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Promising therapies: TOT, duloxetine, botulinum A

December 2004 · Vol. 16, No. 12
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Ob/Gyns are being called on more than ever to initiate treatment for urinary incontinence, and new treatment options are enabling us to play a more active role than ever before in treating one of the most common and distressing of chronic diseases in women. Urinary incontinence affects women after menopause, primarily. Prevalence increases (though not in a linear fashion)—from 20% to 30% in reproductive-aged women, to 30% to 40% in postmenopausal women. Approximately 16 million Americans are affected, and the number of women affected is more than double that of men.

20% cancel surgery after duloxetine therapy

Cardozo L, Drutz HP, Baygani SK, Bump RC for the Duloxetine Severe UI Study Group. Pharmacological treatment of women awaiting surgery for stress urinary incontinence. Obstet Gynecol. 2004;104:511–519.

Efforts to treat stress incontinence with drugs have not succeeded well in the past, but the development of duloxetine may change that.

Duloxetine (Cymbalta; Eli Lilly, Indianapolis, Ind) is a balanced serotonin-norepinephrine reuptake inhibitor that may act by stimulating pudendal nerve output and improving urethral closure. The FDA approved duloxetine for treatment of major depression for adults in August 2004, and for management of diabetic peripheral neuropathic pain in September 2004. However, duloxetine is not yet FDA-approved for the treatment of stress incontinence.

A randomized, placebo-controlled, double-blinded study involving 14 centers in Australia, Canada, the Netherlands, and the United Kingdom enrolled women aged 18 to 75 years, all of whom had severe stress incontinence, and had already scheduled surgery. All patients had at least 14 episodes of stress incontinence per week. The dose of duloxetine started at 40 mg twice daily for 4 weeks, then increased to 60 mg twice daily for another 4 weeks.

The study randomized 109 women and included 98 in the intention-to-treat analyses, 46 of whom took duloxetine, and 52, placebo.

Response was defined as at least a 50% reduction in incontinence episode frequency. Of the women taking duloxetine, 63% were responders, compared with 13.5% of the placebo group.

Using the Patient Global Impression of Improvement (PGI-I), one third of women taking duloxetine described themselves as “very much better” or “much better,” compared with 8% of women taking placebo.

Ten of 49 women (20%) indicated they were not interested in surgery while taking duloxetine, compared with 0 of 45 women taking placebo. Drug discontinuation occurred more frequently in the duloxetine group: 18 of 55 (33%), compared with 3 of 54 (6%) in the placebo group.

Cure rate low, but so is risk

Even if the “cure” rate is relatively low, duloxetine offers a low-risk form of treatment for women who might otherwise be considered surgical candidates.

In addition, pharmacological treatment may be indicated for women whose incontinence is not severe enough to warrant surgery.

While there are no studies that report long-term results of duloxetine use, it seems appropriate that duloxetine be included in the discussion of nonsurgical options, along with pelvic muscle exercises and behavioral treatment, before surgery is considered.

Botulinum A toxin for refractory detrusor overactivity

Kuo H-C. Urodynamic evidence of effectiveness of botulinum A toxin injection in treatment of detrusor overactivity refractory to anticholinergic agents. Urology. 2004;63:868–872.

Cystoscopic detrusor injection of botulinum toxin A appears to be a promising alternative to more invasive treatments for refractory detrusor overactivity.

Urinary incontinence due to detrusor overactivity can be especially difficult to treat when first-line treatment with anticholinergic drugs is unsuccessful. Although newer slow-release or long-acting formulations are tolerated better than the original formulations, many patients still have bothersome symptoms or intolerable side effects.

Previously, such women might have been treated with electrical stimulation.

This less invasive treatment might be an effective option, although further study is needed to identify patients most likely to benefit.

Effectiveness has been observed in patients with detrusor overactivity due to spinal cord injury and, in the study cited above, in patients with neurogenic, idiopathic, and postobstructive detrusor over-activity. Botulinum toxin A is not FDA-approved for incontinence indications.

In the Kuo study, 30 patients (12 women and 18 men) with detrusor overactivity refractory to anticholinergic agents were treated with cystoscopic detrusor injection of 200 units botulinum toxin A at 40 sites in the posterior and lateral bladder (sparing the anterior bladder). Eight patients (27%) regained urinary continence; 14 (46%) had improvement in frequency, urgency, and incontinence; and treatment failed in 8 (27%).

Excellent results were most likely in patients with previous bladder outlet obstruction, and least likely in patients with neurogenic detrusor overactivity. Men were more often successfully treated (83%) than women (58%). Maximal effect was noted at 10 to 14 days after treatment, and the effect lasted 3 to 9 months (average, 5.3 months).

Side effects were not serious: urinary tract infection in 3 patients and transient urinary retention in 4. Six patients with detrusor overactivity and impaired contractility were treated with intermittent self-catheterization for 1 month, after treatment resulted in increased postvoid residual urine volumes.

