Muscarinic receptor antagonists for overactive bladder

Authors

  • Paul Abrams,

    1. Bristol Urological Institute, Southmead Hospital, Bristol, UK and Wake Forest Institute for Regenerative Medicine, Winston-Salem, NC, USA
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  • Karl-Erik Andersson

    1. Bristol Urological Institute, Southmead Hospital, Bristol, UK and Wake Forest Institute for Regenerative Medicine, Winston-Salem, NC, USA
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Paul Abrams, British Urological Institute, Southmead Hospital, Westbury-on-Trym, Bristol, BS10 5NB, UK.
e-mail:paul_abrams@bui.ac.uk

Abstract

From time to time we publish a full review of drugs that are available for the treatment of common conditions. In this issue, the review is written by two of the leading authorities in the world, Paul Abrams and Karl-Erik Andersson, on the topic of overactive bladder and antimuscarinic agents. This in-depth review covers the entire range of questions that might be asked about this common area of interest.

Overactive bladder (OAB) is a syndrome characterized by urinary urgency, with or without urgency urinary incontinence, usually with frequency and nocturia. OAB symptoms are often associated with detrusor overactivity (DO). Like OAB symptoms, the prevalence of DO increases with age and can have a neurogenic and/or myogenic aetiology. Bladder outlet obstruction can be a contributing factor in DO, possibly through cholinergic denervation of the detrusor and supersensitivity of muscarinic receptors to acetylcholine, although the prevalence of OAB is similar in men and women across age groups. Acetylcholine is the primary contractile neurotransmitter in the human detrusor, and antimuscarinics exert their effects on OAB/DO by inhibiting the binding of acetylcholine at muscarinic receptors M2 and M3 on detrusor smooth muscle cells and other structures within the bladder wall. Worldwide, there are six antimuscarinic drugs currently marketed for the treatment of OAB: oxybutynin, tolterodine, propiverine, trospium, darifenacin, and solifenacin. Each has demonstrated efficacy for the treatment of OAB symptoms, but their pharmacokinetic and adverse event profiles differ somewhat due to structural differences (tertiary vs quaternary amines), muscarinic receptor subtype selectivities, and organ selectivities. Antimuscarinics are generally well tolerated, even in special populations (e.g. men with bladder outlet obstruction, elderly patients, children). The most frequently reported adverse events in clinical studies of antimuscarinics are dry mouth, constipation, headache, and blurred vision; few patients withdraw from clinical trials because of adverse events.

Development of an antimuscarinic with functional selectivity for the bladder would reduce the occurrence of antimuscarinic adverse events. The therapeutic potential of several other agents, such as α3-adrenoceptor agonists, purinergic receptor antagonists, phosphodiesterase inhibitors, neurokinin-1 receptor antagonists, opioids, and Rho-kinase inhibitors, is also under investigation for the treatment of OAB.

Abbreviations
OAB

overactive bladder

DO

detrusor overactivity

UUI

urgency urinary incontinence

HR(QoL)

health-related (quality of life)

AE

adverse event

PROs

patient-reported outcomes

PVR

postvoid residual urine volume

Qmax

maximum urinary flow rate

ICI(Q)

International Consultation on Incontinence (questionnaires)

IR

immediate release

ER

extended release

BBB

blood–brain barrier

AUR

acute urinary retention

BPO

benign prostatic obstruction

RR

relative risk.

INTRODUCTION

Overactive bladder (OAB) is a syndrome characterized by urinary urgency, with or without urgency urinary incontinence (UUI), usually with frequency and nocturia [1]. Population-based estimates suggest that OAB affects 12–17% of adults in Europe and the United States [2–4], and compromises health-related quality of life (HRQoL) [5–7]. Muscarinic receptor antagonists are a first-line pharmacotherapy for OAB.

BASIC SCIENCE

MICTURITION REFLEX

Bladder function during storage and voiding is regulated by the peripheral and central nervous systems (CNS), and bladder contraction is primarily under parasympathetic control [8–12]. In adults, the micturition reflex is mediated by a spino-bulbo-spinal pathway, which passes through relay centres in the brain [13]. During bladder filling, afferent impulses generated by myogenic activity, bladder distension, and urothelial signals are conveyed to CNS centres via the pelvic and hypogastric nerves [13]. It has been proposed that the afferent neurones send information to the periaqueductal grey nucleus, which in turn communicates with the pontine tegmentum, where two different regions involved in micturition control have been described [14]. One is a dorsomedially located ‘M’ region, corresponding to Barrington’s nucleus or the pontine micturition centre. A more laterally located ‘L’ region might serve as a pontine urine storage centre, which has been suggested to suppress bladder contraction and to regulate the activity of the striated musculature of the bladder outlet during urine storage [15] (Fig. 1) [10].

Figure 1.


Voiding reflexes involve supraspinal pathways and are under voluntary control. During bladder emptying, the spinal parasympathetic outflow is activated (+ +), leading to bladder contraction. Simultaneously, the sympathetic outflow to urethral smooth muscle and the somatic outflow to urethral and pelvic floor striated muscles are turned off, and the outflow region relaxes. PAG, periaqueductal grey; PMC, pontine micturition centre. Reprinted with permission: Andersson and Wein, 2004 [10].

The efferent arm of the micturition reflex starts at the pontine micturition centre; the spinal parasympathetic outflow is activated and conveyed to the sacral (S2–S4) parasympathetic nucleus. This nucleus, which receives modulatory input from stimulatory and inhibitory neurones, contains the preganglionic neurones projecting to the bladder. In major parasympathetic ganglia, contact is made with the cholinergic neurones innervating the bladder. Detrusor contraction is initiated via release of acetylcholine and nonadrenergic noncholinergic (mainly ATP) transmitters [10] (Fig. 2).

Figure 2.

During filling, there is continuous and increasing afferent activity from the bladder. There is no spinal parasympathetic outflow that can contract the bladder. The sympathetic outflow to urethral smooth muscle (α-adrenoceptors, α+), and the somatic outflow to urethral and pelvic floor striated muscles (nicotinic receptors, N+) keep the outflow region closed. Whether the sympathetic innervation to the bladder contributes to bladder relaxation during filling (α-adrenoceptors, α+) in humans has not been established. PAG, periaqueductal grey; PMC, pontine micturition storage centre. Reprinted with permission: Andersson and Wein, 2004 [10].

Centres rostral to the pons determine the start of micturition. Thus, even if the forebrain is not essential for the basic micturition reflex, it plays a role in decisions concerning when and where micturition should take place [16]. Furthermore, evidence suggests that γ-aminobutyric acid, opioid, serotonin, noradrenaline, dopamine, nitric oxide, histamine, and glutamate signalling are involved in the control of micturition [10]. Muscarinic receptors within the CNS might also influence micturition [17–19].

CAUSES OF OAB

Detrusor overactivity (DO) is frequently associated with OAB symptoms and is urodynamically characterized by involuntary detrusor contractions during bladder filling [1]. DO and OAB do not always coexist [20–22], but Hashim and Abrams [22] reported that 83% of patients with DO had symptoms of OAB, and 64% of patients with OAB symptoms had DO. The causes of DO are multifactorial and might involve both peripheral (urothelial, myogenic/autonomous) and central signalling [23,24].

Studies designed to investigate changes in neurotransmitter signalling that contribute to bladder dysfunction have often focused on acetylcholine. During the storage phase, the parasympathetic drive that causes acetylcholine release resulting in detrusor contraction is normally suppressed [9,25]. However, a basal release of acetylcholine from non-neuronal (i.e. urothelial) as well as neuronal sources has been shown in isolated human detrusor muscle [26]. This release, which is stimulated by stretch during filling and increases with age, increases bladder afferent activity during storage [27]. Such spontaneous activity can be seen in the whole bladder or as relatively isolated contractions in parts of the bladder wall. These contractions, or ‘micromotions’[28,29], have been studied in isolated guinea-pig and mouse bladders [30,31] and can be demonstrated in humans [32]. They are enhanced by muscarinic receptor stimulation [33]. Enhanced myogenic contractions can generate enhanced afferent activity, ‘afferent noise’, contributing to urgency and/or initiation of the micturition reflex [24,31,34].

