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Bupropion for Control of Hot Flashes in Breast Cancer Survivors: A Prospective, Double-Blind, Randomized, Crossover, Pilot Phase II Trial
Vol. 45 No. 6 June 2013
Journal of Pain and Symptom Management
969
Original Article
Bupropion for Control of Hot Flashes in Breast Cancer Survivors: A Prospective, Double-Blind, Randomized, Crossover, Pilot Phase II Trial Geila Ribeiro Nu~ nez, MD, H elio Pinczowski, MD, Rebecca Zanellato, Lı´via Tateyama, Fernanda Schindler, MSc, Fernando Fonseca, PhD, and Auro del Giglio, MD, PhD ABC Foundation School of Medicine, S~ a o Paulo, Brazil
Abstract Context. Hot flashes (HFs) and sexual dysfunction often affect breast cancer (BC) survivors and compromise their quality of life. Bupropion is an antidepressive medication used for smoking cessation and also has been previously studied for the treatment of sexual dysfunction. Objectives. We aimed to evaluate bupropion’s efficacy in controlling HFs in BC survivors. Methods. This was a randomized, double-blind, crossover, placebo-controlled pilot study that enrolled 55 BC survivors who reported more than seven HFs per week. Subjects were randomized to receive either bupropion 150 mg twice daily for four weeks followed by one week of washout and four more weeks of placebo twice daily or vice versa. The primary end point was average daily HF activity (number of HFs and a score combining number and severity) reported while on bupropion or on placebo. Secondary end points were sexual dysfunction, depression, and quality of life evaluated with the Arizona Sexual Experience Scale, Beck Depression Inventory, and European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30, respectively. Results. Bupropion reduced HFs by 1.26 per day and the HF score by 6.31%, whereas placebo reduced HFs by 2.11 per day (P > 0.05) and the HF score by 30.47% (P > 0.05). There were no statistically significant differences between bupropion and placebo in the Arizona Sexual Experience Scale, Beck Depression Inventory, and European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30. At the end of the study, 47% of the patients preferred bupropion, whereas 53% preferred placebo. There were no statistically significant differences in side effects between the study groups.
Address correspondence to: Geila Ribeiro Nu~ nez, MD, Rua Piratancara number 278 apt 201, Frida Kahlo, Horto Florestal, 40295560 Salvador, BA, Brazil. E-mail: [email protected] Ó 2013 U.S. Cancer Pain Relief Committee. Published by Elsevier Inc. All rights reserved.
Accepted for publication: June 25, 2012.
0885-3924/$ - see front matter http://dx.doi.org/10.1016/j.jpainsymman.2012.06.011
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Conclusion. Compared with placebo, bupropion did not control HFs in this group of BC survivors. J Pain Symptom Manage 2013;45:969e979. Ó 2013 U.S. Cancer Pain Relief Committee. Published by Elsevier Inc. All rights reserved. Key Words Bupropion, hot flashes, breast cancer
Introduction Breast cancer (BC) is the most common cancer in women, excluding nonmelanoma skin cancer. Approximately one in eight women will be afflicted with this disease during their lifetime.1 Because of early diagnosis as a result of screening programs2 and improvement in treatment,3 the rate of BC cure has increased in recent decades.4 Therefore, concern for the quality of life of these patients has become increasingly more relevant.5 In fact, adverse effects such as hot flashes (HFs) and sexual dysfunction significantly impair quality of life in this population.6,7 Approximately 65% of BC survivors complain of HFs, and 59% of them describe the symptom as severe.6,8 Hot flashes are even more prevalent among tamoxifen users (72%) and those undergoing postchemotherapy treatment (78%).8 A HF is a sudden sensation of warmth associated with vasomotor symptoms, such as peripheral vasodilation and profuse perspiration, often followed by palpitations and anxiety. Commonly, HFs interfere with work and daily activities, disturb sleep, and can lead to fatigue, loss of concentration, depression and, therefore, deterioration of quality of life.8 Furthermore, HFs can compromise patient adherence to treatment. In fact, the rate of noncompliance to endocrine treatment varies from 25% to 55%, with adverse effects rated as the primary reason.9 Interestingly, one study reported poor compliance in more than 50% of patients within 180 days of using an antiestrogen medication. Considering that poor compliance to antineoplastic treatment is a risk factor for disease recurrence, HFs, therefore, may have a profound impact on this patient population.10 The pathophysiology of HFs is not completely understood. It is hypothesized that the postmenopausal decrease in estrogen levels is responsible for narrowing the amplitude of normal thermoregulation in the hypothalamus.
Thus, small variations in temperature may be able to trigger vasomotor symptoms.11 Estrogen therapy is the gold standard for the treatment of HFs, reducing the frequency of events by 77%.12 However, the association between estrogen use, with or without progesterone, and an increased risk of BC, thromboembolic events, and cardiovascular events may be limiting, especially for patients with a history of BC or who are at high risk for this disease.13 Several nonhormonal medications have been reported to decrease HFs in BC patients14 in Phase III, randomized, placebo-controlled studies. Among the treatments already evaluated for HFs, two classes are the most promising. The first class comprises antidepressants that act as either selective serotonin reuptake inhibitors or serotonin and norepinephrine reuptake inhibitors, such as venlafaxine,15e17 desvenlafaxine,18,19 fluoxetine,20 paroxetine,21 citalopram,22 and sertraline.23 The second class comprises gabapentin24,25 and pregabalin,26 analogues of gamma-aminobutyric acid. Bupropion (2-terbutilamino-3cloropropionfenone) belongs to a second class of antidepressants, the atypical antidepressants, and has been approved to treat depression and smoking cessation. It acts by inhibiting the reuptake of norepinephrine and dopamine without affecting serotonin activity. Bupropion, unlike other antidepressants, is not associated with sexual dysfunction, weight gain, or sedation.27,28 Some studies have shown its effectiveness in increasing libido and sexual performance, even among survivors of BC undergoing hormone therapy.29 A single pilot study evaluated the use of bupropion in 14 patients (seven men and seven women) for four weeks. Bupropion reduced the score for HFs by 23% compared with baseline. Because the placebo effect on HFs varies from 20% to 30%, the researchers labeled the drug as nonactive.30 Nevertheless, 50% of the
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Bupropion for Hot Flashes
study participants were men, and it is unknown whether the mechanism of action of a drug in the treatment of HFs is the same for postmenopausal women as for men on androgen deprivation. A growing concern in clinical practice is the coadministration of tamoxifen and inhibitors of cytochrome P450 2D6 (CYP2D6).31 Tamoxifen is a prodrug and CYP2D6 is an essential enzyme for the conversion of tamoxifen into endoxifen (4-hydroxy-N-desmethyltamoxifen), the main active metabolite responsible for antiestrogenic activity in breast cells.32 There is controversy in the literature regarding the association between the endoxifen plasma concentration and the risk of BC recurrence.33,34 Some antidepressants were directly screened for their effects on endoxifen concentration when used concomitantly with tamoxifen in vivo. As a result, fluoxetine and paroxetine are classified as strong inhibitors of CYP2D6, sertraline and citalopram as weak inhibitors, and venlafaxine as having minimal or no effect on the inhibition of CYP2D6.32 The effect of bupropion on endoxifen concentration has never been evaluated in vivo. A pharmacokinetic study with dextromethorphan, however, categorized bupropion as a potent inhibitor of CYP2D6.35 We conducted this randomized pilot study to evaluate the effect of bupropion on HFs in BC survivors undergoing hormone therapy.
Methods Patients From 2008 to 2009, we recruited women aged 18 years and older who had a history of BC without evidence of active disease, who underwent hormonal therapy for at least three months, and who complained of seven or more HFs per week that were considered severe enough for the patient to desire therapeutic intervention. Patients who underwent local surgery, chemotherapy, or radiotherapy also were included if these interventions were completed at least three months before patient participation in the study. The patients had to be capable of understanding the nature and purpose of the study, completing the questionnaires alone or with assistance, and providing informed consent. Exclusion criteria were evidence of neoplastic disease or local
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recurrence, any other current cancer diagnosis, history of epilepsy or isolated seizure(s), or prior use of antidepressants. We excluded patients who were currently using or who had used gabapentin, pregabalin, clonidine, or any other medications reported in the literature in the previous month to have activity against HFs. All the patients signed informed consent before entering the study. The study was approved by the local ethics committee (ABC Foundation School of Medicine). At the time we designed this study, the evidence regarding the interaction of bupropion with tamoxifen was limited, coming mainly from one small study without the measurement of endoxifen.35 Our institutional review board did not find a four-week exposure to bupropion in patients taking tamoxifen to be detrimental to them and approved this study.
