Toulis et al. [22] showed that gabapentin (900–2400 mg/day) reduced the severity and frequency of hot flashes by 20%–30% among women with natural or tamoxifeninduced menopause. Reddy et al. [10] showed that 2400 mg/day gabapentin for 12 weeks was as effective as 0.625 mg/day conjugated estrogen for treatment of hot flashes in postmenopausal women. Similarly, Allameh et al. [20]
Please cite this article as: Rahmanian M, et al, A crossover study comparing gabapentin and fluoxetine for the treatment of vasomotor symptoms among postmenopausal women, Int J Gynecol Obstet (2015), http://dx.doi.org/10.1016/j.ijgo.2015.04.042
M. Rahmanian et al. / International Journal of Gynecology and Obstetrics xxx (2015) xxx–xxx
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Assessed for eligibility (n=96) Excluded (n=16) Enrolled (n=80)
Group A (n=40)
Group B (n=40)
Received fluoxetine (n=40)
Received gabapentin (n=40)
Excluded (irregular drug intake; n=1) Received gabapentin (n=39)
Received fluoxetine (n=40)
Analyzed (n=39)
Analyzed (n=40)
Fig. 1. Flow of participants through the study.
showed that the reduction in frequency and severity of hot flashes did not differ between women who received 300 mg/day gabapentin and those who received 0.625 mg/day conjugated estrogen for 12 weeks. Biglia et al. [23] showed that 900 mg/day gabapentin reduced hot flashes and improved the patients’ quality of sleep more effectively than did vitamin E. In terms of what dose of gabapentin is most effective, Pandya et al. [18] examined the effect of different doses on hot flashes among women with breast cancer. After 8 weeks, patients who had been receiving 900 mg/day reported significant reductions in the severity of hot flushes, but 300 mg/day had no significant effect. Additionally, Allameh
Table 1 Baseline characteristics.a Characteristic
Group A (n = 39)b
Group B (n = 40)c
P value
Age, y Body mass indexd Age at menopause, y Time since menopause, y
51.7 ± 2.5 27.5 ± 3.6 49.3 ± 2.6 2.4 ± 1.7
51.1 ± 2.4 26.8 ± 3.0 49.2 ± 2.1 2.0 ± 1.2
0.307 0.383 0.527 0.287
a
Values are given as mean ± SD unless indicated otherwise. 20 mg/day fluoxetine in the first round of treatment and 300 mg/day gabapentin in the second round. c 300 mg/day gabapentin in the first round of treatment and 20 mg/day fluoxetine in the second round. d Calculated as weight in kilograms divided by the square of height in meters. b
et al. [20] showed that 100 mg/day gabapentin was less effective than were 300 mg/day gabapentin or 0.625 mg/day conjugated estrogen [20]. In the systematic review by Toulis et al. [22], dizziness, unsteadiness, fatigue, and drowsiness were the most commonly reported adverse effects of gabapentin. These symptoms resulted in a higher dropout rate among patients who received gabapentin than among controls [22]. However, the only adverse effects of gabapentin reported in the present study were tremors, which affected only four participants. The difference in the frequency of adverse effects with gabapentin between the present and previous studies could be attributable to the different doses used. In the studies reviewed by Toulis et al. [22], the minimum dose of gabapentin was 900 mg/day, which is three times higher than the dose used in the present study (300 mg/day). The lower dose of gabapentin used in the present study could have been sufficient to control the VMS associated with the menopause without causing multiple adverse effects. However, in another previous study [20], 8% of patients who received gabapentin (100 mg/day or 300 mg/day) reported gastrointestinal disturbances. Although it is not clear what caused this difference in findings, variation in the daily diet of participants in the two studies might have contributed to the presence or absence of gastrointestinal adverse effects. Fundamental differences in dietary habits of people from various regions might impact how their gastrointestinal system responds to certain medications. The effect of fluoxetine on VMS associated with the menopause has also been studied by many researchers. In a placebo-controlled double-
Table 2 Severity of hot flashes and night sweats before and after intervention.a,b Symptom
Hot flashes Night sweats a b c d
Before treatment
End of 1st round of treatment
End of 2nd round of treatment
Group A (n = 39)c
Group B (n = 40)d
P value
Group A (n = 39)c
Group B (n = 40)d
P value
Group A (n = 39)c
Group B (n = 40)d
P value
1.68 ± 0.73 1.70 ± 0.76
1.85 ± 0.80 1.73 ± 0.91
0.210 0.816
1.30 ± 0.91 1.40 ± 0.90
0.60 ± 0.93 0.65 ± 0.70
b0.001 b0.001
0.75 ± 1.06 0.75 ± 0.78
1.48 ± 0.85 1.02 ± 0.92
b0.001 0.071
Values are given as mean score ± SD unless indicated otherwise. Scores ranged from 0 (not feeling the symptom at all) to 3 (feeling the symptom very severely). 20 mg/day fluoxetine in the first round of treatment and 300 mg/day gabapentin in the second round. 300 mg/day gabapentin in the first round of treatment and 20 mg/day fluoxetine in the second round.