Altered structure of the detrusor smooth muscle has also been implicated in DO [35]. Studies in humans and animal models of DO have shown infiltration of the smooth muscle of the bladder wall by elastin and collagen, denervation of the bladder wall, and changes in protrusion junctions that allow electrical activity to spread between smooth muscle cells [35]. Facilitation of electrical coupling between smooth muscle cells could result in a coordinated myogenic response [35,36].

BOO can also cause DO through cholinergic denervation of the detrusor [37] and subsequent supersensitivity of muscarinic receptors to acetylcholine [35]. However, data from the EPIC study, a recent large, multinational epidemiologic survey that used the current ICS definitions showed that the prevalence of OAB is similar in men and women across all age groups [4], suggesting that the role of BOO in causing DO in men might be overemphasized. Another source of neurogenic bladder dysfunction might be a change in the excitability of unmyelinated, capsaicin-sensitive C-afferents in the urothelium. C-fibre afferents might mediate the feeling of bladder fullness and sensation of urgency [38,39]. C-afferent signalling might initiate bladder contraction in response to chemical stimuli [40,41] before stretch receptors are activated. These events might contribute to urgency at low bladder volumes, a symptom characteristic of OAB.

MUSCARINIC RECEPTORS

Acetylcholine activates muscarinic receptors on detrusor myocytes and is the main contractile transmitter. Muscarinic receptors comprise five subtypes encoded by five distinct genes [42]. The mRNAs for all muscarinic receptor subtypes have been detected in the human bladder [43,44], with mRNA and protein levels of the M2 subtype outnumbering the M3 receptor subtype [43–46]. These receptors have been detected in the urothelium, interstitial cells, nerve fibres, and detrusor layers [47]. Detrusor smooth muscle contains muscarinic receptors mainly of the M2 and M3 subtypes [9,48–50]. Both subtypes are coupled to G proteins, but the signal transduction pathways differ [9,48,49].

Detrusor smooth muscle

M3 receptors in the human detrusor are thought to be most important for detrusor contraction [10]. Evidence for this functional role comes from studies in M3 knockout mice. In the presence of carbachol, bladder strips from these mice had a maximal contractile response only 5% of that found in wild-type mice [51]. However, these mice have a nearly normal cystometric pattern due to the remaining purinergic activation mechanism [52].

Even in the obstructed rat bladder, M3 receptors were found to play a predominant role in mediating detrusor contraction [53]. Stimulation of M3 receptors is generally thought to cause contraction through phosphoinositide hydrolysis [54,55]. However, Jezior et al. [56] suggested that muscarinic receptor–mediated detrusor contraction also includes both nonselective cation channels and activation of Rho-kinase. Wibberley et al. [57] reported that Rho-kinase inhibitors (Y-27632, HA 1077) inhibited contractions evoked by carbachol without affecting the contractile response to KCl in rat bladder strips. They also reported high levels of Rho-kinase isoforms (I and II) in rat detrusor muscle. A role for Rho-kinase in the regulation of rat detrusor contraction and tone is supported by other investigators. For instance, Schneider et al. [58] confirmed that, in the human detrusor, carbachol-induced contraction is mediated via M3 receptors, and they concluded that detrusor contraction largely depends on Ca2+ entry through nifedipine-sensitive channels and activation of the Rho-kinase pathway. Although there might be species differences in the signalling pathways used by the different muscarinic receptor subtypes [59], data suggests that the main pathways for M3 receptor–mediated contraction in the human detrusor are calcium influx via l-type calcium channels and inhibition of myosin light-chain phosphatase through activation of Rho-kinase and protein kinase C, which leads to increased sensitivity of the contractile machinery to calcium [58,60] (Fig. 3). Inhibition of potassium channels might also be involved [10].

Figure 3.

Acetylcholine (ACh) causes contraction of detrusor muscle by stimulation of M3 receptors via activation of Rho-kinase and protein kinase C (PKC), and by increasing influx of Ca2+. ACh also induces contraction indirectly by inhibiting the production of cyclic adenosine monophosphate (cyclic AMP) and reversing the relaxation induced by β-adrenoceptors after stimulation by noradrenaline (NA).

Although a functional role for the M2 receptor has not been definitively identified, it has been suggested that stimulation of this receptor opposes sympathetically (β-adrenoceptor) mediated smooth muscle relaxation by inhibition of adenylate cyclase [61]. M2 receptor stimulation might also activate nonspecific cation channels [62] or inhibit KATP channels through activation of protein kinase C [63,64]. An investigation using M2, M3, and M2/M3 double knockout mice showed that the M2 receptor might play an indirect role in mediating bladder contractions by enhancing the contractile response to M3 receptor activation and that minor M2 receptor–mediated contractions might also occur [65].

Although the contribution of M2 receptors to detrusor contraction may be less than that of M3 receptors in the healthy bladder, in certain disease states, the contribution of M2 receptors to detrusor contraction might increase. In the denervated rat bladder, M2 receptors, or a combination of M2 and M3 receptors, mediated contractile responses [66–70]. In obstructed, hypertrophied rat bladders there was an increase in total muscarinic receptor and M2 receptor density and a reduction in M3 receptor density [71]. The functional significance of this change has not been established, and preliminary experiments on the human detrusor [72,73] could not confirm these observations. Pontari et al. [74] analysed bladder muscle specimens from patients with neurogenic bladder dysfunction to determine whether the muscarinic receptor subtype mediating detrusor contraction shifts from the M3 to the M2 subtype, as seen in the denervated, hypertrophied rat bladder. They concluded that, whereas normal detrusor contractions are mediated by the M3 receptor subtype, in patients with neurogenic bladder dysfunction, contractions can be partly mediated by the M2 receptors.

Presynaptic nerve terminals

Muscarinic receptors might also be located on the presynaptic nerve terminals and contribute to the regulation of transmitter release. The inhibitory prejunctional muscarinic receptors have been classified as M2 in the rabbit [75,76] and rat [77], and as M4 in the guinea-pig [78], rat [79] and human [80] bladders. Prejunctional facilitatory muscarinic receptors appear to be the M1 subtype in the rat and rabbit urinary bladder [75–77]. Prejunctional muscarinic facilitation has also been detected in human bladders [81]. The muscarinic facilitatory mechanism seems to be up-regulated in overactive bladders from chronic spinal cord transected rats. The facilitation in these preparations is primarily mediated by M3 muscarinic receptors [81,82].

Urothelium and suburothelium

Muscarinic receptors have also been detected on the urothelium/suburothelium [47,49,83], but their functional importance has not been definitively identified. In a study by Mukerji et al. [47], there was M2 and M3 receptor immunoreactivity in the urothelium, nerve fibres, and detrusor layers. In addition, strong myofibroblast-like cell staining was present in the suburothelial region and detrusor muscle. There was a significant increase in suburothelial myofibroblast-like M2 and M3 receptor immunoreactivity in patients with idiopathic DO compared with controls. M2 and M3 receptor immunoreactivities each significantly correlated with the urgency score, and M2 immunoreactivity also correlated with the frequency score in these patients. The authors concluded that the increase in M2 and M3 receptor immunostaining in myofibroblast-like cells in clinical bladder syndromes, including painful bladder syndrome and idiopathic DO, and its correlation with clinical scores suggests a potential role for these receptors in pathophysiological mechanisms and in the therapeutic effect of antimuscarinic agents. It has also been suggested that muscarinic receptors on structures other than the myocyte (e.g. urothelium/suburothelium) might be involved in the release of a factor that inhibits contractile responses [49,84,85].