Study Design This was a prospective, randomized, doubleblind, placebo-controlled, crossover, pilot study. The study duration was 10 weeks. The primary objective was to evaluate the efficacy of bupropion in reducing HF frequency and severity scores. Secondary objectives were evaluation of sexual dysfunction, depression, and quality of life. At the beginning of the study, each patient was randomized to receive either bupropion or placebo. Bupropion was given at a dose of one 150 mg tablet a day for three days and then one tablet twice daily for the remainder of the four weeks. After a one-week washout period, patients received placebo at doses of one tablet for three consecutive days and then one tablet twice daily for the remainder of the four weeks. If the patient was initially randomized to placebo, the aforementioned sequence was inverted (i.e., four weeks of placebo followed by a one-week washout and then four weeks of bupropion). After randomization, but before initiating any treatment, patients were instructed to fill out a daily diary of their HFs. Over the course of one week (Week 1), each patient freely recorded their HFs, classifying them as mild, moderate, severe, or very severe. To assist in this classification, patients were provided with a description of HF severity based on reports made previously by other women.36 Along
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with the HF diary, there also were questions about symptoms such as loss of appetite, insomnia, nausea, dizziness, fatigue, dry mouth, profuse sweating, constipation, nervousness, mood swings, and headaches. At the beginning of Week 2, patients completed the questionnaires related to HF interference in daily life, the Beck Depression Inventory (BDI), and the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30), and had their blood pressure and heart rate assessed. At the end of the interview, patients received the medication that they had been randomly assigned. At Week 3, patients were contacted by telephone and asked about side effects and adherence to medication, and at Week 5, patients were reminded to fill out a second diary recording their HFs. The completion of the second diary occurred at the end of the first randomization round when patients finished taking their first randomly assigned medication. At Week 6, patients underwent interviews that consisted of completing the aforementioned questionnaires and having their blood pressure and heart rate checked. There was a week of washout between the first and second rounds of medication to avoid a crossover effect. At Week 7, patients started the second medication phase of the study. At Week 8, patients were contacted by phone to assess side effects and adherence to the assigned medication, and at the beginning of Week 10, patients were reminded to fill out the third diary recording their HFs. At the end of Week 10, patients completed the last interview, had their blood pressure and heart rate checked, and were asked, although still fully blinded, about their medication preference (first or second study phase medications). Discontinuation of medication was allowed for unacceptable side effects or at the request of the patient. When undesirable side effects occurred only at the highest dose, dose reduction to one tablet of placebo or 150 mg per day of bupropion was permitted. Patient adherence was verified by counting the remaining capsules in each medication box.
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education, profession, menopause, and sexual activity) and information about their BC history (clinical staging, use of chemotherapy, radiotherapy, and hormonal therapy) were collected. Daily Diary on HFs. For seven days in Weeks 1 (baseline), 5, and 10, patients recorded all flares that occurred, classifying severity as mild, moderate, severe, or very severe. The daily frequency was the sum of the number of flares occurring per day, and the HF scores were calculated by multiplying the number of HFs with their severity (mild 1, moderate 2, severe 3, and very severe 4). Patients also were asked about the presence of symptoms (loss of appetite, insomnia, nausea, dizziness, fatigue, dry mouth, abnormal sweating, constipation, nervousness, mood swings, and headaches) during the same weeks that they filled out the HF diaries, rating their symptoms on a scale that ranged from none to very severe.15,36 Impact of HFs on Daily Activities. Interference of HFs with daily activities was assessed using a questionnaire comprising 10 questions about the impact of HFs on different aspects of life (work, social activities, leisure activities, sleep, mood, concentration, sexuality, relationships with others, enjoyment of life, and quality of life). The answers range from ‘‘no interference’’ to ‘‘high interference.’’ This questionnaire was adapted from a scale in English (the Hot Flash Related Daily Interference Scale created and validated by Carpenter in 2001).37 As this scale was not validated in Portuguese, standardized scores could not be calculated, but responses were used for descriptive purposes. Arizona Sexual Experience Scale. The Arizona Sexual Experience Scale (ASEX) is a scale that includes five questions from categories related to sexual function (sexual desire, sexual arousal, vaginal lubrication, orgasm, and sexual satisfaction).38 Each question has five response options ranging from 1 to 6. A higher score indicates a greater degree of sexual dysfunction. The scale used in this study was the validated Brazilian version and the cutoff for diagnosis of sexual dysfunction was >19.39
Questionnaires and Assessment Tools Demographic and Medical History. For each patient, demographic variables (age, marital status,
Beck Depression Inventory. The BDI was used to assess the degree of depression, using 21
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Bupropion for Hot Flashes
questions, each with four response options ranging from 0 to 3.40 Questions cover topics such as sadness, guilt, punishment, suicidal ideation, crying, and attitudes during the previous week. Higher scores indicate a higher level of depression. A score of >20 indicates that the respondent is depressed. In this study, we used the Brazilian version, which was previously validated.41 European Organization for Research and Treatment of Cancer Quality of Life Questionnaire. The EORTC QLQ-C30 was used to assess quality of life through 36 questions that measure functional status; cognitive function; mood; symptoms such as fatigue, pain, vomiting, and other physical symptoms; social interaction; and overall quality of life.42 The score for each topic ranges from 1 to 4. For the topics of functional status and overall quality of life, a higher score indicates better quality of life. For topics related to physical symptoms, a higher score indicates poorer quality of life. The questionnaire used in this study was the Portuguese version, which was previously validated.43
Statistical Analysis The power of the study was 80% and the significance level was set at 5%. We also considered the possibility of a loss of 20% to 30% of the patients. We aimed to detect a 50% reduction in the HF severity score. We estimated that, with these parameters, a sample size of 52 patients would be necessary. We performed a descriptive analysis of the variables according to group (placebo vs. bupropion) and time point (first vs. second period). Analysis of variance (ANOVA) was used to assess changes in the number of HFs, HF severity score, ASEX score (only for patients who were sexually active), BDI score, and overall quality-of-life score both between groups and at different time points. Analysis of the same group at different study time points required ANOVA with repeated measures.44 The Bonferroni multiple comparisons procedure44 was used on comparisons that showed statistical significance by ANOVA to determine which groups or specific time points had those significant differences. The differences between bupropion and placebo for number of HFs and ASEX are absolute differences and are calculated by subtracting the
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initial value from the final value. For the HFs’ index, what is shown is the result of the respective HF values (initial final)/initial 100 from each patient and divided by the number of patients. For nonparametric variables, such as side effects and symptoms, we compared the groups using the Mann-Whitney45 and Friedman tests.45 We used the Chi-square test to evaluate patient preference for placebo vs. bupropion. The null hypothesis of this study was that there would be no difference in frequency and/or severity of HFs between the use of bupropion and placebo; assessment was performed with the Student’s t-test.
Results Patients were enrolled in this study from September 2009 through October 2010. During this period, 91 patients were screened; of these, 13 refused to participate and 23 were excluded. Fifty-five patients were randomized, and of these, six withdrew during the first step, but none withdrew during the second step. Side effects were the reason for withdrawal in four patients; three of these were using placebo and one bupropion (Fig. 1). One patient was excluded because of inappropriate completion of daily HF diaries. The average patient age was 49 years; 45% were white, 61% were married, 69.4% were postmenopausal, 45% had an average of nine years of study, and about 60% were sexually active. Regarding BC treatment, 75% received chemotherapy, 92% received radiotherapy, and 86% of patients were taking tamoxifen (Table 1). Differences in the average number of HFs per day and severity of HF scores between the bupropion and placebo study arms are shown in Table 2. Bupropion decreased HFs by 1.26 per day, whereas the placebo reduced HFs by 2.11 per day (P ¼ 0.528). Regarding the severity score, bupropion reduced the average score by 6.31% and placebo by 30.47% (P ¼ 0.595). When groups and different study time points were evaluated separately, there was no difference between groups for frequency of HFs and HF severity score. However, evaluation at different time points of the study showed that, regardless of
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Fig. 1. Flow diagram and retention of study patients.
what medication was being used, there was statistically significant improvement in the number of HFs (P ¼ 0.002) and the HF severity score (P ¼ 0.040) as the study progressed (from beginning to final measurements; Appendix I). There was no crossover effect (P > 0.05). No difference in sexual dysfunction was observed between the use of bupropion and placebo (Table 2) nor for the analyses of each question of the ASEX scale (Appendix II). There were no differences between groups when evaluated separately. The difference in sexual dysfunction scores was statistically significant (P ¼ 0.003) when the sexual dysfunction score was evaluated for different stages of the study, regardless of which medication was being used. There was no statistically significant difference in BDI or EORTC QLQ-C30 scores between groups or between different time points of the study. There was no statistically significant difference in frequency of adverse effects between groups. Only one withdrawal was attributed to bupropion’s side effects (headache, dizziness, and palpitations). Of the 48 patients who completed the study, 45 expressed a preference for one of the study stages. Of these, 47% preferred the stage at which they used bupropion (P ¼ 0.673).
