(Laurie Barclay, MD, May 2003)

Although estimates of urinary incontinence (UI) prevalence vary, it is a common affliction with devastating economic costs and psychosocial effects. According to the World Health Organization, UI affects about 50 million people in the U.S., Europe and Japan, and worldwide direct and indirect costs exceed $16 billion annually. The market for drugs treating UI is growing at a rate of about 30% each year.

More than 13 million people in the U.S. have UI from an underlying medical condition. UI is twice as common in women as in men because of pregnancy, childbirth, menopause, and female urinary tract anatomy. About 15% of the female population over 15 years of age has UI. Although UI can affect both sexes at any age, the prevalence of UI increases with aging, in part because of decreased bladder volume and increased urinary frequency.

Especially in the elderly, UI often leads to functional dependence and institutionalization. At least 15% of community-dwelling elderly and 50% of institutionalized elderly have significant UI. Regardless of age, UI may cause embarrassment, restriction of activities and sexual dysfunction.

Adult women with UI mostly have stress, urge or mixed incontinence. Stress incontinence refers to leakage of small amounts of urine during physical movement, urge incontinence to leakage of large amounts of urine during sleep or at unexpected times, and mixed incontinence to the coexistence of stress and urge incontinence. Other forms of UI include functional UI related to physical or cognitive impairment, overflow UI caused by leakage of small amounts of urine from a full bladder, and transient UI resulting from temporary conditions such as infection or use of medications. Interstitial cystitis and atrophic vaginitis are additional risk factors.

Evaluation for UI may require formal urodynamic testing, including cystometry, uroflow measurement, urethral pressure profile and selected imaging studies. Cystometry measures pressures during bladder filling and can detect early contractions of the detrusor muscle in the bladder wall. Multichannel urodynamic testing can differentiate between various types of UI through simultaneous measurements of intravesical, intra-abdominal and urethral pressures at rest, in response to provocative maneuvers and during voiding and incontinence.

Urinary flow measurement may help detect an obstruction to urinary outflow. By measuring intraurethral pressure and functional length, the urethral pressure profile indicates whether resistance is sufficient to prevent urine leakage from the urinary bladder, which may be useful in evaluating the patient with urinary stress incontinence.

Imaging studies to rule out structural abnormalities include intravenous pyelogram for upper urinary tract defects, and voiding cystourethrogram, which may reveal bladder diverticula, pelvic floor relaxation, bladder outlet incompetence, urinary reflux, or outlet obstruction.

Treatment for detrusor overactivity may include bladder retraining in motivated, cognitively intact individuals, or pharmacotherapy, mostly with anticholinergic medications that suppress early detrusor contractions. Oxybutynin (Ditropan), flavoxate, or imipramine should be started at low doses and gradually increased to minimize anticholinergic adverse effects including dry mouth, dry eyes, constipation, confusion, orthostatic hypotension and tachycardia.

Calcium-channel blockers may also decrease detrusor overactivity because of their direct effect on smooth muscle relaxation, but they are not approved specifically for use in UI. In patients with urinary outflow obstruction, these drugs can precipitate urinary retention. Only about 20% of patients with overactive bladder or UI are currently treated with pharmacotherapy.

Stress UI may respond to pelvic floor exercises, which increase internal sphincter tone and urethral resistance to prevent urine loss with transient increases in bladder pressure. Alpha-adrenergic agonists such as phenylpropanolamine and pseudoephedrine have a similar effect, and these drugs may be useful intermittently for planned activities. However, they should be used cautiously, if at all, in patients with hypertension or a history of cardiac arrhythmias. Topical estrogen therapy may improve periurethral and vaginal tissue thickness and quality in postmenopausal women. Surgical treatment of stress UI is typically a last resort.

On the other hand, overflow UI may require surgery to relieve outflow obstruction, or temporary catheterization to improve bladder drainage. Pharmacologic agents of potential benefit include alpha-adrenergic antagonists, such as prazosin, terazosin, or doxazosin, to reduce internal sphincter tone and improve urinary flow. Caution is warranted in the elderly to avoid orthostatic hypotension.

When overflow UI results from a hypotonic or atonic bladder, cholinergic agonists like bethanechol may be helpful, but rarely in the long-term. Assistive voiding techniques including the Crede maneuver, or intermittent self-catheterization or indwelling catheterization, may be needed.

CenterWatch has identified a pipeline of 16 drugs in various phases of development for UI, including new and improved anticholinergic and adrenergic agents with fewer adverse effects.

