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Carroll et al. carried out a systematic review study that consisted of prospective RCTs, retrospective and prospective cohort studies, and case–control trials published in the English language focusing on the primary outcome of vasomotor symptoms of menopause mainly hot flashes and studies on paroxetine versus active or placebo treatment.[22] Data were derived from 194 women with vasomotor symptoms with a history of breast cancer and 1407 women with vasomotor symptoms but without a history of breast cancer. They found that treatment with paroxetine (mesylate and hydrochloride) showed a remarkable decline of hot flash frequency by 33– 67% compared to only 13.7–37.8% decline with placebo treatment of females with menopause irrespective of the history of breast cancer over the period of 6–12 weeks.[22] Treatment of menopausal women with paroxetine for the vasomotor symptoms is safer and effective in a lower-dose range of 7.5–12.5 mg/day. Hence, paroxetine can be regarded as a mainstay treatment modality for menopausal women for whom MHT is either intolerable or inappropriate.[22]
Riemma et al. conducted a systematic review and meta-analysis study consisting of four RCTs conducted on 1482 women with physiological or surgical menopause experiencing hot flushes and insomnia that were randomized to either placebo or lower strength paroxetine.[31] They found that episodes of hot flashes significantly declined among females on paroxetine in contrast to females on placebo treatment.[31] Paroxetine in lower doses can be considered as an efficacious option in managing the menopausal vasomotor symptoms, mainly hot flashes. Paroxetine-treated postmenopausal women showed marked attenuation of hot flush frequency compared to placebo with mean weekly attenuation with mean difference (MD) – 7.97 episodes/week. The hot flush reduction was – 7.89 MD and – 7.63 MD among women having physiological and surgical menopause, respectively. Evidence quality regarding the role of paroxetine in managing vasomotor symptoms was good.[31]
Wei et al. conducted a systematic review and meta-analysis study consisting of RCTs on assessing paroxetine’s effect compared to no treatment or placebo among postmenopausal as well as perimenopausal women with moderate and severe levels of vasomotor symptoms.[32] A total of 2717 perimenopausal and postmenopausal women from nine RCTs were assessed for the efficacy of paroxetine with regard to the frequency of hot flashes. A total of 2667 perimenopausal and postmenopausal women from eight RCTs were assessed for the efficacy of paroxetine with regard to the severity of hot flashes. They found that the treatment of vasomotor symptoms with paroxetine showed a marked mean decline in hot flash frequency by MD of 8.82/week in the 4th week, 8.86/week in the 6th week, and 7.27/week in the 12th week.[32] The same study also showed a marked mean decline in hot flash severity score by MD 3.18 and 2.4/week at the 4th and 12th weeks, respectively. Paroxetine use was linked with side effects such as dizziness and nausea. Evidence quality regarding the role of paroxetine in managing vasomotor symptoms was found to be moderate.[32]
Simon et al. conducted RCT based on 2003 FDA guidance regarding the clinical assessment of MHT in vasomotor symptoms of menopause.[33] A total of 591 and 593 postmenopausal females were randomly allocated to paroxetine 7.5 mg and placebo treatment groups, respectively. In the 12-week study, mean weekly attenuations of vasomotor symptom (VMS) frequencies were –33.0 versus –23.5 at week 4 and were –43.5 versus –37.3 at week 12 on paroxetine 7.5 mg versus placebo, respectively. In the 24-week study, mean weekly attenuations of frequencies of VMS were –28.9 versus –19.0 at week 4 and were –37.2 versus –27.6 at week 12 on paroxetine 7.5 mg versus placebo, respectively. Regarding VMS severity, in the 12-week study, the mean weekly attenuations were –0.09 versus –0.05 at week 4 and were –0.10 and –0.09 at week 12 on paroxetine 7.5 mg versus placebo, respectively. In the 24-week study, mean weekly attenuations in the severity of VMS were –0.09 versus –0.06 at week 4 and were –0.12 versus –0.07 at week 12 on paroxetine 7.5 mg versus placebo, respectively. Hence, they found that paroxetine in the lower dose of 7.5 mg/day lowered the mean weekly frequency as well as the severity of vasomotor symptoms of menopause in comparison to the placebo on weeks 4 and 12 in 24 weeks of treatment. The majority of the treatment-emergent side effects were mild to moderate in intensity, with no notable alterations found in the vitals and laboratory parameters of the study participants. There occurred no paroxetine discontinuation symptoms after stopping the treatment.