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Abstract

Urinary incontinence is a common and distressing condition that is known to adversely affect quality of life. Overactive bladder is the term used to describe the symptom complex of urinary frequency and urgency, with or without urge incontinence. Drug therapy, in addition to behavioral modification, remains integral in the management of women with overactive bladder, and the development of new drugs, treatment regimens and methods of delivery should improve patient compliance and acceptability. This article critically reviews the current pharmacological treatment of overactive bladder in addition to providing a rationale for treatment.

Keywords

antimuscarinics detrusor overactivity overactive bladder urinary incontinence

Overactive bladder (OAB) is the term used to describe the symptom complex of urinary frequency and urgency, with or without urge incontinence [1]. Recent 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, being 4.8% in women aged under 25 years and 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 or over was 16.6% and increased with age. Frequency was the most commonly reported symptom (85%), while 54% complained of urgency and 36% urge incontinence. When considering management, 60% had consulted a physician, although only 27% were currently receiving treatment.

Drug treatment continues to have an important role in the management of women with urinary incontinence, although many of the earlier agents used have not been subjected to controlled clinical trials [4]. 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 [5]. 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 purpose of this article is to review the current pharmacological treatment of OAB in women, as well as introducing some of the newer developments within the field.

Detrusor overactivity

The symptoms of OAB are thought to be 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 [6]. 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 [7].

Muscarinic receptors

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 [8]. In the human bladder, the occurrence of mRNA encoding M₂ and M₃ subtypes has been previously demonstrated [9], and more recently for M₁ receptors [10]. Stimulation of the M₃ receptor is thought to cause a direct smooth-muscle contraction [11]. While the role of the M₂ receptor has not yet been clarified, it may oppose sympathetically mediated smooth-muscle relaxation [12] or result in the activation of a nonspecific cationic channel and inactivation of potassium channels [13]. In general, it is thought that the M₃ receptor is responsible for the normal micturition contraction, although in certain disease states, such as neurogenic bladder dysfunction, the M₂ receptors may become more important in mediating detrusor contractions [14].

Drugs that have a mixed action

Oxybutynin

Oxybutynin is a tertiary amine that undergoes extensive first-pass metabolism to an active metabolite, N-desmethyl oxybutynin [15], which occurs in high concentrations and is thought to be responsible for a significant part of the action of the parent drug [16]. 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 given intravesically but probably has no effect when given systemically. Oxybutynin has been shown to have a high affinity for muscarinic receptors in the bladder [17] and has a higher affinity for M₁ and M₃ receptors over M₂ [18].

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 [19]. Similar results have also been demonstrated in further placebo-controlled trials [20,21].

In addition, oxybutynin has been compared with other treatments for detrusor overactivity. It has been found to be significantly more effective than previously used 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%) [22]. More recently, a placebo-controlled, multicenter study comparing the tolerability and efficacy of propiverine with oxybutynin in patients with urgency and urge incontinence was performed. This demonstrated oxybutynin to be as efficacious as propiverine, although the study found it was associated with more severe adverse effects [23].

The antimuscarinic adverse effects of oxybutynin are well documented and are often dose limiting [24]. Using an intravesical route of administration, higher local levels of oxybutynin can be achieved while limiting the systemic adverse effects. Using this method, oxybutynin has been demonstrated to increase bladder capacity and lead to a significant clinical improvement [25]. Rectal administration has also been shown to be associated with fewer adverse effects when compared with oral administration [26].

More recently, a controlled-release oxybutynin preparation using an osmotic system has been developed, which has been shown to have comparable efficacy when compared with immediate-release (IR) oxybutynin, although it is associated with fewer adverse effects [27]. These findings are in agreement with a further study of controlled-release oxybutynin, which reported the incidence of moderate-to-severe dry mouth to be 23% and the number of participants discontinuing the medication due to adverse effects to be 1.6% [28].

In order to maximize efficacy and minimize adverse effects, alternative delivery systems are currently under evaluation. An oxybutynin transdermal delivery system (available as Oxytrol^© in the USA and Kentera^© in Europe) has recently been developed and compared with extended-release (ER) tolterodine in 361 patients with mixed urinary incontinence. Both agents significantly reduced incontinence episodes, increased volume voided and led to an improvement in quality of life (QoL) when compared with placebo. 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 [29].