ANTIMUSCARINIC MECHANISMS OF ACTION

It has been suggested that antimuscarinics act at muscarinic receptors on detrusor smooth muscle cells to reduce spontaneous myocyte activity during the storage phase [86], eventually decreasing the frequency and intensity of detrusor contractions. Other evidence suggests that antimuscarinics affect micturition through additional mechanisms. Yokoyama et al. [87] administered tolterodine i.v. or intravesically to rats with DO induced by cerebral artery occlusion with and without pretreatment with resiniferatoxin, a capsaicin analogue that induces C-fibre afferent desensitization. At low doses, tolterodine increased bladder capacity in untreated rats but was ineffective in those that had received resiniferatoxin. The authors concluded that tolterodine exerted an inhibitory effect on C-fibre bladder afferent nerves, thereby reducing detrusor activity and improving bladder capacity. An effect on afferent mechanisms by tolterodine in rats was also reported by Hedlund et al. [88], who found an effect of this drug even after resiniferatoxin treatment. Antimuscarinic-mediated inhibition of afferent signalling from the bladder via effects on both Aδ- and C-fibres might explain this apparent discrepancy in results. Studies in which afferent activity has been directly recorded from the pelvic nerve of rats have shown that systemic oxybutynin [89] and darifenacin [90] reduce activity in both Aδ- and C-fibre bladder afferents. Boy et al. [91] studied the effect of tolterodine on sensations evoked by intravesical electrical stimulation and during bladder filling in healthy women and reported that the drug had a significant effect on afferent fibres, probably located in the suburothelium. These findings are consistent with the clinical observations that, at clinically recommended doses, antimuscarinics might increase bladder capacity largely during the bladder storage phase [92].

CLINICAL DATA

Pharmacological agents used in the past to treat OAB include antimuscarinics, such as propantheline, methantheline, emepronium, dicyclomine, terodiline, and oxybutynin; ‘spasmolytics’, such as flavoxate; tricyclic antidepressants, such as imipramine; and prostaglandin synthetase inhibitors, such as indomethacin. However, with the exception of oxybutynin, none of these agents remain commonly used owing to lack of efficacy and/or poor tolerability [93,94]. Newer antimuscarinic drugs, which have proven efficacy in patients that have OAB symptoms with or without urodynamically confirmed DO, are a first-line treatment [92]. In addition to oxybutynin, several antimuscarinics, each with varied affinity for muscarinic receptor subtypes, are currently available, including propiverine, tolterodine, trospium, solifenacin, and darifenacin. Key approval dates for these agents are listed in Table 1, and their structures are depicted in Fig. 4. Structural differences between these two classes of amines affect their pharmacokinetic, pharmacodynamic, and adverse event (AE) profiles.

Table 1. 
Key launch dates for antimuscarinics used to treat OAB
DrugUSAUKEuropean Union
  1. NA, drug not yet launched.

Oxybutynin ER199920002002
Tolterodine ER200120012001
Trospium200420002000
Darifenacin2005NANA
Solifenacin2005NA2004
Propiverine ERNA2006NA
Figure 4.


Antimuscarinic structures.

OUTCOMES MEASURES

Management of OAB should initially be based on the patient’s report of symptoms. Clinical trials typically use objective measures of efficacy, including bladder diary variables. However, there is currently a growing appreciation of the importance of subjective patient-reported outcomes (PROs) in clinical research [95,96]. Objective measures of efficacy often correlate poorly with PROs, suggesting that objective and subjective assessments measure different aspects of the patient’s clinical profile; they should not be interpreted as different methods for assessing the same outcome. Subjective and objective measures have limitations, and investigators should carefully consider the outcome of interest when choosing a means of assessment. However, studies that include assessments of both subjective and objective outcomes can yield results that represent a more global patient experience than can be captured by evaluating either type of measure alone. Furthermore, the overall patient experience can be better understood by identifying the relative contribution of objective endpoints to treatment-related changes in HRQoL, symptom bother, and patient satisfaction.

The most common method of objective assessment in clinical trials of antimuscarinics is the bladder diary. Bladder diaries document voiding patterns during a patient’s routine activities and can be completed for any duration. Bladder diaries differ between studies, but generally require a patient to keep records of micturition frequency, number of urgency and incontinence episodes, and volume voided per micturition. Urodynamic studies are another common means of objective assessment and provide a graphical representation of intravesical pressure as a function of bladder volume [97]. Conventional studies usually involve artificial bladder filling, and ambulatory studies use natural bladder filling [1]. Bladder volume at first involuntary detrusor contraction, involuntary detrusor contraction amplitude, postvoid residual urine volume (PVR), maximum cystometric capacity, and maximum urinary flow rate (Qmax) are frequent urodynamic endpoints. Pad tests represent another type of objective measure and are used to quantify the volume of urine lost during incontinence episodes [98].

Common subjective endpoints include investigator- and patient-assessed variables such as HRQoL impact, symptom severity, and perceived treatment benefit. PROs include many different questionnaires designed to evaluate various aspects of OAB symptoms and their impact on HRQoL. The International Consultation on Incontinence (ICI) is developing a range of questionnaires (ICIQ modules) for use in patients with LUTS and other pelvic conditions. The ICIQ-OABq (OAB questionnaire), is a disease-specific tool that assesses symptom bother and HRQoL in those with OAB [99]. Another questionnaire, the Patient Perception of Bladder Condition ([100], provides a more general assessment of bladder function. The ICIQ-LUTSqol (King’s Health Questionnaire) includes 21 questions in eight domains and is validated for assessment of QoL in patients with OAB [101].

EFFICACY

There is ample evidence to support the efficacy of all of the antimuscarinics considered here in the treatment of OAB. Large-scale, randomized, placebo-controlled studies have shown that patients receiving these agents report significant reductions in urinary frequency, urgency episodes, and UUI episodes [102,103]. Two published systematic reviews have examined the efficacy of these agents in detail, but these reports possess important methodological differences that influenced their conclusions. Herbison et al. [102] included data from 32 randomized, placebo-controlled trials of antimuscarinics used to treat OAB. The included studies were published between January 1966 and January 2002 and involved all routes of administration. The data from all of the trials were combined for efficacy comparisons of antimuscarinic vs placebo. Weighted mean differences in the change in incontinence episodes per 24 h, micturitions per 24 h, and maximum cystometric capacity were calculated. Patients receiving antimuscarinics reported a weighted mean difference (vs placebo) of −0.56 (95% CI −0.93 to −0.15) for the change in incontinence episodes and −0.59 (−0.83 to −0.36) for the change in micturitions per 24 h. The changes in maximum cystometric capacity, at weighted mean difference (95% CI) of +54 mL (43–66) also favoured active treatment. Although these were statistically significant differences and favoured antimuscarinic treatment over placebo, the authors challenged the clinical significance of the efficacy findings because the magnitude of improvement in these endpoints was small.

