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Pharmacotherapy of overactive bladder syndrome Dudley Robinson† and Linda Cardozo

CONTENTS Muscarinic receptors New developments Intravesical therapy in the management of OAB Estrogens in the management of OAB NICE guidelines Conclusion Expert commentary Five-year view Financial & competing interests disclosure Key issues References Affiliations

†

Author for correspondence Kings College Hospital, Department of Urogynaecology, 3rd Floor, Golden Jubilee Wing, London, UK Fax: +44 207 346 3449 [email protected] KEYWORDS: antimuscarinics, detrusor overactivity, overactive bladder, urinary incontinence

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Urinary incontinence is a common and distressing condition that is known to adversely affect quality of life. Overactive bladder (OAB) is the term used to describe the symptom complex of urgency with or without urge incontinence, usually with frequency and nocturia. Drug therapy, in addition to behavioral modification, remains integral in the management of women with OAB, and the development of new drugs, treatment regimens and methods of delivery should improve patient compliance and acceptability. Developments over the last 10 years have led to the launch of several new drugs for the treatment of OAB that may offer greater efficacy while minimizing adverse effects. This article critically reviews the current pharmacological treatment of OAB in addition to providing a rationale for treatment. Expert Rev. Clin. Pharmacol. 1(1), 163–175 (2008)

Overactive bladder (OAB) is the term used to describe the symptom complex of urgency with or without urge incontinence, usually with frequency and nocturia [1]. Epidemiological studies have reported the overall prevalence of OAB in women to be 16.9%, suggesting that there could be 17.5 million women in the USA who suffer from the condition. The prevalence increases with age, from 4.8% in women aged under 25 years to 30.9% in those over the age of 65 years [2]. This is supported by recent prevalence data from Europe, in which 16,776 interviews were conducted in a population-based survey [3]. The overall prevalence of OAB in individuals aged 40 years and above was 16.6% and increased with age. Frequency was the most commonly reported symptom (85%), while 54% complained of urgency and 36% of urge incontinence. When considering management, 60% had consulted a physician, although only 27% were currently receiving treatment. More recently, a further population-based survey of lower urinary tract symptoms in Canada, Germany, Italy, Sweden and the UK has reported on 19,165 men and women over the age of 18 years [4]. Overall, 11.8% were found to complain of symptoms suggestive of OAB and 64.3% reported

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at least one urinary symptom. Nocturia was the most prevalent lower urinary tract symptom, reported by 48.6% of men and 54.5% of women. Drug treatment continues to have an important role in the management of women with urinary incontinence, although historically many of the agents used were not subjected to controlled clinical trials [5]. From the number of preparations studied, it is clear that there are no ideal drugs and very often the clinical results have been disappointing, partly due to poor efficacy and side effects [6]. Comparison of drug therapies for incontinence is compounded by a placebo effect of 30–40% and, since the response to any drug is only likely to be in the region of 60%, any differences detected are likely to be small and thus require large-scale studies to demonstrate an effect. The clinical effectiveness of antimuscarinic agents in the treatment of OAB has also been questioned in a systematic review of 32 trials including 6800 participants [7]. Following treatment with antimuscarinic drugs, cure or improvement (relative risk: 1.41; 95% confidence interval [CI]: 1.29–1.54), incontinence episode frequency per 24 h (mean difference 0.6; 95% CI: 0.4–0.8), number of voids per

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24 h (mean difference 0.6; 95% CI: 0.4–0.8), maximum cystometric capacity (mean difference 54 ml; 95% CI: 43–66 ml) and volume at first contraction (mean difference 52 ml; 95% CI: 37–67 ml) were all significantly in favor of antimuscarinic therapy (p < 0.0001). While these findings are statistically significant, the authors concluded that the differences from placebo were small and hence maybe of questionable clinical significance. However, these findings contradict those of a more recent systematic review and meta-analysis examining the use of antimuscarinics in patients with lower urinary tract symptoms [8]. In total, 56 trials were reviewed and, overall, antimuscarinic agents were found to be safe and efficacious. Dry mouth was the most commonly reported adverse event and, while no drug was associated with an increase in any serious adverse events, there were significant differences among drugs in terms of withdrawal rates and efficacy outcomes. Consequently, it is important to incorporate subjective measures, such as quality of life (QoL), in any trial assessing the treatment of OAB. The purpose of this review is to consolidate the evidence base for the current pharmacological treatment of OAB in women. Muscarinic receptors

The symptoms of OAB are due to involuntary contractions of the detrusor muscle during the filling phase of the micturition cycle. These involuntary contractions are termed detrusor overactivity [1] and are mediated by acetylcholine-induced stimulation of bladder muscarinic receptors [9]. It has been estimated that 64% of patients with OAB have urodynamically proven detrusor overactivity and that 83% of patients with detrusor overactivity have symptoms suggestive of OAB [10]. If the detrusor overactivity is thought to be secondary to a neurological cause, such as multiple sclerosis, a spinal cord lesion or cerebrovascular accident, then the term neurogenic detrusor overactivity is used [1]. Molecular cloning studies have revealed five distinct genes for muscarinic acetylcholine receptors in rats and humans and it has been shown that five receptor subtypes (M1–M5) correspond to these gene products [11]. In the human bladder, the occurrence of mRNA encoding M2 and M3 subtypes has been demonstrated, although not for M1 [12]. The M3 receptor is thought to cause direct smooth muscle contraction [13]. While the role of the M2 receptor has not yet been clarified, it may oppose sympathetically mediated smooth muscle relaxation [14] or result in the activation of a nonspecific cationic channel and inactivation of potassium channels [15]. In general, it is thought that the M3 receptor is responsible for the normal micturition contraction [9], although in certain disease states, such as neurogenic bladder dysfunction, the M2 receptors may become more important in mediating detrusor contractions [16]. In addition, M1 receptors are found in the brain, M2 receptors in cardiac muscle and M3 receptors are present in the gastrointestinal tract and eye – hence explaining some of the adverse effects associated with antimuscarinic agents.