Propiverine

Propiverine has been shown to combine anticholinergic and calcium channel blocking actions [30], and is the most popular drug for detrusor overactivity in Germany, Austria and Japan. Open studies in patients with detrusor overactivity have demonstrated a beneficial effect [31] and in a double blind, placebo-controlled trial of its use in neurogenic detrusor overactivity, it was shown to significantly increase bladder capacity and compliance compared with placebo. Dry mouth was experienced by 37% of patients in the treatment group as opposed to 8% in the placebo group, with drop-out rates being 7 and 4.5%, respectively [32]. In a review of nine randomized studies of propiverine, with a total of 230 patients overall, there was a 30% reduction in frequency and a 17% reduction in micturitions/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 [33].

The efficacy and cardiac safety of propiverine have been assessed in a double-blind, multi-center, placebo-controlled, randomized study of 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 [34].

Antimuscarinic drugs

Tolterodine

Tolterodine is a competitive muscarinic receptor antagonist with relative functional selectivity for bladder muscarinic receptors [35], and while it shows no specificity for receptor subtypes it does appear to target the bladder over the salivary glands [36]. The drug is metabolized in the liver to the 5-hydroxymethyl derivative, which is an active metabolite with a similar pharmacokinetic profile, and is thought to significantly contribute to the therapeutic effect [37].

Several randomized, double-blind, placebo-controlled trials, both on patients with idiopathic and neurogenic detrusor overactivity, have demonstrated a significant reduction in incontinent episodes and micturition frequency [38 –40]. Further studies have confirmed the safety of tolterodine and, at the recommended daily dosage, the incidence of adverse events was no different to that found in patients receiving placebo [41].

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 [42]. 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 [43].

More recently, tolterodine has also been developed as an ER once-daily preparation. A recent double-blind, multicenter trial of 1235 women compared tolterodine ER with tolterodine IR 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 [44]. In addition to increased efficacy, tolterodine ER has been shown to have better tolerability. In a double-blind, multicenter, randomized, placebo-controlled trial of 1529 patients, tolterodine ER was found to be 18% more effective in the reduction of episodes of urge incontinence, while having a 23% lower incidence of dry mouth [45].

Oxybutynin ER and tolterodine ER 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 the frequency of micturition. Significantly more women receiving oxybutynin were completely dry (23 vs 16.8%; p = 0.03), although dry mouth was significantly more common in the oxybutynin group [46].

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 [47]. 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, oxybutynin ER 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 receiving oxybutynin ER and tolterodine, respectively. The authors concluded that oxybutynin ER was more effective than tolterodine IR and that the rates of dry mouth and other adverse events were similar in both treatment groups.

In the Antimuscarinic Clinical Effectiveness Trial (ACET), patients with OAB were randomized to 8 weeks of open treatment with either 2 or 4 mg of tolterodine ER or, in the other group, 5 or 10 mg of oxybutynin ER [48]. Overall, 1289 patients were included. Fewer patients prematurely withdrew from the trial in the tolterodine ER 4-mg group (12%) than either the oxybutynin ER 5-mg (19%) or 10-mg groups (21%). More patients in the oxybutynin ER 10-mg group than the tolterodine 4-mg group withdrew due to poor tolerability (13 vs 6%). After 8 weeks, 70% of patients in the tolterodine ER 4 mg group noticed an improvement in their bladder condition, compared with 60% in the tolterodine ER 2-mg group, 59% in the oxybutynin ER 5-mg group and 60% in the oxybutynin ER 10-mg group. While dry mouth was dose dependent with both drugs, those patients treated with tolterodine ER 4 mg reported a significantly lower severity of dry mouth when compared with oxybutynin ER 10 mg. Overall, the authors concluded that tolterodine ER 4 mg was more efficacious than oxybutynin ER 10 mg in the treatment of OAB.

Trospium

Trospium chloride is a quaternary ammonium compound, which is nonselective for muscarinic receptor subtypes and shows low biological availability [49]. It crosses the blood–brain barrier to a limited extent and hence would appear to have few cognitive effects [50]. In a recent placebo-controlled, randomized, double-blind, 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 [51]. 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 receiving trospium had a lower incidence of dry mouth (4 vs 23%) and were also less likely to withdraw (6 vs 16%) when compared with the group receiving oxybutynin [52].