Please cite this article as: Rahmanian M, et al, A crossover study comparing gabapentin and fluoxetine for the treatment of vasomotor symptoms among postmenopausal women, Int J Gynecol Obstet (2015), http://dx.doi.org/10.1016/j.ijgo.2015.04.042
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M. Rahmanian et al. / International Journal of Gynecology and Obstetrics xxx (2015) xxx–xxx
blind clinical study, Suvanto-Luukkonen et al. [17] examined the effectiveness of fluoxetine among postmenopausal women. They concluded that fluoxetine should not be used for postmenopausal women with VMS, because its effect did not differ from that of placebo after 9 months. However, 20 mg/day fluoxetine significantly reduced the severity of hot flashes among postmenopausal women when compared with placebo in two previous crossover studies [13,15]. Additionally, other studies have shown that 20 mg/day fluoxetine led to a positive clinical response more often than did placebo [14,16]. Lack of appetite was the only adverse effect of fluoxetine in the present study, and it was reported by only three participants. In a previous study [16] 14.8% of participants in the experimental group complained of different degrees of dry mouth, nausea, lack of appetite, or dizziness. However, the exact percentages of participants with each of these symptoms were not reported, making a comparison with the present study difficult. In the present study, participants received 4 weeks of treatment with each drug, with a 2-week washout period between the treatments. A 4-week treatment period has been used in previous studies examining the effectiveness of gabapentin [11,24,25] or fluoxetine [13,15,16] for treatment of hot flashes. Furthermore, Loprinzi et al. [13] showed that, among women receiving 20 mg/day fluoxetine for the treatment of hot flashes, the greatest effect was observed during the third week of treatment; after the third week, the effect reached a plateau. There is no evidence showing that using fluoxetine for a longer period will further decrease the severity of hot flashes. Additionally, previous studies have considered a 2-week washout period for gabapentin [25] and a washout period of 1 week or even less for fluoxetine [13,15]. Therefore, the 2-week washout period practiced in the present study is certainly long enough to allow the blood concentration of both medications return to their levels before the medical intervention. One of the limitations of the present study is that it was not doubleblinded. Furthermore, there was no follow-up period to allow comparison of the lasting effects of the two medications. In conclusion, 300 mg/day gabapentin seems to be a more effective approach for treatment of hot flashes and night sweats among postmenopausal women than is 20 mg/day fluoxetine. Gabapentin could be used for the treatment of VMS in postmenopausal women with contraindications to hormonal therapy or those who prefer alternatives to hormonal therapy. Future studies should investigate the lowest effective dose of gabapentin to minimize its adverse effects. Acknowledgments The Deputy Director of Research and Technology, Semnan University of Medical Sciences provided financial support. Conflict of interest The authors have no conflicts of interest.
[2] Arias E. United States life tables, 2010. Natl Vital Stat Rep 2014;63(7):1–63. [3] Pachman DR, Jones JM, Loprinzi CL. Management of menopause-associated vasomotor symptoms: Current treatment options, challenges and future directions. Int J Womens Health 2010;2:123–35. [4] Umland EM. Treatment strategies for reducing the burden of menopause-associated vasomotor symptoms. J Manag Care Pharm 2008;14(3 Suppl):14–9. [5] Utian WH, Archer DF, Bachmann GA, Gallagher C, Grodstein F, Heiman JR, et al. Estrogen and progestogen use in postmenopausal women: July 2008 position statement of The North American Menopause Society. Menopause 2008;15(4 Pt 1): 584–602. [6] Fritz MA, Speroff L. Clinical Gynecologic Endocrinology and Infertility. 8th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2011. [7] Kronenberg F. Hot flashes: epidemiology and physiology. Ann N Y Acad Sci 1990; 592:52–86. [8] Nelson HD, Vesco KK, Haney E, Fu R, Nedrow A, Miller J, et al. Nonhormonal therapies for menopausal hot flashes: systematic review and meta-analysis. JAMA 2006;295(17):2057–71. [9] Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg C, Stefanick ML, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women's Health Initiative randomized controlled trial. JAMA 2002;288(3):321–33. [10] Reddy SY, Warner H, Guttuso Jr T, Messing S, DiGrazio W, Thornburg L, et al. Gabapentin, estrogen, and placebo for treating hot flushes: a randomized controlled trial. Obstet Gynecol 2006;108(1):41–8. [11] Butt DA, Lock M, Lewis JE, Ross S, Moineddin R. Gabapentin for the treatment of menopausal hot flashes: a randomized controlled trial. Menopause 2008;15(2): 310–8. [12] Crundwell JK. Fluoxetine and suicidal ideation—a review of the literature. Int J Neurosci 1993;68(1–2):73–84. [13] Loprinzi CL, Sloan JA, Perez EA, Quella SK, Stella PJ, Mailliard JA, et al. Phase