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Drugs that have a mixed action Oxybutynin

Oxybutynin is a tertiary amine that undergoes extensive firstpass metabolism to an active metabolite, N-desmethyl oxybutynin [17], which occurs in high concentrations [18] and is thought to be responsible for a significant part of the action of the parent drug. It has a mixed action consisting of both an antimuscarinic and a direct muscle relaxant effect in addition to local anesthetic properties. The latter is important when administered intravesically but probably has no effect when given systemically. Oxybutynin has been shown to have a high affinity for muscarinic receptors in the bladder [19] and has a higher affinity for M1 and M3 receptors over M2 [20]. The effectiveness of oxybutynin in the management of patients with detrusor overactivity is well documented. A double-blind, placebo-controlled trial found oxybutynin to be significantly better than placebo in improving lower urinary tract symptoms, although 80% of patients complained of significant adverse effects, principally dry mouth or dry skin [21]. Similar results have also been demonstrated in further placebo-controlled trials [22,23]. In addition, oxybutynin has been compared with other treatments for detrusor overactivity. It has been found to be significantly better than previous antimuscarinic agents, such as propantheline, in the treatment of detrusor overactivity; (58 vs 45% improvement) although it is associated with a higher rate of adverse effects (63 vs 44%) [24]. More recently, a placebocontrolled, multicenter study comparing the tolerability and efficacy of propiverine and oxybutynin in patients with urgency and urge incontinence has been performed. This showed oxybutynin to be as efficacious as propiverine, although found that it was associated with more severe adverse effects [25]. The antimuscarinic adverse effects of oxybutynin are well documented and are often dose limiting [26]. Using an intravesical route of administration, higher local levels of oxybutynin can be achieved while limiting systemic adverse effects. Using this method, oxybutynin has been shown to increase bladder capacity and lead to a significant clinical improvement [27]. Rectal administration has also been shown to be associated with fewer adverse effects compared with oral administration [28]. More recently, a controlled-release oxybutynin preparation using an oral osmotic system (OROS) has been developed that has been shown to have comparable efficacy compared with immediate-release oxybutynin, although it is associated with fewer adverse effects [29]. These findings are in agreement with a further study of controlled-release oxybutynin (Ditopan XL®; Lyrinel XL®), which reported the incidence of moderate-tosevere dry mouth to be 23%, with only 1.6% of participants discontinuing the medication due to adverse effects [30]. In order to maximize efficacy and minimize adverse effects, alternative delivery systems have been developed. An oxybutynin transdermal delivery system (Kentera®) has recently been developed and compared with extended-release (ER) tolterodine in 361 patients with mixed urinary incontinence. Both agents significantly reduced incontinence episodes,

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increased volume voided and led to an improvement in QoL when compared with placebo and there was no significant difference in efficacy between the oxybutynin patch and ER tolterodine. The most common adverse event in the oxybutynin patch arm was application-site pruritis in 14%, although the incidence of dry mouth was reduced to 4.1% compared with 7.3% in the tolterodine arm [31]. Consequently, transdermal oxybutynin may offer an attractive alternative to oral preparations in those women who suffer from intolerable antimuscarinic adverse effects. Propiverine

Propiverine has been shown to combine anticholinergic and calcium channel-blocking actions [32] and is the most popular drug for detrusor overactivity in Japan. Open studies in patients with detrusor overactivity have demonstrated a beneficial effect [33] and, in a double-blind, placebo-controlled trial of its use in neurogenic detrusor overactivity, it has been shown to significantly increase bladder capacity and compliance compared with placebo. Dry mouth was experienced by 37% in the treatment group as opposed to 8% in the placebo group, with dropout rates being 7 and 4.5%, respectively [34]. In a review of nine randomized studies of propiverine in a total of 230 patients, there was a 30% reduction in frequency and 17% reduction in micturitions per 24 h. In addition, there was a mean 64-ml increase in bladder capacity and a reported 77% subjective improvement in symptoms. Side effects were found in 14% of patients [35]. The efficacy and cardiac safety of propiverine have been assessed in a double-blind, multicenter, placebo-controlled, randomized study in 98 elderly patients suffering from urgency, urge incontinence or mixed urge–stress incontinence. After a 2-week placebo run-in period, the patients received propiverine (15 mg three-times daily) or placebo (three-times daily) for a 4-week period. Propiverine caused a significant reduction in micturition frequency and a significant decrease in episodes of incontinence. Only 2% of patients complained of dry mouth and resting and ambulatory electrocardiograms showed no significant changes [36]. Antimuscarinic drugs Tolterodine

Tolterodine is a competitive muscarinic receptor antagonist with relative functional selectivity for bladder muscarinic receptors [37] and, while it shows no specificity for receptor subtypes, it does appear to target the bladder over the salivary glands [38]. The drug is metabolized in the liver to the 5-hydroxymethyl derivative, which is an active metabolite that has a similar pharmacokinetic profile and is thought to significantly contribute to the therapeutic effect [39]. Several randomized, double-blind, placebo-controlled trials both in patients with idiopathic detrusor overactivity and neurogenic detrusor overactivity have demonstrated a significant reduction in incontinent episodes and micturition frequency [40–42]. Further studies have confirmed the safety of