However, the clinical significance of the efficacy of individual antimuscarinics in patients with OAB is supported by a 2005 meta-analysis by Chapple et al. [103] that included data published from 1966 to August 2004 and that permitted the inclusion of studies evaluating the efficacy and tolerability of two new antimuscarinics, darifenacin and solifenacin. This meta-analysis also assessed the effects of antimuscarinics on PROs, which are increasingly being evaluated in clinical trials of OAB. Chapple et al. [103] included data from 56 blinded, randomized, placebo- and active-controlled trials of oral and transdermal antimuscarinics used to treat OAB. Importantly, whereas Herbison et al. [102] combined data for all antimuscarinics, Chapple et al. [103] did individual comparisons between each antimuscarinic and placebo or active controls. The weighted mean difference (95% CI) vs placebo for the change in incontinence episodes per 24 h was significant for oxybutynin immediate release (IR) (8.8–15.0 mg/day; −0.72, −1.09 to −0.34), transdermal oxybutynin (−0.55, −1.05 to −0.04), solifenacin (5 mg/day; −0.66, −1.13 to −0.19; 10 mg/day, −0.69, −1.19 to −0.19), tolterodine IR (4 mg/day, −0.50, −0.70 to −0.30), and tolterodine extended release (ER) (−0.73, −0.93 to −0.53). For changes in micturition frequency per 24 h, there were significant improvements vs placebo for transdermal oxybutynin (−0.55, −1.03 to −0.07), solifenacin (5 mg/day, −0.99, −1.52 to −0.46; 10 mg/day, −1.41, −1.97 to −0.85), tolterodine IR (2 mg/day, −0.68, −1.15 to −0.22; 4 mg/day, −0.67, −0.92 to −0.42), and tolterodine ER (− 0.73, −0.96 to −0.49). Chapple et al. [103] found some evidence suggesting that propiverine IR and ER might also reduce incontinence episodes and micturition frequency [104,105] relative to placebo; however, these data were not suitable for inclusion in the meta-analysis. The changes in urgency episodes per 24 h vs placebo were significant for solifenacin (5 and 10 mg/day) and tolterodine ER. Improvements in volume voided per micturition were significant for oxybutynin IR (8.8–15.0 mg/day), transdermal oxybutynin, solifenacin (5 mg and 10 mg/day), tolterodine IR (2 mg and 4 mg/day), and tolterodine ER. The ‘relative risk’ (RR, 95% CI) for return to continence was significant for oxybutynin IR (5.0–7.5 mg/day; 3.53, 1.94–6.41), transdermal oxybutynin (1.75, 1.16–2.62), tolterodine ER (1.72, 1.14–2.58), and trospium (2.00, 1.40–2.86). Thus, patients receiving these antimuscarinics were nearly twice as likely to return to continence compared with placebo-treated patients. HRQoL data were available for transdermal oxybutynin, tolterodine IR (4 mg/day), tolterodine ER, and trospium. The meta-analysis revealed significant weighted mean differences vs placebo for 27 of 37 HRQoL domains [106]. For example, the weighted mean differences for change in overall HRQoL assessed by the Incontinence Impact Questionnaire were significant and favoured transdermal oxybutynin, tolterodine ER, and trospium vs placebo. Weighted mean differences for the change in ICIQ-LUTSqol domains for ‘incontinence impact’, ‘role limitations’, ‘physical limitations’, and ‘sleep/energy’ were significant and favoured patients treated with tolterodine IR or ER vs placebo. A meta-analysis of three active-controlled studies of tolterodine ER and tolterodine IR revealed no significant differences in the change in HRQoL measures between active treatments [106].

Twenty-four of the 56 trials included in the Chapple et al. [103] meta-analysis were active-controlled. Most comparisons that resulted in significant findings were based on one study alone, and none of the significant comparisons came from studies that were powered to show a significant difference between active treatments. The authors reported that patients receiving solifenacin (5 or 10 mg/day) had up to one fewer urgency episodes per day than did those receiving tolterodine IR (4 mg/day). Solifenacin (10 mg/day) was also associated with significantly fewer micturitions per 24 h than was tolterodine IR (4 mg/day). Oxybutynin ER (10 mg/day) was associated with approximately two fewer incontinence episodes per week than was tolterodine ER (4 mg/day). A greater proportion of patients treated with oxybutynin ER (10 mg/day) returned to continence compared with those receiving tolterodine ER (4 mg/day). Finally, volume voided was significantly greater in patients treated with oxybutynin IR (15 mg/day) or solifenacin (5 and 10 mg/day) compared with patients receiving tolterodine IR (4 mg/day).

Unlike the report by Herbison et al. [102], the Chapple et al. [103] meta-analysis permitted the discernment of within-class differences in efficacy. Although data for each drug were not available for each endpoint, this study might help clinicians select the most appropriate antimuscarinic for individual patients depending on their most bothersome symptoms. The return to continence and HRQoL data presented in the Chapple et al. [103] report are particularly important to consider when evaluating the conclusion by Herbison et al. [102] that the benefits of antimuscarinics are of limited clinical significance.

Responder analyses are a recent trend in evaluating efficacy of antimuscarinics for OAB. These analyses, which provide a comprehensive survey of benefit by examining the proportion of patients who achieve various levels of improvement, also support the clinical significance of improvements in OAB symptoms with antimuscarinic treatment. For instance, in one study 57% of patients receiving darifenacin (15 mg) reported a ≥70% reduction in incontinence episodes from baseline compared with 39% receiving placebo (P < 0.001), and 28% of patients receiving darifenacin had a ≥90% reduction compared with 17% in the placebo group (P < 0.005) [107]. Similarly, Sussman et al. [108] reported that after 12 weeks of treatment with tolterodine ER (4 mg), 78%, 66%, and 54% of patients had reductions of 50%, 70%, and 100% in urgency episodes, respectively, and 75%, 61%, and 51% of patients had reductions of 50%, 70%, and 100% in UUI episodes, respectively. Such analyses represent an alternative to the expression of efficacy in terms of whole-group mean numeric or median percentage changes and might better reflect the likelihood of specific levels of treatment benefit with antimuscarinics.

ONSET OF ACTION

Few studies have specifically examined the onset of therapeutic efficacy of an antimuscarinic for OAB, and between-study comparisons should be made with caution because of differences in study designs and populations. A post hoc analysis of an open-label study showed that tolterodine ER reduced micturitions, urgency episodes, and UUI episodes as early as treatment day 5 [108]. In a trial of darifenacin, patients with OAB had significant reductions in micturitions, urgency episodes, UUI episodes, and urgency severity compared with placebo after 2 weeks of treatment [109]. Patients with OAB who were treated with trospium showed significant improvements in the frequency of UUI episodes, urgency episodes, and micturitions as early as day 1, 3, and 5, respectively [110]. However, it should be noted that patients in this study were required to have ≥7 UUI episodes per week for enrolment. Thus, these results should be interpreted in light of the fact that increased symptom severity at baseline is directly related to the magnitude of potential symptom improvement [111].

PHARMACOKINETICS

Structural differences in the tertiary and quaternary amines impart pharmacokinetic heterogeneity among the antimuscarinics (Table 2) [112]. Tertiary amines bear no charge and are therefore more lipophilic than the positively charged quaternary amines [113]. Tertiary amines are more easily absorbed from the gastrointestinal tract, have greater oral bioavailability, and more easily cross the blood–brain barrier (BBB) than do the hydrophilic quaternary amines. Tertiary amines undergo significant metabolism via the cytochrome P450 enzymes, whereas trospium has little P450 metabolism. Consequently, ≈80% of trospium is excreted unchanged in the urine compared with <5% of oxybutynin or tolterodine. The lack of P450 metabolism also reduces the potential for drug–drug interactions with trospium [113]. Elimination half-lives for antimuscarinics range from 2 h for oxybutynin IR [114] and tolterodine IR [115] to 45–68 h for solifenacin. The half-life of solifenacin probably exceeds that of the other antimuscarinics because of its comparatively large volume of distribution [116].

Table 2.  Factors contributing to the pharmacokinetic profiles of antimuscarinic treatments for OAB
 DarifenacinOxybutynin IR/EROxybutynin transdermalPropiverine IR/ERSolifenacinTolterodine IR/ERTrospium
  1. CYP, cytochrome P450; NA, not available; *Evidence suggests that trospium is primarily excreted in feces [112].

Molecular weight507.5393.9357403.95480.55475.6427.97
Relative lipophilicityHighly lipophilicLipophilicLipophilicNALipophilicSlightly lipophilicNot lipophilic
Polarity (9.20 pKa)PositiveNeutralNeutralNANA (9.87 pKa)Positive polarHighly
Metabolizing enzymesCYP2D6, CYP3A4CYP3A4CYP3A4CYP2D6, CYP3A4CYP3A4CYP2D6, CYP3A4 dependent mechanismEster hydrolysis by nonCYP450-
Metabolites contributing to clinical effectNoneDesethyl- oxybutyninDesethyl- oxybutyninPropiverine N-oxideNone5-hydroxy-methyl- tolterodineNone
Compound excreted  intact (urine),%
 Intact compound3<0.1<0.1<1<15<13*
 Active metaboliteNANA<0.11–6NA5–14NA
Half-life, h122/137–81545–682/820

ADMINISTRATION

Of the antimuscarinics considered, only oxybutynin can be administered transdermally. The sustained-delivery patch allows for more stable serum concentrations of oxybutynin than oral formulations and avoids presystemic metabolism [117]. The implications of these altered pharmacokinetic parameters are discussed in more detail below.