[33] The discontinuation emergent signs and symptoms (DESS) scale was applied within 7 ± 3 days of the final paroxetine dose. DESS did not show any significant difference between the placebo arm and low dose 7.5 mg paroxetine arm which means that paroxetine did not cause any increased risk of discontinuation symptoms after its stoppage. Low-dose paroxetine was well tolerated by the menopausal women with noteworthy attenuation of frequency as well as severity of menopausal vasomotor symptoms. The beneficial outcome of the paroxetine treatment was persistent over 24-week period of the study.[33]
Capriglione et al. conducted an RCT consisting of 86 women with surgical menopause due to gynecological cancer who had postmenopausal hot flashes and sleep disturbance.[34] Out of the total of 86 women, 80 had completed the study intervention. The mean age of study subjects was 53 years with a range of 36–75 years. Of those 80 participants, 42 and 38 belonged to the 7.5 mg paroxetine and placebo groups, respectively. They found a statistically significant decline in the frequency as well as the severity of vasomotor symptoms of menopause on lower strength of paroxetine (7.5 mg) compared to the placebo on week 4 and week 16. Mean weekly attenuations of VMS frequencies were –31.0 versus –21.5 at week 4 and were –46.5 versus –39.3 at week 16 on 7.5mg paroxetine and placebo treatments, respectively. As regards VMS severity, the mean weekly attenuations were –0.09 versus –0.05 at week 4 on 7.5 mg paroxetine versus placebo treatment, respectively. Statistically significant attenuation of vasomotor symptoms related to night-sleep awakening and improved sleep duration were also seen among the study participants who received paroxetine than those who received placebo. Treatment with paroxetine was beneficial in improving the sleep duration and reducing the severity as well as frequency of hot flashes. Paroxetine was well tolerated and the level of compliance was high.[34]
Stearns et al. conducted RCT consisting of women with physiologic menopause who experienced at the minimum 2–3 episodes of troublesome hot flashes per day or no <14 troublesome hot flashes per week, and those who have quit MHT for a period of at least 6 weeks.[35] Of the total of 165 menopausal women, 56 randomly received placebo treatment while 51 received 12.5 mg/day of CR paroxetine and 58 received 25 mg/day of paroxetine CR. Randomization was done on the ratio of 1:1:1 for a period of 6 weeks. By the 6th week of treatment, the mean frequency of the daily hot flashes was turned down from 7.1 to 3.8 (mean reduction of 3.3.) in women who received 12.5 mg/day of paroxetine CR, from 6.4 to 3.2 (mean reduction of 3.2) in women who received 25 mg/day paroxetine CR, and from 6.6 to 4.8 (mean reduction of 1.8) in those who received placebo treatment for hot flashes. At the end of 6 weeks of management, the median reduction in hot flash composite scores was 64.6%, 62.2%, and 37.8% among menopausal women who received 25 mg/day of paroxetine CR, 12.5 mg/day of paroxetine CR, and placebo treatment, respectively.[35] CR formulation of paroxetine can be effectively used as a non-hormonal treatment alternative to MHT for managing postmenopausal hot flashes.
Soares et al. conducted a controlled clinical trial in which 64 women in perimenopausal as well as postmenopausal phases without anxiety and depression who were experiencing vasomotor symptoms were included in the study.[36] Fifty women completed the study. At the entry point of the study, women who had 17 hot flashes every week received MHT over a period of >5 years and ceased the treatment for <1 year before the onset of the study. Treatment with paroxetine CR in a dose range of 12.5–25 mg/day was found to be more efficacious compared to placebo in controlling the hot flashes of menopause. The mean reduction in hot flashes was 6.1 versus 2.8 per week with paroxetine CR and placebo, respectively, at P = 0.03.[36] Paroxetine CR can be effectively used as an alternative treatment option in treating postmenopausal as well as perimenopausal vasomotor symptoms among females who have discontinued the MHT.