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tolterodine and, at the recommended daily dosage, the incidence of adverse events was no different to that in patients taking placebo [43]. In addition, the safety and efficacy of tolterodine has also been compared with that of oxybutynin. A randomized, double-blind, placebo-controlled, parallel-group study of 293 patients reported that the clinical efficacy of the two drugs was comparable, although oxybutynin was associated with higher withdrawal rates and a higher incidence of adverse events, notably dry mouth [44]. A pooled analysis of the safety, efficacy and acceptability of tolterodine in 1120 patients in four randomized, double-blind, parallel, multicenter trials found that both tolterodine and oxybutynin significantly decreased incontinent episodes, although tolterodine was associated with fewer adverse events, dose reductions and patient withdrawals than oxybutynin [45]. More recently, tolterodine has also been developed as an ER once-daily preparation, Detrusitol XL®. A recent double-blind multicenter trial of 1235 women has compared ER tolterodine with immediate-release tolterodine and placebo. While both formulations were found to reduce the mean number of urge incontinence episodes per week, the ER preparation was found to be significantly more effective [46]. In addition to increased efficacy, ER tolterodine has been shown to have better tolerability. In a double-blind, multicenter, randomized, placebo-controlled trial of 1529 patients, ER tolterodine was found to be 18% more effective in the reduction of episodes of urge incontinence and had a 23% lower incidence of dry mouth [47]. ER oxybutynin and ER tolterodine have also been compared. In the Overactive bladder: Performance of Extended Release Agents (OPERA) study, which involved 71 centers in the USA, improvements in episodes of urge incontinence were similar for the two drugs, although oxybutynin ER was significantly more effective than tolterodine ER in reducing frequency of micturition. Significantly more women taking oxybutynin were also completely dry (23 vs 16.8%; p = 0.03), although dry mouth was significantly more common in the oxybutynin group [48]. The Overactive Bladder: Judging Effective Control and Treatment (OBJECT) trial compared oxybutynin ER 10 mg once daily with tolterodine 2 mg twice daily in a 12-week randomized, double-blind, parallel-group study including 378 patients with OAB [49]. The outcome measures were the difference in number of episodes of urge incontinence, total incontinence and micturition frequency at 12 weeks compared with baseline. Overall, ER oxybutynin was found to be significantly more effective than tolterodine in each of the main outcome measures adjusted for baseline. Dry mouth, the most common adverse event, was reported by 28 and 33% of participants taking ER oxybutynin and tolterodine, respectively. The authors concluded that oxybutynin ER was more effective than immediate-release tolterodine and that the rates of dry mouth and other adverse events were similar in both treatment groups. In the Antimuscarinic Clinical Effectiveness Trial (ACET) study, patients with OAB were randomized to 8 weeks of open treatment with either 2 or 4 mg of ER tolterodine and, in the

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other, 5 or 10 mg of ER oxybutynin [50]. Overall, 1289 patients were included. Fewer patients prematurely withdrew from the trial in the ER tolterodine 4-mg group (12%) than either the ER oxybutynin 5-mg (19%) or ER oxybutynin 10-mg groups (21%). More patients in the ER oxybutynin 10-mg group than in the tolterodine 4-mg group withdrew because of poor tolerability (13 vs 6%). After 8 weeks, 70% of patients in the ER tolterodine 4-mg group noticed an improvement in their bladder condition using a perception of bladder condition questionnaire, compared with 60% in the ER tolterodine 2-mg group, 59% in the ER oxybutynin 5-mg group and 60% in the ER oxybutynin 10-mg group. While dry mouth was dose dependent with both drugs, those patients treated with ER tolterodine 4 mg reported a significantly lower severity of dry mouth compared with ER oxybutynin 10 mg. Overall, the authors concluded that ER tolterodine 4 mg was more efficacious than ER oxybutynin 10 mg in the treatment of OAB. Trospium

Trospium chloride is a quaternary ammonium compound that is nonselective for muscarinic receptor subtypes and shows low biological availability [51]. It crosses the blood–brain barrier to a limited extent and hence would appear to have few cognitive effects [52]. In a recent placebo-controlled, randomized, doubleblind, multicenter trial, trospium chloride produced significant improvements in maximum cystometric capacity and bladder volume at first unstable contraction. Clinical improvement was significantly greater in the group receiving trospium and the frequency of adverse events was similar in both groups [53]. Trospium chloride has also been compared with oxybutynin in a randomized, double-blind, multicenter trial. With both agents, there was a significant increase in bladder capacity, a decrease in maximum voiding detrusor pressure and a significant increase in compliance, although there were no statistically significant differences between the two treatment groups. Those taking trospium had a lower incidence of dry mouth (4 vs 23%) and were also less likely to withdraw (6 vs 16%) compared with the group receiving oxybutynin [54]. Solifenacin

Solifenacin is a potent M3 receptor antagonist that has selectivity for the M3 receptors over M2 receptors and has a much higher potency against M3 receptors in smooth muscle than it does against M3 receptors in salivary glands. Despite solifenacin expressing a higher potency than that of darifenacin in a model of inhibition of M3 receptor-mediated calcium ion mobilization in guinea pig colonic smooth muscle cells [55], it has been shown to be 40-fold less potent than oxybutynin and 79-fold less potent than tolterodine in its inhibition of salivary secretion [56], as well as being more selective for the M3 receptor. The clinical efficacy of solifenacin has been assessed in a multicenter, randomized, double-blind, parallel-group, placebo-controlled study of solifenacin 5 and 10 mg once daily in patients with OAB [57]. The study consisted of a single-blind