Discussion Compared with placebo, bupropion did not show a minimum of 50% activity for the control of HFs in this group of BC survivors. These findings are consistent with a pilot study that evaluated 14 patients with more than 14 HFs per week (seven men and seven women). In this study, patients underwent treatment for four weeks with bupropion at a dose of 150 mg twice daily. This small pilot study found a 23% reduction in the severity score of HFs, which could be attributed to the placebo effect.30 In our trial, within the placebo group, when we considered all data in aggregate, HFs were reduced by 30.47%, which is compatible with the reported placebo effect of 20%e30%.36 However, when we considered all data in aggregate for bupropion, the reduction in the HFs within the bupropion group was lower than expected (6.31%), and it was not statistically significant. We also saw no statistically significant differences between groups. The lack of bupropion-mediated reduction of HFs in comparison with other antidepressants, such as serotonin and norepinephrine reuptake inhibitors and selective serotonin reuptake inhibitors, may be explained by the distinct mechanism of action of this atypical antidepressant. Bupropion is a norepinephrine
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Bupropion for Hot Flashes
pathophysiological mechanism of HFs involves the serotonergic pathway. Narrowing the hypothalamic thermostat amplitude triggers HFs. Thus, small variations in temperature are capable of triggering vasomotor symptoms. This narrowing is thought to be caused by a decrease in estrogen levels11 that increases the synthesis of serotonin and endorphins, which in turn are responsible for inhibiting the production of norepinephrine. Once there is a decrease in estrogen levels during menopause or in patients treated with hormonal deprivation, levels of endorphins and serotonin decrease and the number of serotonin receptors increases.11 The improvement of HFs and sexual dysfunction was statistically significant for different study time points, regardless of which treatment was being used (bupropion or placebo). This confirms the inactivity of bupropion for HF control in this study and stresses the important effect of medical care and the prescription of any medications used to treat self-reported symptoms. In this study, we could not demonstrate that bupropion improves sexual dysfunction compared with placebo. Recent studies have shown that patients with sexual dysfunction who used bupropion experienced improvements in sexual function. These studies were randomized and included samples of around 200 patients.46,47 The number of patients evaluated in the present study was smaller. In fact, because the evaluation of sexual dysfunction
Table 1 Patient Characteristics at Baseline Characteristics
n (%)
Median age, yrs (range) Race Caucasian Latin Black Marital status Married Single Divorced Widowed Menopause status Pre Post Sexually active Yes No Stage In situ I/II III Prior chemotherapy Yes No Prior radiotherapy Yes No Hormone therapy Tamoxifen GnRH agonist þ tamoxifen AI GnRH agonist þ AI Number of HFs <14 HFs/week $14 HFs/week
49 (33e71) 22 (44.9) 18 (36.7) 9 (18.4) 30 6 8 5
(61.2) (12.2) (16.3) (10.2)
34 (69.4) 15 (30.6) 29 (59.2) 20 (40.8) 6 (12.2) 26 (53.1) 15 (30.6) 37 (75.5) 11 (22.4) 45 (91.8) 3 (6.1) 39 3 6 1
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(79.6) (6.1) (12.2) (2)
42 (85.7) 7 (14.3)
GnRH ¼ gonadotropin releasing hormone; AI ¼ aromatase inhibitor; HF ¼ hot flash.
and dopamine reuptake inhibitor with no serotonergic activity.27,28 Although not completely understood, it is believed that the
Table 2 Comparison of the Index and Number of HFs and ASEX Scores in Patients Stratified by the Beginning and End of Treatment With Bupropion or Placebo Treatment Bupropion Variables HFs index Number of HFs ASEX
Placebo
Timing
Average
SD
n
Average
SD
n
Beginning Final Difference Beginning Final Difference Beginning Final Difference
9.94 7.75 6.31 5.32 4.06 1.26 12.88 11.52 1.36
12.28 10.10 211.29 4.70 4.18 3.01 10.16 9.50 3.77
48 48 48 48 48 48 48 48 48
11.78 7.66 30.47 6.72 4.61 2.11 12.83 12.26 0.57
15.61 8.55 229.82 11.93 4.25 10.35 10.30 9.49 3.41
48 47 47 48 47 47 48 47 47
P-value
0.595 0.528 0.497
HF ¼ hot flash; ASEX ¼ Arizona Sexual Experience Scale. Because there was no crossover effect (P > 0.05), the data shown here represent the aggregate of the two phases in which each patient received placebo or bupropion regardless of the order in which these medications were given. The differences between bupropion and placebo for number of HFs and ASEX scores are absolute differences and are calculated by subtracting the initial from the final value. For the HFs index, what is shown is the result of the respective HF values (initial final)/initial 100 from each patient and divided by the number of patients.
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was a secondary objective of this study, only 29 patients were sexually active, and of those, only 25 had sexual dysfunction according to the ASEX scale. The evaluation of a small sample may not have been sufficient to show a potential benefit. An open nonrandomized trial evaluated the eight-week use of 150 mg/day of bupropion in 20 female BC survivors who were undergoing hormone therapy; there was improvement in sexual function, but the trial’s lack of a placebo group may have contributed to an overestimation of bupropion’s effects.29 The efficacy of bupropion as an antidepressant is well established in the literature. However, this study found no difference in BDI scores between the bupropion and placebo groups. Among the 48 patients who completed the study, only seven had a diagnosis of depression according the BDI, which could explain this finding. We also observed no statistically significant difference between overall health and qualityof-life scores. Although there was a decrease in the number of HFs, severity of HFs, and sexual dysfunction during treatment (for both placebo and bupropion), we believe that the concept of quality of life encompasses many physical, psychological, and social aspects. Therefore, it is possible that the nonspecific HF improvement we observed, regardless of the medication used, may not have been sufficient to reflect a change in quality-of-life scores. Finally, 47% of the patients preferred bupropion, whereas 53% preferred placebo. Therefore, at the end of the study, most patients did not have a significant preference for either placebo or bupropion, which corroborates our finding that there is a lack of bupropion activity for HFs, as seen in our primary end point. Although our study was only powered to disclose a 50% reduction in HF scores between placebo and bupropion, which would be higher than that expected according to other studies,15e26 we observed not even a trend in favor of bupropion in this study. Therefore, we do not believe that a larger sample would be able to show a clinically significant effect in favor of bupropion. Most of our patients used tamoxifen because of its lower costs compared with aromatase inhibitors in Brazil. Although there is in vitro evidence of a high inhibition potential of CYPD6
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activity by bupropion, there are no in vivo data to support this contention. Because of its negative effects in patients with HF, we do not recommend bupropion for this indication even for those patients on aromatase inhibitors in whom no drug-drug interactions are expected to occur. In conclusion, compared with placebo, bupropion did not show activity for the control of HFs in this group of BC survivors.
Disclosures and Acknowledgments No financial support was received for this study, and the authors declare no conflicts of interest.
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33. Aubert RE, Stanek EJ, Yao J, et al. Risk of breast cancer recurrence in women initiating tamoxifen with CYP2D6 inhibitors. J Clin Oncol 2009; 27(Suppl 9):abstr CRA508.
19. Speroff L, Gass M, Constantine G, Olivier S, for the Study 315 Investigators. Efficacy and tolerability of desvenlafaxine succinate treatment for menopausal vasomotor symptoms: a randomized controlled trial. Obstet Gynecol 2008;111:77e87. 20. Loprinzi CL, Sloan JA, Perez EA, et al. Phase III evaluation of fluoxetine for treatment of hot flashes. J Clin Oncol 2002;20:1578e1583. 21. Stearns V, Beebe KL, Iyengar M, Dube E. Paroxetine controlled release in the treatment of menopausal hot flashes: a randomized controlled trial. JAMA 2003;289:2827e2834. 22. Barton DL, LaVasseur BI, Sloan JA, et al. Phase III, placebo-controlled trial of three doses of citalopram for the treatment of hot flashes: NCCTG trial N05C9. J Clin Oncol 2010;28:3278e3283. 23. Wu MF, Hilsenbeck SG, Tham YL, et al. The efficacy of sertraline for controlling hot flashes in women with or at high risk of developing breast cancer. Breast Cancer Res Treat 2009;118:369e375. 24. Butt DA, Lock M, Lewis JE, et al. Gabapentin for the treatment of menopausal hot flashes: a randomized controlled trial. Menopause 2008; 15:310e318.