III evaluation of fluoxetine for treatment of hot flashes. J Clin Oncol 2002;20(6):1578–83. [14] Ghomian N, Tavasoli F, Lotfalizadeh M. Comparison of fluoxetine with a placebo in treating postmenopausal hot flash. J Birjand Univ Med Sci 2009;15(4):5–11. [15] Yazdizadeh V, Kazemnejad A, Modares Gilani M. The effect of fluoxetin on hot flashes in menopaused women. Daneshvar 2009;16(81):23–8. [16] Sakhavat L, Karimzadeh-Maibodi MA. Evaluation of fluoxetine for treatment of menopausal hot flashes. JSSU 2004;12(3):30–4. [17] Suvanto-Luukkonen E, Koivunen R, Sundström H, Bloigu R, Karjalainen E, Häivä-Mällinen L, et al. Citalopram and fluoxetine in the treatment of postmenopausal symptoms: a prospective, randomized, 9-month, placebo-controlled, double-blind study. Menopause 2005;12(1):18–26. [18] Pandya KJ, Morrow GR, Roscoe JA, Zhao H, Hickok JT, Pajon E, et al. Gabapentin for hot flashes in 420 women with breast cancer: a randomised double-blind placebocontrolled trial. Lancet 2005;366(9488):818–24. [19] Saadati N, Mohammadjafari R, Natanj S, Abedi P. The effect of gabapentin on intensity and duration of hot flashes in postmenopausal women: a randomized controlled trial. Glob J Health Sci 2013;5(6):126–30. [20] Allameh Z, Rouholamin S, Valaie S. Comparison of gabapentin with estrogen for treatment of hot flashes in post-menopausal women. J Res Pharm Pract 2013; 2(2):64–9. [21] Greene JG. Constructing a standard climacteric scale. Maturitas 2008;61(1–2): 78–84. [22] Toulis KA, Tzellos T, Kouvelas D, Goulis DG. Gabapentin for the treatment of hot flashes in women with natural or tamoxifen-induced menopause: a systematic review and meta-analysis. Clin Ther 2009;31(2):221–35. [23] Biglia N, Sgandurra P, Peano E, Marenco D, Moggio G, Bounous V, et al. Non-hormonal treatment of hot flushes in breast cancer survivors: gabapentin vs. vitamin E. Climacteric 2009;12(4):310–8. [24] Pandya KJ, Thummala AR, Griggs JJ, Rosenblatt JD, Sahasrabudhe DM, Guttuso TJ, et al. Pilot study using gabapentin for tamoxifen-induced hot flashes in women with breast cancer. Breast Cancer Res Treat 2004;83(1):87–9. [25] Bordeleau L, Pritchard KI, Loprinzi CL, Ennis M, Jugovic O, Warr D, et al. Multicenter, randomized, cross-over clinical trial of venlafaxine versus gabapentin for the management of hot flashes in breast cancer survivors. J Clin Oncol 2010;28(35): 5147–52.
References [1] Shifren JL, Schiff I. Menopause. In: Berek JS, Berek DL, editors. Berek & Novak's Gynecology. 15th Edn. Philadelphia, PA: Lippincott Williams & Wilkins; 2012. p. 1233–47.
Please cite this article as: Rahmanian M, et al, A crossover study comparing gabapentin and fluoxetine for the treatment of vasomotor symptoms among postmenopausal women, Int J Gynecol Obstet (2015), http://dx.doi.org/10.1016/j.ijgo.2015.04.042
Contents lists available at ScienceDirect
International Journal of Gynecology and Obstetrics journal homepage: www.elsevier.com/locate/ijgo
CLINICAL ARTICLE
A crossover study comparing gabapentin and fluoxetine for the treatment of vasomotor symptoms among postmenopausal women Mojgan Rahmanian a, Arash Mohseni a, Raheb Ghorbani b,⁎ a b
Research Center of Abnormal Uterine Bleeding, Semnan University of Medical Sciences, Semnan, Iran Research Center for Social Determinants of Health, Department of Community Medicine, Faculty of Medicine, Semnan University of Medical Sciences, Semnan, Iran
a r t i c l e
i n f o
Article history: Received 29 November 2014 Received in revised form 31 March 2015 Accepted 18 June 2015 Keywords: Fluoxetine Gabapentin Hot flash Night sweats Vasomotor symptoms
a b s t r a c t Objective: To compare the effectiveness of fluoxetine and gabapentin for treatment of vasomotor symptoms (VMS) after the menopause. Methods: Between March 2011 and March 2012, a randomized crossover study was performed at a center in Semnan, Iran, among postmenopausal women aged 45–57 years with hot flashes (≥ 2 per day for previous 4 months) for which they had received no previous treatment. Participants were divided into two groups with consecutive numbers assigned in order of recruitment. In the first treatment round (4 weeks), group A received 20 mg/day fluoxetine and group B received 300 mg/day gabapentin. After a 2-week washout period, group A received gabapentin and group B received fluoxetine in a second round (4 weeks). Information about VMS was obtained with the Greene Climacteric Scale questionnaire. Participants and all investigators except one were masked to group assignment. Results: Data for 79 participants (39 in group A, 40 in group B) were analyzed. In both treatment rounds, gabapentin caused greater reductions in the severity of hot flashes than did fluoxetine (P b 0.001 for both). After the first round of treatment, those who had received gabapentin reported greater reductions in the severity of night sweats (P b 0.001). Conclusion: Gabapentin at a dose of 300 mg/day is more effective for treatment of VMS among postmenopausal women than is 20 mg/day fluoxetine. Iranian Registry of Clinical Trials: IRCT2014092711019N3. © 2015 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.
