Overactive Bladder: Management And Treatment Options

Main Category: Urology / Nephrology
Article Date: 11 Aug 2008 - 0:00 PDT

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UroToday.com - Overactive Bladder (OAB) is a disease defined by its symptoms, consisting of urgency with or without urge incontinence, frequency and nocturia.1 OAB is a very common problem with an estimated 16 - 33 million sufferers in the US.2

The standard treatment of OAB is a combination of behavioral and pharmacologic treatments. Behavioral treatments consist of bladder training, timed voiding, dietary modification, pelvic floor muscle exercises and behavioral modification. Burgio et al have shown that combination therapy is more effective than either therapy alone.3 There are a number of pharmacologic mechanisms that in theory could reduce detrusor muscle activity. To date approved treatments primarily consist of anticholinergic, specifically antimuscarinic, drugs. Since urgency is the 'driving' symptom in OAB4; those experiencing OAB frequently experience urgency at inconvenient and unpredictable times and consequently often lose control before reaching the toilet. This adversely affects their physical and psychological state by limiting daily activities, intimacy, compromising sexual function, and worsening self-esteem. It is no surprise therefore that improvements in urgency are often noted by patients to be the most noticeable response to therapy. Urgency and the other symptoms of OAB result in a significant deterioration in health related quality of life (HRQoL).5, 6

Cholinergic Receptors: The detrusor smooth muscle is rich in cholinergic-muscarinic receptors. Electrical stimulation of an intact cholinergic nerve or application of a cholinergic agonist to a strip of detrusor muscle is known to result in detrusor muscle contraction. All of the drugs approved to date for OAB work on the basis of blocking cholinergic receptors which stabilizes the bladder smooth muscle making it relatively refractory to stimulation via postganglionic parasympathetic (ie, cholinergic) neural impulses. At least 5 muscarinic receptor subtypes, M1-M5, have been identified.7

Clinical Trials Data: Review of the currently available pharmacotherapy was carried out by the pharmacotherapy committee of the 3rd International Consultation on Incontinence, held in Monaco 2004.8 Drugs were evaluated with particular attention to different types of evidence . Pharmacological and/or physiological efficacy evidence was reviewed and clearly defined to mean that a drug has been shown to have desired effects in relevant pre-clinical experiments or in healthy volunteers (or in experimental situations in patients). Clinical drug recommendations are based on evaluations made using a modification of the Oxford system, in which emphasis was given to the quality of the trials assessed (Table 1)

Table I: Drugs used in the treatment of detrusor overactivity. Assessments according to the Oxford system (modified)

	Level of evidence	Grade of recommendation
Antimuscarinic drugs
Tolterodine	1	A
Trospium	1	A
Darifenacin	1	A
Solifenacin	1	A
Propantheline	2	B
Atropine, hyoscyamine	2	D
Drugs with mixed actions
Oxybutynin	1	A
Propiverine	1	A
Dicyclomine	4	C
Flavoxate	4	D
Antidepressants
Imipramine	2	C**
Vasopressin analogues
Desmopressin	1	A***
Other drugs
Baclofen	2	C****
Capsaicin	2	B
Resiniferatoxin	2	B
Botulinum toxin	2	B

** SHOULD BE USED WITH CAUTION
*** NOCTURIA
**** INTRATHECAL USE

It is clear that amongst the many drugs tried for the treatment of OAB, acceptable efficacy, documented in RCTs of good quality, has only been shown for a limited number. The antimuscarinics; tolterodine, trospium, solifenacin and darifenacin the drugs with mixed actions; oxybutynin and propiverine, and the vasopressin analogue; desmopressin, were found to fullfil the criteria for level 1 evidence according to the Oxford assessment system and were given grade A recommendations by the International Consultation on Incontinence.

A Cochrane meta-analysis of 32 randomized controlled trials (RCTs) of antimuscarinic treatment for OAB concluded that there were small but statistically significant differences between active drugs and placebo. However it became controversial when the clinical significance of these differences was questioned.9 These conclusions were most probably related to an incomplete literature set which did not include many of the more modern studies. In particular for 60% of the included studies, the primary efficacy variables were objective measures. Only 8 studies evaluated patients' perception of cure or improvement in symptoms; 2 examined HRQL outcomes. With these shortcomings in mind a further meta-analysis has been conducted.10 Fifty-six trials were included and the antimuscarinics were found to be both safe and efficacious. All antimuscarinics apart from oxybutynin IR were found to be well tolerated. Dry mouth was the most commonly reported adverse event and no drug was associated with an increase in any serious adverse event. There were significant differences between the antimuscarinics both in rates of withdrawal and the rates and range of adverse events and efficacy outcomes. Clearly there are limitations to any meta-analysis including the quality of the individual studies and the circumstances under which such a study is conducted; in particular inclusion, exclusion criteria, ethic and environmental factors.

Despite the plethora of anticholinergics there remains a need for more efficacious drugs with fewer side effects.

References:

1. Abrams P, Cardozo L, Fall M. et al. Neurourol Urodyn. The standardization of terminology of lower urinary tract function: report from the standardization subcommittee of the International Continence Society, 2002:21, 167-178.

2. Stewart W, Herzoz RAW. Neurourol Urodyn. The prevelance and impact of overactive bladder in the US: results from the NOBLE program. 2001: 20, 406-8.

3. Burgio KL, Locher JL, Goode PS. J Am Geriatr Soc. Combined behavioural and drug therapy for urge incontinence in older women. . 2000: 48, 370-374.

4. Chapple CR, Artibani W, Cardozo LD, Castro-Diaz D, Craggs M, Haab F, Khullar V, Versi E. BJU Int. The role of urinary urgency and its measurement in the overactive bladder symptom syndrome: current concepts and future prospects. 2005: 95(3), 335-40. Erratum in: BJU Int. 2005: 95(6), 924.

5. Kobelt G, Kirchberger I, Malone-Lee J. BJU Int Quality-of life aspects of the overactive bladder and the effect of treatment with tolterodine. 1998: 83, 583-590.

6. Conor R, Johannesson M, Hass S, Kobelt-Nguyen G. Pharmacoeconomics . Urge incontinence: quality of life and patients' valuation of symptom reduction. 1998: 14, 531-539.

7. Caulfield MP, Birdsall N: Pharmacol Rev . International Union of Pharmacology: XVI. Classification of muscarinic acetylcholine receptors. 1998: 50, 279-290.

8. Andersson K-E, Appell R, Cardozo L, Chapple C, Drutz H, Fourcroy J, Nishizawa O, Vela Navarette R, Wein A. Pharmacological treatment of urinary incontinence. In Incontinence, 3rd International Consultation on Incontinence , Volume 2 Abrams P, Cardozo L, Khoury S & Wein A (eds), Health Publication Ltd , Chapter 14 p809- 855.

9. Herbison P, Hay-Smith J, Ellis G, et al: BMJ . Effectiveness of anticholinergic drugs compared with placebo in the treatment of overactive bladder: systematic review. 2003: 326, 841-844.

10. Chapple C, Khullar V, Gabriel Z, Dooley JA. Eur Urol. The effects of antimuscarinic treatments in overactive bladder: a systematic review and meta-analysis. 2005: 48(1):5-26.

Presented by: E. Ann Gormley, MD, FACS, at the Masters in Urology Meeting - July 31, 2008 - August 2, 2008, Elbow Beach Resort, Bermuda

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