TOLERABILITY AND SAFETY

RECEPTOR AND ORGAN SELECTIVITY

Muscarinic receptor and organ selectivities are key components of the therapeutic potential for antimuscarinics and affect their AE profiles. As mentioned, the M2 and M3 receptors are the main muscarinic receptors involved in bladder control. Antimuscarinic agents might block acetylcholine binding at more than one muscarinic receptor subtype. Furthermore, receptor-selective agents might block muscarinic receptors outside the bladder and cause AEs. For example, blockade of M3 receptors in the salivary gland, lower bowel, and ciliary smooth muscle are thought to contribute to three of the most frequently reported AEs associated with antimuscarinics: dry mouth, constipation, and blurred vision, respectively [118].

Estimates of binding affinity of antimuscarinics for human muscarinic receptor subtypes are provided in Table 3[118,119]. Trospium and propiverine are the least selective, but trospium has the highest affinity for each of the muscarinic receptor subtypes. Darifenacin is clearly M3 selective, and oxybutynin and solifenacin have a moderate selectivity for the M3 receptor over the M2 receptor. Tolterodine shows a similar degree of selectivity for all five muscarinic receptor subtypes. It has been suggested that tolterodine [120–122] and solifenacin [121,123] have greater selectivity for muscarinic receptors of the bladder than for those in the salivary gland. Reports differ for the organ selectivity of oxybutynin [120–122], darifenacin [120,121,124], and propiverine [124,125]; to our knowledge, organ selectivity data for trospium have not been published. It is important to note that information on organ selectivity is based mainly on studies using animal models and in vitro experiments. Apparent organ selectivity might in fact be model specific and might not necessarily be valid in humans.

Table 3. 
Affinity* of antimuscarinics for human muscarinic receptor subtypes
MoleculeM1M2M3M4M5
  1. NR, not reported. *Binding affinity estimates (Ki in nM). Adapted from Hegde et al., 2004 [118]. Propiverine data from Wuest et al., 2006 [119].

Oxybutynin 1.0  6.7 0.67 2.0 11.0
Tolterodine 3.0  3.8 3.4 5.0 3.4
Darifenacin 7.3 46.0 0.7946.0 9.6
Solifenacin2512510NRNR
Trospium 0.75  0.65 0.50 1.0 2.3
Propiverine 6.58  5.79 6.39 6.46 6.43

ADVERSE EVENTS AND WITHDRAWALS

Dry mouth, constipation, headache, and blurred vision are generally the most frequently reported AEs among patients treated with oxybutynin, tolterodine, trospium, propiverine, darifenacin, and solifenacin in clinical trials (Table 4[109,112,116,126–141] and Table 5[142–162]). Chapple et al. [103] reported that the RR (95% CI) of reporting any AE was significantly greater for darifenacin (7.5 mg/day; 1.24, 1.05–1.47; 15 mg/day, 1.35, 1.14–1.60), oxybutynin IR (8.8–15.0 mg; 1.39, 1.12–3.72), propiverine IR (30 mg/day; 1.90, 1.40–2.56), and propiverine ER (30 mg/day; 1.69, 1.24–2.29). There were no differences in the RR for any AE between placebo and the other antimuscarinic agents. Dry mouth, constipation, and blurred vision are consistent with the mechanism of action of antimuscarinics.

Table 4.  Percentage of patients reporting common AEs in double-blind, placebo-controlled trials* of antimuscarinics for OAB
 Daily dose, mgDry mouthConstipationHeadacheAbnormal vision
  1. NR, not reported; PI, prescribing information. *Limited to randomized, double-blind, placebo-controlled phase III or postmarketing trials of oral antimuscarinic agents used to treat OAB.

Oxybutynin IR
Burgio et al. 1998 [126] 2.5, 5, 7.5, 10, 159739NR15
Oxybutynin transdermal
Dmochowski et al. 2002 [127] 3.910 1NR 0
Oxybutynin PI [128] 3.910NRNRNR
Tolterodine IR
Jonas et al. 1997 [129] 2 8 2 3 3
 410 3 3 5
Malone-Lee et al. 2001 [130] 230 5 5 0
 448 0 7 3
Tolterodine IR PI [131] 435 7 7 2
Tolterodine ER
Abrams et al. 2006 [132] 414 3 4 2
Tolterodine ER PI [133] 423 6 6 1
Rackley et al. 2006 [134] 4 9 3 1 0
Zinner et al. 2002 [135] 423 6 6 1
Trospium
Alloussi et al. 1998 [136]40 3NRNRNR
Cardozo et al. 2000 [137]40    
Trospium PI [112]4041NR24NR
Zinner et al. 2004 [138]402210 7NR
Solifenacin
Cardozo et al. 2004 [139] 5 8 4NR 4
1023 9NR 6
Solifenacin PI [116] 5 11 5NR 4
102813NR 5
Darifenacin
Haab et al. 2004 [109] 7.51914 1NR
153114 4NR
Darifenacin PI [140] 7.5, 151921 7NR
Steers et al. 2005 [141] 7.51820 8NR
152022 5NR
Table 5.  Percentage of patients reporting common AEs in active-controlled studies* of antimuscarinics for OAB
 Daily dose, mgDry mouthConstipationHeadacheAbnormal vision
  1. NR, not reported; *Limited to active-controlled phase III or postmarketing trials of oral antimuscarinic agents used to treat OAB; †Placebo- and active-controlled studies.

Oxybutynin IR
Abrams et al. 1998[142] 7.5, 1586NRNR 7
Anderson et al. 1999 [143] 5, 10, 15, 208731NR17
Barkin et al. 2004 [144] 5, 10, 15, 20721022NR
Birns et al. 2000 [145]1017NR 5 5
Davila et al. 2001[146]10, 15, 22.58250NR24
Drutz et al. 1999[147]10, 1569NR10NR
Halaska et al. 2003 [148]1050 4 9 6
Homma et al. 2003[149] 954 6 5 3
Lee et al. 2002 [150]1063NR 5NR
Malone-Lee et al. 2001 [151] 5, 1061 610 5
Stöhrer et al. 2007 [157]1567 9 4 6
Versi et al. 2000 [152] 5, 10, 15, 2059NRNRNR
Oxybutynin ER
Anderson et al. 1999 [143] 5, 10, 15, 20, 25, 306830NR28
Barkin et al. 2004 [144] 5, 10, 15, 2068 812NR
Birns et al. 2000 [145]1023NR 0 7
Diokno et al. 2003 [153]1030 6 6NR
Sand et al. 2004 [154]1028 9 9 3
Versi et al. 2000 [152] 5, 10, 15, 2048NRNRNR
Oxybutynin transdermal
Davila et al. 2001[146] 3.93921NR18
Dmochowski et al. 2003[155] 3.9 4 3NRNR
Propiverine IR
Junemann et al. 2005 [156]3020NRNRNR
Stöhrer et al. 2007 [157]454717 320
Junemann et al. 2006 [158]3023 4 2 4
Propiverine ER
Junemann et al. 2006 [158]3022 3 2 5
Tolterodine IR
Abrams et al. 1998[142] 2, 450NRNR 3
Chapple et al. 2004[159] 419 3NR 2
Drutz et al. 1999[147] 2, 430NR15NR
Junemann et al. 2005 [156] 419NRNRNR
Lee et al. 2002 [150] 435NR 4NR
Malone-Lee et al. 2001 [151] 437 8 11 5
Sand et al. 2004 [154] 434 710 1
Swift et al. 2003[160] 431 7 3 1
van Kerrebroeck et al. 2001[161] 430 7 4 1
Tolterodine ER
Chapple et al. 2005 [162] 424 3NR 2
Diokno et al. 2003 [153] 422 8 6NR
Dmochowski et al. 2003[155] 4 7 6NRNR
Homma et al. 2003[149] 434 7 4 1
Swift et al. 2003[160] 425 7 7 1
van Kerrebroeck et al. 2001[161] 423 6 6 1
Trospium
Halaska et al. 2003 [148]4033 7 4 3
Solifenacin
Chapple et al. 2004[159] 514 7NR 4
1021 8NR 6
Chapple et al. 2005 [162] 5, 1030 3NR 1

