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Clinical Reviews


Drug therapy for incontinence: New agents, new applications

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

August 2006 · Vol. 18, No. 8

IN THIS ARTICLE

  • A simple questionnaire to differentiate urge and stress incontinence

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.

Duloxetine may avert surgery. Taken together, these studies indicate that duloxetine is effective and may improve incontinence enough to render surgery unnecessary.

Anatomy of a drug decision: The FDA and trospium chloride
INTEGRATING EVIDENCE AND EXPERIENCE

Zinner N, Gittleman M, Harris R, et al. Trospium chloride improves overactive bladder symptoms: a multicenter phase III trial. J Urol. 2004;171:2311–2315

What goes into a drug approval? In weighing the merits of trospium chloride (Sanctura), one of the studies the US Food and Drug Administration considered was a 12-week multicenter, double-blind, parallel, placebo-controlled trial that compared 20 mg of the drug (twice daily) with placebo.

Trospium significantly reduced the frequency of toilet voids and urge incontinence episodes, compared with placebo. It also increased the average volume per void and decreased urge severity and daytime frequency.

However, several factors limited this study’s application to “real-life” women with overactive bladder.

1. Most participants were older white women

A total of 523 patients were enrolled, more than 70% of them women. The mean age was over 60 years, and about 80% of participants were white. More than half had already used a drug for overactive bladder.

2. Brief duration did not reflect real life

Most patients with overactive bladder need treatment for much longer than 12 weeks, so this study does not address the long-term efficacy or tolerability of trospium chloride.

3. Placebo response was substantial

Patients in the placebo arm had less frequent urination, decreased nocturia, fewer episodes of urge incontinence in 24 hours, and reduced urgency with voiding. Although these outcomes were statistically significant in the treatment group, were they clinically meaningful?

A difference of 2 tablespoons. The mean increase in average voided volume in the trospium group was 32.1 mL, compared with an increase of 7.7 mL in the placebo group. Although the P value was outstanding (P≤0.0001), one could argue that an increase in bladder capacity of less than 2 tablespoons is clinically meaningless.

Try non-drug measures first

In this study, 54% of patients taking placebo reduced the number of incontinence episodes in 24 hours, compared with 71% on the active drug. In addition, 10% of patients taking placebo became completely dry, compared with 21% on the active drug.

Because the placebo effect in these studies is always strong, focused behavioral therapy (“bladder drill” or bladder retraining) should be the first line of treatment for overactive bladder, reserving drugs for those in whom behavioral treatment is not effective, or as an initial “crutch” to help advance the behavioral program, weaning patients off medications whenever possible.

REFERENCES

1. Wall LL. Diagnosis and management of urinary incontinence due to detrusor instability. Obstet Gynecol Surv. 1990;45:1S-47S.

2. Guay DRP. Clinical pharmacokinetics of drugs used to treat urge incontinence. Clin Pharmacol. 2003;42:1243-1285.

3. Kreder K, Mayne C, Jonas U. Long-term safety, tolerability and efficacy of extended-release tolterodine in the treatment of overactive bladder. Eur Urol. 2002;41:588-595.

4. Diokno AC, Appell RA, Sand PK, et al. Prospective, randomized, double-blind study of the efficacy and tolerability of the extended-release formulations of oxybutynin and tolterodine for overactive bladder: results of the OPERA trial. Mayo Clin Proc. 2003;78:687-695.

5. Cardozo L, Lisec M, Millard R, et al. Randomized, double-blind placebo-controlled trial of the once daily antimuscarinic agent solifenacin succinate in patients with overactive bladder. J Urol. 2004;172:1919-1924.

6. Chapple CR, Rechberge T, Al-Shukri S, et al. Randomized, double-blind placebo- and tolterodine-controlled trial of the once-daily antimuscarinic agent solifenacin in patients with symptomatic overactive bladder. BJU International. 2004;93:303-310.

7. Haab F, Stewart L, Dwyer P. Darifenacin, an M3 selective receptor antagonist, is an effective and well-tolerated once-daily treatment for overactive bladder. Eur Urol. 2004;45:420-429.

8. Cardozo L, Dixon A. Increased warning time with darifenacin: a new concept in the management of urinary urgency. J Urol. 2005;173:1214-1218.

9. Angel M. The Truth About the Drug Companies: How They Deceive Us and What to Do About It. New York: Random House; 2004.

10. Solifenacin and darifenacin for overactive bladder. Med Lett Drugs Ther. 2005;14:23-24.

11. Trospium chloride (Sanctura): another anticholinergic for overactive bladder. Med Lett Drugs Ther. 2004;46:63-64.

12. Hofner K, Oelke M, Machtens S, et al. Trospium chloride: an effective drug in the treatment of overactive bladder and detrusor hyperreflexia. World J Urol. 2001;19:336-343.

13. Nygaard IE, Heit M. Stress urinary incontinence. Obstet Gynecol. 2004;104:607-620.

14. Wall LL, Addison WA. Prazosin-induced stress incontinence. Obstet Gynecol. 1990;75:558-560.

15. Kernan WN, Viscoli CM, Brass LM, et al. Phenylpropanolamine and the risk of hemorrhagic stroke. N Engl J Med. 2000;343:1826-1832.

16. Zinner NR, Koke SC, Viktrup L. Pharmacotherapy for stress urinary incontinence: present and future options. Drugs. 2004;14:1503-1516.

17. Duloxetine (Cymbalta): a new SNRI for depression Med Lett Drugs Ther. 2004;46:81-82.

18. van Kerrebroeck P, Abrams P, Lange R, et al. Duloxetine versus placebo in the treatment of European and Canadian women with stress urinary incontinence. BJOG. 2004;111:249-257.

19. Dmochowski RR, Mikos JR, Norton PA, et al. Duloxetine versus placebo for the treatment of North American women with stress urinary incontinence. J Urol. 2003;170:1259-1263.

20. Cardozo L, Drutz HP, Baygani SK, Bump RC. Pharmacological treatment of women awaiting surgery for stress urinary incontinence. Obstet Gynecol. 2004;104:511-519.

Dr. Wall reports no financial relationship with any company whose products are mentioned in this article.

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