Duloxetine, a Serotonin and Noradrenaline Reuptake Inhibitor (SNRI) for the Treatment of Stress Urinary Incontinence: A Systematic Review

european urology 51 (2007) 67 74 available at www.sciencedirect.com journal homepage: www.europeanurology.com Review Female Urology Incontinence Duloxetine, a Serotonin and Noradrenaline Reuptake Inhibitor (SNRI) for the Treatment of Stress Urinary Incontinence: A Systematic Review Paramananthan Mariappan a, *, Ammar Alhasso a, Zoe Ballantyne b, Adrian Grant c, James N Dow d a Department of Urology, Western General Hospital, Edinburgh, United Kingdom b Department of Obstetrics and Gynaecology, The Simpson Centre, Edinburgh Royal Infirmary, Edinburgh, United Kingdom c Health Services Research Unit & Cochrane Incontinence Group, University of Aberdeen, Aberdeen, United Kingdom d Academic Urology Unit & Cochrane Incontinence Group, University of Aberdeen, Aberdeen, United Kingdom Article info Article history: Accepted August 23, 2006 Published online ahead of print on September 15, 2006 Keywords: Duloxetine Medical management Meta-analysis Serotonin and noradrenaline reuptake inhibitor Stress urinary incontinence Abstract Objective: Surgery and pelvic floor muscle training are established methods for treating stress urinary incontinence (SUI). A new serotonin and noradrenaline reuptake inhibitor, duloxetine, has been studied in multiple phase 3 trials as a form of medical management of this condition. This systematic review determined the effectiveness and acceptability of duloxetine in managing SUI. Methods: We reviewed all randomised controlled trials comparing duloxetine with placebo or no treatment. The search included the Cochrane Incontinence Group specialised register, CENTRAL, MEDLINE, PREMEDLINE, dissertation abstracts, and the reference lists of relevant articles. The primary outcome was the number of participants whose symptoms were cured while on treatment. Secondary outcomes included subjective improvement, incontinent episodes, quality of life,, and discontinuation rates. Results: Nine trials were included, totalling 3063 women with predominantly SUI, all randomised to receive duloxetine or placebo. Treatment duration was 3 36 wk. Subjective cure favoured duloxetine (from three trials, 10.8% vs. 7.7%; RR = 1.42; 95%CI, 1.02 1.98, p = 0.04). The limited data available to assess objective cure rates were consistent with this. Individual studies showed a significant reduction in the Incontinence Episode Frequency (IEF) by approximately 50% during treatment. Duloxetine groups had significantly better quality-of-life scores (weighted mean difference for Incontinence Quality of Life Index for participants on 80 mg daily: 4.5; 95%CI, 2.83 6.18; p < 0.00001) and rates of symptom improvement. Adverse effects were common (71% vs. 59%) but are reported as not serious and were equivalent to about one in eight participants reporting adverse effects (most commonly nausea) directly related to duloxetine treatment. About one in eight stopped treatment as a consequence of taking duloxetine (17% vs. 4%). Conclusions: Duloxetine can significantly improve the quality of life of patients with SUI, but it is unclear whether or not benefits are sustainable. Side-effects such as nausea are common. # 2006 European Association of Urology. Published by Elsevier B.V. All rights reserved. * Corresponding author. Department Of Urology, Western General Hospital, Crewe Road South, EH4 2XU, Edinburgh, United Kingdom. Tel. +44 131 5371581; Fax: +44 131 537 1019. E-mail address: param.mariappan@nhs.net, sorna9@yahoo.co.uk (P. Mariappan). 0302-2838/$ see back matter # 2006 European Association of Urology. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.eururo.2006.08.041

