RECONSTRUCTIVE UROLOGY

A randomized controlled trial of duloxetine alone, pelvic floor muscle training alone, combined treatment and no active treatment in women with stress urinary incontinence
Ghoniem GM, Van Leeuwen JS, Elser DM, Freeman RM, Zhao YD, Yalcin I, Bump RC; Duloxetine/Pelvic Floor Muscle Training Clinical Trial Group
Cleveland Clinic Florida, Weston, Florida, USA
J Urol. 2005; 173: 1647-53

• Purpose: We primarily compared the effectiveness of combined pelvic floor muscle training (PFMT) and duloxetine with imitation PFMT and placebo for 12 weeks in women with stress urinary incontinence (SUI). In addition, we compared the effectiveness of combined treatment with single treatments, single treatments with each other and single treatments with no treatment.
• Materials and Methods: This blinded, doubly controlled, randomized trial enrolled 201 women 18 to 75 years old with SUI at 17 incontinence centers in the Netherlands, United Kingdom and United States. Women averaged 2 or more incontinence episodes daily and were randomized to 1 of 4 combinations of 80 mg duloxetine daily, placebo, PFMT and imitation PFMT, including combined treatment (in 52), no active treatment (in 47), PFMT only (in 50) and duloxetine only (in 52). The primary efficacy measure was incontinence episode frequency. Other efficacy variables included the number of continence pads used and the Incontinence Quality of Life questionnaire score.
• Results: The intent to treat population incontinence episode frequency analysis demonstrated the superiority of duloxetine with or without PFMT compared with no treatment or with PFMT alone. However, pad and Incontinence Quality of Life analyses suggested greater improvement with combined treatment than single treatment. A complete population analysis demonstrated the efficacy of duloxetine with or without PFMT and suggested combined treatment was more effective than either treatment alone.
• Conclusions: The data support significant efficacy of combined PFMT and duloxetine in the treatment of women with SUI. We hypothesize that complementary modes of action of duloxetine and PFMT may result in an additive effect of combined treatment.

[Drug therapy of female urinary incontinence]
[Article in German]
Hampel C, Gillitzer R, Pahernik S, Melchior SW, Thuroff JW
Urologische Klinik, Johannes-Gutenberg-Universitat, Mainz
Urologe A. 2005; 44: 244-55

• Drug treatment for female urinary incontinence requires a thorough knowledge of the differential diagnosis and pathophysiology of incontinence as well as of the pharmacological agents employed. Pharmacotherapy has to be tailored to suit the incontinence subtype and should be carefully balanced according to efficacy and side effects of the drug. Women with urge incontinence require treatment that relaxes or desensitizes the bladder (antimuscarinics, estrogens, alpha-blockers, beta-mimetics, botulinum toxin A, resiniferatoxin, vinpocetine), whereas patients with stress incontinence need stimulation and strengthening of the pelvic floor and external sphincter (alpha-mimetics, estrogens, duloxetine).Females with overflow incontinence need reduction of outflow resistance (baclofen, alpha-blockers, intrasphincteric botulinum toxin A) and/or improvement of bladder contractility (parasympathomimetics). If nocturia or nocturnal incontinence are the major complaints, control of diuresis is obtained by administration of the ADH analogue desmopressin. Future developments will help to further optimize the pharmacological therapy for female urinary incontinence.
  
  
• Editorial Comment
  Almost a year after the introduction of duloxetine.
  In the past the possibilities to treat female urinary stress incontinence with drugs was almost impossible. A drug treatment requires knowledge of differential diagnosis and pathophysiology beside the pharmacologic influence of the used drug.
  Women with urinary stress incontinence need stimulation and strengthening of the external sphincter and the pelvic floor, which can be aimed by the one or the other drug (duloxetine, estrogen, alpha-mimetics).
  Although duloxetine is so fare only approved in Europe the recommendation of the third international Consultation of Incontinence (2004) concluded, “there is level 1B evidence to suggest that women with stress incontinence should have pelvic floor muscle training (PFMT) alone or in combination with a serotonin-norepinephrine reuptake inhibitor before they are forwarded to an other special treatment (surgery)”.
  In the recent published study of Ghoneim et al. the influence of the last year introduced duloxetine in combination with pelvic floor exercise vs. each approach alone was evaluated against no treatment at all.
  The presented data concludes that the combined treatment of PFMT and the oral drug duloxetine is the most efficient of all groups. The individual approach with the one or the other was better than no treatment at all, but any of the two did demonstrate a significant better outcome in comparison to the other.
  The most mentioned side effect of duloxetine was nausea with 44%, which is higher than prior published in the initiative studies. Although it is already recommended by the pharmaceutics to decrease the drug in steps before stopped, it should be recommended in addition that duloxetine should be introduced by twice 20 mg before the daily dose of twice 40 mg is taken. By titrating the drug the side effect of nausea can be reduced significantly.
  The medication probably gives a fast relive of the major symptom of incontinence whereas the PFMT gives a further support with the strengthening of the muscle structure. The fast improvement might help to motivate the patient to continue the PFMT, which will insure the lasting efficiency to delay the surgical approach.
  Both the recommendation of the International Consultation of Incontinence 2004 and the published data suggest and might even request in the future to treat female urinary stress incontinence first with a serotonin-norepinephrine reuptake inhibitor to stimulate the pudendal nerve in combination with PFMT. Both approaches have an impact but only the combination demonstrated in the presented study a significant improvement of female urinary stress incontinence.
  In the moment the serotonin-norepinephrine reuptake inhibitor duloxetine is not approved for male patients with urinary stress incontinence. With the small experience we have we see the two major results. First male seem not to have the high percentage of nausea, Second, in two groups of patients the following improvement are noticed; those who look for a fast relive right after radical prostatectomy and those where the surgery is “long” ago and still face urinary incontinence. These are only small case numbers but trials will be done in the near future to prove and hopefully verify these findings.

Dr. Karl-Dietrich Sievert & Dr. Arnulf Stenzl
Department of Urology
Eberhard-Karls-University Tuebingen
Tuebingen, Germany