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PubMed1999

The overactive bladder: neuropharmacological basis of clinical management.

The overactive bladder continues to pose a major challenge to clinicians treating lower urinary tract disorders, not least because our understanding of the pathogenesis of detrusor overactivity is still relatively limited. However, progress in understanding the basis of the overactive bladder is moving steadily forward, accompanied by a growing number of different forms of treatment. New pharmacological treatments and variations in the mode of delivery of older agents offer hope of efficacy with fewer side-effects. Neuromodulation is also offering a viable alternative to surgery in patients unresponsive to medical treatment.

Female↗

PubMed2006

Newer agents for the management of overactive bladder.

The anticholinergics tolterodine and oxybutynin are well established in the management of overactive bladder. However, their activity at muscarinic receptors distant from the target site (i.e., bladder) produces anticholinergic side effects leading to poor tolerability. In 2004, trospium, solifenacin, and darifenacin were approved by the U.S. Food and Drug Administration for the treatment of overactive bladder. Trospium is water soluble and therefore is less likely to enter the central nervous system, and solifenacin and darifenacin are more selective for the bladder than older agents. Although these attributes could improve tolerability, clinical trials comparing relevant agents to validate this are lacking. Trials have shown that these newer agents decrease the frequency of incontinence episodes, the number of voids per day, and the number and severity of urgency episodes compared with placebo. These agents also have been shown to improve quality of life in women with overactive bladder and urinary incontinence. Head-to-head studies of the newer agents and immediate-release oxybutynin and tolterodine have suggested similar effectiveness across the class, although the newer agents are better tolerated. Trospium and darifenacin have not been compared with extended-release formulations of tolterodine or oxybutynin, which are better tolerated than the immediate-release versions. In one study, solifenacin produced a somewhat greater decrease in the number of incontinence episodes than extended-release tolterodine, with no difference in tolerability. In general, the newer agents appear to be at least as effective as their predecessors, although it is unclear whether they are better tolerated. Important pharmacokinetic differences among the agents (e.g., route of elimination) allow for selection of an appropriate agent based on individual factors such as cost and tolerability.

Humans↗

PubMed2006

Multicenter phase III trial studying trospium chloride in patients with overactive bladder.

OBJECTIVES: To study the efficacy and safety of trospium chloride in treating overactive bladder. Trospium chloride is an anticholinergic agent with predominantly peripheral nonselective antimuscarinic activity and thus has potential therapeutic value in treating patients with overactive bladder. METHODS: Patients with overactive bladder were randomized on a 1:1 basis to either placebo or trospium chloride 20 mg twice daily in this 12-week, multicenter, parallel, double-blind, placebo-controlled study. The primary endpoint was the change in the average number of toilet voids per 24 hours. The secondary efficacy variables were changes in the average void urgency severity, volume per toilet void, urge frequency, number of daily urge urinary incontinence episodes, and daytime sleepiness. RESULTS: A total of 658 patients were randomized at 52 sites. Trospium chloride significantly decreased the average number of daily toilet voids, average urgency severity, urge frequency, and urge urinary incontinence episodes and increased the average volume per void at weeks 1, 4, and 12. All effects occurred by the end of week 1 and all improved and were sustained throughout the 12-week study. Adverse events included dry mouth and constipation. CONCLUSIONS: Trospium chloride had significant and sustained effectiveness beginning at the end of week 1 and continuing through 12 weeks of treatment. Trospium chloride was also safe and generally well tolerated.

Benzilates↗

PubMed1997

Diagnosis and significance of idiopathic overactive bladder.

OBJECTIVES: To offer a critical overview of the basis for the International Continence Society (ICS) classification of detrusor instability, to summarize current diagnostic methodologies, and to outline the etiologic factors that should be excluded in the diagnosis of idiopathic overactive bladder. METHODS: The current ICS definitions of overactive bladder are discussed. Issues related to the diagnosis of detrusor instability (DI) are addressed through a review of the literature. RESULTS: The term idiopathic overactive bladder reflects the present lack of knowledge concerning vesicourethral function and dysfunction. The term is used to apply to a wide spectrum of different conditions that may have a common final pathophysiologic pathway. This heterogeneous group of conditions could be subdivided on the basis of presumptive etiopathogenesis, urodynamic patterns, and response to treatment. The diagnosis of DI, its rate of detection, and its urodynamic patterns depend on the type of urodynamic test used and the way the test is performed. The ICS definitions of DI have been called into question by the results of studies using urodynamic tests in addition to, or instead of, provocative cystometry--for instance, ambulatory urodynamics, urethrocystometry, the ice-water test, and evaluation of the voiding phase. The literature supports a broadening of the ICS criteria for excluding all known causes of DI when establishing the diagnosis of idiopathic overactive bladder. CONCLUSIONS: Appropriate longitudinal studies, using contemporary urodynamic tests and knowledge, are needed to improve the identification of subsets of patients with overactive bladder who have different prognoses and outcomes. The ICS definitions and classification should be updated.