68 european urology 51 (2007) 67 74 1. Introduction 2. Methods Urinary incontinence (UI), as defined by the International Continence Society (ICS), is the complaint of any involuntary leakage of urine. It is a common and socially debilitating problem and can be clinically divided into (1) stress urinary incontinence (SUI), which is incontinence on effort, exertion, coughing or sneezing; (2) urge urinary incontinence (UUI), which is incontinence accompanied by or immediately preceded by urinary urgency, and (3) mixed urinary incontinence (MUI), which is a combination of SUI and UUI. A recent large population-based survey on 27,936 women aged >20 yr confirmed that SUI is the most common, followed by MUI and UUI with reported prevalence of 50%, 36%, and 11%, respectively [1]. The majority of women with SUI find the symptoms bothersome and SUI is an emotional, social, and financial burden [2]. The current management options for stress incontinence are either conservative measures such as pelvic floor muscle training (PFMT) or surgical treatment including colposuspension and urethral sling surgery. These operations have reported cure rates of up to 90%. But there are risks of surgery [3] such as voiding difficulty and urethral erosion by the sling and not all patients with stress incontinence are suitable for surgery. PFMT, on the other hand, has lower cure rates than surgery and requires a substantial investment of patients time; its effectiveness also depends on long-term compliance by the patients. There clearly appears to be a treatment gap between the conservative measures and surgical management with the absence of an effective, safe, and evidence-based pharmacologic treatment for SUI [4]. Recent evidence on the help-seeking behaviour among European women with UI has revealed that only about one third of women with UI sought help for their condition and women willing to use longterm medication for UI were more likely to consult their doctor [5]. An effective drug treatment with an acceptable adverse effect profile would therefore be a useful addition to the UI treatment armamentarium. The World Health Organization-sponsored International Consultation on Incontinence (ICI) in 2002 did not recommend pharmacologic agents for the treatment of SUI. Since then, however, duloxetine, a new serotonin and noradrenaline reuptake inhibitor (SNRI), has become available with reported benefit in patients with stress incontinence; it is the focus of this systematic review. This review was performed under the auspices of the Cochrane Incontinence Group. Relevant trials were primarily identified from the Cochrane Incontinence Group trials register, which contains trials identified from MEDLINE, CINAHL, the Cochrane Central Register of Controlled Trials (CENTRAL), hand searching of journals, conference proceeding and dissertation abstracts, without language or any other limitations imposed. The date of the most recent search of MEDLINE was 20 December 2005. The review was based on a protocol published in the Cochrane Library (Issue 3, February 2004) and assessed all randomised, or quasi-randomised, controlled trials of treatment for SUI or MUI, comparing an SNRI with placebo or no treatment. Trials involving adults with SUI and MUI, as defined by the trialists, were included. Two reviewers (P.M. and A.A.) checked all identified titles and abstracts and selected potentially eligible studies. Three reviewers (P.M., Z.B., and A.A.) independently assessed the trial reports for eligibility and methodologic quality. Allocation sequence generation, allocation concealment, and blinding during treatment and at follow-up were graded as adequate, unclear, or inadequate. Loss to follow-up was described as adequate (analysis included 90% of patients), unclear (not reported), and inadequate (analysis included <90% of patients). Any disagreement was resolved by discussion with other authors. The primary outcome measure was the number of participants whose symptoms were cured, determined by the participants subjective assessments or clinicians observations. Secondary outcomes included subjective improvement, number of incontinent episodes, quality of life (QOL),, and discontinuation rates. Datawereindependentlyabstractedbythreereviewers(P.M., A.A., and Z.B.) and cross-checked. We attempted to contact authors for clarification or missing data when necessary. Included trial data