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2-week, placebo run-in period followed by a randomized, double-blind, placebo-controlled, 12-week treatment period. In total, 857 men and women were recruited; 281 received placebo, 286 received solifenacin 5 mg once daily and 290 received solifenacin 10 mg once daily. The primary efficacy analysis showed a statistically significant reduction of the micturition frequency following treatment with both 5 and 10 mg doses compared with placebo, although the largest effect was with the higher dose. In addition, solifenacin was found to be superior to placebo with respect to the secondary efficacy variables of mean volume voided per micturition, episodes of urgency per 24 h, number of incontinence episodes and episodes of urge incontinence. Overall, the incidence of adverse events was 38.9% in the placebo group, 43.5% in the 5-mg group and 48.2% in the 10-mg group. The discontinuation rate because of adverse events was low and was comparable among treatment groups (2.3, 3.9 and 3.3% in the 5-, 10-mg and placebo groups, respectively). The most frequently reported adverse events leading to discontinuation were dry mouth and constipation, while the antimuscarinic adverse effects of dry mouth, constipation and blurred vision were the most frequently reported adverse effects overall. These were also found to be dose related. Solifenacin has also been directly compared with tolterodine 2 mg twice daily in a Phase III randomized, double-blind, parallel-group, placebo- and active-controlled, multicenter study in Europe and South Africa [58]. The primary aim of the study was to assess the efficacy of solifenacin 5 and 10 mg while the secondary aims were to compare the safety and efficacy with that of tolterodine 2 mg twice daily. In total, 1033 men and women were recruited. There was a statistically significant reduction of micturition frequency with both solifenacin 5 and 10 mg compared with placebo, the former equating to a reduction of 2.2 micturitions per 24 h and the latter 2.6. Tolterodine showed a smaller reduction of 1.9 micturitions per 24 h. In addition, solifenacin was statistically superior to placebo with respect to the secondary outcome variables. In those patients who were incontinent, 37.3% of the placebo group were continent at the end of study compared with 51.1, 50.6 and 48.4% in the 5-, 10-mg and tolterodine groups respectively. When considering safety, the incidence of one or more adverse event was 45.3% in the placebo group compared with 48.4, 51.9 and 48.3% in the 5-, 10-mg and tolterodine groups, respectively. Most adverse events were anticholinergic and mild or moderate in severity. However, while this study suggested that solifenacin may be superior to tolterodine 2 mg twice daily, the trial was not appropriately powered for this outcome variable and hence no definite conclusion may be drawn. In order to assess the long-term safety and efficacy of solifenacin (5 and 10 mg once daily) a multicenter, open-label, long-term, follow-up study has recently been completed. This was essentially an extension of two previous double-blind, placebo-controlled studies and 1637 patients elected to continue taking solifenacin 5 or 10 mg once daily [59]. Overall, the efficacy of solifenacin was maintained in the extension study and

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the mean number of micturitions per 24 h was reduced by 22.1% at the end of the study. Understandably those patients who had received placebo in the initial studies noticed an improvement in mean number of micturitions per 24 h, mean volume voided and the mean number of urge incontinence episodes per 24 h. Interestingly, those patients who had originally received tolterodine in the previous studies noticed a similar improvement in the number of micturitions per 24 h, volume voided per micturition and the number of urgency episodes per 24 h, comparable with those in the solifenacin arms of the prior trials. Overall, 63.7% of patients reported at least one adverse event, although most of these were mild or moderate in severity with only 7.2% being described as severe. The most commonly reported adverse events were dry mouth (20.5% of all patients), constipation (9.2%) and blurred vision (6.6%), and were the primary reason for discontinuation in 4.7% of patients. Most recently, solifenacin and tolterodine have been compared in the Solifenacin (flexible dosing) Once Daily and Tolterodine Extended Release as an Active Comparator in a Randomised Trial (STAR) study [60]. This was a prospective, double-blind, double-dummy, two-arm, parallel-group, 12-week study with the primary aim of demonstrating noninferiority of solifenacin to ER tolterodine in a manner reflecting real-life clinical practice. A total of 1200 patients (593 on solifenacin and 607 on ER tolterodine) were recruited in 117 study sites in 17 countries. The outcome of the primary efficacy analysis was that solifenacin was noninferior to ER tolterodine with respect to change from baseline in the mean number of micturitions per 24 h (reduction of 2.45 micturitions per 24 h vs 2.24 micturitions per 24 h; p = 0.004). In addition, solifenacin resulted in a statistically significant improvement in urgency (p = 0.035), urge incontinence (p = 0.001) and overall incontinence when compared with tolterodine ER. Also, 59% of solifenacin-treated patients who were incontinent at baseline became continent by the study end point compared with 49% of those on ER tolterodine (p = 0.006). The most commonly reported adverse events were dry mouthy, constipation and blurred vision and were mostly mild-to-moderate in severity. The number of patients discontinuing medication was similar in both treatment arms (3.5% in the solifenacin arm vs 3.0% in the tolterodine arm). Darifenacin

Darifenacin is a tertiary amine with moderate lipophilicity and is a highly selective M3 receptor antagonist that has been found to have a fivefold higher affinity for the human M3 receptor relative to the M1 receptor [61]. Darifenacin is equipotent with atropine in the ileum and bladder and six-times less potent at inhibiting muscarinic receptors in the salivary gland. Salivary responses are inhibited at doses six- to tenfold higher than those required to inhibit bladder responses. The efficacy of darifenacin has been investigated in a multicenter, double-blind, placebo-controlled, parallel-group study that enrolled 561 patients with symptoms of OAB [62]. Patients were randomized (1:4:2:3) to once-daily oral

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darifenacin controlled-release tablets 3.75 (n = 53), 7.5 (n = 229) or 15 mg (n = 115) or matching placebo (n = 164) for 12 weeks. Darifenacin 7.5 and 15 mg were found to have a rapid onset of action, with significant improvement compared with placebo being seen for most parameters at the first clinic visit (week 2). Darifenacin 7.5 and 15 mg, respectively, were significantly superior to placebo for improvements in micturition frequency, bladder capacity, frequency of urgency, severity of urgency and number of incontinence episodes leading to a change in clothing or pads. However, there was no significant reduction in nocturia. The most common adverse events were mild-to-moderate dry mouth and constipation, with a CNS and cardiac safety profile comparable with placebo. No patients withdrew from the study as a result of dry mouth and discontinuation related to constipation was rare (0.6% placebo vs 0.9% darifenacin). More recently, a review of the pooled darifenacin data from the three Phase III, multicenter, double-blind clinical trials in patients with OAB has been carried out [63]. In total, 1059 adults (85% female) with symptoms of OAB were randomized to once-daily oral treatment with darifenacin 7.5 (n = 337) or 15 mg (n = 334) or matching placebo (n = 388) for 12 weeks. When compared with baseline, treatment with darifenacin resulted in a dose-related significant reduction in median number of incontinence episodes per week (7.5 mg, -8.8 [-68.4%]; 15 mg, -10.6 [-76.8%]). Significant decreases in the frequency and severity of urgency, micturition frequency and number of incontinence episodes resulting in a change of clothing or pads were also apparent, along with an increase in bladder capacity. Darifenacin was well tolerated. The most common treatment-related adverse events were dry mouth and constipation, although together these resulted in few discontinuations (darifenacin 7.5 mg 0.6% of patients; darifenacin 15 mg 2.1% of patients; placebo 0.3% of patients). The incidence of CNS and cardiovascular adverse events was comparable to placebo. Antidepressants Imipramine