Humans↗

PubMed2005

Role of cyclooxygenase-2 in the development of bladder overactivity after cerebral infarction in the rat.

PURPOSE: We investigated the role of cyclooxygenase (COX) isoforms in bladder overactivity induced by cerebral infarction (CI) in rats. MATERIALS AND METHODS: CI was induced by left middle cerebral artery occlusion (MCAO) in female Sprague-Dawley rats. Bladder activity was monitored with continuous infusion cystometrography of conscious rats. Specimens were obtained from the pontine tegmental area (PTA) 1, 3, 5, 12 and 24 hours after CI or sham operation (SO). The effects of MK-801 (0.1 mg/kg intravenously), an NMDA (N-methyl-D-aspartate) glutamatergic receptor antagonist, on bladder activity, and on COX-1 and 2 mRNA expression following MCAO were examined. Real-time quantitative reverse transcriptase-polymerase chain reaction was performed to evaluate the effects of CI on gene expression in the PTA. The effects of the COX-2 inhibitor NS398 (0.01 to 10 mg/kg intravenously) on bladder activity were examined. RESULTS: The bladder capacity of CI rats was significantly decreased 1 to 24 hours after MCAO compared with that of SO rats (p <0.05 or 0.01). One and 3 hours after MCAO mean COX-2 mRNA expression +/- SE had increased significantly to 22.4 +/- 3.5 in terms of its expression relative to the outer control in a sample obtained immediately after MCAO, in contrast to that in SO rats (p <0.01). The expression level returned to the control level within 12 hours after MCAO. COX-1 expression was not influenced by MCAO. Pretreatment with MK-801 inhibited the development of bladder overactivity and significantly decreased the expression of COX-2 mRNA in the PTA (p <0.01). Treatment with NS398 before MCAO prevented the development of bladder overactivity in a dose dependent manner and did not influence infarct volume. CONCLUSIONS: These results indicate that the development of bladder overactivity following MCAO is accompanied by an increase in COX-2 mRNA expression in the PTA and is mediated by NMDA receptor activity. COX-2 in the brain may be a new target for the treatment of neurogenic voiding dysfunction after cerebral infarction.

Animals↗

PubMed2006

[Comparative study of overactive bladder prevalence in patients younger than 50 years with and without hyperprolactinemia].

OBJECTIVE: To determine if the hyperprolactinemia is associated with idiopathic overactive bladder. PATIENTS AND METHODS: We performed a transversal and analytic two groups study. We included all the patients whom plasma levels of prolactin were measured in the National Institute of Perinatology from March 1st to May 31, 2005 and fulfilled the selection criteria. To all these patients we applied a questionnaire of eight questions for the overactive bladder diagnostic. We used chi square statistical technique to establish if hyperprolactinemia is associated with the overactive bladder. RESULTS: One hundred sixty years patients were studied, establishing a relative prevalence of 2.82 (IC 95%: 1.45-3.17), determining association between the variables. CONCLUSIONS: hyperprolactinemia is associated with overactive bladder.

Adult↗

PubMed2005

Trospium chloride for the treatment of overactive bladder with urge incontinence.