In February 2003, the Food and Drug Administration approved Oxytrol, a transdermal oxybutynin patch from Watson Pharmaceuticals. This parasympathetic blocker treats overactive bladder by preventing muscle contractions, yet anticholinergic side effects are comparable to those seen with placebo. In clinical trials involving more than 1,000 subjects at over 50 U.S. centers, Oxytrol applied twice weekly effectively controlled UI, urgency and frequency over a three-to-four day period. Oxytrol was well-tolerated overall, with the most common adverse events being application site reactions. However, urinary retention, gastric retention, and uncontrolled narrow-angle glaucoma are contraindications to use of Oxytrol.

Another variation on the theme of oxybutynin (Ditropan) is (S)-oxybutynin, a single-isomer version of racemic oxybutynin thought to have fewer anticholinergic side effects. Sepracor's program to study this compound is now on hold due to budgetary constraints, but they plan to complete a phase III trial in overactive bladder.

In a phase IIB twelve-week study in over 650 patients, (S)-oxybutynin, 120 mg three times daily, significantly reduced combined micturitions and voluntary micturitions and increased the number of patients achieving complete continence, compared with placebo. It was also significantly better than Ditropan as determined by spontaneous reports of dry mouth.

Eli Lilly has submitted an NDA for duloxetine hydrochloride, a selective dual reuptake inhibitor of serotonin and norepinephrine. In a double-blind, placebo-controlled trial of 553 women with stress UI, duloxetine was safe and increasingly effective at higher doses. Of women taking 80 mg per day, half had at least a 64% reduction in incontinence episode frequency (P<.001) and two-thirds had at least a 50% reduction compared with placebo (P=.001).
Discontinuation rates for adverse events, most commonly nausea, were 5% for placebo, 9% for duloxetine 20 mg daily, 12% for 40 mg daily, and 15% for 80 mg daily (P=.04).
Large multinational trials are ongoing.

For stress and mixed UI, Hoffmann-La Roche is in Phase II testing of R450, an alpha-1 adrenoceptor agonist that improves muscle tone of the urethra and bladder neck.

Darifenacin (Enablex) is a selective muscarinic antagonist thought to be effective for overactive bladder. Although Pfizer submitted an NDA for Enablex in December 2002, Novartis announced on March 19, 2003 that it would buy the drug for up to $225 million. This deal helps Pfizer divest certain products, as required by the US Federal Trade Commission before allowing the $60 billion dollar merger of Pfizer and Pharmacia. If approved by the FDA, this drug should be available in the U.S. and in Europe in 2004.

Yamanouchi Pharmaceutical has also submitted an NDA in December 2002 for YM-905 (solifenacin succinate), another orally administered muscarinic antagonist used to treat UI, urinary frequency and urgency associated with overactive bladder.

Indevus Pharmaceuticals has completed Phase III testing of Trospium, a bladder-selective muscarinic receptor antagonist used to treat detrusor instability associated with urge incontinence. In two placebo-controlled, double-blind, multicenter studies enrolling 517 patients in Europe, Trospium produced significant improvements in maximum cystometric bladder capacity. Self-rating assessment of "cure" or "marked improvement" occurred in 47.9% of the Trospium group and in 19.7% of the placebo group.

About one-third of patients in both groups reported adverse effects. Unlike other drugs for overactive bladder, Trospium does not cross the blood-brain barrier and therefore may cause fewer central nervous system effects. It is excreted primarily unchanged in the urine, which may limit its potential for drug interactions.

A novel approach to UI is RTX (resiniferatoxin), in Phase II development by ICOS. This small molecule drug, which has been used to treat interstitial cystitis, is delivered to the bladder to desensitize afferent neurons by blocking C-fiber sensory output. Although it is a vanilloid receptor agonist like capsaicin from the chili pepper, it is far less irritating and 1,000 times more potent.

In a study of 13 neurologically intact patients with idiopathic overactive bladder, a 30-minute intravesical instillation of RTX led to significant improvement in all but one patient at 30-day follow-up. Mean number of incontinent episodes decreased from 4.3 to 0.9 daily (P = .001). Three patients achieved complete continence and six had improvement in continence of 50% or greater. All of the patients tolerated RTX instillation without local anesthetics, analgesia, or complaints of significant discomfort or pain.

Kyowa Hakko is trying a similar approach with KW-7158, in phase IIa testing in Europe. This non-cholingergic tricyclic controls bladder activities by acting on peripheral sensory nerves, and it is expected to be clinically effective against urinary urgency, frequency and UI associated with bladder overactivity, hopefully with fewer anticholinergic side effects.

At this point, the tried-and-true approach to UI still seems to be the anticholinergic route, now with fewer side effects such as dry mouth, urinary retention, and blurred vision. To minimize these problems, pharmaceutical companies are testing novel delivery methods and formulas. Promising new approaches include local instillation of compounds interfering with bladder sensation, or variations on chemical structure which allow muscarinic actions on the bladder while reducing CNS and other side effects.