1. Introduction Menopause is the permanent cessation of a woman's menstrual cycle. Despite the increasing life expectancy worldwide, the average age at menopause has remained at approximately 51 years [1]. Considering that the average life expectancy of US women is 81 years [2], they are postmenopausal for more than one-third of their lives [1]. The main consequence of menopause is a reduced estrogen level [1], which in turn causes a wide range of symptoms. The most prevalent of these symptoms are vasomotor symptoms (VMS) [1,3,4], such as hot flashes and night sweats [4,5]. The underlying physiological mechanisms of hot flashes are not well understood. However, it is speculated that a central process initiates in the hypothalamus due to increased central body temperature, metabolism, and skin temperature, which leads to peripheral vasodilation and sweating in some women [1]. Over 65% of menopausal women report some type of VMS [3,4,6]. VMS usually diminish within the first year after the menopause; ⁎ Corresponding author at: Research Center for Social Determinants of Health, Department of Community Medicine, Faculty of Medicine, Semnan University of Medical Sciences, Semnan 35198–9951, Iran. Tel.: +98 23 33654367; fax: +98 23 33654209. E-mail addresses: [email protected], [email protected] (R. Ghorbani).
however, in some women these symptoms last for over 30 years [7]. VMS can interfere with a woman’s work and activities of daily living [2], negatively affecting the quality of her life [6]. Estrogen-replacement therapy is the most effective treatment for VMS among postmenopausal women [1]. It is also the only common method of treatment approved by the US Food and Drug Administration [1,3,5]. Estrogen has been used as a hormonal supplement for treatment of menopausal symptoms for over 60 years [8]. However, recent studies have revealed multiple adverse effects of prolonged estrogen therapy, including cardiovascular events and cancers [5,9], and therefore many women are reluctant to use such treatment. Additionally, estrogen therapy is contraindicated for the treatment of VMS among women with estrogensensitive tumors, chronic liver dysfunction, acute thrombosis (with or without embolism), and vascular diseases of visual nervous system [6]. Other hormones, and non-hormonal and non-medical treatments have been considered for VMS among postmenopausal women. Gabapentin is an antiseizure medication that reduces VMS [10,11]. Fluoxetine has also been reported to reduce the symptoms of hot flashes when used for treatment of depression [12]. Although it is not clear how fluoxetine works, it is assumed to work centrally through changes in dopamine, serotonin, or norepinephrine pathways, rather than through changes in hormonal (e.g. estrogen, progesterone, or androgen) pathways [13].
http://dx.doi.org/10.1016/j.ijgo.2015.04.042 0020-7292/© 2015 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.