BACKGROUND: Urinary incontinence is caused by an overactive bladder, leading to symptoms of urgency, frequency, and incontinence. Urge incontinence occurs predominantly in women as they age. OBJECTIVES: This article reviews the current primary literature concerning the efficacy and tolerability of the anticholinergic agent trospium chloride (TCl) in the treatment of overactive bladder with symptoms of urge incontinence, urgency, and frequency. The pharmacokinetics of TCl are also reviewed. METHODS: Pertinent articles in English were identified through a search of MEDLINE (1966-present), EMBASE Drugs & Pharmacology (1980-third quarter 2004), Current Contents/Clinical Medicine (week 42, 2003-week 41, 2004), Cochrane Database of Systematic Reviews, MICROMEDEX Healthcare Series, and International Pharmaceutical Abstracts (1970-present). The search terms were overactive bladder, urinary incontinence, trospium, randomized controlled clinical trial, oxybutynin, tolterodine, scopolamine, imipramine, desipramine, and propantheline. RESULTS: TCl, a quaternary amine, exhibits high solubility in water but low oral bioavailability (9.6%) and poor central nervous system penetration. Approximately 80% of the absorbed fraction is renally eliminated as unchanged drug via active tubular secretion, with approximately 15% hepatically metabolized into a spiroalcohol and hydrolysis/oxidation products. In 3 placebo-controlled studies, patients who received TCl had an increase in maximum bladder filling capacity and bladder compliance, with a reduction in maximum cystometric capacity (P < 0.005); however, only 1 of these studies showed an increase in bladder compliance, with reductions in maximum detrusor pressure (P < 0.001), number of voids/d (P < or = 0.001), and incontinence episodes/d (P < or = 0.001). In another placebo-controlled study, TCl reduced the number of voids/d and incontinence episodes/d (both, P < or = 0.001). In 2 double-blind studies, TCl and oxybutynin were similarly effective in significantly increasing maximum cystometric capacity and bladder compliance, and in significantly reducing maximum detrusor pressure compared with baseline (all, P < 0.001); there were no significant differences between the 2 treatments at end point. In a third double-blind study comparing TCl and tolterodine with placebo, only TCl significantly reduced the frequency of micturitions/d (P = 0.01). Commonly reported adverse effects in patients receiving TCl included dry mouth, constipation, and headache. CONCLUSIONS: In the 7 studies reviewed, TCl was effective and well tolerated in patients with urge incontinence caused by idiopathic detrusor muscle overactivity or neurogenic detrusor overactivity resulting from spinal cord injury. However, this agent was associated with anticholinergic adverse effects similar to those of other anticholinergic agents; careful monitoring of tolerability is required.

Aging↗

PubMed2001

How widespread are the symptoms of an overactive bladder and how are they managed? A population-based prevalence study.

OBJECTIVE: To determine the prevalence of chronic and debilitating symptoms of the overactive bladder, defined here as the presence of chronic frequency, urgency and urge incontinence (either alone or in any combination), and presumed to be caused by involuntary detrusor contractions. Subjects and methods Data were collected using a population-based survey (conducted by telephone or direct interview) of men and women aged >/= 40 years, selected from the general population in France, Germany, Italy, Spain, Sweden and the United Kingdom, using a random stratified approach. The main outcome measures were: prevalence of urinary frequency (> 8 micturitions/24 h), urgency and urge incontinence; the proportion of participants who had sought medical advice for symptoms of an overactive bladder; and current or previous therapy received for these symptoms. RESULTS: In all, 16 776 interviews were conducted in the six European countries. The overall prevalence of overactive bladder symptoms in individuals aged >/= 40 years was 16.6%. Frequency (85%) was the most commonly reported symptom, followed by urgency (54%) and urge incontinence (36%). The prevalence of overactive bladder symptoms increased with advancing age. Overall, 60% of respondents with symptoms had consulted a doctor but only 27% were currently receiving treatment. Conclusion Symptoms of an overactive bladder, of which frequency and urgency are as bothersome as urge incontinence, are highly prevalent in the general population. However, only a few affected individuals currently receive treatment. Taken together, such findings indicate that there is considerable scope for improvement in terms of how physicians diagnose and treat this condition.

Activities of Daily Living↗

PubMed2006

The overactive bladder: review of current pharmacotherapy in adults. Part 2: treatment options in cases refractory to anticholinergics.

In the first part of this review the potential pathophysiological factors involved in the overactive bladder were outlined, and the wide range of first-line anticholinergic pharmacotherapies available for such patients were reviewed. The second part will focus on the intravesical instillation of resiniferatoxin and injections of botulinum toxin into the bladder to treat overactive bladder and detrusor overactivity. Resiniferatoxin has been shown to increase bladder capacity and improve incontinence in patients with neurogenic and non-neurogenic detrusor overactivity. Botulinum toxin has successfully been used to treat neurogenic and idiopathic detrusor overactivity, with improvements observed in bladder capacity, decreases in detrusor pressures on filling and voiding, and increased volumes at first contraction. Further validation is required for both treatments, in the form of large randomised controlled trials, before their use can be considered routine, with particular focus on dosing required.

Administration, Intravesical↗

PubMed2006

[Oral anticholinergics in overactive bladder].