34. Dezentje V, van Blijderveen NJ, Gelderblom H, et al. Concomitant CYP2D6 inhibitor use and tamoxifen adherence in early-stage breast cancer: a pharmacoepidemiologic study. J Clin Oncol 2009;27(Suppl 9):abstr CRA509. 35. Kotlyar M, Brauer LH, Tracy TS, et al. Inhibition of CYP2D6 activity by bupropion. J Clin Psychopharmacol 2005;25:226e229. 36. Sloan JA, Loprinzi CL, Novotny PJ, et al. Methodologic lessons learned from hot flashes studies. J Clin Oncol 2001;19:4280e4290. 37. Carpenter JS. The Hot Flashes Related Daily Scale: a tool for assessing the impact of hot flashes on quality of life following breast cancer. J Pain Symptom Manage 2001;22:979e989. 38. McGahuey CA, Gelenberg AJ, Laukes CA, et al. The Arizona Sexual Experience Scale (ASEX): reliability and validity. J Sex Marital Ther 2000;26: 25e40. 39. Mathias C, Athanazio RA, Braghiroli MI, et al. Use of the Arizona Sexual Experience Scale (ASEX) in the evaluation of sexual dysfunction in Brazilian cancer patients. [in Spanish]. J Bras Psiquiatr 2005;54:216e220.
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of Medicine. [in Spanish]. Revista da Sociedade Brasileira de Cancerologia 2001;15:19.
40. Beck AT, Steer RA. Internal consistencies of the original and revised Beck Depression Inventory. J Clin Psychol 1984;40:1365e1367.
44. Neter J, Kutner M, Nachtsheim CJ, Wasserman W. Allied linear statistical models, 4th ed. New York: McGraw Hill/Irwin, 1996:1408.
41. Andrade L, Gorenstein C, Vieira-Filho AH, et al. Psychometric properties of the Portuguese version of the State-Trait Anxiety Inventory applied to college students: factor analysis and relation to the Beck Depression Inventory. Braz J Med Biol Res 2001;34:367e374.
45. Kirkwood BR, Sterne JAC. Essential medical statistics, 2nd ed. Malden, MA: Blackwell Science, Inc., 2006:502.
42. Aaronson NK, Ahmedzai S, Bergman B, et al. The European Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology. J Natl Cancer Inst 1993;85:365e376.
46. Safarinejad MR. Reversal of SSRI-induced female sexual dysfunction by adjunctive bupropion in menstruating women: a double-blind, placebo-controlled and randomized study. J Psychopharmacol 2011;25: 370e378.
43. Soares HP, Zatta SM, Bezerra AS, et al. Application of questionnaires on quality of life ‘‘FLIE’’ and ‘‘EORTC QLQ C-30’’ for cancer patients undergoing chemotherapy: pilot study of oncology and hematology department of ABC Foundation School
47. Safarinejad MR. The effects of the adjunctive bupropion on male sexual dysfunction induced by a selective serotonin reuptake inhibitor: a doubleblind placebo-controlled and randomized study. BJU Int 2010;106:840e847.
Appendix I Statistical Analyses Using Analysis of Variance Comparing the Difference in Each Variable Between Different Treatment Groups and Different Study Time Points (Initial/First/Second Phase Medications) Variables HFs index Number of HFs ASEX BDI EORTC QLQ-C30
Factors Group Time point Group time Group Time point Group time Group Time point Group time Group Time point Group time Group Time point Group time
point point point point point
No. of Factors
No. of Patients
F-value
P-value
1 2 2 1 1 1 1 2 2 1 2 2 1 2 2
45 75 75 45 55 55 27 47 47 58 74 74 45 75 75
0.09 7.26 0.65 0.54 4.10 1.16 1.90 7.32 0.55 0.33 1.98 0.40 0.17 1.46 0.38
0.760 0.002 0.497 0.465 0.040 0.297 0.179 0.003 0.558 0.568 0.153 0.633 0.680 0.238 0.649
HF ¼ hot flash; ASEX ¼ Arizona Sexual Experience Scale; BDI ¼ Beck Depression Inventory; EORTC QLQ-C30 ¼ European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30. When groups (bupropion or placebo) were evaluated separately, there was no difference between them in HFs index, number of HFs, ASEX, BDI, or EORTC QLQ-C30 scales. However, evaluation at different time points of the study showed that, regardless of what medication was being used, there was statistically significant improvement in the HFs index (P ¼ 0.002), number of HFs (P ¼ 0.04), and ASEX (P ¼ 0.003) as the study progressed (initial/first/second phase medications) (bold numbers). There was no crossover effect (group time points; P > 0.05).
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Appendix II Comparison of Each Question of the ASEX Scale Stratified by the Beginning and End of Treatment With Bupropion or Placebo (McNemar Test) Bupropion
Questions How strong is your sex drive? Not applicable (not sexually active) Extremely strong Very strong Somewhat strong Somewhat weak Very weak No sex drive Improvement, n (%) How easily are you sexually aroused? Not applicable (not sexually active) Extremely easily Very easily Somewhat easily Somewhat difficult Very difficult Never aroused Improvement, n (%) How easily does your vagina become wet during sex? Not applicable (not sexually active) Extremely easily Very easily Somewhat easily Somewhat difficult Very difficult Never Improvement, n (%) How easily can you reach orgasm? Not applicable (not sexually active) Extremely easily Very easily Somewhat easily Somewhat difficult Very difficult Never reach orgasm Improvement, n (%) Are your orgasms satisfying? Not applicable (not sexually active) Extremely satisfying Very satisfying Somewhat satisfying Somewhat unsatisfying Very unsatisfying Cannot reach orgasm Improvement, n (%)
Placebo
Initial
Final
Initial
Final
n (%)
n (%)
n (%)
n (%)
17 0 0 5 8 8 10 17 0 1 10 14 4 2 17 0 0 12 10 8 1 17 0 0 12 9 6 4 17 1 6 15 4 1 4
(35.4) 16 (0.0) 1 (0.0) 2 (10.4) 14 (16.7) 4 (16.7) 8 (20.8) 3 17 (35.4)
(33.3) (2.1) (4.2) (29.2) (8.3) (16.7) (6.3)
(35.4) 16 (0.0) 2 (2.1) 1 (20.8) 12 (29.2) 11 (8.3) 3 (4.2) 3 9 (18.8)
(33.3) (4.2) (2.1) (25.0) (22.9) (6.3) (6.3)
(35.4) 18 (0.0) 0 (0.0) 0 (25.0) 14 (20.8) 9 (16.7) 5 (2.1) 2 11 (22.9)
(37.5) (0.0) (0.0) (29.2) (18.8) (10.4) (4.2)
(35.4) 17 (0.0) 1 (0.0) 0 (25.0) 10 (18.8) 13 (12.5) 5 (8.3) 2 8 (16.7)
(35.4) (2.1) (0.0) (20.8) (27.1) (10.4) (4.2)
(35.4) 17 (2.1) 2 (12.5) 6 (31.3) 18 (8.3) 3 (2.1) 0 (8.3) 2 6 (12.5)
(35.4) (4.2) (12.5) (37.5) (6.3) (0.0) (4.2)
16 0 2 10 3 9 8 17 1 0 7 17 3 3 17 0 0 9 12 6 4 17 0 0 9 12 5 5 17 2 5 16 3 0 5
(33.3) 17 (0.0) 0 (4.2) 1 (20.8) 13 (6.3) 8 (18.8) 2 (16.7) 7 14 (29.2)
(35.4) (0.0) (2.1) (27.1) (16.7) (4.2) (14.6)
(35.4) 17 (2.1) 0 (0.0) 1 (14.6) 12 (35.4) 14 (6.3) 3 (6.3) 1 11 (22.9)
(35.4) (0.0) (2.1) (25.0) (29.2) (6.3) (2.1)
(35.4) 17 (0.0) 0 (0.0) 0 (18.8) 15 (25.0) 8 (12.5) 7 (8.3) 1 14 (29.2)
(35.4) (0.0) (0.0) (31.3) (16.7) (14.6) (2.1)
(35.4) 17 (0.0) 0 (0.0) 0 (18.8) 14 (25.0) 10 (10.4) 4 (10.4) 3 13 (27.1)
(35.4) (0.0) (0.0) (29.2) (20.8) (8.3) (6.3)
(35.4) 17 (4.2) 2 (10.4) 6 (33.3) 15 (6.3) 4 (0.0) 1 (10.4) 3 8 (16.7)
(35.4) (4.2) (12.5) (31.3) (8.3) (2.1) (6.3)
P-value
0.664
0.815
0.648
0.267
0.754
ASEX ¼ Arizona Sexual Experience Scale. There was no statistically significant difference between the improvement observed with the use of bupropion or placebo treatment in any of the questions of the ASEX scale (P > 0.05).