Dry mouth

Dry mouth is the most commonly reported AE in clinical trials of oral antimuscarinic therapies for OAB and is listed among the AEs in the full prescribing information for each agent. Dry mouth is probably a consequence of antagonism of the M3 receptors that regulate salivary secretion in the parotid glands [8,117]. In placebo- and active-controlled trials, the incidence of dry mouth in patients taking oxybutynin IR was 17–97%, oxybutynin ER 23–68%, transdermal oxybutynin 4–39%, propiverine IR 20–47%, propiverine ER 22%, tolterodine IR 8–50%, tolterodine ER 7–34%, trospium 3–41%, solifenacin 8–30%, and darifenacin 18–31% generally exceeded the combined incidence of constipation, headache, and abnormal vision (Table 4[109,112,116,126–141] and Table 5[142–162]). In the Chapple et al. [103] meta-analysis the RR (95% CI) for dry mouth was significantly greater than placebo for patients receiving all of the antimuscarinics considered here with the exceptions of low-dose oxybutynin IR (5.0–7.5 mg/day; 1.06, 0.90–1.29), transdermal oxybutynin (1.35, 0.67–2.72), and propiverine IR (45 mg/day; 3.00, 0.13–71.9). Herbison et al. [102] reported a RR (95% CI) for dry mouth of 2.56 (2.24–2.92; P < 0.001) in patients receiving any antimuscarinic vs placebo. Transdermal oxybutynin circumvents ‘first-pass’ metabolism and results in lower concentrations of the active metabolite N-desethyloxybutynin. This metabolite has a greater affinity than oxybutynin for muscarinic receptors in the parotid gland and might contribute to dry mouth reported by many patients receiving oral oxybutynin [117]. In a study of 76 patients randomized to oxybutynin IR or transdermal oxybutynin, the incidence of dry mouth was 94% and 38%, respectively [146].

Constipation

Constipation is generally the second most common AE reported by patients receiving oxybutynin IR (4–50%), transdermal oxybutynin (1–21%), propiverine IR (4–17%), propiverine ER (3%), tolterodine ER (3–8%), solifenacin (3–13%), and darifenacin (14–22%). Constipation was reported by 0–8% of patients administered tolterodine IR and 7–10% of those receiving trospium (Table 4[109,112,116,126–141] and Table 5[142–162]). The higher rates of constipation in patients treated with darifenacin compared with other antimuscarinics might be explained by its relatively high selectivity for the M3 receptor [163], which regulates contraction of intestinal smooth muscle [140]; however, withdrawal rates due to constipation and laxative use among patients who received darifenacin were similar or only mildly elevated compared with those who received placebo [109,141]. It should be noted that elderly patients account for a large percentage of the OAB population and are at higher risk for pharmacotherapy-related constipation than are younger patients. Constipation might cause or exacerbate urinary symptoms [164], which makes this AE an important consideration in the development of pharmacotherapies for OAB.

Blurred vision

M3 receptors mediate constriction [51] and are the predominant muscarinic receptor subtype in the cells of the human ciliary and iris sphincter muscles [165]. Thus, abnormal or blurred vision in patients taking antimuscarinics is consistent with their mechanism of action. The results of placebo-controlled trials to date indicate that incidence rates of abnormal vision were 15% for oxybutynin IR, 0% for transdermal oxybutynin, 4% for propiverine IR, 5% for propiverine ER, 0–5% for tolterodine IR, 0–2% for tolterodine ER, and 4–6% for solifenacin (Table 4[109,112,116,126–141]). Active-controlled studies have also provided incidence rates for abnormal vision in patients administered oxybutynin IR (3–24%), oxybutynin ER (3–28%), transdermal oxybutynin (18%), tolterodine IR (1–5%), tolterodine ER (1–2%), trospium (3%), and solifenacin (1–6%) (Table 5[142–162]).

Withdrawals

Withdrawals due to AEs have generally been infrequent in placebo- and active-controlled trials of oral antimuscarinic treatments for OAB. Herbison et al. [102] reported that patients receiving placebo were equally likely to withdraw owing to AEs as were those receiving antimuscarinics (RR 1.01, 95% CI, 0.78–1.31). In the Chapple et al. [103] meta-analysis, the RR (95% CI) for all-cause withdrawals was significantly greater in patients receiving oxybutynin IR (8.8–15.0 mg/day, 1.40, 1.06–1.84) compared with placebo. On the other hand, the risk of all-cause withdrawal for patients receiving tolterodine ER (0.71, 0.51–0.99) was significantly less than placebo. There were no other statistically significant differences in RR for all-cause withdrawal between placebo and antimuscarinics. Only patients receiving oxybutynin IR (8.8–15.0 mg/day; 1.82, 1.21–2.73) had a significantly greater risk of withdrawal due to AEs compared with placebo.

In summary, an extensive literature supports the tolerability of antimuscarinics for the treatment of OAB symptoms. The AE profiles of antimuscarinics are determined by their organ and muscarinic receptor subtype selectivities and pharmacokinetic parameters. The most commonly reported AEs associated with antimuscarinics are dry mouth, constipation, headache, and blurred vision. The favourable AE profiles of antimuscarinics are supported by low withdrawal rates due to AEs in clinical studies.

CARDIAC EFFECTS

Among the more serious concerns related to antimuscarinic use is the risk of cardiac AEs, particularly increases in heart rate and QT prolongation and induction of polymorphic ventricular tachycardia (torsade de pointes). It should be emphasized that QT prolongation and its consequences are not related to blockade of muscarinic receptors, but rather linked to inhibition of the hERG potassium channel in the heart [166]. Thus, QT prolongation is not a class effect of antimuscarinics, despite the fact that terodiline was withdrawn from the market owing to an association with QT prolongation [167].

It is well established that ‘classical’ (nonsubtype receptor selective) antimuscarinics may increase heart rate through blockade of vagal inhibitory input [168,169]. Although cardiac arrhythmia and tachycardia are among the precautions listed in the full prescribing information for oxybutynin IR, a study of 21 elderly patients with OAB who had been treated with oxybutynin IR for ≥4 weeks had no significant change from baseline for heart rate, PR interval, or QTc parameters [170]. Furthermore, a postmarketing study of 14 526 patients receiving tolterodine IR identified only 17 cases (0.1%) of tachycardia or palpitations that were possibly or probably related to the drug [171]. Four of 29 other arrhythmias were judged to be possibly or probably related to tolterodine. None represented a serious arrhythmia, such as ventricular tachycardia or fibrillation. The full prescribing information for tolterodine ER [172] states that there has been no association of torsade de pointes in the international postmarketing experience with tolterodine IR or tolterodine ER.

Results of cardiac electrophysiology studies are included in the full prescribing information for tolterodine IR, tolterodine ER, trospium, solifenacin, and darifenacin. The full prescribing information for tolterodine IR and tolterodine ER include the results of a study of the IR formulation in healthy volunteers. In this study, treatment with the recommended (2 mg twice a day) and supratherapeutic (4 mg twice a day) doses of tolterodine IR for 4 days was not associated with clinically significant QTc interval prolongation in healthy adults. Treatment with trospium for 5 days was not associated with prolongation of the QTc interval [112], and electrocardiogram variables for trospium-treated patients in a 12-week placebo-controlled trial raised no concerns [138]. QTc interval prolongation did not occur in patients treated with darifenacin for 6 days [140], nor was darifenacin treatment associated with clinically relevant changes in vital signs during a 12-week, placebo-controlled study [141]. QTc interval changes with 10-mg (2 ms) or 30-mg (8 ms) daily doses of solifenacin were not clinically significant [116]. Similarly, a placebo-controlled study of propiverine IR (45 mg) found no changes in heart rate, P–Q interval, QRS interval, QT interval, or QTc interval after 4 weeks of treatment [173]. Thus, there is little evidence to suggest that antimuscarinics increase the risk of cardiac AEs when administered at recommended therapeutic doses.

SAFETY AND EFFICACY IN SPECIAL POPULATIONS

Men with BOO

There is concern among clinicians that the inhibitory effect of antimuscarinics on detrusor muscle contraction could theoretically impair detrusor contractility and thus cause urinary retention in men with OAB symptoms and possible BOO. However, there is little published evidence to support the concern. Kaplan et al. [174] reported a significant increase in Qmax, a decrease in PVR, and no incidence of acute urinary retention (AUR) in men with suspected benign prostatic obstruction (BPO), a form of BOO caused by prostatic enlargement due to BPH, and LUTS who had failed α-receptor antagonist therapy and were subsequently treated with tolterodine ER for 6 months.