Behavioural therapy and anticholinergics are the mainstays in the treatment of symptoms of overactive bladder in patients with idiopathic and neurogenic detrusor overactivity; they are the first-line treatment. Oxybutynin, propiverine, tolterodine and trospium chloride as well as the "newcomers" solifenacin and darifenacin are comparable in regards to their efficacy. However, based on different pharmacokinetics and pharmacodynamics with different resorption velocity, different metabolisation and different CNS penetration, the profile of adverse events is different, qualitatively and quantitatively. Substances that are resorbed slowly or available as slow-release formulations are tolerated better. Lipophilic anticholinergics which pass the blood-brain barrier may compromise cognitive functions, especially in geriatric patients, who are already on cholinesterase inhibitors due to memory disorders. The following article gives an overview of the anticholinergics currently prescribed in patients with symptoms of overactive bladder with special attention to the influence of pharmacokinetics/pharmacodynamics on the adverse events profile including possible CNS side effects.

Administration, Oral↗

PubMed2005

Darifenacin in the treatment of overactive bladder.

Darifenacin is a novel muscarinic M(3) selective receptor antagonist developed for the once-daily treatment of overactive bladder, a chronic, debilitating and highly prevalent condition affecting adults of all ages. Preclinical research has confirmed the pharmacological profile of darifenacin as a potent antimuscarinic agent with up to 59-fold higher affinity for M(3) receptors than other muscarinic receptor subtypes and selectivity for the bladder over other tissues expressing these receptors. Extensive research in large, randomized, placebo-controlled trials have demonstrated that darifenacin, at doses of 7.5 and 15 mg once daily (q.d.), is efficacious in the treatment of overactive bladder, improving the core symptoms of urinary urgency, urge incontinence, increased micturition frequency and bladder capacity. In addition, post-hoc analyses have shown that many patients can achieve clinically meaningful continence levels, e.g., > or =90% reduction in incontinence episodes or > or =7 consecutive dry days. These results are supported by significant improvements in quality of life, which have paralleled the overactive bladder symptom reductions. Both fixed and flexible darifenacin dosing regimens produce these beneficial effects, which extend to the more vulnerable population of older patients. Hence, in conjunction with data showing that this agent has a good safety and tolerability profile, these findings indicate that darifenacin may provide an effective alternative pharmacotherapy for the treatment of patients with overactive bladder.

Animals↗

PubMed2004

Solifenacin: treatment of overactive bladder.

An investigational muscarinic antagonist, solifenacin is indicated in the treatment of overactive bladder. Solifenacin works to decrease bladder activity by inhibiting contraction of the smooth muscle wall surrounding the bladder. Micturition normally occurs following stimulation of acetylcholine muscarinic M3 receptors within the detrusor muscle wall. As a potent and selective muscarinic receptor antagonist, solifenacin acts specifically at the M3 receptor site. Initial data have shown solifenacin to be more bladder-selective than its predecessors. It is this selective mode of action that gives solifenacin the potential to limit commonly experienced anticholinergic side effects. These developments could translate into higher patient compliance with the potential for better long-term results. Solifenacin has been shown to have a favorable risk/benefit ratio. At a once-daily oral dose of 5 mg/day, clinical data have shown solifenacin to be effective in reducing the symptoms of overactive bladder, with an incidence of dry mouth comparable to that associated with placebo. Results from phase I, II and III clinical trials have shown solifenacin to have a promising efficacy and safety profile for the treatment of overactive bladder. Comparative clinical trials are now needed to determine whether these initial results can prove solifenacin to be more beneficial than other commonly administered antimuscarinics.

Animals↗

PubMed2000

Muscarinic receptor antagonists in the treatment of overactive bladder.

A wealth of clinical evidence supports the view that muscarinic receptor antagonists are effective in the treatment of overactive bladder. However, treatment-limiting adverse effects such as dry mouth, constipation, and blurred vision have restricted the usefulness of previously available agents, such as oxybutynin. A real need therefore existed for effective and well-tolerated agents for the long-term management of the troublesome symptoms of overactive bladder. This review outlines the various approaches that have been used in attempts to overcome the tolerability problems of oxybutynin. It also describes how advances in our understanding of muscarinic receptors and bladder function has led to the potential development of either tissue- or subtype-selective antimuscarinic agents with improved tolerability. Drugs that have been developed in this way include tolterodine and darifenacin, each of which shows some bladder selectivity in animal models. Unlike darifenacin, however, the bladder selectivity of tolterodine has been confirmed by numerous clinical studies. Tolterodine's improved tolerability compared with oxybutynin, along with its equivalent therapeutic efficacy at recommended dosages, permits patients to experience the beneficial effects of long-term treatment. Tolterodine therefore represents a real alternative for the long-term management of overactive bladder. The results of ongoing clinical studies with darifenacin are awaited before it can be concluded that selective antagonism of M(3) receptors leads to improved tolerability over existing agents in the treatment of overactive bladder. Similarly, the potential improvements in tolerability associated with different dosage formulations of oxybutynin, and the clinical utility of S-oxybutynin, are yet to be conclusively demonstrated.