Journal of Pain and Symptom Management
969
Original Article
Bupropion for Control of Hot Flashes in Breast Cancer Survivors: A Prospective, Double-Blind, Randomized, Crossover, Pilot Phase II Trial Geila Ribeiro Nu~ nez, MD, H elio Pinczowski, MD, Rebecca Zanellato, Lı´via Tateyama, Fernanda Schindler, MSc, Fernando Fonseca, PhD, and Auro del Giglio, MD, PhD ABC Foundation School of Medicine, S~ a o Paulo, Brazil
Abstract Context. Hot flashes (HFs) and sexual dysfunction often affect breast cancer (BC) survivors and compromise their quality of life. Bupropion is an antidepressive medication used for smoking cessation and also has been previously studied for the treatment of sexual dysfunction. Objectives. We aimed to evaluate bupropion’s efficacy in controlling HFs in BC survivors. Methods. This was a randomized, double-blind, crossover, placebo-controlled pilot study that enrolled 55 BC survivors who reported more than seven HFs per week. Subjects were randomized to receive either bupropion 150 mg twice daily for four weeks followed by one week of washout and four more weeks of placebo twice daily or vice versa. The primary end point was average daily HF activity (number of HFs and a score combining number and severity) reported while on bupropion or on placebo. Secondary end points were sexual dysfunction, depression, and quality of life evaluated with the Arizona Sexual Experience Scale, Beck Depression Inventory, and European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30, respectively. Results. Bupropion reduced HFs by 1.26 per day and the HF score by 6.31%, whereas placebo reduced HFs by 2.11 per day (P > 0.05) and the HF score by 30.47% (P > 0.05). There were no statistically significant differences between bupropion and placebo in the Arizona Sexual Experience Scale, Beck Depression Inventory, and European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30. At the end of the study, 47% of the patients preferred bupropion, whereas 53% preferred placebo. There were no statistically significant differences in side effects between the study groups.
Address correspondence to: Geila Ribeiro Nu~ nez, MD, Rua Piratancara number 278 apt 201, Frida Kahlo, Horto Florestal, 40295560 Salvador, BA, Brazil. E-mail: [email protected] Ó 2013 U.S. Cancer Pain Relief Committee. Published by Elsevier Inc. All rights reserved.
Accepted for publication: June 25, 2012.
0885-3924/$ - see front matter http://dx.doi.org/10.1016/j.jpainsymman.2012.06.011
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Conclusion. Compared with placebo, bupropion did not control HFs in this group of BC survivors. J Pain Symptom Manage 2013;45:969e979. Ó 2013 U.S. Cancer Pain Relief Committee. Published by Elsevier Inc. All rights reserved. Key Words Bupropion, hot flashes, breast cancer
Introduction Breast cancer (BC) is the most common cancer in women, excluding nonmelanoma skin cancer. Approximately one in eight women will be afflicted with this disease during their lifetime.1 Because of early diagnosis as a result of screening programs2 and improvement in treatment,3 the rate of BC cure has increased in recent decades.4 Therefore, concern for the quality of life of these patients has become increasingly more relevant.5 In fact, adverse effects such as hot flashes (HFs) and sexual dysfunction significantly impair quality of life in this population.6,7 Approximately 65% of BC survivors complain of HFs, and 59% of them describe the symptom as severe.6,8 Hot flashes are even more prevalent among tamoxifen users (72%) and those undergoing postchemotherapy treatment (78%).8 A HF is a sudden sensation of warmth associated with vasomotor symptoms, such as peripheral vasodilation and profuse perspiration, often followed by palpitations and anxiety. Commonly, HFs interfere with work and daily activities, disturb sleep, and can lead to fatigue, loss of concentration, depression and, therefore, deterioration of quality of life.8 Furthermore, HFs can compromise patient adherence to treatment. In fact, the rate of noncompliance to endocrine treatment varies from 25% to 55%, with adverse effects rated as the primary reason.9 Interestingly, one study reported poor compliance in more than 50% of patients within 180 days of using an antiestrogen medication. Considering that poor compliance to antineoplastic treatment is a risk factor for disease recurrence, HFs, therefore, may have a profound impact on this patient population.10 The pathophysiology of HFs is not completely understood. It is hypothesized that the postmenopausal decrease in estrogen levels is responsible for narrowing the amplitude of normal thermoregulation in the hypothalamus.
Thus, small variations in temperature may be able to trigger vasomotor symptoms.11 Estrogen therapy is the gold standard for the treatment of HFs, reducing the frequency of events by 77%.12 However, the association between estrogen use, with or without progesterone, and an increased risk of BC, thromboembolic events, and cardiovascular events may be limiting, especially for patients with a history of BC or who are at high risk for this disease.13 Several nonhormonal medications have been reported to decrease HFs in BC patients14 in Phase III, randomized, placebo-controlled studies. Among the treatments already evaluated for HFs, two classes are the most promising. The first class comprises antidepressants that act as either selective serotonin reuptake inhibitors or serotonin and norepinephrine reuptake inhibitors, such as venlafaxine,15e17 desvenlafaxine,18,19 fluoxetine,20 paroxetine,21 citalopram,22 and sertraline.23 The second class comprises gabapentin24,25 and pregabalin,26 analogues of gamma-aminobutyric acid. Bupropion (2-terbutilamino-3cloropropionfenone) belongs to a second class of antidepressants, the atypical antidepressants, and has been approved to treat depression and smoking cessation. It acts by inhibiting the reuptake of norepinephrine and dopamine without affecting serotonin activity. Bupropion, unlike other antidepressants, is not associated with sexual dysfunction, weight gain, or sedation.27,28 Some studies have shown its effectiveness in increasing libido and sexual performance, even among survivors of BC undergoing hormone therapy.29 A single pilot study evaluated the use of bupropion in 14 patients (seven men and seven women) for four weeks. Bupropion reduced the score for HFs by 23% compared with baseline. Because the placebo effect on HFs varies from 20% to 30%, the researchers labeled the drug as nonactive.30 Nevertheless, 50% of the
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study participants were men, and it is unknown whether the mechanism of action of a drug in the treatment of HFs is the same for postmenopausal women as for men on androgen deprivation. A growing concern in clinical practice is the coadministration of tamoxifen and inhibitors of cytochrome P450 2D6 (CYP2D6).31 Tamoxifen is a prodrug and CYP2D6 is an essential enzyme for the conversion of tamoxifen into endoxifen (4-hydroxy-N-desmethyltamoxifen), the main active metabolite responsible for antiestrogenic activity in breast cells.32 There is controversy in the literature regarding the association between the endoxifen plasma concentration and the risk of BC recurrence.33,34 Some antidepressants were directly screened for their effects on endoxifen concentration when used concomitantly with tamoxifen in vivo. As a result, fluoxetine and paroxetine are classified as strong inhibitors of CYP2D6, sertraline and citalopram as weak inhibitors, and venlafaxine as having minimal or no effect on the inhibition of CYP2D6.32 The effect of bupropion on endoxifen concentration has never been evaluated in vivo. A pharmacokinetic study with dextromethorphan, however, categorized bupropion as a potent inhibitor of CYP2D6.35 We conducted this randomized pilot study to evaluate the effect of bupropion on HFs in BC survivors undergoing hormone therapy.
Methods Patients From 2008 to 2009, we recruited women aged 18 years and older who had a history of BC without evidence of active disease, who underwent hormonal therapy for at least three months, and who complained of seven or more HFs per week that were considered severe enough for the patient to desire therapeutic intervention. Patients who underwent local surgery, chemotherapy, or radiotherapy also were included if these interventions were completed at least three months before patient participation in the study. The patients had to be capable of understanding the nature and purpose of the study, completing the questionnaires alone or with assistance, and providing informed consent. Exclusion criteria were evidence of neoplastic disease or local
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recurrence, any other current cancer diagnosis, history of epilepsy or isolated seizure(s), or prior use of antidepressants. We excluded patients who were currently using or who had used gabapentin, pregabalin, clonidine, or any other medications reported in the literature in the previous month to have activity against HFs. All the patients signed informed consent before entering the study. The study was approved by the local ethics committee (ABC Foundation School of Medicine). At the time we designed this study, the evidence regarding the interaction of bupropion with tamoxifen was limited, coming mainly from one small study without the measurement of endoxifen.35 Our institutional review board did not find a four-week exposure to bupropion in patients taking tamoxifen to be detrimental to them and approved this study.
