Duloxetine hydrochloride is a dual-action serotonin and noradrenaline reuptake inhibitor. In animal studies, duloxetine significantly increases bladder capacity and sphincteric muscle activity in the catacetic acid bladder model by a central nervous system action that appears to be mediated via both motor and sensory afferent modulation [2,3]; and it has been suggested that duloxetine promotes urine storage by relaxing the bladder and increasing urethral resistance. These effects have not been duplicated by the administration of two separate single reuptake inhibitors [4].

On the basis of animal studies, it has been postulated that duloxetine may be beneficial in the management of SUI in women by means of blocking reuptake of serotonin and noradrenaline in Onuf's nucleus, an area in the sacral spinal cord, which has a high density of serotonin and noradrenaline receptors. The pudendal motor neurones located in Onuf's nucleus regulate the urethral striated muscle sphincter. In animal studies, serotonin and noradrenaline stimulate these neurones, thereby increasing the strength of urethral sphincter contractions [2–5]. These suppositions await a robust proof-of-mechanism study in humans.

One phase 2 and two phase 3 double-blind placebo-controlled trials have evaluated the therapeutic use of duloxetine for SUI in women. In the phase 2 study, 553 women with SUI predominantly with an incontinence episode frequency (IEF) of at least four per wk were treated with placebo or 20, 40, or 80mg duloxetine for 12 wk [6]. Median IEF decreases, determined using the last diary entry, in the four treatment groups were 40%, 44%, 59%* (*=statistically significant), and 58%,* respectively. Using a pooled diary analysis, comparable values were 41%, 54%,* 59%,* and 64%.* The changes for those scoring in the “very much better” or “much better” category of the Patient Global Impression of Improvement (PGI-I) scale were 27%, 31%, 37%,* and 44%* for the four treatment cohorts. Mean changes in Incontinence Quality of Life scale scores were 5.8, 5.3, 7.8, and 9.3.* For those with an IEF =14, the decreases were similar for all except the placebo group (30%). There were no significant differences in cure rates as measured by the stress pad test, the cough stress test, or diary card data. Side-effects included nausea (2% of the placebo group, 9% of women receiving 20mg duloxetine, 9% of those receiving 40mg duloxetine, 13% of those receiving 80mg duloxetine), insomnia (1%, 2%, 7%, 7%), fatigue (3%, 1%, 8%, 10%), constipation (1%, 4%, 4%, 6%), and dry mouth (1%, 4%, 5%, 7%).

A phase 3 trial of placebo versus 40mg duloxetine bid was conducted in 683 North American women [7]. Median IEF decreases in the intent-to-treat (ITT) groups were 27.5% (placebo) and 50% (duloxetine),* with baseline values of 19.0 and 18.2, respectively. For completers, IEF decreases for the two treatment groups were 29.3% and 50%, respectively. For those with an IEF =14, there were comparable decreases (25% and 51.8% for the two groups). At the time of the last diary entry, 5.9% of those on placebo had no incontinence episodes, versus 10.5% of duloxetine-treated patients. The average voiding interval increased 20min* in the duloxetine group, as contrasted with only 1.7min in the placebo group, suggesting that the decreased IEF was not due to an increase in voiding frequency. In the completer group, 62%* of drug-treated patients rated their condition as “improved” on the PGI-I scale, versus 39.6% of placebo patients. Side-effects were frequent and noticeable by their presence. Specific incidences, all significant at p<0.05 from placebo, were as follows: nausea, 22.7% (6.4% discontinued the drug because of the side-effect); fatigue, 14.8% (2.6% discontinued); insomnia, 14.2% (2.0%); dry mouth, 12.2% (0%); constipation, 9.6% (<1%); somnolence, 8.7% (2%); dizziness, 7.6% (1.5%); headache, 7.3% (<1%); and diarrhoea, 6.1% (<1%). 24.1% of drug patients and 4.1% of placebo patients dropped out of the study. Nausea was noted to be mild to moderate in 87% of cases and mostly resolved within 1–4 wk.