Please cite this article as: Rahmanian M, et al, A crossover study comparing gabapentin and fluoxetine for the treatment of vasomotor symptoms among postmenopausal women, Int J Gynecol Obstet (2015), http://dx.doi.org/10.1016/j.ijgo.2015.04.042
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M. Rahmanian et al. / International Journal of Gynecology and Obstetrics xxx (2015) xxx–xxx
However, previous studies conducted to examine the effectiveness of these drugs for treatment of VMS among postmenopausal women have used varying doses of fluoxetine (10–40 mg/day [14–17]) and gabapentin (100–2700 mg/day [18–20]). Furthermore, the effectiveness of gabapentin and fluoxetine and their adverse effects do not seem to have been directly compared. Therefore, the purpose of the present study was to compare the effectiveness of fluoxetine (20 mg/day) and gabapentin (300 mg/day) in reducing VMS among postmenopausal women. The adverse effects were also monitored and compared. 2. Methods Women aged 45–57 years who visited the Amir-al-Momenin University Hospital in Semnan, Iran, between March 21, 2011, and March 19, 2012, complaining of hot flashes were enrolled in a randomized crossover study. Women were eligible when their last menstrual cycle was at least 1 year previously, they reported at least two hot flashes per day for the previous 4 months, and they had not previously received any treatment for hot flashes. Women taking multivitamins, blood thinners (e.g. warfarin), or other antidepressants were excluded, as were those undergoing chemotherapy. Women with thyroid disorders, hemophilia, autoimmune disorders, diabetes, hypertension, or rheumatic heart disease were also excluded. All participants were informed about the experimental procedure and the potential adverse effects of the medications used in the study before signing a consent form. All procedures were approved by the Office of Research Ethics of Semnan Medical Science University. Each participant was assigned a number in order of recruitment. Participants with an odd number formed group A, and those with an even number formed group B. Both groups received two rounds of treatment (4 weeks each) with a 2-week washout period in between. In the first round of treatment, group A received 20 mg/day fluoxetine (Abidi Pharmaceutical Company, Tehran, Iran) while group B received 300 mg/day gabapentin (Razak Pharmaceutical Company, Tehran, Iran). In the second round of treatment, group A received 300 mg/day gabapentin while group B received 20 mg/day fluoxetine. Participants were masked to group assignment throughout the study; all drugs were provided in unlabeled containers. Among the investigators, only one (M.R.) was not masked to group assignment. Participants were asked to complete items 19 and 20 of the Greene Climacteric Scale questionnaire (vasomotor symptoms) [21] before the first round of treatment, on completion of the first round, and on completion of the second round. Items 19 and 20 relate to hot flashes and sweating at night, which are the symptoms of interest in the present study. The severity of these symptoms was rated by participants using a four-point rating scale. The instructions were: “Please indicate the extent to which you are bothered at the moment by each of these symptoms by placing a tick in the appropriate box.” They could answer “Not at all,” “A little,” “Quite a bit,” and “Extremely.” A trained research assistant (A.M.), masked to group assignment, helped the participants to fill out the questionnaire. The instructions were given in Farsi and an example was provided to ensure participants understood the instructions correctly. Before each round of treatment, participants were provided with a list of potential adverse effects of gabapentin and fluoxetine (e.g. tremor, loss of appetite, sleepiness, dizziness, headache, fatigue, gastrointestinal disturbances, dry mouth and ataxia). Participants were given a diary and asked to record whether they experienced any of these adverse effects during the course of the study, when they occurred, and for how long. They were also instructed to contact the primary researcher (M.R.) if they experienced any severe adverse effect, and the plan was to discontinue the medication in such cases. The checklists and the diaries were collected at the end of each round of treatment. Additionally, participants’ age, years since menopause, weight, height, and body mass index (BMI; calculated as weight in kilograms divided by the square of height in meters) were recorded.
Statistical analyses were performed using the Kolmogorov–Smirnov test, t test, Mann–Whitney test, paired t test, and Wilcoxon test. SPSS version 18.0 (SPSS Inc, Chicago, IL, USA) was used for statistical analyses. P b 0.05 was considered statistically significant. 3. Results A total of 80 women were enrolled (Fig. 1). One participant assigned to group A failed to comply with the instructions regarding use of the medications; her data were excluded from the analysis. Therefore, data from 79 participants—39 in group A and 40 in group B—were used for the analysis. None of the participants had severe adverse effects that led to discontinuation of their treatment. There was no significant difference between the two groups in age, BMI, mean age at menopause, and time since menopause (Table 1). Before the first round of treatment, there was no significant difference between the two groups in the severity of hot flashes (P = 0.210) or night sweats (P = 0.816) (Table 2). Both fluoxetine and gabapentin significantly reduced the severity of hot flashes for both groups: compared with baseline measures, fluoxetine reduced the severity of hot flashes in group A by 23% (P = 0.011) and in group B by 20% (P b 0.001), and gabapentin reduced the severity of hot flashes in group A by 55% (P b 0.001) and in group B by 68% (P b 0.001). At the end of the first round of treatment, group B (who had received gabapentin) had a lower score for the severity of hot flashes than did group A (who had received fluoxetine; P b 0.001) (Table 2). At the end of the second round of treatment, group A (who had then received gabapentin) reported significantly less severe hot flashes than did group B (who had then received fluoxetine; P b 0.001) (Table 2). Both drugs significantly reduced the severity of night sweats for both groups: compared with baseline measures, fluoxetine reduced the severity of night sweats in group A by 18% (P = 0.001) and in group B by 41% (P b 0.001); and gabapentin reduced the severity of night sweats in group A by 56% (P b 0.001) and in group B by 62% (P b 0.001). At the end of the first round of treatment, group B (who had received gabapentin) had a significantly lower score for the severity of night sweats than did group A (who had received fluoxetine; P b 0.001) (Table 2). However, the scores for the severity of night sweats did not differ significantly at the end of the second round of treatment (P = 0.071) (Table 2). Adverse effects were rare for both groups. Tremors were the only adverse effects reported while patients were taking gabapentin, and only 4 (5%) participants (two from each group) were affected. Lack of appetite was the only adverse effect reported for fluoxetine, and only 3 (4%) participants (one from group A and two from group B) were affected. 