Stearns et al. conducted a prospective RCT study on 151 women who experienced not <2 bothersome hot flashes every day or 14 bothersome hot flashes every week over a period of 1 month or longer.[37] They found that hot flash frequency was minimized by 40.6% by paroxetine 10 mg/day compared to 13.7% by placebo (P = 0.0006). Hot flash frequency was minimized by 51.7% by paroxetine 20 mg/day compared to 26.6% by placebo (P = 0.002). The hot flash composite score was reduced by 45.6% by 10 mg paroxetine compared to 13.7% by placebo (P = 0.0008). On the other hand, 20 mg paroxetine administration was associated with a reduction of hot flash composite score by 56.1% compared to 28.8% by placebo (P = 0.004).[37] The efficacy of both doses of paroxetine was found to be similar, but treatment discontinuation was lesser at lower doses. There was a significant improvement in sleep with paroxetine 10 mg/day compared to placebo (P = 0.01).[37] Paroxetine can be effectively used as a treatment option for hot flashes of premenopausal, perimenopausal, and postmenopausal women with or without earlier history of breast cancer.[37]
David et al. conducted a clinical review study on menopausal women experiencing bothersome vasomotor symptoms and observed that paroxetine in a lower dose was effectively used as non-hormonal therapy in managing menopausal vasomotor symptoms.[38] The recommended daily dose of paroxetine is 7.5 mg at bedtime. Treatment with paroxetine was associated with a significant decline in severity as well as frequency of hot flashes. Paroxetine can be used for menopausal females for the management of vasomotor symptoms where MHT is either not preferred or contraindicated. Level I evidence has been shown in the case of treatment of vasomotor symptoms with paroxetine. Both the mesylate and hydrochloride salts of paroxetine have shown efficacy, but paroxetine hydrochloride can be used when there exist issues such as cost and availability.[38] Dose-dependent side effects of paroxetine are dizziness, fatigue, and nausea.[38] As paroxetine is a strong cytochrome P450 2D6 isoenzyme (CYP2D6) inhibitor, its utilization must be avoided among females suffering from carcinoma of the breast who are on tamoxifen because there are more chances of recurrence of carcinoma of the breast with a marked increase in the likelihood of death.[38] In such populations, other safer antidepressants such as desvenlafaxine, venlafaxine, citalopram, or escitalopram can be used, of which desvenlafaxine and venlafaxine have no CYP2D6 inhibiting property. On the other hand, escitalopram and citalopram have weak CYP2D6 inhibiting properties.[38]
Simon et al. conducted an RCT on 42 menopausal women aged 40 years or more with 5–50 hot flashes per week.[39] Those 42 women were randomized to 3:3:1–60 mg raloxifene, placebo, and 20 mg paroxetine over a period of 12 weeks. Diaries related to the severity and frequencies of hot flashes were appraised at intervals of 1 week. After 12 weeks, frequencies of the hot flashes showed mean percent changes of – 14.2%, – 37.4%, and – 49.8% with raloxifene, placebo, and paroxetine, respectively. After 12 weeks, the severity of hot flashes showed mean percent changes of – 9.6%, – 39.9%, and – 36.6% with raloxifene, placebo, and paroxetine, respectively.[39] Hot flash frequencies were lower among the paroxetine group in contrast to the raloxifene group (−49.8% versus −14.2%). The hot flash diary showed reliable trends toward the expected differences between paroxetine and raloxifene groups, indicating that a hot flash diary can be very handy for assessing attenuation in hot flash severity as well as frequencies among postmenopausal females.[39]
Naz et al. conducted an open-label control clinical trial on 180 outpatients with postmenopausal hot flashes.[40] They divided study participants into three groups receiving 12.5 mg paroxetine, 20 mg paroxetine, and placebo. Greene climacteric score (GCS) scaling was used in those three groups to assess the effects of placebo, 12.5 mg paroxetine, and 20 mg paroxetine on the frequency of hot flashes among menopausal females. With regard to baseline, mean GCS scoring frequencies were 2.64 ± 0.29, 2.76 ± 0.23, and 2.76 ± 0.24 among 12.5 mg paroxetine, 20 mg paroxetine, and placebo groups, respectively. At 12 weeks, the mean GCS scoring frequencies were 1.97 ± 0.31, 2.04 ± 0.12, and 2.80 ± 0.24 among 12.5 mg paroxetine, 20 mg paroxetine, and placebo groups, respectively.[40] The frequency of hot flashes with both 12.5 mg and 20 mg paroxetine doses was significantly reduced when compared with placebo among the postmenopausal women.