A 12-week, double-blind, placebo-controlled study designed to evaluate the safety of tolterodine ER in men (aged >40 years) with symptoms of OAB and urodynamic evidence of DO and BOO was also performed. Changes in Qmax and detrusor pressure at Qmax were comparable to placebo, and volume to first detrusor contraction and maximum cystometric capacity were significantly improved in men receiving tolterodine ER. A statistically significant increase in PVR (+33 mL vs placebo) was not considered clinically significant, and tolterodine ER was not associated with an increased incidence of symptoms suggestive of AUR (placebo 3%; tolterodine ER 3%). Micturition disorders led to withdrawals in one of 72 (1%) patients receiving placebo and three of 150 (2%) patients receiving tolterodine ER [132].

Several studies have also suggested that antimuscarinics can be safely combined with α1-receptor antagonists to treat OAB symptoms and other LUTS in men who were either known to have or suspected of having BOO [175–178]. In fact, studies have shown that combination treatment might be more effective for reducing LUTS than α1-receptor antagonists alone. Athanasopoulos et al. [176] treated 50 men with BOO and DO with tamsulosin for 1 week and then randomly assigned them to 3-month therapy with tamsulosin/tolterodine combined therapy or tamsulosin alone. There were significant reductions from baseline for maximum detrusor pressure during micturition and maximum involuntary contraction pressure in men who received the combined treatment. Combined therapy was also associated with significantly increased Qmax and volume at first involuntary contraction, as well as improvements in QoL measures from baseline. Changes from baseline in maximum detrusor pressure, maximum involuntary contraction pressure, and QoL measures did not reach statistical significance in men receiving tamsulosin alone. There was no incidence of urinary retention in either treatment group [176].

Thirty-two of 44 men (73%) with DO and BOO who failed treatment with doxazosin monotherapy had symptomatic improvements after 3-month treatment with doxazosin and tolterodine [175]. Combined treatment was not associated with an increased incidence of AUR (Lee 2005, personal communication). It should be noted that the three studies [132,175,176] used urodynamic criteria for patient enrolment, which might limit their applicability to clinical practice, where patients are initially treated based on symptoms rather than urodynamic findings. More recently, Kaplan et al. [179] studied the efficacy and safety of tolterodine ER and/or the α1-receptor antagonist tamsulosin in 879 men who met research criteria for both OAB and BPO. A significantly greater proportion of patients receiving combined therapy (80%) reported treatment benefit by week 12 compared with placebo (62%), tamsulosin (71%), or tolterodine ER (65%). Combined therapy also resulted in significant improvements in bladder diary variables (i.e. UUI, urgency, 24-h micturition frequency, and nocturnal frequency) and the IPSS total and QoL scores vs placebo. The incidence of AUR requiring catheterization was low (tolterodine ER plus tamsulosin, 0.4%; tolterodine ER, 0.5%; tamsulosin, 0%; placebo, 0%). Similarly, Lee et al. [177] reported significantly greater improvements in micturition frequency, volume voided per micturition, and the IPSS Storage Index among men with OAB symptoms and BPO treated with doxazosin plus propiverine than among those treated with doxazosin alone; there was no difference between the two groups in the rate of AUR. There remains a need for similar large-scale, placebo-controlled studies evaluating the efficacy and safety of other antimuscarinics in men with OAB and possible BOO.

Elderly patients

Because the prevalence of OAB is greatest among the elderly, it is important that OAB pharmacotherapies are safe for older patients. Safety considerations specific to the elderly include increased permeability of the BBB, altered hepatic and renal function, and coadministration of other drugs with antimuscarinic properties [180]. Of the antimuscarinics used to treat OAB, the published literature only includes safety data stratified by age for tolterodine. Phase III clinical trials showed no significant differences in the overall safety of tolterodine ER in older vs younger patients [172]. These results are consistent with a 12-week postmarketing study in which all AEs occurred with equal or lesser frequencies among patients aged ≥65 years compared with those aged <65 years [135]. Furthermore, Sand et al. [154] reportd no significant difference in the frequency of any AE between women aged ≤64 years, 65–74 years, and ≥75 years who received tolterodine ER for 12 weeks. These findings are supported by a recent study of pooled data from five placebo-controlled trials of tolterodine ER. In this report, Wilson et al. [unpublished data] reported that neither the frequency nor the severity of any tolterodine ER–related AE differed between older (65–74 or ≥75 years) and younger (<65 years) patients. Although the literature lacks similar comparisons for the other antimuscarinics, the epidemiology of the disease is such that many clinical trial populations include large percentages of older patients.

Cognitive impairment associated with antimuscarinic use in the elderly is of particular concern. A decline in CNS cholinergic activity occurs with normal ageing, possibly owing to decreased concentrations of acetylcholine or a reduction in the density of functioning muscarinic receptors. All five muscarinic receptor subtypes have been identified in brain tissue [181]. The M1 subtype is the most abundant in hippocampal and cortical tissues, which play important roles in working and reference memory. Thus, the affinity of antimuscarinics for the M1 receptor contributes to the likelihood of cognitive impairment with antimuscarinics. Oxybutynin has a moderate selectivity for the M1 and M3 receptors, and its size and structure make it the most likely to cross the BBB [180]. In a convenience sample of 12 older adults, Katz et al. [182] reported that oxybutynin IR was associated with significant deficits in reaction time compared with placebo. On the other hand, darifenacin is selective for the M3 subtype, and trospium is unlikely to cross the BBB owing to its polarity. The propensity of propiverine to cross the BBB is currently unknown [183]; there is a paucity of data available on this topic, and little insight can be gained from its molecular structure. A large-scale study in patients with OAB showed no significant differences in measures of sleepiness or CNS AEs between trospium- and placebo-treated patients [184]. In a placebo-controlled study designed to assess the effects of darifenacin on cognitive function in elderly men and women, Wesnes et al. [185] found no significant between-group differences in memory scanning sensitivity, speed of choice reaction time, or word recognition sensitivity. Diefenbach et al. [186] reported that healthy volunteers aged ≥50 years had no impairment of concentration or cognitive function 1 h after administration of oxybutynin IR, tolterodine IR, or trospium. Although several case reports of hallucinations in elderly high-risk patients using tolterodine have been published [187–189], they are of limited value for determining a causal relationship between tolterodine treatment and cognitive impairment. None of these reports included control subjects, and most involved unusual cases that cannot be generalized to the patient population at large. Higher-quality studies, such as randomized controlled trials, prospective epidemiological studies, and large case series, are required to determine if any causal relationship exists between antimuscarinic treatment and cognitive impairment.

Children

Currently, oxybutynin IR and oxybutynin ER are the only antimuscarinics approved for the treatment of OAB symptoms in children (5 years and 6 years of age and under, respectively) in the USA [114,190]. However, some studies suggest that oxybutynin IR is associated with a high incidence of AEs in the paediatric population, and long-term data for children treated with oxybutynin ER are limited. Youdim and Kogan [191] studied 11 children with non-neurogenic OAB symptoms who were treated with oxybutynin ER for a mean of 6 months. All 11 children were cured of daytime incontinence, and seven were still taking oxybutynin ER at last follow-up. Dry mouth was the most frequent AE and was reported by four of the 11 patients. Sommer et al. [192] evaluated cognitive function in a non-randomized study of 25 children receiving either behavioural modification alone or with oxybutynin IR for 4 weeks. There was no significant affect of either treatment regimen on measures of memory, speed of processing, or attention.

Propiverine is approved for use in children in Germany and other countries. In a retrospective study of children with neurogenic DO, Grigoleit et al. [193] found that the percentage of patients with incontinence decreased from 87% before treatment to 32% after 6–12 months. No serious AEs occurred during propiverine treatment; rates of dry mouth were not reported. Lopez Pereira et al. [194] studied 50 children with DO and urgency who received trospium for 21 days. Forty-one patients had a positive therapeutic result based on improvements in urodynamic variables and incontinence episodes. AEs were infrequent (headache, 6%; dizziness, 2%; abdominal cramps, 2%; dry mouth, 2%).