4. Discussion In the present study, both fluoxetine and gabapentin reduced the severity of VMS among postmenopausal women. However, participants who received 300 mg/day gabapentin had a greater reduction in their VMS than did those who received 20 mg/day fluoxetine. Gabapentin has been previously shown to effectively reduce hot flashes when compared with placebo. In a clinical experiment, Butt et al. [11] showed that 300 mg gabapentin three times per day (i.e. 900 mg/day) for 4 weeks significantly reduced the frequency of hot flashes. Similarly, Saati et al. [19] showed that 300 mg gabapentin three times per day for 3 months decreased the severity, frequency, and duration of hot flashes in menopausal women. In a systematic review of seven randomized controlled trials, Toulis et al. [22] showed that gabapentin (900–2400 mg/day) reduced the severity and frequency of hot flashes by 20%–30% among women with natural or tamoxifeninduced menopause. Reddy et al. [10] showed that 2400 mg/day gabapentin for 12 weeks was as effective as 0.625 mg/day conjugated estrogen for treatment of hot flashes in postmenopausal women. Similarly, Allameh et al. [20]
Please cite this article as: Rahmanian M, et al, A crossover study comparing gabapentin and fluoxetine for the treatment of vasomotor symptoms among postmenopausal women, Int J Gynecol Obstet (2015), http://dx.doi.org/10.1016/j.ijgo.2015.04.042
M. Rahmanian et al. / International Journal of Gynecology and Obstetrics xxx (2015) xxx–xxx
3
Assessed for eligibility (n=96) Excluded (n=16) Enrolled (n=80)
Group A (n=40)
Group B (n=40)
Received fluoxetine (n=40)
Received gabapentin (n=40)
Excluded (irregular drug intake; n=1) Received gabapentin (n=39)
Received fluoxetine (n=40)
Analyzed (n=39)
Analyzed (n=40)
Fig. 1. Flow of participants through the study.
showed that the reduction in frequency and severity of hot flashes did not differ between women who received 300 mg/day gabapentin and those who received 0.625 mg/day conjugated estrogen for 12 weeks. Biglia et al. [23] showed that 900 mg/day gabapentin reduced hot flashes and improved the patients’ quality of sleep more effectively than did vitamin E. In terms of what dose of gabapentin is most effective, Pandya et al. [18] examined the effect of different doses on hot flashes among women with breast cancer. After 8 weeks, patients who had been receiving 900 mg/day reported significant reductions in the severity of hot flushes, but 300 mg/day had no significant effect. Additionally, Allameh
Table 1 Baseline characteristics.a Characteristic
Group A (n = 39)b
Group B (n = 40)c
P value
Age, y Body mass indexd Age at menopause, y Time since menopause, y
51.7 ± 2.5 27.5 ± 3.6 49.3 ± 2.6 2.4 ± 1.7
51.1 ± 2.4 26.8 ± 3.0 49.2 ± 2.1 2.0 ± 1.2
0.307 0.383 0.527 0.287
a
Values are given as mean ± SD unless indicated otherwise. 20 mg/day fluoxetine in the first round of treatment and 300 mg/day gabapentin in the second round. c 300 mg/day gabapentin in the first round of treatment and 20 mg/day fluoxetine in the second round. d Calculated as weight in kilograms divided by the square of height in meters. b
et al. [20] showed that 100 mg/day gabapentin was less effective than were 300 mg/day gabapentin or 0.625 mg/day conjugated estrogen [20]. In the systematic review by Toulis et al. [22], dizziness, unsteadiness, fatigue, and drowsiness were the most commonly reported adverse effects of gabapentin. These symptoms resulted in a higher dropout rate among patients who received gabapentin than among controls [22]. However, the only adverse effects of gabapentin reported in the present study were tremors, which affected only four participants. The difference in the frequency of adverse effects with gabapentin between the present and previous studies could be attributable to the different doses used. In the studies reviewed by Toulis et al. [22], the minimum dose of gabapentin was 900 mg/day, which is three times higher than the dose used in the present study (300 mg/day). The lower dose of gabapentin used in the present study could have been sufficient to control the VMS associated with the menopause without causing multiple adverse effects. However, in another previous study [20], 8% of patients who received gabapentin (100 mg/day or 300 mg/day) reported gastrointestinal disturbances. Although it is not clear what caused this difference in findings, variation in the daily diet of participants in the two studies might have contributed to the presence or absence of gastrointestinal adverse effects. Fundamental differences in dietary habits of people from various regions might impact how their gastrointestinal system responds to certain medications. The effect of fluoxetine on VMS associated with the menopause has also been studied by many researchers. In a placebo-controlled double-
Table 2 Severity of hot flashes and night sweats before and after intervention.a,b Symptom
Hot flashes Night sweats a b c d
Before treatment
End of 1st round of treatment
End of 2nd round of treatment
Group A (n = 39)c
Group B (n = 40)d
P value
Group A (n = 39)c
Group B (n = 40)d
P value
Group A (n = 39)c
Group B (n = 40)d
P value
1.68 ± 0.73 1.70 ± 0.76
1.85 ± 0.80 1.73 ± 0.91
0.210 0.816
1.30 ± 0.91 1.40 ± 0.90
0.60 ± 0.93 0.65 ± 0.70
b0.001 b0.001
0.75 ± 1.06 0.75 ± 0.78
1.48 ± 0.85 1.02 ± 0.92
b0.001 0.071
Values are given as mean score ± SD unless indicated otherwise. Scores ranged from 0 (not feeling the symptom at all) to 3 (feeling the symptom very severely). 20 mg/day fluoxetine in the first round of treatment and 300 mg/day gabapentin in the second round. 300 mg/day gabapentin in the first round of treatment and 20 mg/day fluoxetine in the second round.