Study Design This was a prospective, randomized, doubleblind, placebo-controlled, crossover, pilot study. The study duration was 10 weeks. The primary objective was to evaluate the efficacy of bupropion in reducing HF frequency and severity scores. Secondary objectives were evaluation of sexual dysfunction, depression, and quality of life. At the beginning of the study, each patient was randomized to receive either bupropion or placebo. Bupropion was given at a dose of one 150 mg tablet a day for three days and then one tablet twice daily for the remainder of the four weeks. After a one-week washout period, patients received placebo at doses of one tablet for three consecutive days and then one tablet twice daily for the remainder of the four weeks. If the patient was initially randomized to placebo, the aforementioned sequence was inverted (i.e., four weeks of placebo followed by a one-week washout and then four weeks of bupropion). After randomization, but before initiating any treatment, patients were instructed to fill out a daily diary of their HFs. Over the course of one week (Week 1), each patient freely recorded their HFs, classifying them as mild, moderate, severe, or very severe. To assist in this classification, patients were provided with a description of HF severity based on reports made previously by other women.36 Along
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with the HF diary, there also were questions about symptoms such as loss of appetite, insomnia, nausea, dizziness, fatigue, dry mouth, profuse sweating, constipation, nervousness, mood swings, and headaches. At the beginning of Week 2, patients completed the questionnaires related to HF interference in daily life, the Beck Depression Inventory (BDI), and the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30), and had their blood pressure and heart rate assessed. At the end of the interview, patients received the medication that they had been randomly assigned. At Week 3, patients were contacted by telephone and asked about side effects and adherence to medication, and at Week 5, patients were reminded to fill out a second diary recording their HFs. The completion of the second diary occurred at the end of the first randomization round when patients finished taking their first randomly assigned medication. At Week 6, patients underwent interviews that consisted of completing the aforementioned questionnaires and having their blood pressure and heart rate checked. There was a week of washout between the first and second rounds of medication to avoid a crossover effect. At Week 7, patients started the second medication phase of the study. At Week 8, patients were contacted by phone to assess side effects and adherence to the assigned medication, and at the beginning of Week 10, patients were reminded to fill out the third diary recording their HFs. At the end of Week 10, patients completed the last interview, had their blood pressure and heart rate checked, and were asked, although still fully blinded, about their medication preference (first or second study phase medications). Discontinuation of medication was allowed for unacceptable side effects or at the request of the patient. When undesirable side effects occurred only at the highest dose, dose reduction to one tablet of placebo or 150 mg per day of bupropion was permitted. Patient adherence was verified by counting the remaining capsules in each medication box.
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education, profession, menopause, and sexual activity) and information about their BC history (clinical staging, use of chemotherapy, radiotherapy, and hormonal therapy) were collected. Daily Diary on HFs. For seven days in Weeks 1 (baseline), 5, and 10, patients recorded all flares that occurred, classifying severity as mild, moderate, severe, or very severe. The daily frequency was the sum of the number of flares occurring per day, and the HF scores were calculated by multiplying the number of HFs with their severity (mild 1, moderate 2, severe 3, and very severe 4). Patients also were asked about the presence of symptoms (loss of appetite, insomnia, nausea, dizziness, fatigue, dry mouth, abnormal sweating, constipation, nervousness, mood swings, and headaches) during the same weeks that they filled out the HF diaries, rating their symptoms on a scale that ranged from none to very severe.15,36 Impact of HFs on Daily Activities. Interference of HFs with daily activities was assessed using a questionnaire comprising 10 questions about the impact of HFs on different aspects of life (work, social activities, leisure activities, sleep, mood, concentration, sexuality, relationships with others, enjoyment of life, and quality of life). The answers range from ‘‘no interference’’ to ‘‘high interference.’’ This questionnaire was adapted from a scale in English (the Hot Flash Related Daily Interference Scale created and validated by Carpenter in 2001).37 As this scale was not validated in Portuguese, standardized scores could not be calculated, but responses were used for descriptive purposes. Arizona Sexual Experience Scale. The Arizona Sexual Experience Scale (ASEX) is a scale that includes five questions from categories related to sexual function (sexual desire, sexual arousal, vaginal lubrication, orgasm, and sexual satisfaction).38 Each question has five response options ranging from 1 to 6. A higher score indicates a greater degree of sexual dysfunction. The scale used in this study was the validated Brazilian version and the cutoff for diagnosis of sexual dysfunction was >19.39
Questionnaires and Assessment Tools Demographic and Medical History. For each patient, demographic variables (age, marital status,
Beck Depression Inventory. The BDI was used to assess the degree of depression, using 21
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Bupropion for Hot Flashes
questions, each with four response options ranging from 0 to 3.40 Questions cover topics such as sadness, guilt, punishment, suicidal ideation, crying, and attitudes during the previous week. Higher scores indicate a higher level of depression. A score of >20 indicates that the respondent is depressed. In this study, we used the Brazilian version, which was previously validated.41 European Organization for Research and Treatment of Cancer Quality of Life Questionnaire. The EORTC QLQ-C30 was used to assess quality of life through 36 questions that measure functional status; cognitive function; mood; symptoms such as fatigue, pain, vomiting, and other physical symptoms; social interaction; and overall quality of life.42 The score for each topic ranges from 1 to 4. For the topics of functional status and overall quality of life, a higher score indicates better quality of life. For topics related to physical symptoms, a higher score indicates poorer quality of life. The questionnaire used in this study was the Portuguese version, which was previously validated.43
Statistical Analysis The power of the study was 80% and the significance level was set at 5%. We also considered the possibility of a loss of 20% to 30% of the patients. We aimed to detect a 50% reduction in the HF severity score. We estimated that, with these parameters, a sample size of 52 patients would be necessary. We performed a descriptive analysis of the variables according to group (placebo vs. bupropion) and time point (first vs. second period). Analysis of variance (ANOVA) was used to assess changes in the number of HFs, HF severity score, ASEX score (only for patients who were sexually active), BDI score, and overall quality-of-life score both between groups and at different time points. Analysis of the same group at different study time points required ANOVA with repeated measures.44 The Bonferroni multiple comparisons procedure44 was used on comparisons that showed statistical significance by ANOVA to determine which groups or specific time points had those significant differences. The differences between bupropion and placebo for number of HFs and ASEX are absolute differences and are calculated by subtracting the
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initial value from the final value. For the HFs’ index, what is shown is the result of the respective HF values (initial final)/initial 100 from each patient and divided by the number of patients. For nonparametric variables, such as side effects and symptoms, we compared the groups using the Mann-Whitney45 and Friedman tests.45 We used the Chi-square test to evaluate patient preference for placebo vs. bupropion. The null hypothesis of this study was that there would be no difference in frequency and/or severity of HFs between the use of bupropion and placebo; assessment was performed with the Student’s t-test.
Results Patients were enrolled in this study from September 2009 through October 2010. During this period, 91 patients were screened; of these, 13 refused to participate and 23 were excluded. Fifty-five patients were randomized, and of these, six withdrew during the first step, but none withdrew during the second step. Side effects were the reason for withdrawal in four patients; three of these were using placebo and one bupropion (Fig. 1). One patient was excluded because of inappropriate completion of daily HF diaries. The average patient age was 49 years; 45% were white, 61% were married, 69.4% were postmenopausal, 45% had an average of nine years of study, and about 60% were sexually active. Regarding BC treatment, 75% received chemotherapy, 92% received radiotherapy, and 86% of patients were taking tamoxifen (Table 1). Differences in the average number of HFs per day and severity of HF scores between the bupropion and placebo study arms are shown in Table 2. Bupropion decreased HFs by 1.26 per day, whereas the placebo reduced HFs by 2.11 per day (P ¼ 0.528). Regarding the severity score, bupropion reduced the average score by 6.31% and placebo by 30.47% (P ¼ 0.595). When groups and different study time points were evaluated separately, there was no difference between groups for frequency of HFs and HF severity score. However, evaluation at different time points of the study showed that, regardless of
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Fig. 1. Flow diagram and retention of study patients.
what medication was being used, there was statistically significant improvement in the number of HFs (P ¼ 0.002) and the HF severity score (P ¼ 0.040) as the study progressed (from beginning to final measurements; Appendix I). There was no crossover effect (P > 0.05). No difference in sexual dysfunction was observed between the use of bupropion and placebo (Table 2) nor for the analyses of each question of the ASEX scale (Appendix II). There were no differences between groups when evaluated separately. The difference in sexual dysfunction scores was statistically significant (P ¼ 0.003) when the sexual dysfunction score was evaluated for different stages of the study, regardless of which medication was being used. There was no statistically significant difference in BDI or EORTC QLQ-C30 scores between groups or between different time points of the study. There was no statistically significant difference in frequency of adverse effects between groups. Only one withdrawal was attributed to bupropion’s side effects (headache, dizziness, and palpitations). Of the 48 patients who completed the study, 45 expressed a preference for one of the study stages. Of these, 47% preferred the stage at which they used bupropion (P ¼ 0.673).