Solifenacin

Solifenacin is a potent M₃ receptor antagonist that has selectivity for M₃ over M₂ receptors and has a much higher potency against M₃ receptors in smooth muscle than in the 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 [53], 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 [54], 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 [55]. The study consisted of a single-blind, 2-week placebo run-in period followed by a randomized, double-blind, placebo-controlled, 12-week treatment period. Overall, 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 demonstrated a statistically significant reduction in micturition frequency following treatment with both 5-and 10-mg doses compared with placebo, although the largest effect was found 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/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 due to 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 [56]. 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 when compared with placebo, the former equating to a reduction of 2.2 and the latter 2.6 micturitions/24 h. Tolterodine showed a smaller reduction of 1.9 micturitions. 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 including 1637 patients who elected to continue taking solifenacin 5 or 10 mg once daily [57]. Overall, the efficacy of solifenacin was maintained in the extension study and the mean number of micturitions/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 the mean number of micturitions/24 h, mean volume voided and mean number of urge incontinence episodes/24 h. Interestingly, those patients who had originally received tolterodine in the previous studies noticed a similar improvement in the number of micturitions/24 h, volume voided per micturition and number of urgency episodes/24 h, comparable to 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 of mild or moderate 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 5 and 10 mg once daily have been compared with tolterodine (ER 4 mg once daily) in the Solifenacin (flexible dosing) once daily and Tolterodine ER 4 mg once daily as an Active comparator in a Randomized trial (STAR) study [58]. This was a prospective, double-blind, placebo-controlled, two-arm, parallel-group, 12-week study with the primary aim of demonstrating noninferiority of solifenacin to tolterodine ER in a manner reflecting clinical practice. A total of 1200 patients (593 receiving solifenacin and 607 receiving tolterodine ER) were recruited in 117 study sites in 17 countries. The outcome of the primary efficacy analysis was that solifenacin was not inferior to tolterodine ER with respect to change from baseline in the mean number of micturitions/24 h (reduction of 2.45 vs 2.24 micturitions/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. In addition, 59% of solifenacin-treated patients who were incontinent at baseline became continent by the study end point compared with 49% of those receiving tolterodine ER (p = 0.006). The most commonly reported adverse events were dry mouth, 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% 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 [59]. 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. These data support the potential for the use of darifenacin as a bladder-selective antimuscarinic agent.

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 [60]. Patients were randomized (1:4:2:3) to once-daily oral darifenacin controlled-release tablets: 3.75 mg (n = 53), 7.5 mg (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 effect, with significant improvement compared with placebo being observed 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 to 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, multi-center, double-blind clinical trials in patients with OAB has been carried out [61]. In total, 1059 adults (85% female) with symptoms of OAB were randomized to once-daily oral treatment with darifenacin 7.5 mg (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 the median number of incontinence episodes/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%; placebo: 0.3%). The incidence of CNS and cardiovascular adverse events were comparable to placebo.

While currently still not licensed in the UK, darifenacin has been launched in Europe and North America and, since it is the most selective of the newer antimuscarinic agents for the M₃ receptor subtype, it may offer a better balance between efficacy and unwanted effects by targeting muscarinic receptors in the bladder in preference to those in the salivary glands and bowel.

Antidepressants

Imipramine

Imipramine has been shown to have systemic anticholinergic effects [62] and blocks the reuptake of serotonin and noradrenaline [63]. Some authors have found a significant effect in the treatment of patients with detrusor overactivity [64], although others report little effect [65]. In light of this evidence and the serious adverse effects associated with tricyclic antidepressants, their role in detrusor overactivity remains of uncertain benefit (International Consultation on Incontinence [ICI] Level 3; Grade C) [66], 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 a given bladder volume. A double-blind, controlled study of flurbiprofen in women with detrusor overactivity demonstrated that this drug had 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 events was also high (59%) [69]. At present, the evidence does not support their use in detrusor overactivity.

Antidiuretic agents

Desmopressin

Desmopressin (1-desamino-8-d-arginine vasopressin [DDAVP]) is a synthetic vasopressin analog. 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 in a multicenter, multinational, randomized, double-blind, placebo-controlled, 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 [72]. Overall, there was a higher incidence of periods without leakage in the first 4 h receiving 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 among patients receiving 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 among patients receiving desmopressin was 68 ± 35% compared with 63 ± 41% among those receiving placebo, and thereafter the incidence was similar. The time from administration to first incontinence episode was longer among those receiving desmopressin (6.3 ± 2.5 vs 5.2 ± 3.3 h), while volume leaked per incontinence episode was lower among patients receiving desmopressin compared with those receiving placebo.