Imipramine has been shown to have systemic anticholinergic effects [64], blocks the reuptake of serotonin and has some β-agonist activity. Some studies have found a significant effect in the treatment of patients with detrusor overactivity [65], although others report little effect [66]. In light of this evidence and the serious adverse effects associated with tricyclic antidepressants, their role in detrusor overactivity remains of uncertain benefit, although they are often useful in patients complaining of nocturia or bladder pain. Prostaglandin synthetase inhibitors

Bladder mucosa has been shown to have the ability to synthesise eicosanoids [67], although it is uncertain whether they contribute to the pathogenesis of unstable detrusor contractions. However, they may have a role in sensitizing sensory afferent nerves, increasing the afferent input produced by

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a given bladder volume. A double-blind controlled study of flurbiprofen in women with detrusor overactivity was shown to have an effect, although it was associated with a high incidence of adverse effects (43%), including nausea, vomiting, headache and gastrointestinal symptoms [68]. Indomethacin has also been reported to give symptomatic relief, although the incidence of adverse effects was also high (59%) [69]. At present, this evidence does not support their use in detrusor overactivity. Antidiuretic agents Desmopressin

Desmopressin (1-desamino-8-D-arginine vasopressin [DDAVP]) is a synthetic vasopressin analogue. It has strong antidiuretic effects without altering blood pressure. The drug has been used primarily in the treatment of nocturia and nocturnal enuresis in children [70] and adults [71]. More recently, nasal desmopressin has been reported as a ‘designer drug’ for the treatment of daytime urinary incontinence [72] in a multicenter, multinational, randomized, double-blind, placebocontrolled, crossover exploratory study of women, aged 18–80 years, complaining of severe daytime urinary incontinence. The primary efficacy end point was the number of periods without leakage for 4 h following drug administration. Secondary efficacy parameters included time to first void or incontinence episode, volume leaked per incontinence episode, total volume voided and number of periods without leakage. Overall, there was a higher incidence of periods without leakage in the first 4 h on desmopressin (62 ± 35%) compared with placebo (48 ± 40%) and during the first 8 h (55 ± 37 vs 40 ± 41%). Furthermore, there was a higher frequency of dry days on desmopressin compared with placebo; 36% of patients had no leakage on virtually all treatment days (6 or 7) for 4 h after drug administration. At 4–8 h, the incidence of periods without leakage on desmopressin was 68 ± 35% compared with 63 ± 41% on placebo, and thereafter the incidence was similar. Time from administration to first incontinence episode was longer on desmopressin (6.3 ± 2.5 vs 5.2 ± 3.3 h), while volume leaked per incontinence episode was lower on desmopressin compared with placebo. Desmopressin is safe for long-term use; however, the drug should be used with care in the elderly owing to the risk of hyponatremia and the current recommendations are that serum sodium should be checked on day 3 and 5 following the start of treatment. To review the safety of DDAVP, a recent systematic review and meta-analysis has been performed of cohort studies and randomized, controlled trials using the oral and intranasal preparations in the treatment of nocturia. In total, 75 papers were identified, of which seven reported the incidence of hyponatremia, giving an overall pooled estimate of 7.6% (95% CI: 3.7–15.1). The authors concluded that hyponatremia is a relative common adverse event associated with the use of desmopressin and regular monitoring should be used, particularly in the elderly [73].

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α-adrenoreceptor antagonists

The lower urinary tract is innervated by both the parasympathetic and the sympathetic nervous systems, which act via muscarinic and adrenergic receptors, respectively. During the storage phase, continence is maintained by inhibition of the parasympathetic system and by activation of the sympathetic system, which, by acting on β2- and α-adrenergic receptors, lead to bladder relaxation and urethral sphincter contraction, respectively. Conversely, during voiding, the pontine micturition center inhibits the sympathetic system and activates the parasympathetic system, resulting in urethral relaxation and a sustained bladder contraction. The adrenergic receptors found at the bladder neck are α1-adrenergic and three subtypes have been identified: α1A, α1B and α1D [74]. Those receptors present in the bladder are predominantly α1A and α1D, while α1B-receptors are found in the vasculature and are involved in blood pressure control. Consequently, α1-adrenergic-blocking agents with subselectivity for α1A and α1D may be most useful in the management of lower urinary tract dysfunction and it has been speculated that the α1D-receptor may mediate the overactive symptoms of OAB while the α1A-receptor subtype mediates the obstructive symptoms [75]. Anecdotal evidence has demonstrated that tamsulosin, a selective α1-adrenoceptor antagonist, may improve urinary symptoms secondary to detrusor overactivity in men and for some time it has been used ‘off label’ in women with symptoms of OAB. A randomized, double-blind, placebo-controlled study evaluating the efficacy of tamsulosin in the management of women complaining of OAB has been reported recently [76]. Overall, 364 women (53.3% treatment naive) were randomized to receive one of four doses of tamsulosin (0.25, 0.5, 1.0 or 1.5 mg), 4 mg of ER tolterodine or placebo for 6 weeks. The primary efficacy analysis showed that the difference from placebo in the mean number of micturitions per 24 h was not statistically significant for tamsulosin 1.5 mg (p = 0.189). Interestingly, there was also no statistically significant difference observed for ER tolterodine 4 mg (p = 0.353). Similarly, when considering the secondary outcome parameters there was no statistically significant difference between tamsulosin and placebo. Although women taking ER tolterodine 4 mg once daily demonstrated a consistently greater increase in mean volume voided and consistent decreases in incontinence episodes per 24 h, urgency episodes per 24 h and episodes of nocturia per 24 h, when compared with placebo, this was not statistically significant. In addition, there was no significant improvement in QoL scores across the treatment groups. The results from this study would suggest that α-adrenoreceptor antagonists alone are not clinically useful in the management of OAB in women. New developments Calcium channel-blocking agents

