Clinical Review

Drug therapy for incontinence: New agents, new applications

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Profiles and practice recommendations for 3 new drugs for urinary incontinence, plus new potential for an “old” medication

IN THIS ARTICLE

  • A simple questionnaire to differentiate urge and stress incontinence


 

References

Urinary incontinence is more prevalent with age, but it is never “normal.” Every woman with bothersome symptoms deserves evaluation and treatment, which can often proceed without exhaustive testing (page 14.

Cost vs side effects for overactive bladder drugs

All of the long-acting preparations for overactive bladder have proven more effective than placebo. However, undesirable side effects have led to high rates of discontinuation over the long term.

The new preparations have a better side-effect profile than older medications such as oxybutynin. Now that oxybutynin is available in generic form, however, the new drugs are usually at least 3 times more expensive than short-acting oxybutynin. Although “none of these drugs are as effective as advertisements to the public have suggested” (The Medical Letter11), nonetheless, pharmacologic therapy is a useful option for women with symptoms of overactive bladder. Most women on these medications for a long time tend to take the drugs intermittently, depending on symptoms, or discontinue them because of side effects.

Use non-drug tactics, too

I recommend a bladder behavioral modification program with fluid management and timed voiding or bladder drills, in addition to the drug regimen, for maximum therapeutic benefit.

Treatment of stress incontinence

Stress incontinence is widespread among women of all ages, due to the vulnerability of the anatomical supports of the female urethra and bladder neck. It occurs when the force to which the sphincter mechanism is subjected during moments of exertion exceeds the sphincter’s ability to remain closed (“sphincter strength”).

Physical therapy sometimes suffices

A wide variety of treatments have been used for this problem. Because urethral closure depends largely on coordinated contractions of the pelvic floor in synchrony with increased intra-abdominal pressure, rehabilitation of the pelvic muscles through structured, supervised programs of physical therapy improves or cures many women.13

How drugs affect the urethra

The urethra and bladder neck contain alpha-adrenergic receptors, stimulation of which can increase urethral tone. Conversely, blockade of these receptors can lead to urinary stress incontinence by reducing urethral outlet resistance.14

Alpha-agonist drugs are common components of many over-the-counter cold remedies (eg, pseudoephedrine, ephedrine, phenylpropanolamine, etc) and have been readily available. Besides increasing urethral tone, however, alpha-agonists can also raise blood pressure by constricting arteriolar smooth muscle.

In 2000, an epidemiological study15 of phenylpropanolamine found that use of this medication raised the risk for stroke, even in young women, and the drug was later removed from the market by the FDA. These events led to a decline in use of such medications for stress incontinence, even for preparations that remain on the market.

How duloxetine works

It is a selective serotonin and norepinephrine reuptake inhibitor that is FDA-approved for major depressive disorder in adults, and for diabetic peripheral neuropathic pain. Besides inhibiting serotonin and norepinephrine reuptake in the brain, duloxetine inhibits reuptake in the sacral spinal cord, where the drug exerts an interesting effect on Onuf’s nucleus, which regulates tone of the urethral striated muscle sphincter through the pudendal nerve.16 The accumulation of serotonin and norepinephrine at Onuf’s nucleus (by reuptake blockade) increases efferent activity to the urethra, improving urethral tone. This is thought to have a therapeutic effect.

Dosage. The usual dose for depression is 20 to 30 mg twice daily or 60 mg once daily.

Contraindications include severe renal impairment and hepatic disease.

Side effects include nausea, dry mouth, constipation, dizziness, fatigue, increased sweating, and somnolence.17

Performance in clinical trials. Van Kerrebroeck and colleagues18 conducted a multicenter, randomized, double-blind, placebo-controlled trial of duloxetine in the treatment of stress incontinence. The trial involved 494 women from 6 European nations and Canada. Episodes of stress incontinence decreased 50% in women taking the drug (40 mg twice daily), compared with 29% among women taking placebo.

Nausea was the main side effect noted in the study and tended to be moderate and transient, rather than progressive. However, 22% of women taking duloxetine discontinued it because of side effects, compared with 5% of the women who were taking placebo.

A multicenter, randomized, double-blind, placebo-controlled trial involving 683 women from the United States and Canada, who took 40 mg of duloxetine twice daily, found a decrease in episodes of stress incontinence similar to that demonstrated by van Kerrebroeck et al,18 with comparable discontinuation rates.19

Cardozo and colleagues20 compared duloxetine with placebo in patients with stress incontinence symptoms severe enough that they had been placed on a waiting list for surgery. After taking duloxetine, 20% of these women were no longer interested in surgery, compared with none of the women in the placebo group.

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