Bolduc et al. [195] published a crossover study in which 34 children with dysfunctional voiding who reported AEs with oxybutynin were administered tolterodine IR for a median of 12 months. Efficacy of tolterodine IR was comparable to oxybutynin IR, and 68% of patients reported >90% reductions in incontinence episodes after 1 year of treatment. Dry mouth or no sweating occurred in a significantly greater percentage of patients during the oxybutynin (79%) treatment phase than during tolterodine treatment (24%). Ayan et al. [196] administered tolterodine IR to 44 children with dysfunctional voiding. The mean dysfunctional voiding symptom score was significantly reduced after 3 months of treatment. Dry mouth was reported by 31% of patients. A recent study comparing the efficacy and tolerability of oxybutynin IR and tolterodine IR in 60 children with DO showed similar efficacy but significantly fewer total AEs in children treated with tolterodine IR (13 vs 27 AEs). Eight children (27%) who were initially randomized to oxybutynin IR treatment crossed over to tolterodine IR because of AEs [197]. In a combined analysis of two placebo-controlled studies of tolterodine ER in children aged 5–10 years with incontinence suggestive of DO, changes in incontinence episodes per week, micturitions per 24 h, and urine volume per micturition with active treatment did not differ significantly from placebo. The authors attributed these results to a high placebo response and a possible under-dosage in heavier children. UTI (9%), nasopharyngitis (7%), and headache (4%) were the most frequently reported AEs [198]. In a 12-month, open-label extension of these two studies [199], the most frequent AEs were reported at rates comparable to tolterodine-treated patients in the double-blind phase (UTI, 7%; nasopharyngitis, 5%; headache, 5%). Ten patients (3%) withdrew because of AEs.

Two larger retrospective analyses of antimuscarinics in children with symptoms suggestive of DO have been reported. Reinberg et al. [200] compared the therapeutic efficacy of tolterodine ER, tolterodine IR, and oxybutynin ER among 132 children with OAB. A significantly greater percentage of patients receiving tolterodine ER (47%) or oxybutynin ER (45%) had significant improvements in daytime incontinence episodes compared with those receiving tolterodine IR (21%; P < 0.05). There were no significant between-group differences in the occurrence of central or peripheral antimuscarinic AEs. A second retrospective study by Raes et al. [201] evaluated the efficacy and tolerability of tolterodine IR in 256 patients aged 3–17 years with suspected DO. Tolterodine treatment was associated with significant reductions in incontinence episodes, urgency episodes, and micturitions per 24 h. Bladder capacity was also significantly increased with tolterodine treatment. CNS disorders, flushing, gastrointestinal complaints, and blurred vision reported by those previously treated with oxybutynin or oxyphencyclimine resolved after they switched to tolterodine. Although the current literature suggests that oxybutynin, trospium, and tolterodine offer therapeutic benefit for some children with OAB symptoms, only tolterodine ER has been studied in a large-scale, long-term tolerability study. Studies are needed to evaluate the safety and therapeutic potential of the newer antimuscarinics (i.e. darifenacin and solifenacin) in children.

DIAGNOSIS AND TREATMENT OPTIONS FOR PATIENTS WITH OAB

Many patients with bladder conditions develop ways to manage and adapt to the symptoms rather than seeking medical attention [202]. Misunderstandings about the causes of, and treatments for, urinary symptoms might contribute to low rates of treatment seeking among patients with OAB [203]. In a survey conducted in six European countries, 60% of respondents aged 40–74 years with OAB symptoms consulted a clinician about their symptoms. More than half who had not sought help thought that no effective treatment was available for OAB [2]. In a study of incontinent women aged 31–50 years, participants expressed beliefs that UI was the result of heredity, childbirth, heavy lifting, or getting older [204]. More recently, Milne [205] reported that 78% of community-dwelling adults (aged ≥55 years) who had not sought treatment for UI reported beliefs that UI was a natural consequence of ageing, and 22% thought UI resulted from childbirth.

The meeting of the third ICI [206] recently published an algorithm for initial management of UI in women. Many elements of the ICI recommendations can be applied to the treatment of men and women with UUI, with or without other OAB symptoms. The ICI recommends that patients with incontinence associated with urgency and frequency undergo a general physical examination and assessment of urinary symptoms. This assessment might be aided by an OAB-specific questionnaire, such as the Overactive Bladder-Validated 8, which evaluates the degree of bother associated with the symptoms of urgency, frequency, UUI, and nocturia [207]. The ICI recommends evaluation of pelvic floor muscle function and PVR, and urine analysis to exclude infection. The algorithm suggests that women with symptoms consistent with DO be evaluated for oestrogen deficiency and treated accordingly. The ICI recommends lifestyle interventions (e.g. weight reduction, smoking cessation, and modified fluid intake) as well as supervised pelvic floor muscle training and bladder retraining as part of an initial treatment plan. If these interventions fail to adequately reduce UUI episodes after 8–12 weeks, the addition of antimuscarinics is recommended. Specialized management should be considered if improvement is not achieved with pharmacotherapy.

Specialized management might include referral to a specialist for urodynamic studies. Urodynamic testing is invasive and expensive and is typically not needed for OAB diagnosis. In one study, patients with OAB symptoms but normal urodynamic findings responded as well to antimuscarinic treatment as did those with urodynamically confirmed DO [208]. However, urodynamic studies are particularly helpful in cases of nonspecific urinary symptoms and/or possible BOO [209]. Urodynamic evaluations should be reserved for patients in whom the findings will influence treatment [209].

As with any medical condition, fulfillment of positive expectations is a key element of patient satisfaction in OAB [210]. Thus, an integral step in achieving patient satisfaction is the negotiation of realistic expectations between patient and clinician.

FUTURE PROSPECTS

One of the most significant obstacles in the development of new antimuscarinic agents for OAB is lack of ‘clinical uroselectivity’[10,211]. The ideal antimuscarinic would exert its effects solely on the detrusor and the neural pathways involved in bladder filling (storage), but not on emptying, so as to reduce the occurrence of AEs [212]. Improved uroselectivity might be achieved through alterations in structure or route of administration [10]. In addition to new antimuscarinics, drug classes under investigation for OAB include α3-adrenoceptor agonists, purinergic receptor antagonists, phosphodiesterase inhibitors, neurokinin-1 receptor antagonists, opioids, and Rho-kinase inhibitors [10].

CONCLUSIONS

OAB is a highly prevalent condition that can be diagnosed easily and managed effectively with both nonpharmacological and pharmacological therapies. Antimuscarinics are the drug class of choice for OAB symptoms; each currently available antimuscarinic has proven efficacy, but their AE profiles differ somewhat. Enhanced bladder selectivity might limit the occurrence of anticholinergic AEs with the next generation of OAB medications. Until then, physicians can individualize OAB treatment by working with each patient to identify the most effective and best tolerated agent. For a symptom-defined condition such as OAB, patient input on the effectiveness of therapy is crucial to identifying the best treatment.

ACKNOWLEDGEMENTS

This review was solicited by BJU International and was supported by an unrestricted educational grant provided by Pfizer Inc. The authors would like to acknowledge the editorial assistance of Melinda Ramsey, PhD, and Colin P. Mitchell, PhD, from Complete Healthcare Communications, Inc., in the preparation of this manuscript.

CONFLICT OF INTEREST

Paul Abrams is a Consultant and Study Investigator for Pfizer Inc.

EDITORIAL COMMENT

The article by Professors Paul Abrams and Karl-Erik Andersson is the second in our series “Great Drug Classes”. Ironically it follows the original in the series on the new entrant to the field, the review of phosphodiesterase V inhibitors. Chronologically, obviously, antimuscarinics should have come before, representing the first widely used class of agents for benign urological conditions. This article shows how far the antimuscarinics have evolved. The reader can decide whether there is need or indeed scope for further improvement. We aim to bring the next article on Great Drug Classes in about six months.

Michael G. Wyllie, Associate Editor, BJU International

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