Discussion Compared with placebo, bupropion did not show a minimum of 50% activity for the control of HFs in this group of BC survivors. These findings are consistent with a pilot study that evaluated 14 patients with more than 14 HFs per week (seven men and seven women). In this study, patients underwent treatment for four weeks with bupropion at a dose of 150 mg twice daily. This small pilot study found a 23% reduction in the severity score of HFs, which could be attributed to the placebo effect.30 In our trial, within the placebo group, when we considered all data in aggregate, HFs were reduced by 30.47%, which is compatible with the reported placebo effect of 20%e30%.36 However, when we considered all data in aggregate for bupropion, the reduction in the HFs within the bupropion group was lower than expected (6.31%), and it was not statistically significant. We also saw no statistically significant differences between groups. The lack of bupropion-mediated reduction of HFs in comparison with other antidepressants, such as serotonin and norepinephrine reuptake inhibitors and selective serotonin reuptake inhibitors, may be explained by the distinct mechanism of action of this atypical antidepressant. Bupropion is a norepinephrine
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Bupropion for Hot Flashes
pathophysiological mechanism of HFs involves the serotonergic pathway. Narrowing the hypothalamic thermostat amplitude triggers HFs. Thus, small variations in temperature are capable of triggering vasomotor symptoms. This narrowing is thought to be caused by a decrease in estrogen levels11 that increases the synthesis of serotonin and endorphins, which in turn are responsible for inhibiting the production of norepinephrine. Once there is a decrease in estrogen levels during menopause or in patients treated with hormonal deprivation, levels of endorphins and serotonin decrease and the number of serotonin receptors increases.11 The improvement of HFs and sexual dysfunction was statistically significant for different study time points, regardless of which treatment was being used (bupropion or placebo). This confirms the inactivity of bupropion for HF control in this study and stresses the important effect of medical care and the prescription of any medications used to treat self-reported symptoms. In this study, we could not demonstrate that bupropion improves sexual dysfunction compared with placebo. Recent studies have shown that patients with sexual dysfunction who used bupropion experienced improvements in sexual function. These studies were randomized and included samples of around 200 patients.46,47 The number of patients evaluated in the present study was smaller. In fact, because the evaluation of sexual dysfunction
Table 1 Patient Characteristics at Baseline Characteristics
n (%)
Median age, yrs (range) Race Caucasian Latin Black Marital status Married Single Divorced Widowed Menopause status Pre Post Sexually active Yes No Stage In situ I/II III Prior chemotherapy Yes No Prior radiotherapy Yes No Hormone therapy Tamoxifen GnRH agonist þ tamoxifen AI GnRH agonist þ AI Number of HFs <14 HFs/week $14 HFs/week
49 (33e71) 22 (44.9) 18 (36.7) 9 (18.4) 30 6 8 5
(61.2) (12.2) (16.3) (10.2)
34 (69.4) 15 (30.6) 29 (59.2) 20 (40.8) 6 (12.2) 26 (53.1) 15 (30.6) 37 (75.5) 11 (22.4) 45 (91.8) 3 (6.1) 39 3 6 1
975
(79.6) (6.1) (12.2) (2)
42 (85.7) 7 (14.3)
GnRH ¼ gonadotropin releasing hormone; AI ¼ aromatase inhibitor; HF ¼ hot flash.
and dopamine reuptake inhibitor with no serotonergic activity.27,28 Although not completely understood, it is believed that the
Table 2 Comparison of the Index and Number of HFs and ASEX Scores in Patients Stratified by the Beginning and End of Treatment With Bupropion or Placebo Treatment Bupropion Variables HFs index Number of HFs ASEX
Placebo
Timing
Average
SD
n
Average
SD
n
Beginning Final Difference Beginning Final Difference Beginning Final Difference
9.94 7.75 6.31 5.32 4.06 1.26 12.88 11.52 1.36
12.28 10.10 211.29 4.70 4.18 3.01 10.16 9.50 3.77
48 48 48 48 48 48 48 48 48
11.78 7.66 30.47 6.72 4.61 2.11 12.83 12.26 0.57
15.61 8.55 229.82 11.93 4.25 10.35 10.30 9.49 3.41
48 47 47 48 47 47 48 47 47
P-value
0.595 0.528 0.497
HF ¼ hot flash; ASEX ¼ Arizona Sexual Experience Scale. Because there was no crossover effect (P > 0.05), the data shown here represent the aggregate of the two phases in which each patient received placebo or bupropion regardless of the order in which these medications were given. The differences between bupropion and placebo for number of HFs and ASEX scores are absolute differences and are calculated by subtracting the initial from the final value. For the HFs index, what is shown is the result of the respective HF values (initial final)/initial 100 from each patient and divided by the number of patients.
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was a secondary objective of this study, only 29 patients were sexually active, and of those, only 25 had sexual dysfunction according to the ASEX scale. The evaluation of a small sample may not have been sufficient to show a potential benefit. An open nonrandomized trial evaluated the eight-week use of 150 mg/day of bupropion in 20 female BC survivors who were undergoing hormone therapy; there was improvement in sexual function, but the trial’s lack of a placebo group may have contributed to an overestimation of bupropion’s effects.29 The efficacy of bupropion as an antidepressant is well established in the literature. However, this study found no difference in BDI scores between the bupropion and placebo groups. Among the 48 patients who completed the study, only seven had a diagnosis of depression according the BDI, which could explain this finding. We also observed no statistically significant difference between overall health and qualityof-life scores. Although there was a decrease in the number of HFs, severity of HFs, and sexual dysfunction during treatment (for both placebo and bupropion), we believe that the concept of quality of life encompasses many physical, psychological, and social aspects. Therefore, it is possible that the nonspecific HF improvement we observed, regardless of the medication used, may not have been sufficient to reflect a change in quality-of-life scores. Finally, 47% of the patients preferred bupropion, whereas 53% preferred placebo. Therefore, at the end of the study, most patients did not have a significant preference for either placebo or bupropion, which corroborates our finding that there is a lack of bupropion activity for HFs, as seen in our primary end point. Although our study was only powered to disclose a 50% reduction in HF scores between placebo and bupropion, which would be higher than that expected according to other studies,15e26 we observed not even a trend in favor of bupropion in this study. Therefore, we do not believe that a larger sample would be able to show a clinically significant effect in favor of bupropion. Most of our patients used tamoxifen because of its lower costs compared with aromatase inhibitors in Brazil. Although there is in vitro evidence of a high inhibition potential of CYPD6
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activity by bupropion, there are no in vivo data to support this contention. Because of its negative effects in patients with HF, we do not recommend bupropion for this indication even for those patients on aromatase inhibitors in whom no drug-drug interactions are expected to occur. In conclusion, compared with placebo, bupropion did not show activity for the control of HFs in this group of BC survivors.
Disclosures and Acknowledgments No financial support was received for this study, and the authors declare no conflicts of interest.
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10. Tuma RS. Non-compliance with tamoxifen increases risk of death. Oncol Times 2007;29:28. 11. Freedman RR. Pathophysiology and treatment of hot flashes. Semin Reprod Med 2005;23: 117e125. 12. Nelson HD. Commonly used types of postmenopausal estrogen for treatment of hot flashes: scientific review. JAMA 2004;291:1610e1620. 13. Rossouw JE, Anderson GL, Prentice RL, 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;288:321e333. 14. Avis NE. Breast cancer survivors and hot flashes: the search for nonhormonal treatments. J Clin Oncol 2008;26:5008e5010. 15. Loprinzi CL, Kugler JW, Sloan JA, et al. Venlafaxine in management of hot flashes in survivors of breast cancer: a randomized controlled trial. Lancet 2000;356:2059e2063. 16. Evans ML, Pritts E, Vittinghoff E, et al. Management of postmenopausal hot flashes with venlafaxine hydrochloride: a randomized controlled trial. Obstet Gynecol 2005;105:161e166.
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25. Pandya KJ, Morrow GR, Roscoe JA, et al. Gabapentin for hot flashes in 420 women with breast cancer: a randomized double-blind placebo-controlled trial. Lancet 2005;366:818e824. 26. Loprinzi CJ, Qin R, Baclueva EP, et al. Phase III, randomized, double-blind, placebo-controlled evaluation of pregabalin for alleviating hot flashes, N07C1. J Clin Oncol 2010;28:641e647. 27. Foley KF, DeSanty KP, Kast RE. Bupropion: pharmacology and therapeutic applications. Expert Rev Neurother 2006;6:1249e1265. 28. Wilkes S. Bupropion. Drugs Today (Barc) 2006; 42:671e681. 29. Mathias C, Mendes CM, Sena EP, et al. An openlabel, fixed-dose study of bupropion effect on sexual function scores in women treated for breast cancer. Ann Oncol 2006;17:1792e1796. 30. P erez DG, Loprinzi CL, Sloan J, et al. Pilot evaluation of bupropion for the treatment of hot flashes. J Palliat Med 2006;9:631e637. 31. Sideras K, Ingle JN, Ames MM, et al. Coprescription of tamoxifen and medications that inhibit CYP2D6. J Clin Oncol 2010;28:2768e2776.