Benzhydryl Compounds↗

PubMed2006

Human idiopathic and neurogenic overactive bladders and the role of M2 muscarinic receptors in contraction.

OBJECTIVES: This study examines whether M(2) receptors contribute to direct contraction of the detrusor in human neurogenic and idiopathic overactive bladders. METHODS: Control detrusor muscle was obtained from patients undergoing cystectomy for bladder cancer, whilst overactive detrusor muscle was obtained from patients undergoing clam cystoplasty for idiopathic or neurogenic detrusor overactivity. The affinities of a range of subtype selective antagonists (DAMP, darifenacin, methoctramine R0-320-6206, and pirenzepine) were obtained in tissue bath experiments by using carbachol as the agonist. These affinity values were then compared with the known affinities for these antagonists at the muscarinic receptor subtypes. RESULTS: An increased sensitivity to carbachol was observed in both the neurogenic and idiopathic overactive detrusors compared with the control human detrusor. The M(2)-selective antagonists (methoctramine, R0-320-6206) and M(1)-selective antagonist (pirenzepine) had low affinities, whilst the M(3)-selective antagonists (4-DAMP and darifenacin) had high affinities for the human detrusor muscarinic receptor in all three groups of tissues. The affinities (pK(B) values) for the five antagonists were consistent with antagonisms at the M(3) receptor in all three groups; Schild plot analysis indicated an action at this single receptor subtype. CONCLUSIONS: Contraction mediated by muscarinic receptors is enhanced in idiopathic and neurogenic overactive detrusors compared with control detrusor. The direct contractile response to carbachol is mediated by the M(3) receptor in both human normal and overactive bladders, indicating no change in receptor subtype contribution to contraction in the disease state.

Adult↗

PubMed2000

Electrical stimulation in overactive bladder.

Electrical stimulation is an effective and well-tolerated treatment for overactive bladder. Initial work in animals indicated the potential of this treatment, and early clinical experience in Europe further supported its likely efficacy. Although the mechanism of action of electrical stimulation remains unproven in humans, it is believed to be a neuromodulating therapy which affects the neural signaling that controls continence. There is also strong evidence that electrical stimulation affects striated muscle. The therapy can cause hypertrophy of skeletal muscle fibers, possibly by the recruitment of faster-conducting motor units, which would not normally be recruited during voluntary efforts. In addition, electrical stimulation can alter the expression of myosin isoforms, favoring a conversion to type I muscle. Despite our incomplete understanding of the mechanism of action of electrical stimulation, clinical devices have been developed quickly. Case series have been reported throughout Europe. These were followed by controlled clinical trials in the United States. There is good evidence that the use of vaginal electrical stimulators can reduce the occurrence of symptoms of overactive bladder in about half of the patients treated. Multiple uses of nonimplanted stimulation, including thigh stimulation, anal stimulation, and direct pelvic muscle stimulation, have been reported. In these trials, it is common for objective findings to be poorly correlated with subjective reports of improvements or cure. Patients frequently report that the urge-to-leak time improves, but this is difficult to measure objectively. The use of nonimplanted devices is effective and well tolerated, and should precede the use of implanted devices. A direct comparison with other effective methods of treatment for overactive bladder is warranted.

Adult↗

PubMedDate not supplied

The impact of urinary urgency and frequency on health-related quality of life in overactive bladder: results from a national community survey.