There were no serious or severe adverse events reported. Desmopressin is safe for long-term use; however, the drug should be used with care in the elderly due to the risk of hyponatremia and the current recommendations are that serum sodium should be checked on days 3 and 5 following the start of treatment.

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 is mediated by membrane depolarization and the movement of calcium into the smooth muscle cell through L-type calcium channels [73]. The inhibition of the entrance of calcium can prevent spontaneous and evoked contractile activity [74], with L-type calcium-blocking agents such as nifedipine inhibiting the entry of extracellular calcium.

Nifedipine has been shown to reduce the frequency and amplitude of detrusor contractions [75], although these findings have not been confirmed in a further study, which found that there was no significant effect on detrusor contractions [76]. Similar contradictory findings have been reported regarding the use of flunarizine [6,77]. Diltiazem has also been shown to significantly increase bladder capacity, lower bladder pressure and decrease the number of episodes of incontinence [78].

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 potassium ion channels in the membrane of the detrusor muscle cell results in an increase in potassium movement out of the cell, leading to membrane hyperpolarization [79]. This reduces the opening probability of ion channels involved in membrane depolarization and, hence, excitability is reduced [80]. At present, the relationship between each of these types of channel 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 in development [81].

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 [82]. 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 [83]. More recently, newer drugs with potassium ATP channel opening properties have been described [84], which may be useful for the treatment of bladder overactivity, although at present there is no evidence to suggest that potassium channel openers represent a viable treatment alternative.

Estrogens in the management of urge incontinence

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 double-blind, 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 [85]. However, a double-blind, multicenter study of the use of estriol (3 mg/day) in postmenopausal women complaining of urgency failed to confirm these findings [86], showing both subjective and objective improvement but not significantly different from placebo. Estriol is a naturally occurring weak estrogen, which 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 has also been examined in post-menopausal 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 [87]. 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 [88]. A further double-blind, randomized, placebo-controlled trial of vaginal 17β-estradiol vaginal tablets has shown lower urinary tract symptoms of frequency, urgency, urge and stress incontinence to be significantly improved, although no objective urodynamic assessment was performed [89]. In both of these 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 with estriol vaginal pessaries in the treatment of postmenopausal women with bothersome lower urinary tract symptoms [90]. 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 reported by the Hormones and Urogenital Therapy (HUT) Committee [91]. 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 receiving estrogens, there was also a significant increase in first sensation and bladder capacity compared with placebo.

However, further large-scale studies examining the role of hormone replacement therapy (HRT) in the prevention of cardiovascular disease have raised doubts regarding the use of estrogens in the management of postmenopausal women with lower urinary tract dysfunction.

The role of estrogen replacement therapy in the prevention of ischemic heart disease has been assessed in a 4-year randomized trial, the Heart and Estrogen/progestin Replacement Study (HERS) [92], involving 2763 postmenopausal women younger than 80 years with intact uteri and ischemic heart disease. In the study, 55% of women reported at least one episode of urinary incontinence each week and were randomly assigned to oral conjugated estrogen plus medroxyprogesterone acetate (MPA) or placebo daily.

Incontinence improved in 26% of women assigned to placebo compared with 21% receiving HRT, while 27% of the placebo group complained of worsening symptoms compared with 39% in the HRT group (p = 0.001). The incidence of incontinent episodes per week increased by an average of 0.7 in the HRT group and decreased by 0.1 in the placebo group (p < 0.001). Overall, combined HRT was associated with worsening stress and urge urinary incontinence, although there was no significant difference in daytime frequency, nocturia or number of urinary tract infections.

These findings have also been confirmed in the Nurses' Health Study, which followed 39,436 postmenopausal women aged 50–75 years over a 4-year period. The risk of incontinence was found to be elevated in those women receiving HRT when compared with those who had never received HRT. There was an increase in risk in women receiving oral estrogen (relative risk [RR]: 1.54; 95% confidence interval [CI]: 1.44–1.65), transdermal estrogen (RR: 1.68; 95% CI: 1.41–2.00), oral estrogen and progesterone (RR: 1.34; 95% CI: 1.24–1.34), and transdermal estrogen and progesterone (RR: 1.46; CI: 1.16–1.84). In addition, while there remained a small risk after the cessation of HRT (RR: 1.14; 95% CI: 1.06–1.23), by 10 years the risk was identical (RR: 1.02; 95% CI: 0.91–1.41) and was also identical to those women who had never taken HRT [93].