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19. Speroff L, Gass M, Constantine G, Olivier S, for the Study 315 Investigators. Efficacy and tolerability of desvenlafaxine succinate treatment for menopausal vasomotor symptoms: a randomized controlled trial. Obstet Gynecol 2008;111:77e87. 20. Loprinzi CL, Sloan JA, Perez EA, et al. Phase III evaluation of fluoxetine for treatment of hot flashes. J Clin Oncol 2002;20:1578e1583. 21. Stearns V, Beebe KL, Iyengar M, Dube E. Paroxetine controlled release in the treatment of menopausal hot flashes: a randomized controlled trial. JAMA 2003;289:2827e2834. 22. Barton DL, LaVasseur BI, Sloan JA, et al. Phase III, placebo-controlled trial of three doses of citalopram for the treatment of hot flashes: NCCTG trial N05C9. J Clin Oncol 2010;28:3278e3283. 23. Wu MF, Hilsenbeck SG, Tham YL, et al. The efficacy of sertraline for controlling hot flashes in women with or at high risk of developing breast cancer. Breast Cancer Res Treat 2009;118:369e375. 24. Butt DA, Lock M, Lewis JE, et al. Gabapentin for the treatment of menopausal hot flashes: a randomized controlled trial. Menopause 2008; 15:310e318.
34. Dezentje V, van Blijderveen NJ, Gelderblom H, et al. Concomitant CYP2D6 inhibitor use and tamoxifen adherence in early-stage breast cancer: a pharmacoepidemiologic study. J Clin Oncol 2009;27(Suppl 9):abstr CRA509. 35. Kotlyar M, Brauer LH, Tracy TS, et al. Inhibition of CYP2D6 activity by bupropion. J Clin Psychopharmacol 2005;25:226e229. 36. Sloan JA, Loprinzi CL, Novotny PJ, et al. Methodologic lessons learned from hot flashes studies. J Clin Oncol 2001;19:4280e4290. 37. Carpenter JS. The Hot Flashes Related Daily Scale: a tool for assessing the impact of hot flashes on quality of life following breast cancer. J Pain Symptom Manage 2001;22:979e989. 38. McGahuey CA, Gelenberg AJ, Laukes CA, et al. The Arizona Sexual Experience Scale (ASEX): reliability and validity. J Sex Marital Ther 2000;26: 25e40. 39. Mathias C, Athanazio RA, Braghiroli MI, et al. Use of the Arizona Sexual Experience Scale (ASEX) in the evaluation of sexual dysfunction in Brazilian cancer patients. [in Spanish]. J Bras Psiquiatr 2005;54:216e220.
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Appendix I Statistical Analyses Using Analysis of Variance Comparing the Difference in Each Variable Between Different Treatment Groups and Different Study Time Points (Initial/First/Second Phase Medications) Variables HFs index Number of HFs ASEX BDI EORTC QLQ-C30
Factors Group Time point Group time Group Time point Group time Group Time point Group time Group Time point Group time Group Time point Group time
point point point point point
No. of Factors
No. of Patients
F-value
P-value
1 2 2 1 1 1 1 2 2 1 2 2 1 2 2
45 75 75 45 55 55 27 47 47 58 74 74 45 75 75
0.09 7.26 0.65 0.54 4.10 1.16 1.90 7.32 0.55 0.33 1.98 0.40 0.17 1.46 0.38
0.760 0.002 0.497 0.465 0.040 0.297 0.179 0.003 0.558 0.568 0.153 0.633 0.680 0.238 0.649
HF ¼ hot flash; ASEX ¼ Arizona Sexual Experience Scale; BDI ¼ Beck Depression Inventory; EORTC QLQ-C30 ¼ European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30. When groups (bupropion or placebo) were evaluated separately, there was no difference between them in HFs index, number of HFs, ASEX, BDI, or EORTC QLQ-C30 scales. However, evaluation at different time points of the study showed that, regardless of what medication was being used, there was statistically significant improvement in the HFs index (P ¼ 0.002), number of HFs (P ¼ 0.04), and ASEX (P ¼ 0.003) as the study progressed (initial/first/second phase medications) (bold numbers). There was no crossover effect (group time points; P > 0.05).
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Bupropion for Hot Flashes
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Appendix II Comparison of Each Question of the ASEX Scale Stratified by the Beginning and End of Treatment With Bupropion or Placebo (McNemar Test) Bupropion
Questions How strong is your sex drive? Not applicable (not sexually active) Extremely strong Very strong Somewhat strong Somewhat weak Very weak No sex drive Improvement, n (%) How easily are you sexually aroused? Not applicable (not sexually active) Extremely easily Very easily Somewhat easily Somewhat difficult Very difficult Never aroused Improvement, n (%) How easily does your vagina become wet during sex? Not applicable (not sexually active) Extremely easily Very easily Somewhat easily Somewhat difficult Very difficult Never Improvement, n (%) How easily can you reach orgasm? Not applicable (not sexually active) Extremely easily Very easily Somewhat easily Somewhat difficult Very difficult Never reach orgasm Improvement, n (%) Are your orgasms satisfying? Not applicable (not sexually active) Extremely satisfying Very satisfying Somewhat satisfying Somewhat unsatisfying Very unsatisfying Cannot reach orgasm Improvement, n (%)
Placebo
Initial
Final
Initial
Final
n (%)
n (%)
n (%)
n (%)
17 0 0 5 8 8 10 17 0 1 10 14 4 2 17 0 0 12 10 8 1 17 0 0 12 9 6 4 17 1 6 15 4 1 4
(35.4) 16 (0.0) 1 (0.0) 2 (10.4) 14 (16.7) 4 (16.7) 8 (20.8) 3 17 (35.4)
(33.3) (2.1) (4.2) (29.2) (8.3) (16.7) (6.3)
(35.4) 16 (0.0) 2 (2.1) 1 (20.8) 12 (29.2) 11 (8.3) 3 (4.2) 3 9 (18.8)
(33.3) (4.2) (2.1) (25.0) (22.9) (6.3) (6.3)
(35.4) 18 (0.0) 0 (0.0) 0 (25.0) 14 (20.8) 9 (16.7) 5 (2.1) 2 11 (22.9)
(37.5) (0.0) (0.0) (29.2) (18.8) (10.4) (4.2)
(35.4) 17 (0.0) 1 (0.0) 0 (25.0) 10 (18.8) 13 (12.5) 5 (8.3) 2 8 (16.7)
(35.4) (2.1) (0.0) (20.8) (27.1) (10.4) (4.2)
(35.4) 17 (2.1) 2 (12.5) 6 (31.3) 18 (8.3) 3 (2.1) 0 (8.3) 2 6 (12.5)
(35.4) (4.2) (12.5) (37.5) (6.3) (0.0) (4.2)
16 0 2 10 3 9 8 17 1 0 7 17 3 3 17 0 0 9 12 6 4 17 0 0 9 12 5 5 17 2 5 16 3 0 5
(33.3) 17 (0.0) 0 (4.2) 1 (20.8) 13 (6.3) 8 (18.8) 2 (16.7) 7 14 (29.2)
(35.4) (0.0) (2.1) (27.1) (16.7) (4.2) (14.6)
(35.4) 17 (2.1) 0 (0.0) 1 (14.6) 12 (35.4) 14 (6.3) 3 (6.3) 1 11 (22.9)
(35.4) (0.0) (2.1) (25.0) (29.2) (6.3) (2.1)
(35.4) 17 (0.0) 0 (0.0) 0 (18.8) 15 (25.0) 8 (12.5) 7 (8.3) 1 14 (29.2)
(35.4) (0.0) (0.0) (31.3) (16.7) (14.6) (2.1)
(35.4) 17 (0.0) 0 (0.0) 0 (18.8) 14 (25.0) 10 (10.4) 4 (10.4) 3 13 (27.1)
(35.4) (0.0) (0.0) (29.2) (20.8) (8.3) (6.3)
(35.4) 17 (4.2) 2 (10.4) 6 (33.3) 15 (6.3) 4 (0.0) 1 (10.4) 3 8 (16.7)
(35.4) (4.2) (12.5) (31.3) (8.3) (2.1) (6.3)
P-value
0.664
0.815
0.648
0.267
0.754
ASEX ¼ Arizona Sexual Experience Scale. There was no statistically significant difference between the improvement observed with the use of bupropion or placebo treatment in any of the questions of the ASEX scale (P > 0.05).