Portman et al. carried out RCT in which females in a postmenopausal phase aged 40 years and more with seven to eight hot flushes every day or 50–60 hot flushes every week of moderate to severe intensities over the period of 1 month were included in the study by randomly assigning them to 7.5 mg paroxetine and placebo groups for 12 or 24 weeks period.[41] A total of 1184 study subjects were included of which 570 belonged to 24 weeks study and 614 belonged to 12 weeks study. They pooled the data from the 1st to 12th weeks of both 12 and 24 week’s studies. Women who were “hot flash responders” among the paroxetine 7.5 mg group (i.e., those who showed 50% or more attenuation in hot flash frequency from baseline) showed marked improvement in Arizona Sexual Experiences Scale scores at weeks 4, 12, and 24 than women who were hot flash non-responders. No statistically significant alterations from baseline sexual functioning or weight were recorded in the 7.5 mg paroxetine group. Rather, a small significant increase in parameters such as body mass index and body weight was seen among women from the placebo group at week 4 of the treatment.[41] Paroxetine with a least strength of 7.5 mg/day is a potent non-hormonal treatment of choice in managing the menopausal vasomotor symptoms of moderate and severe intensities. Such a low-dose paroxetine formulation is not associated with any significant alteration in sexual functioning and body weight over a treatment period of 24 weeks.[41]
Pinkerton et al. carried out RCT in which menopausal women who had >7 or 8 hot flashes every day, or 50–60 hot flashes every week of moderate to severe intensities over the period of at least 30 days or more before the entry point of the study were incorporated.[42] Postmenopausal women with vasomotor symptoms of moderate and severe grades were randomly allocated placebo (n=593) and paroxetine 7.5 mg (n=591) groups. At the onset of the study, participants experienced 3.6 awakenings per night due to the vasomotor symptoms of menopause. Such night-time sleep fragmentations due to vasomotor symptoms were found to be greatly decreased within 4 weeks of onset of treatment with 7.5 mg paroxetine (39% reduction with paroxetine vs. 28% reduction with placebo at P = 0.0049). Attenuation in night-time awakening was persistent throughout a period of 12–24 weeks of management with paroxetine. Furthermore, pharmacotherapy with 7.5 mg paroxetine significantly improved the total sleep duration during night-time (at week 4, total sleep duration was increased by +31 min with paroxetine versus +16 min with placebo at P = 0.0075).[42] The use of lower-strength paroxetine (7.5 mg) in managing the vasomotor symptoms of menopause increases total nighttime sleep duration as well as significantly reduces night-time awakenings that occur secondary to vasomotor symptoms.[42]
Stearns et al. conducted a pilot trial in which 30 breast cancer survivor females (three premenopausal and 27 postmenopausal) who had a minimum of two hot flashes every day or a minimum of 14 hot flashes every week over a minimum 1 month period were selected for the participation in the study to assess the effectiveness of paroxetine on frequency and severity related with hot flashes.[43] Twenty-seven females completed the 6 week long study. Those women were asked to complete hot flash diaries throughout the study on a daily basis. For the initial 1 week period, women did not receive paroxetine, for another 1 week, they received 10 mg paroxetine/day, and for another 4 weeks period, they received 20 mg paroxetine/ day. Mean reductions in the severity and the frequency of hot flashes were 75% and 67%, respectively.[43] The study also showed a significant improvement in other parameters such as sleep, anxiety, quality of life, and depression among the study participants.[43] Twenty-five (83%) participants continued taking paroxetine until the end of the study. Two women discontinued and the other two women had dose reduction due to somnolence caused by paroxetine. One woman discontinued paroxetine due to perceived anxiety while on treatment.[43] Paroxetine hydrochloride is an effective treatment option in treating hot flashes among pre-and postmenopausal women who are survivors of carcinoma breast.[43]
Weitzner et al. conducted a pilot trial to assess the safety and effectiveness of paroxetine in the management of hot flashes and disturbances of sleep among females with carcinoma of the breast.[44] A total of 13 females took part in the study. The mean age of study subjects was 52 years with a range of 43– 60 years. Of those 13, 3, and 10 women were perimenopausal and postmenopausal, respectively. All the study subjects were suffering from hot flashes. After treatment with 20 mg/ day paroxetine, the mean rating of severity of hot flashes notably minimized from “quite a bit” or “extremely severe” to “moderately severe” (mean of 2.08 and P = 0.002). There was a reduction of percentage from 100 to 38 regarding the subjects who marked the rating of hot flashes as “extremely severe” or “quite a bit” (P = 0.008). After paroxetine therapy, the quality of sleep also showed noteworthy improvement from a rating of “fairly bad” to “very good” (mean of 1.85 vs. 0.77).[44] Evidence of quality regarding treatment with paroxetine for vasomotor symptoms was Level I.[45]Table 1 above summarizes various findings from all the 15 studies included in this review in a concise manner.
Table 1: Summarizes the findings of all the 15 studies in concise manner.
Author, Year and Reference number Type of study Sample size Dose of Paroxetine Frequency of Hot flashes Severity of Hot flashes Placebo treated group Paroxetine
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