Contractile activity in the bladder smooth muscle is activated by the movement of extracellular calcium into the cell. Spontaneous and evoked contractile activity are mediated by membrane

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depolarization and the movement of calcium into the smooth muscle cell through L-type Ca2+ channels [77]. The inhibition of the entrance of Ca2+ can prevent spontaneous and evoked contractile activity [78] with L-type Ca2+-blocking agents, such as nifedipine, inhibiting the entry of extracellular calcium. Nifedipine has been shown to reduce the frequency and amplitude of detrusor contractions [79], although these findings were not confirmed in a further study that found there was no significant effect on detrusor contractions [80]. Similar contradictory findings have been reported regarding the use of flunarizine [6,81]. Diltiazem has also been shown to significantly increase bladder capacity, lower bladder pressure and decrease the number of episodes of incontinence [82]. At present, there is insufficient evidence to suggest that calcium channel-blocking agents are effective in the treatment of detrusor overactivity, although the development of a selective calcium channel-blocking agent that eliminates spontaneous contractions without affecting micturition may prove to be of use in the treatment of detrusor overactivity. Potassium channel-opening agents

The opening of K+ ion channels in the membrane of the detrusor muscle cell results in an increase in K+ movement out of the cell, resulting in membrane hyperpolarization [83]. This reduces the opening probability of ion channels involved in membrane depolarization, hence excitability is reduced [84]. Two types of potassium channels have been identified in the detrusor muscle: ATP-sensitive channels and calcium-dependent large conductance channels [32]. At present, the relationship between each of these types of channels and the myogenic, neurogenic and micturition forms of detrusor contraction has not been determined. To date, cromakalim, nicorandil and pinacidil have been investigated, although newer agents are currently under development [85]. Potassium channel openers are thought to be active during the bladder filling phase and, while abolishing spontaneous detrusor contractions, are not thought to affect normal bladder contractions. However, their clinical usefulness is limited by significant cardiovascular effects, with cromakalim and pinacidil being found to be up to 200-times more potent as inhibitors of vascular preparations than of detrusor muscle [86]. In clinical trials assessing the use of these drugs in patients with detrusor overactivity, no bladder effects have been found at doses that already lower blood pressure [87]. More recently, newer drugs with KATP channel-opening properties have been described [88], which may be useful for the treatment of bladder overactivity although, at present, there is no evidence to suggest that K+ channel openers represent a viable treatment alternative. This is supported by a recently reported randomized, double-blind, placebo-controlled Phase II study evaluating the efficacy and safety of a novel ATP-sensitive potassium channel opener in 299 patients with detrusor overactivity. While treatment was safe and well tolerated, there was no difference over placebo in mean volume voided per micturition and micturition frequency [89].

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Fesoterodine

Fesoterodine is a new and novel derivative of 3,3-diphenylpropyl-amine, which is a potent antimuscarinic agent that is currently under investigation for the management of OAB. A Phase II dose-finding study has recently been conducted in 728 patients at 81 sites throughout Europe and South Africa [90]. Fesoterodine 4, 8 and 12 mg were all found to show significantly greater decreases in micturition frequency than placebo. The most commonly reported side effect was dry mouth, with an incidence of 25% in the 4-mg group rising to 34% in the 12mg group. Discontinuation rates were 6 and 12%, respectively. Subsequently, a Phase III randomized, placebo-controlled trial has been reported comparing fesoterodine 4 and 8 mg with ER tolterodine 4 mg in patients complaining of OAB in 1135 patients at 150 sites throughout Australia, New Zealand, South Africa and Europe [91]. Both doses of fesoterodine demonstrated significant improvements over placebo in reduction of daytime frequency and number of urge incontinence episodes per day and were found to be superior to tolterodine. Dry mouth was the most commonly reported adverse effect in 22, 34 and 17% in the fesoterodine 4, 8 mg and tolterodine arms, respectively. Intravesical therapy in the management of OAB Capsaicin

Capsaicin is the pungent ingredient found in red chillies and is a neurotoxin of substance P-containing (C) nerve fibers. Patients with neurogenic detrusor overactivity secondary to multiple sclerosis appear to have abnormal C fiber sensory innervation of the detrusor, which leads to premature activation of the holding reflex arc during bladder filling [92]. Intravesical application of capsaicin dissolved in 30% alcohol solution appears to be effective for up to 6 months. The effects are variable [93] and clinical effectiveness remains undefined. Resiniferatoxin

Resiniferatoxin is a phorbol-related diterpene isolated from the cactus and is a potent analogue of capsaicin that appears to have a similar efficacy but with fewer side effects of pain and burning during intravesical instillation [94]. It is 1000-times more potent than capsaicin at stimulating bladder activity [95]. As with capsaicin, the currently available evidence does not support the routine clinical use of the agents, although they may prove to have a role as an intravesical preparation in neurological patients with neurogenic detrusor overactivity. Botulinum toxin

In 1817, an illness caused by Clostridium botulinum toxin was first recorded, when Justinus Kerner described a link between a sausage and a paralytic illness that affected 230 people. He was a district health officer and made botulism (Latin ‘botulus’ meaning sausage) a notifiable disease [96]. In 1897, the microbiologist Emile-Pierre van Ermengen identified a Gram-positive, sporeforming, anerobic bacterium in a ham that caused 23 cases of botulism in a Belgian nightclub. He termed the bacterium Bacillus botulinus; it was later retermed Clostridium Botulinum [97].