Patients with impaired bladder emptying before treatment may be at higher risk of posttreatment retention, although even when retention occurs, it seems to be transient and responds well to time-limited management with intermittent self-catheterization.

Stress incontinence surgery: What’s in, what’s out

Is TVT out?

Costa P, Grise P, Droupy S, et al. Surgical treatment of female stress urinary incontinence with a transobturator-tape (TOT) Uratape: Short-term results of a prospective multicentric study. Eur Urol. 2004;46:102–107.

Faster than you can say “tension-free vaginal tape,” an even newer procedure is coming to the fore: TOT, the transobturator tape.

The TVT operation revolutionized stress incontinence surgery, with placement at the midurethra instead of traditional placement at the bladder neck. Although case series and the first randomized trials showed good results with TVT, concern about retropubic complications fueled development of alternate placement through the obturator foramen. This alternative is intended to avoid complications attributable to penetration of the peritoneal cavity or retropubic space with TVT.

In a study conducted by Costa et al, 183 women with stress or mixed incontinence associated with urethral hypermobility underwent the TOT procedure, which involved midurethral placement of a polypropylene tape with a silicone-coated central part, using a transobturator percutaneous approach. With follow-up at more than 6 months on 130 of the 183 study subjects, 83% were reported as “cured” (absence of subjective complaint of urine leakage and absence of leakage on cough stress testing) and 5.4% as “improved” (decrease of stress incontinence, not further specified).

Obviously, we need more information and, ideally, comparative information to determine how this new technique fits in with other surgical options for stress incontinence. So far, 2 trials comparing TVT and TOT were reported in abstract at the 2004 meeting of the International Continence Society.

Of 17 failures, tape removal was necessary in 5, due to vaginal extrusion in 3 and urethral erosion in 2. Because of this high rate of extrusion, the silicone portion of the tape has been removed.

TOT (but not silicone) is in

Comiter CV, Colegrove PM. High rate of vaginal extrusion of silicone-coated polyester sling. Urology. 2004;63:1066–1070.

This case series reported 10 patients treated with the silicone-coated polyester sling for stress or mixed urinary incontinence. Two patients (20%) developed vaginal extrusion requiring tape removal, at 6 and at 10 months after initial placement. Although the sling was otherwise effective in treating stress incontinence, this high rate of extrusion obviously precludes further use. No silicone on slings!

Laparoscopic Burch is out

Ankardal M, Ekerydh A, Crafoord K, et al. A randomized trial comparing open Burch colposuspension using sutures with laparoscopic colposuspension using mesh and staples in women with stress urinary incontinence. Br J Obstet Gynaecol. 2004;111:974–981.

What about laparoscopy, the grandfather of minimally invasive surgery? In this large, adequately powered, randomized trial of open Burch and laparoscopic colposuspension, the open technique was performed with permanent suture, 2 stitches on each side; the laparoscopic technique used polypropylene mesh and titanium staples. Of 120 subjects randomly assigned to each group, 98 underwent open and 109 underwent laparoscopic colposuspension.

Unfortunately, twice as many subjects (22) assigned to open Burch were excluded after randomization, compared with the laparoscopic group (11). Nonetheless, the results 1 year after surgery unequivocally favored open versus laparoscopic colposuspension: objective cure by pad test in 92% versus 74%, and subjectively dry in 89% versus 62%, respectively.

One wonders why any more trials of laparoscopic colposuspension should be performed at all, although the authors call for future randomized studies comparing different laparoscopic techniques such as suture versus staples and mesh. If the goal is to provide effective, “minimally invasive” surgery for incontinence, with traditional slings updated to include TVT and now TOT, it seems we already have reasonably good alternatives—with the caveat, “pending further studies,” especially for long-term results of the new techniques.

Clinicians who prefer slings have always wondered why laparoscopy—with 3 or 4 abdominal ports, pneumoperitoneum, and general anesthesia—was seen as minimally invasive. Not that laparoscopic continence procedures should never be performed, but it seems likely that they will occupy a narrow niche in the range of surgeries for stress incontinence in women.

Watch for these 2 reports

In other incontinence news, look for results from 2 important trials in 2006:

  • Burch versus sling in 650 women with stress incontinence; performed by the Urinary Incontinence Treatment Network (an NIH-funded network of 9 clinical sites).
  • Burch versus no Burch in 480 women without stress incontinence symptoms with advanced prolapse undergoing abdominal sacral colpopexy; performed by the Pelvic Floor Disorders Network (an NIH-funded network of 7 clinical sites).

A reminder: Inform the patient

We all want better results of surgical treatment in our patients and, to accomplish that, we need surgical experimentation, which I wholeheartedly support. But such research must be carried out with the patient’s knowledge that she is receiving new and experimental therapy. To do otherwise is unethical.

Dr. Weber serves as an NIH consultant, and reports no other financial relationships in any other capacity.

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