OBJECTIVES: Overactive bladder (OAB) is described as urinary urgency, with and without urge incontinence and usually with frequency and nocturia. Most attention to OAB's impact on health-related quality of life (HRQL), however, has focused on urge incontinence. The objective of this study was to evaluate the burden of OAB, specifically urinary urgency and frequency on HRQL. METHODS: In the National Overactive Bladder Evaluation Program (NOBLE), a computer-assisted telephone interview survey was conducted to assess the prevalence of OAB in the United States. Based on interview responses, respondents were classified into three groups: continent OAB, incontinent OAB, and controls. To evaluate the HRQL impact of OAB, HRQL questionnaires were mailed to all respondents with OAB and age- and sex-matched controls as a performed nested case-control study. Continuous data were compared using Student's t tests and analysis of variance with post hoc pairwise comparisons; results were adjusted for age, sex, and comorbid conditions. Multivariable regressions were performed to assess the impact of each urinary variable on symptom bother and HRQL. RESULTS: A total of 919 participants responded to the questionnaires (52% response rate) with a mean age of 54.2 years (SD 16.4 years); 70.4% were female and 85% were white. Continent OAB participants comprised 24.8% of the sample, incontinent OAB 18.3%, and controls 56.9%. In each regression analysis, urinary urge intensity accounted for the greatest variance for increases in symptom bother and decreases in HRQL. CONCLUSIONS: The experience of urinary urgency has a significant negative effect on HRQL and increases symptom bother, an effect that, in this community sample, is greater than that of incontinence, frequency, or nocturia.

Aged↗

PubMed2004

Drug forecast--solifenacin: an investigational anticholinergic for overactive bladder.

OBJECTIVE: To review a new anticholinergic for overactive bladder undergoing review by the U.S. Food and Drug Administration, solifenacin. DATA SOURCE: A MEDLINE/PUBMED search was conducted to identify pertinent studies in the English language. In addition, proceedings of meetings of the Incontinence Society, European Association of Urology, American Urological Association, and American College of Obstetrics and Gynecology were reviewed for relevant abstracts. Additional references were obtained from the bibliographies of these sources. Data over the time period of 1986 through October 2003 were reviewed. STUDY SELECTION: All studies evaluating any aspect of solifenacin in animals and humans. DATA SYNTHESIS: Preclinical studies demonstrated that solifenacin was an antagonist at muscarinic cholinergic M1, M2, and M3 receptors. On the basis of comparative preclinical studies evaluating the effects of solifenacin and oxybutynin on guinea pig detrusor muscle cells, mouse submandibular gland cells, and the intact rat, solifenacin was felt to be a "uroselective" antimuscarinic. Solifenacin is predominantly eliminated via metabolism, with urinary excretion of parent compound being less than 10%. Solifenacin, dosed once daily, is significantly superior to placebo in reducing the number of micturitions, urge episodes, and urge incontinence episodes per day and increasing the volume voided per micturition. In two active-controlled trials, solifenacin was at least equivalent to tolterodine in efficacy and tolerability. The most problematic adverse effects of solifenacin are the anticholinergic effects of dry mouth, blurred vision, and constipation. CONCLUSION: Although promising in preclinical studies, the uroselectivity of the anticholinergic activity of solifenacin has not been validated in clinical trials. No comparative efficacy/tolerability data with oxybutynin are available. On the basis of available data, solifenacin does not appear to be a substantial advance upon existing anticholinergics in the management of overactive bladder.

Journal Article↗

PubMed2000

Treatment of overactive bladder: other drug mechanisms.

The well-known side effects of antimuscarinic drugs have focused interest on other ways of treating overactive bladder. Targets for pharmacologic intervention may be found in the central nervous system (CNS) or peripherally. Several CNS transmitter systems can modulate voiding, but few drugs with a defined CNS site of action have been demonstrated to be clinically useful. The mechanism of action of imipramine, which may be effective in the treatment of overactive bladder, has not yet been clarified. Like imipramine, duloxetine is an inhibitor of serotonin (5-HT) and norepinephrine reuptake. Duloxetine has shown some promise in the treatment of urinary incontinence, but, as with the selective serotonin reuptake inhibitors, its effectiveness in the treatment of overactive bladder has not been proven. Drugs affecting norepinephrine, dopamine or gamma-aminobutyric acid (GABA) receptors and mechanisms may be useful. There is also evidence for a central site of action of alpha(1)-adrenoceptor (AR) antagonists. Traditionally, drugs for the treatment of overactive bladder have had a peripheral site of action. Drugs acting on ARs or membrane channels, as well as prostaglandin synthase inhibitors and several other agents, have been used with moderate success. However, recent developments may lead to more effective drugs, including potassium channel openers, prostaglandins, selective and nonselective inhibitors of cyclooxygenase and those acting on the beta(3)-ARs in the human detrusor. Drugs that reduce afferent activity represent an attractive therapeutic approach, and transmitters of afferent nerves and their receptors are possible targets for pharmacologic interventions.

Central Nervous System↗