More recently, the effect of HRT on urinary incontinence has been reported by the Women's Health Initiative (WHI) [94]. Overall, 27,347 postmenopausal women aged 50–79 years were assessed in a multicenter, double-blind, placebo-controlled trial. Of these, 23,296 were known to complain of lower urinary tract symptoms at baseline and 1-year follow-up. Women were randomized, based on hysterectomy status, to active treatment or placebo in either the estrogen and progestogen or estrogen-only trials. The estrogen was conjugated equine estrogen (CEE), while the progestogen was MPA. The main outcome measure was the incidence of urinary incontinence at 1 year among women who were incontinent at baseline.

Overall, HRT was found to increase the incidence of all types of urinary incontinence at 1 year in those women who were continent at baseline. The risk was highest for stress incontinence (CEE + MPA; RR: 1.87; 95% CI: 1.61–2.18; CEE alone; RR: 2.15; 95% CI: 1.77–2.62) followed by mixed incontinence (CEE + MPA; RR: 1.49; 95% CI: 1.10–2.01; CEE alone; RR: 1.79; 95% CI: 1.26–2.53). However, the effect on urge urinary incontinence was not uniform (CEE + MPA; RR: 1.15; 95% CI: 0.99–1.34; CEE alone; RR: 1.32; 95% CI: 1.10–1.58). When considering those women who were symptomatic at baseline, urinary frequency was found to increase in both arms (CEE + MPA; RR: 1.38; 95% CI: 1.28–1.49; CEE alone; RR: 1.47; 95% CI: 1.35–1.61) and the incidence of urinary incontinence was seen to increase at 1 year (CEE + MPA; RR: 1.20; 95% CI: 1.06–1.36; CEE alone; RR: 1.59; 95% CI: 1.39–1.82). In addition, while no formal QoL assessment was reported, women receiving HRT were more likely to report that urinary incontinence limited their daily activities and bothered and disturbed them.

These results, while supportive of the previously reported HERS study and Nurses' Health Study, would seem to contradict much of the previous work assessing the use of estrogens and, at present, the role of estrogens in the management of women with urinary incontinence remains uncertain.

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 better adverse-event profiles has improved this considerably. The development of new M₃-specific and bladder-selective muscarinic antagonists may also improve efficacy and compliance while limiting adverse effects, and the use of flexible dosing regimens allows treatment to be tailored to the individual. In addition, the introduction of transdermal oxybutynin may offer an alternative treatment strategy for those women who are unable to tolerate oral antimuscarinics.

Alternative treatment regimens may also improve compliance. Previous studies have highlighted that women are unwilling to consider taking medication every day for a condition that may only trouble them intermittently and hence the use of medication on an ‘as required’ basis may also improve patient acceptability [95].

In the future, the development of calcium antagonists and potassium channel opening agents may offer further 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 this common and distressing condition.

Executive summary

Overactive bladder (OAB) is the term used to describe the symptom complex of urinary frequency and urgency, with or without urge incontinence.

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.

A better understanding of the etiology of OAB may drive the development of new agents with alternative mechanisms of action in the future.

Future perspective

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 the efficacy of treatment. In addition, whereas the development of the newer longer-acting agents has only made a small impact on patient compliance, the introduction of 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. The concept of short-acting agents to be used on an ‘as required’ basis may become increasingly popular in those women who do not want to take medication every day 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, 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 OAB detrusor contractions and there is now considerable interest in assessing the use of drugs that block the pain pathways. These may become increasing important and offer an alternative to antimuscarinics in the future.

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Pharmacological Treatment for Overactive Bladder in Women

Abstract

Keywords

Detrusor overactivity

Muscarinic receptors

Drugs that have a mixed action

Oxybutynin

Propiverine

Antimuscarinic drugs

Tolterodine

Trospium

Solifenacin

Darifenacin

Antidepressants

Imipramine

Prostaglandin synthetase inhibitors

Antidiuretic agents

Desmopressin

New developments

Calcium channel blocking agents

Potassium channel opening agents

Estrogens in the management of urge incontinence

Conclusion

Future perspective

References