were processed as described in the Cochrane Reviewers Handbook [6]. Where appropriate, data were combined quantitatively using the Cochrane statistical package RevMan (version 4.2.7) using a fixed effect model, reporting relative risk (RR) for dichotomous data and weighted mean difference (WMD) for continuous data, accompanied by the 95% confidence interval (CI). Evidence of heterogeneity across studies was assessed from visual inspection of the data, from the x 2 test for heterogeneity (at 10%), and the I squared test. If evidence of significant heterogeneity was identified, potential sources were explored within populations, interventions, outcomes, and settings. Where there was no obvious reason for heterogeneity, a random effects model was planned and sensitivity of the results to the choice of model discussed. Analysis in the primary reports had used the last value carried forward approach to address differential drop-out rates. 3. Results 3.1. Study characteristics Of 21 identified reports on duloxetine for SUI [7 27],16 were eligible for inclusion [7 22], and these described

Table 1 Characteristics of included studies Trial Design Interventions and patients Screening lead-in Outcome measures Cardozo [7] Dmochowski [8] (14) Ghoniem [13] (21) (single blinded for PFMT) 109 patients 2 wk Cure, improvement, IEF, I-QOL, PGI-I, 54: placebo for 8 wk; 55: duloxetine 40 mg bid for 4 wk, then escalating to 60 mg bid 4 wk 683 patients 2 wk Cure, improvement, IEF, I-QOL, PGI-I, 339: placebo; 344: duloxetine 40 mg bid 12 wk Beck Depression Inventory II, adverse events 201 patients 2 wk IEF, Stress Pad Test, I-QOL, PGI-I, 47: placebo; 52: duloxetine 40 mg bid; 12 wk Kinchen [22] Double-blind RCT 451 patients NA I-QOL, PGI-I, 227: placebo; 224: duloxetine 40 mg bid 36 wk Millard [9] Mulcahy [15] Norton 2002 [10] (11,16 18) Van Kerrebroeck [12] Zinner [19] (20) Single-centre, double-blind RCT 458 patients 2 wk Cure, improvement, IEF, I-QOL, PGI-I, 231: placebo; 227: duloxetine 40 mg bid 12 wk 92 patients 3 wk IEF, Stress Pad Test, 37: placebo 55: duloxetine 20 mg daily 3 wk 553 patients 2 wk and posttreatment 138: placebo; placebo 4 wk 138: duloxetine 20 mg/d 137: duloxetine 20 mg bid 140: duloxetine 40 mg bid 12 wk Cure, improvement, IEF, I-QOL, PGI-I, Stress Pad Test, Cough Stress Test, 494 patients 2 wk Cure, improvement, IEF, I-QOL, PGI-I, 247: placebo 247: duloxetine 40 mg bid 12 wk 286 patients (140 patients with stress incontinence; 146 with mixed incontinence) Data from stress incontinent patients reported 34: placebo 34: duloxetine 20 mg/d 26: duloxetine 30 mg/d 33: duloxetine 40 mg/d 6 wk 2 wk IEF, 24-h pad weight, Stress Pad Test, I-QOL Primary study reference numbers are shown in brackets [ ]; secondary studies are in parentheses ( ). RCT = randomised controlled trial; IEF = Incontinence Episode Frequency; I-QOL = Incontinence Quality of Life; PGI-I = Patient s Global Impression of Improvement; PFMT = pelvic floor muscle training; NA = not available. european urology 51 (2007) 67 74 69

70 european urology 51 (2007) 67 74 nine randomised trials [7 10,12,13,15,19,22]. Support from Eli Lilly was acknowledged in the primary references in all trials. All trials were described as parallel group, doubleblind, randomised placebo-controlled trials (RCTs). One trial [13] included additional groups managed with PFMT and these are not considered in this review. Description of randomisation, including concealment of allocation, was found to be adequate in the nine trials. The baseline characteristics of participants were described in all full text reports and treatment and placebo arms were well matched (Table 1). In six trials [8 10,12,13,19], participants were women with predominantly SUI based on a clinical diagnosis with or without urodynamic evidence. The inclusion criteria for SUI were predominant symptoms of SUI with incontinent episode frequency from fewer than four times [10] to more than 14 times per week [7], diurnal frequency under seven to nine times a day [9], nocturia fewer than two to three times per night [8], a positive cough stress test, or a positive stress pad test. The reported exclusion criteria included predominant UUI except in one trial [22], first sensation on bladder filling of <100 ml or a maximum bladder capacity of <400 ml. Cardozo et al. [7] included only women with urodynamic stress incontinence, whereas Mulcahy et al. [15] included women with MUI and UUI. Kinchen et al. [22] included women with all types of incontinence with incontinent episode frequency greater than once per week. In general, (except for Cardozo et al. [7] and Kinchen et al. [22]), the patients underwent a 2-wk screening period, followed by a 2-wk placebo lead-in and were then randomised (double-blind) to 12 wk of duloxetine or placebo. They were seen at intervals of 4 wk throughout the treatment period. Patients were required to complete a bladder diary (over a week) at no drug lead-in (baseline), placebo lead-in, and at 4 wk, 8 wk, and 12 wk of treatment. Patient s Global Impression of Severity (PGI-S) was also assessed at baseline. The Incontinence Quality of Life (I-QOL) and Patient s Global Impression of Improvement (PGI-I) were completed at each visit (PGI-I was only done after randomisation). Adverse events and compliance were assessed during the visits. A total of 3066 women were randomised between duloxetine (n = 1712) and placebo (n = 1354). 3.2. Subjective cure and improvement The numbers cured in the groups allocated duloxetine 80 mg daily were higher than in the placebo group in the three trials with data (Fig. 1: 10.8% vs. 7.7%, overall RR = 1.42; 95%CI, 1.02 1.98; p = 0.04). The estimated absolute size of effect was small: about 3 more patients cured among every 100 treated. Data from the 40-mg dose groups were consistent with this, although there appeared to be little or no difference between treated and control groups in the 20-mg stratum. The estimated relative improvement was similar (Fig. 2) and this translated into an absolute effect size estimate of about 15 more improved among every 100 treated. The heterogeneity was largely explained by the larger effect estimate in Cardozo et al. [7] possibly due to trial participants having more severe incontinence. 3.3. Objective parameters Data describing objective cure using pad tests or stress tests were available from only one trial (Norton et al. [10]) and showed no clear difference between the different dosages and placebo (data not Fig. 1 Numbers cured during treatment: Duloxetine vs placebo.

european urology 51 (2007) 67 74 71 Fig. 2 Numbers improved during treatment: Duloxetine vs placebo. shown). The results for cure based on bladder diaries were similar to those for subjective cure. The difference was marginally statistically significant, most participants were not cured, and the result was again equivalent to about 3 more patients cured for every 100 treated (data not shown). Analyses of continuous data on incontinent episode frequency showed better results in duloxetine groups, with a typical difference in median percent change of about 20%. 3.4. QOL parameters The groups allocated duloxetine were reported to have significantly greater overall improvement in I-QOL (Fig. 3: WMD for 80 mg: 4.5; 95%CI 2.83 6.18, p < 0.00001). PGI-I (data not shown) also favoured the duloxetine groups (80 mg: RR for better health status 1.24, 95%CI 1.14 1.36; p < 0.00001). 3.5. Adverse events and discontinuation The majority of those allocated duloxetine (71%) in six trials [7 10,12,22] reported adverse effects. However, 59% of those allocated to placebo also reported adverse effects (Fig. 4). Nausea is the most common side-effect across the trials (ranging from 23% to 25%) in the duloxetine arm and the main cause for discontinuation. Other side-effects reported were vomiting, constipation, headache, dry mouth, fatigue, dizziness, and insomnia. The overall RR was 1.30 (95%CI, 1.23 1.37). Across these six trials, 17% in the duloxetine treatment arms withdrew compared with 4% in the placebo arms (RR = 4.88; 95%CI, 3.61 6.61). Fig. 3 Assessment of I-QoL change: Duloxetine vs placebo.