A second phase 3 trial with duloxetine 40mg bid versus placebo was conducted in 458 women across four continents outside North America [8]. Median IEF decreases in the ITT population were 53.6%* for drug-treated patients and 40% for the placebo group; in the complete population, decreases were 56%* and 41.7%, respectively. For those with a baseline IEF=14, the corresponding numbers in the ITT population at last visit were 54.9%* and 41.7%; in the ITT population, pooled diary results yielded percentages of 54.7%* and 35.9%. The PGI-I scale showed that 73.6%* of drug-treated patients felt “a little better” or “very much better,” versus 64.2% of placebo patients. Intervoid interval increased by 20.4min* in the drug group and 8.5min in the placebo group. Using pooled diary results for the ITT group, the researchers determined that 58.9%* of duloxetine-treated patients had a 50–100% decrease in IEF, versus 43.2% for placebo. A total of 7.1% of drug-treated patients reported no incontinence episodes in their last 7-day diary, versus 6.1% of placebo patients. Reported side-effects in the drug-treated group that differed at the p<0.05 level from placebo included nausea (25.1%), insomnia (13.7%), constipation (12.8%), dry mouth (12.3%), dizziness (11.0%), fatigue (10.1%), somnolence (8.4%), anorexia (6.6%), vomiting (6.2%), and increased sweating (5.7%). A total of 17.2% of drug-treated patients dropped out of the study, as opposed to 1.7% of placebo-treated ones.

Review of these data clearly indicates that the relatively high placebo response seen in the studies has led to both clinically meaningful and statistically significant therapeutic results only in women with moderate or severe SUI. Clearly, the significant placebo effect seen in women with stress incontinence needs to be borne in mind, and these findings in men will need to be substantiated in a placebo-controlled study.

The authors also report the high prevalence of side-effects in these men. Fourteen of 20 men experienced side-effects, and these side-effects precluded any use of the drug in 2 men and led to a further 6 discontinuing the drug (after what period of time?). Clearly, just as in female patients, drug tolerability is an important issue with the use of this drug. The patients who continued the drug did so for a mean of 9.4 mo, and it is not clear what happened to them afterwards and why they stopped taking the drug. Certainly the authors report impressive efficacy in those able to tolerate the drug: efficacy in 15 of 18 patients and dryness in 7.

Although this is interesting work that suggests a potentially valuable tool to add to the limited conservative armamentarium for male patients with postsurgical stress incontinence, definitive conclusions can be drawn only if a formal evaluation is conducted with adequate placebo control and standardized follow-up.

References

1. Schlenker B, Gratzke C, Reich O, Schorsch I, Seitz M, Stief C. Preliminary results on the off-label use of duloxetine for the treatment of stress incontinence after radical prostatectomy or cystectomy. Eur Urol. 2006;49:1075–1078.

2. Danuser H, Bemis K, Thor KB. Pharmacological analysis of the noradrenergic control of central sympathetic and somatic reflexes controlling the lower urinary tract in the anesthetized cat. J Urol. 1995;274:820–825.

3. Thor KB, Katofiasc MA. Effects of duloxetine, a combined serotonin and norepinephrine reuptake inhibitor, on central neural control of lower urinary tract function in the chloralose-anesthetized female cat. J Pharmacol Exp Ther. 1995;274:1014–1024.

4. Katofiasc MA, Nissen J, Audia JE, Thor KB. Comparison of the effects of serotonin selective, norepinephrine selective, and dual serotonin and norepinephrine reuptake inhibitors on lower urinary tract function in cats. Life Sci. 2002;71:1227–1236.

5. Bymaster FP, Dresfield-Ahmad LJ, Threlkeld PG, et al.. Comparative affinity of duloxetine and venlafaxine for serotonin and norepinephrine transporters in vitro and in vivo, human serotonin receptor subtypes, and other neuronal receptors. Neuropsychopharmacology. 2001;25:871–880.

6. Norton PA, Zinner NR, Yalcin I, Bump RC. Duloxetine versus placebo in the treatment of stress urinary incontinence. Am J Obstet Gynecol. 2002;187:40–48.

7. Dmochowski RR, Miklos JR, Norton PA, Zinner NR, Yalcin I, Bump RC. Duloxetine versus placebo for the treatment of North American women with stress urinary incontinence. J Urol. 2003;170:1259–1263.

8. Millard RJ, Moore K, Rencken R, Yalcin I, Bump RCfor the Duloxetine Study Group. Duloxetine vs placebo in the treatment of stress urinary incontinence: a four-continent randomized clinical trial. BJU International. 2004;93:3111–3118.

Christopher R. Chapple

Royal Hallamshire Hospital, UK

published online 24 February 2006.

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