Elsevier

European Urology

Volume 51, Issue 6, June 2007, Pages 1559-1564
European Urology

Prostate Cancer
Pharmacologic Treatment in Postprostatectomy Stress Urinary Incontinence

https://doi.org/10.1016/j.eururo.2006.08.005Get rights and content

Abstract

Objectives

The aim of this study was to assess efficacy and safety of association of duloxetine and rehabilitation compared with rehabilitation alone in men with SUI after radical retropubic prostatectomy (RRP), and to compare continence rate even after planned duloxetine suspension.

Methods

After catheter removal, 112 patients were randomized to receive rehabilitation and duloxetine (group A) or rehabilitation alone (group B), for 16 wk. Inclusion criteria: postprostatectomy SUI with daily incontinent episodes frequency (IEF) of four or greater.

After 16 wk both groups suspended duloxetine/placebo and continued rehabilitation. All patients completed incontinence quality of life (I-QoL) questionnaire and bladder diary. Wilcoxon test was used to analyse changes in IEF and in I-QoL score; Fisher exact test was used to compare continent patients between the groups.

Results

Adverse events for duloxetine was 15.2%. 102 men completed the study. There was a significant decrease in pad use in group A. After 16 wk, 39 patients versus 27 were dry (p = 0.007). At 20 wk, 4 wk after planned interruption of duloxetine, we observed a U-turn, 23 patients were completely dry in group A versus 38 in group B (p = 0.008). Whereas, after 24 wk, 31 in group A versus 41 in group B were dry (p = 0.08). The decrease in IEF and improvements in I-QoL scores were significantly greater in group A for the first 16 wk.

Conclusions

The data suggest that combination therapy might provide another treatment option for SUI in men that might increase the percentage of early postsurgery continence.

Introduction

Stress urinary incontinence (SUI) is the complaint of involuntary loss of urine on effort or exertion, or on sneezing, coughing or laughing [1]. Urinary incontinence remains a serious sequela after radical prostatectomy, despite better understanding of pelvic anatomy and improvement in surgical technique [2]. The recommended first-line treatment for men with postprostatectomy urinary incontinence is pelvic floor muscle training (PFMT) [3].

Duloxetine, a potent serotonine/norepinephrine reuptake inhibitor has been evaluated in a clinical trial program of one phase 2 and three phase 3 placebo-controlled trials worldwide, that involved 1913 patients, and proved an effective and safe treatment on women with SUI [4], [5], [6], [7]. Currently there is no pharmacologic treatment approved for stress urinary incontinence in men.

PFMT decreases the frequency of incontinence episodes and reduces the amount of leakage by compressing the urethra during activity [8]. While duloxetine plays a key role in normal urethral sphincter closure, it is supposed to increase rhabdosphincter tone and contraction by stimulating the Onuf nucleus [9], [10]. Pelvic floor muscle and rhabdosphincter are not supported by the same nerves, and pelvic floor exercises do not activate the urethral sphincter [11]. A recent study demonstrated how early PFMT can halve incontinence time and reduce the degree of leakage in men after radical retropubic prostatectomy (RRP) [12]. A previous study conducted on women indicates that PFMT and duloxetine could have cumulative positive effects on SUI [11].

These preliminary observations supported the hypothesis that duloxetine and PFMT could have an additional effect even on male postprostatectomy SUI if sphincter innervation is undamaged. Furthermore, unlike women with SUI, the majority of male patients recover urinary control 1 yr after surgery because of the natural recovery of the sphincter function, so everything points to the fact that duloxetine in male incontinence could be employed only soon after surgery and for a limited time.

The primary objectives of this study was to assess duloxetine’s efficacy and safety in men with SUI after RRP, to evaluate the effect of association of duloxetine and PFMT, to compare the effectiveness of combined treatment versus PFMT alone, and to evaluate whether duloxetine may have a role in early first-line approach for postprostatectomy incontinence. The secondary objective was to compare the long-term continence rate outcome even after planned duloxetine suspension.

Section snippets

Methods

This prospective, randomized, single-blind, autonomous study was conducted between January 2005 and April 2006. One hundred fifty-three patients who had undergone standard RRP were considered for this protocol. Ten days after catheter removal (average: 8.8 d after surgery; range: 7–14), 112 of 153 RRP patients were randomized to receive PFMT and 40 mg duloxetine twice daily (group A or combined treatment), or PFMT and placebo (group B or PFMT only), for 16 wk (Table 1). A single-blinded

Results

A total of 112 men were randomized for treatment with PFMT alone or in combination with duloxetine. Ten (11.2%) of these patients were removed from the study prematurely for adverse events, 9 (15.2%) for duloxetine and 1 (1.8%) for placebo (p = 0.01), with nausea being the most common reason for discontinuation (70%). Overall, 102 men completed the 24-wk study, 50 in group A and 52 in group B. There were no significant differences between demographic, clinical, surgical, and incontinence

Discussion

Urinary continence is the result of a correct bladder storage and emptying. This mechanism is under the control of the peripheral and central nervous systems. In particular, urethral closure comes from innervations of the pudendal nerve, which determines a good functioning of the urethral rhabdosphincter. The activity of the pudendal nerve is increased by serotoninergic and noradrenergic neurotransmitters in the sacral Onuf nucleus. Duloxetine enhances the concentration of both these amines by

Conclusions

Duloxetine showed a facilitative effect on early continence recovery, while avoiding negative psychological impact on oncologic patients. Moreover, duloxetine was shown to be complementary to PFMT with a synergic clinical effect demonstrated by a significant reduction of incontinence episodes in postprostatectomy incontinence, compared with PFMT alone. The data suggest that combination therapy might provide another treatment option for SUI in men that might increase the percentage of early

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    A cure rate of 10% may be achieved with doses of 80 mg/d but with inconsistent data concerning QoL improvement [107,138,139]. In men with SUI after prostate surgery, RCTs suggest an earlier recovery of continence with duloxetine either alone [140], or in addition to PFMT [141,142]. All studies had a high patient withdrawal rate, which was caused by a lack of efficacy and high incidence of adverse events, including nausea and vomiting (40% or more of patients), dry mouth, constipation, dizziness, insomnia, somnolence, and fatigue [143,144].

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