72 european urology 51 (2007) 67 74 Fig. 4 Adverse events and discontinuation rates: Duloxetine vs placebo. 4. Discussion Our review of published data from randomised trials found that duloxetine (80 mg daily) had better results than placebo in terms of subjective cure and improvement in incontinence (based on individual trial definitions), although the estimated effect on cure was modest only about 3% extra patients cured. The I-QOL and PGI-I measures favoured duloxetine. Almost all trials showed a significant improvement in the median percentage of incontinent episode frequency (IEF) change (usually presented as the primary measure of outcome), but we were not able to derive a typical effect size across the trials from this statistic. Most participants in the duloxetine groups reported an adverse effect. Around 12% of these could be directly attributed to duloxetine because over half in the placebo group also reported adverse effects. Overall, 17% stopped treatment in the duloxetine group, for about 75% of whom the reason was attributable to duloxetine. This is a higher rate than in trials of anticholinergic treatment for overactive bladder symptoms. This adverse effect profile was judged to be acceptable by the authors of the trial reports. However, there were no data with which to rule out longer-term adverse effects. The authors of the trial reports used the last outcome measure carried forward approach in an attempt to overcome any bias introduced by the higher drop-out rate in the duloxetine group. The concern remains, however, that this will still have overestimated differences favouring the duloxetine group. We did not formally compare different doses of duloxetine. An initial dose of 80 mg is now generally recommended on the basis that it is more effective, but in one trial that did compare 20 mg versus 40 mg versus 80 mg, a higher dose of duloxetine was associated with more adverse effects and withdrawals (Norton et al. [7]). It is important to consider differences between the trials in the duration of study: Mulcahy et al. [15], 3 wk; Zinner et al. [19], 6 wk; others, 12 wk; and Kinchen et al. [22], 36 wk. Dmochowski et al. [8] and Millard et al. [9] found an enhanced placebo effect after the fourth week of the study, which would not have been seen in the studies of shorter duration; however, we found no significant heterogeneity between trials with regard to the primary outcomes analysed. From available data, it is not clear what the duration of treatment should be or whether the efficacy of duloxetine is sustainable after long-term treatment. Collecting long-term data to determine sustained efficacy during and after treatment should now be a priority. The trialists recruited women with moderate to severe symptoms (based on PGI-S). Patients currently using pelvic floor exercises ranged from 5% to 19% of participants from the studies where data were available. It was not made clear, in most trials, except Kinchen et al. [22], what proportion of these women had failed (or tried) PFMT or behavioural modification prior to recruitment. The trialists also did not provide evidence that the recruited patients found conservative measures to be unsatisfactory and thus required alternative treatment. No specific drug interactions were mentioned in the trial reports. SNRIs do have recognised interactions with antidepressants, nonsteroidal antiinflammatory drugs, and barbiturates. Duloxetine is used for treating depression and it is possible that central nervous system effects may, in part at least, be a reason for the improvement in measures of QOL described in this review. The Cochrane review addressed broader issues [28]. There were no trials

european urology 51 (2007) 67 74 73 comparing duloxetine with surgery or other drugs. Limited evidence from a single trial [13] suggested that duloxetine alone or in combination with PFMT might have an advantage over PFMT alone. The authors, however, were not explicit about compliance rates for those treated with PFMT even though it is recognised that compliance plays an important role in success of PFMT. From our analyses of the data, the target group of women with perceived moderate to severe SUI (based on PGI-S) responded to duloxetine by QOL improvement. Individual trialists data also found improvement in Incontinence Episode Frequency (IEF) in this group, but we were unable to derive a typical effect size across the trials. With these limitations in mind, women not keen to undergo surgery [5] or those awaiting surgery [7] appear to be potential targets for duloxetine treatment within the context of a large placebo-controlled, randomised trial. Further research is needed to clarify whether management policies incorporating duloxetine are clinically effective and cost effective compared with current approaches such as PFMT, injection therapy, and more invasive surgery in patients with varying severity of SUI. All nine trials considered here were supported by Eli Lilly. Evaluation of duloxetine completely independent of pharmaceutical company involvement should be encouraged. 5. Conclusions The SNRI, duloxetine, improves patients QOL and reduces incontinence. There are, however, sideeffects and about one in eight people discontinue this drug. Longer-term experience is now a priority to determine whether there is sustained efficacy during and after duloxetine use and to rule out complications. References [1] Hannestad YS, Rortveit G, Sandvik H, et al. A communitybased survey of female urinary incontinnce: the Norwegian EPINCONT study. J Clin Epidemiol 2000;53:1150 7. [2] Lose G. The burden of stress urinary incontinence. 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