Please cite this article as: Rahmanian M, et al, A crossover study comparing gabapentin and fluoxetine for the treatment of vasomotor symptoms among postmenopausal women, Int J Gynecol Obstet (2015), http://dx.doi.org/10.1016/j.ijgo.2015.04.042
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M. Rahmanian et al. / International Journal of Gynecology and Obstetrics xxx (2015) xxx–xxx
blind clinical study, Suvanto-Luukkonen et al. [17] examined the effectiveness of fluoxetine among postmenopausal women. They concluded that fluoxetine should not be used for postmenopausal women with VMS, because its effect did not differ from that of placebo after 9 months. However, 20 mg/day fluoxetine significantly reduced the severity of hot flashes among postmenopausal women when compared with placebo in two previous crossover studies [13,15]. Additionally, other studies have shown that 20 mg/day fluoxetine led to a positive clinical response more often than did placebo [14,16]. Lack of appetite was the only adverse effect of fluoxetine in the present study, and it was reported by only three participants. In a previous study [16] 14.8% of participants in the experimental group complained of different degrees of dry mouth, nausea, lack of appetite, or dizziness. However, the exact percentages of participants with each of these symptoms were not reported, making a comparison with the present study difficult. In the present study, participants received 4 weeks of treatment with each drug, with a 2-week washout period between the treatments. A 4-week treatment period has been used in previous studies examining the effectiveness of gabapentin [11,24,25] or fluoxetine [13,15,16] for treatment of hot flashes. Furthermore, Loprinzi et al. [13] showed that, among women receiving 20 mg/day fluoxetine for the treatment of hot flashes, the greatest effect was observed during the third week of treatment; after the third week, the effect reached a plateau. There is no evidence showing that using fluoxetine for a longer period will further decrease the severity of hot flashes. Additionally, previous studies have considered a 2-week washout period for gabapentin [25] and a washout period of 1 week or even less for fluoxetine [13,15]. Therefore, the 2-week washout period practiced in the present study is certainly long enough to allow the blood concentration of both medications return to their levels before the medical intervention. One of the limitations of the present study is that it was not doubleblinded. Furthermore, there was no follow-up period to allow comparison of the lasting effects of the two medications. In conclusion, 300 mg/day gabapentin seems to be a more effective approach for treatment of hot flashes and night sweats among postmenopausal women than is 20 mg/day fluoxetine. Gabapentin could be used for the treatment of VMS in postmenopausal women with contraindications to hormonal therapy or those who prefer alternatives to hormonal therapy. Future studies should investigate the lowest effective dose of gabapentin to minimize its adverse effects. Acknowledgments The Deputy Director of Research and Technology, Semnan University of Medical Sciences provided financial support. Conflict of interest The authors have no conflicts of interest.