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The bacterium produces its effect by the production of a neurotoxin – different strains produce seven distinct serotypes designated A, B, C, D, E, F and G. All seven have a similar structure and molecular weight, consisting of a heavy (H) and light (L) chain, joined by a disulfide bond [98]. They interfere with neural transmission by blocking the calcium-dependent release of the neurotransmitter, acetylcholine, causing the affected muscle to become weak and atrophic. The affected nerves do not degenerate but, as the blockage is irreversible, only the development of new nerve terminals and synaptic contacts allows recovery of function. The use of intravesical botulinum toxin was first described in the treatment of intractable neurogenic detrusor overactivity in 31 patients with traumatic spinal cord injury [99]. Subsequently, a larger European study has reported on 231 patients with neurogenic detrusor overactivity [100]. All were treated with 300 units of botulinum-A toxin (Botox®), which was injected cystoscopically into the detrusor muscle at 30 different sites sparing the trigone. At 12 and 36 weeks follow-up, there was a significant increase in cystometric capacity and bladder compliance. Patient satisfaction was high, the majority stopped taking antimuscarinic medication and there were no significant complications. More recently, the first randomized, placebocontrolled trial has been reported in 59 patients with neurogenic detrusor overactivity [101]. At 6 months, there was a significant reduction in incontinence episodes in the botulinumA toxin group compared with placebo and a corresponding improvement in QoL evaluation. While the role of botulinum toxin has been established in the treatment of neurogenic detrusor overactivity, the data regarding its use in intractable idiopathic detrusor overactivity are less robust. A prospective, open-label study has recently been reported assessing the use of botulinum-A toxin in both neurogenic (300 units) and idiopathic (200 units) detrusor overactivity in 75 patients [102]. When considering urodynamic outcome parameters in both groups, there was a significant increase in cystometric capacity and decrease in maximum detrusor pressure during filling in both groups. Clinically, there was also a significant reduction in frequency and episodes of urge incontinence. Interestingly, however, 69% of patients with neurogenic detrusor overactivity required self catheterization following treatment compared with 19.3% of those with idiopathic detrusor overactivity. A further study of 100 cases of idiopathic OAB syndrome refractory to antimuscarinic treatment has also been reported using 100 IU botulinum-A toxin [103]. Overall, after 4 and 12 weeks, 88% of patients had a significant improvement in both subjective and objective outcome measures, including QoL evaluation. The symptom of urgency was resolved in 82% of patients and mean daytime frequency was reduced from 14 to seven voids per day, with nocturia decreasing from four episodes per night to 1.5. In addition, maximal cystometric capacity increased from 246 to 381 mls. Mean duration of efficacy was approximately 6 ± 2 months and there were four cases of temporary voiding difficulties although no long-term problems.

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At present, the evidence would suggest that intravesical administration of botulinum toxin may offer an alternative to surgery in those women with intractable detrusor overactivity, although the effect is only temporary and at present there are few long-term data regarding the efficacy and complications associated with repeat injections [104]. Estrogens in the management of OAB

Estrogens have been used in the treatment of urinary urgency and urge incontinence for many years, although there have been few controlled trials to confirm their efficacy. A doubleblind, placebo-controlled, crossover study using oral estriol in 34 postmenopausal women produced subjective improvement in eight women with mixed incontinence and 12 with urge incontinence [105]. However, a double-blind, multicenter study of the use of estriol (3 mg/day) in postmenopausal women complaining of urgency has failed to confirm these findings, showing both subjective and objective improvement but not significantly better than placebo [106]. Estriol is a naturally occurring weak estrogen that has little effect on the endometrium and does not prevent osteoporosis, although it has been used in the treatment of urogenital atrophy. Consequently, it is possible that the dosage or route of administration in this study was not appropriate in the treatment of urinary symptoms and higher systemic levels may be required. The use of sustained-release 17β-estradiol vaginal tablets (Vagifem®) has also been examined in postmenopausal women with urgency and urge incontinence or a urodynamic diagnosis of sensory urgency or detrusor overactivity. These vaginal tablets have been shown to be well absorbed from the vagina and to induce maturation of the vaginal epithelium within 14 days [107]. However, following a 6-month course of treatment, the only significant difference between active and placebo groups was an improvement in the symptom of urgency in those women with a urodynamic diagnosis of sensory urgency [108]. A further double-blind, randomized, placebo-controlled trial of vaginal 17β-estradiol vaginal tablets has shown lower urinary tract symptoms of frequency, urgency and urge and stress incontinence to be significantly improved, although there was no objective urodynamic assessment performed [109]. In both studies, the subjective improvement in symptoms may simply represent local estrogenic effects, reversing urogenital atrophy rather than a direct effect on bladder function. More recently, a randomized, parallel-group, controlled trial has been reported comparing the estradiol-releasing vaginal ring (Estring®) with estriol vaginal pessaries in the treatment of postmenopausal women with bothersome lower urinary tract symptoms [110]. Low-dose vaginally administered estradiol and estriol were found to be equally efficacious in alleviating lower urinary tract symptoms of urge incontinence (58 vs 58%), stress incontinence (53 vs 59%) and nocturia (51 vs 54%), although the vaginal ring was found to have greater patient acceptability. To try to clarify the role of estrogen therapy in the management of women with urge incontinence, a meta-analysis of the use of estrogen in women with symptoms of OAB has been

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reported by the Hormones and Urogenital Therapy Committee [111]. In a review of ten randomized, placebo-controlled trials, estrogen was found to be superior to placebo when considering symptoms of urge incontinence, frequency and nocturia, although vaginal estrogen administration was found to be superior for symptoms of urgency. In those taking estrogens, there was also a significant increase in first sensation and bladder capacity compared with placebo. NICE guidelines

The medical management of OAB has recently been reviewed by the National Institute for Health and Clinical Excellence (NICE) [201]. In the first instance, bladder retraining lasting for a minimum of 6 weeks should be offered to all women with mixed or urge incontinence. In those women who do not achieve satisfactory benefit from bladder retraining alone, the combination of an antimuscarinic agent, in addition to bladder retraining, should be considered. When considering drug therapy, immediate-release nonpropriety oxybutynin should be offered to women with OAB or mixed urinary incontinence as first-line drug treatment if bladder retraining has been ineffective. If immediate-release oxybutynin is not well tolerated, darifenacin, solifenacin, tolterodine, trospium or an ER or transdermal formulation of oxybutynin should be considered as alternatives. In addition, women should be counselled regarding the adverse effects of antimuscarinic drugs. Propiverine should be considered as an option to treat frequency of micturition but is not recommended for the treatment of urinary incontinence. Flavoxate, propantheline and imipramine should not be used for the treatment of OAB. While desmopressin may be considered specifically to reduce nocturia in women, this is currently outside the marketing authorization, hence informed consent must be obtained. When considering the role of estrogens, the recommendations are that systemic hormone-replacement therapy should not be recommended, although intravaginal estrogens are recommended for the treatment of OAB in postmenopausal women with urogenital atrophy. Conclusion