[2] Arias E. United States life tables, 2010. Natl Vital Stat Rep 2014;63(7):1–63. [3] Pachman DR, Jones JM, Loprinzi CL. Management of menopause-associated vasomotor symptoms: Current treatment options, challenges and future directions. Int J Womens Health 2010;2:123–35. [4] Umland EM. Treatment strategies for reducing the burden of menopause-associated vasomotor symptoms. J Manag Care Pharm 2008;14(3 Suppl):14–9. [5] Utian WH, Archer DF, Bachmann GA, Gallagher C, Grodstein F, Heiman JR, et al. Estrogen and progestogen use in postmenopausal women: July 2008 position statement of The North American Menopause Society. Menopause 2008;15(4 Pt 1): 584–602. [6] Fritz MA, Speroff L. Clinical Gynecologic Endocrinology and Infertility. 8th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2011. [7] Kronenberg F. Hot flashes: epidemiology and physiology. Ann N Y Acad Sci 1990; 592:52–86. [8] Nelson HD, Vesco KK, Haney E, Fu R, Nedrow A, Miller J, et al. Nonhormonal therapies for menopausal hot flashes: systematic review and meta-analysis. JAMA 2006;295(17):2057–71. [9] Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg C, Stefanick ML, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women's Health Initiative randomized controlled trial. JAMA 2002;288(3):321–33. [10] Reddy SY, Warner H, Guttuso Jr T, Messing S, DiGrazio W, Thornburg L, et al. Gabapentin, estrogen, and placebo for treating hot flushes: a randomized controlled trial. Obstet Gynecol 2006;108(1):41–8. [11] Butt DA, Lock M, Lewis JE, Ross S, Moineddin R. Gabapentin for the treatment of menopausal hot flashes: a randomized controlled trial. Menopause 2008;15(2): 310–8. [12] Crundwell JK. Fluoxetine and suicidal ideation—a review of the literature. Int J Neurosci 1993;68(1–2):73–84. [13] Loprinzi CL, Sloan JA, Perez EA, Quella SK, Stella PJ, Mailliard JA, et al. Phase III evaluation of fluoxetine for treatment of hot flashes. J Clin Oncol 2002;20(6):1578–83. [14] Ghomian N, Tavasoli F, Lotfalizadeh M. Comparison of fluoxetine with a placebo in treating postmenopausal hot flash. J Birjand Univ Med Sci 2009;15(4):5–11. [15] Yazdizadeh V, Kazemnejad A, Modares Gilani M. The effect of fluoxetin on hot flashes in menopaused women. Daneshvar 2009;16(81):23–8. [16] Sakhavat L, Karimzadeh-Maibodi MA. Evaluation of fluoxetine for treatment of menopausal hot flashes. JSSU 2004;12(3):30–4. [17] Suvanto-Luukkonen E, Koivunen R, Sundström H, Bloigu R, Karjalainen E, Häivä-Mällinen L, et al. Citalopram and fluoxetine in the treatment of postmenopausal symptoms: a prospective, randomized, 9-month, placebo-controlled, double-blind study. Menopause 2005;12(1):18–26. [18] Pandya KJ, Morrow GR, Roscoe JA, Zhao H, Hickok JT, Pajon E, et al. Gabapentin for hot flashes in 420 women with breast cancer: a randomised double-blind placebocontrolled trial. Lancet 2005;366(9488):818–24. [19] Saadati N, Mohammadjafari R, Natanj S, Abedi P. The effect of gabapentin on intensity and duration of hot flashes in postmenopausal women: a randomized controlled trial. Glob J Health Sci 2013;5(6):126–30. [20] Allameh Z, Rouholamin S, Valaie S. Comparison of gabapentin with estrogen for treatment of hot flashes in post-menopausal women. J Res Pharm Pract 2013; 2(2):64–9. [21] Greene JG. Constructing a standard climacteric scale. Maturitas 2008;61(1–2): 78–84. [22] Toulis KA, Tzellos T, Kouvelas D, Goulis DG. Gabapentin for the treatment of hot flashes in women with natural or tamoxifen-induced menopause: a systematic review and meta-analysis. Clin Ther 2009;31(2):221–35. [23] Biglia N, Sgandurra P, Peano E, Marenco D, Moggio G, Bounous V, et al. Non-hormonal treatment of hot flushes in breast cancer survivors: gabapentin vs. vitamin E. Climacteric 2009;12(4):310–8. [24] Pandya KJ, Thummala AR, Griggs JJ, Rosenblatt JD, Sahasrabudhe DM, Guttuso TJ, et al. Pilot study using gabapentin for tamoxifen-induced hot flashes in women with breast cancer. Breast Cancer Res Treat 2004;83(1):87–9. [25] Bordeleau L, Pritchard KI, Loprinzi CL, Ennis M, Jugovic O, Warr D, et al. Multicenter, randomized, cross-over clinical trial of venlafaxine versus gabapentin for the management of hot flashes in breast cancer survivors. J Clin Oncol 2010;28(35): 5147–52.
References [1] Shifren JL, Schiff I. Menopause. In: Berek JS, Berek DL, editors. Berek & Novak's Gynecology. 15th Edn. Philadelphia, PA: Lippincott Williams & Wilkins; 2012. p. 1233–47.
Please cite this article as: Rahmanian M, et al, A crossover study comparing gabapentin and fluoxetine for the treatment of vasomotor symptoms among postmenopausal women, Int J Gynecol Obstet (2015), http://dx.doi.org/10.1016/j.ijgo.2015.04.042