Pharmacological therapy, in addition to bladder retraining, remains important in the management of women with symptoms of OAB. While tolerability has previously limited compliance, the development of long-acting agents with a better adverse-event profile has improved this dramatically. The development of new M3-specific and bladder-selective muscarinic antagonists may also improve efficacy and compliance while limiting adverse effects. The development of calcium antagonists and potassium channel-opening agents may offer alternatives to antimuscarinic therapy, although at present, there are no clinically useful drugs available. Ultimately, perhaps a better understanding of the causes and pathophysiology of OAB syndrome may result in the development of new treatments for such a common and distressing condition.

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Expert commentary

Pharmacological therapy used synergistically with behavioral therapy remains integral in the management of women with OAB. Over the last 10 years, we have seen the development of many new antimuscarinic agents in addition to those with more novel modes of action. At present, antimuscarinic agents remain the most widely used preparations and tolterodine is the most commonly prescribed drug in both the UK and North America. However, recent studies would suggest that solifenacin may offer additional efficacy and it also has the benefit of a flexible dosing regimen, allowing greater choice in the management of patients. Darifenacin has only been launched relatively recently in the UK and, as perhaps the most M3 specific of all the antimuscarinic agents, its precise role remains to be determined. In addition, the introduction of transdermal oxybutynin now allows a viable therapeutic alternative for those women who are unable to tolerate oral antimuscarinic agents. The role of intravesical therapy currently remains under investigation. Botulinum toxin has now largely superseded the alternative intravesical preparations. While there is now substantial evidence to support its use in patients with neurogenic detrusor overactivity, there is very little evidence to support its usage in women with idiopathic OAB. In addition, there remains a concern regarding the long-term effects of repeated injections on detrusor muscle function. The recent NICE guidelines may also dictate the use of antimuscarinic therapy within the UK and, consequently, have an impact on prescribing practice and drug usage. Currently, there is only speculation regarding how closely these will be adhered to, although it is likely that, especially in primary care, decisions may be driven by economic factors. Whether this will ultimately lead to improved patient care and a reduction in overall costs, including both direct costs, such as containment products, and indirect costs, such as sick leave and decreased productivity, is less certain. Five-year view

With an increasingly elderly population, the impact of OAB will continue to have an important effect on QoL and may become an increasing economic burden to healthcare providers. While at present the etiology of OAB remains to be determined, a better understanding of the pathophysiology may improve treatment efficacy. Whereas the development of the newer longer acting agents has made only a small impact on patient compliance, the introduction of more bladder-specific agents, such as solifenacin and darifenacin, may lead to greater patient acceptability. Likewise, the use of alternative delivery systems and flexible dosing regimens will also offer physicians and women greater choice. In addition, the concept of short-acting agents to be used ‘as required’ medication may become increasingly popular in those women who do not want to take medication everyday for something that only troubles them occasionally. Currently, the majority of agents used in the treatment of OAB are antimuscarinic drugs. To date, there has been little success with calcium antagonists and potassium channel-opening agents,

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although there remains a need for alternative types of medication. Current research has implied that the efferent response to pain may be partially responsible for detrusor contractions and there is now considerable interest in assessing the use of drugs that block the pain pathways, such as the neurokinin antagonists. These may become increasing important and offer an alternative to antimuscarinics in the future. A further alternative approach is to use combination therapy. While currently there is no evidence to support the use of α-adrenergic antagonists alone, it is possible that, when used concomitantly with an antimuscarinic agent, there may be a synergistic effect leading to the possibility of reduced dosing and consequently reduced adverse effects.

Financial & competing interests disclosure

D Robinson has recieved funding for research, lecturing and consultancies from Ferring Pharmaceuticals, Astellas, Pfizer, NovoNordisk, Gynaecare, Q Med and Uroplasty. L Cardozo has received funding for research, lecturing and consultancies from Astellas, Avera, Bioxell, Cook, Gynaecare, Organon, Pfizer, Plethora and UCB Pharma. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.

Key issues • Overactive bladder (OAB) is the term used to describe the symptom complex of urgency with or without urge incontinence, usually with frequency and nocturia. • The overall prevalence of OAB in women has been estimated to be 16.9%. • The symptoms of OAB are thought to be due to involuntary contractions of the detrusor muscle during the filling phase of the micturition cycle. • Antimuscarinic drugs, in addition to bladder retraining, remain central to the management of women with OAB. • Bladder-selective agents may offer improved efficacy and patient compliance. • Alternative drug-delivery systems and flexible dosing regimens may offer better patient choice and improve acceptability. • The use of intravesical therapy in cases of refractory OAB remains under investigation. • A better understanding of the etiology of OAB may drive the development of new agents with alternative mechanisms of action in the future. References Papers of special note have been highlighted as: • of interest •• of considerable interest 1

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NICE Guideline 40. The Management of Urinary Incontinence in Women. Department of Health www.nice.org.uk Recently introduced guidelines that may have major implications regarding the management of women with overactive bladder in the UK.

Affiliations •

Dudley Robinson, MD, MRCOG Kings college Hospital, Department of Urogynaecology, 3rd Floor, Golden Jubilee Wing, London, UK Fax: +44 207 346 3449 [email protected]

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Linda Cardozo, MD, FROG Kings college Hospital, Department of Urogynaecology, 3rd Floor, Golden Jubilee Wing, London, UK Fax: +44 207 346 3449

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