Urinary incontinence—pharmacotherapy options

Abstract

The impact of incontinence is felt by millions of people worldwide, with tremendous decrement in quality of life and enormous cost reaching billions of dollars. Urinary incontinence is defined as ‘involuntary leakage of urine’ and is categorized into two main types: urgency urinary incontinence (UUI) and stress urinary incontinence (SUI). Behavioral modifications and pharmacologic therapies, primarily antimuscarinic agents, are the mainstay of treatment for UUI. These drugs are moderately efficacious but have troublesome side-effects, the combination resulting in poor compliance and persistence with therapy. There are several agents on the market today, each with some variation in pharmacologic properties. Whether these translate into meaningful differences in clinical efficacy and tolerability remains a matter of debate. Treatment of SUI has seen little success with pharmacologic therapy. In Europe, duloxetine is approved for treatment of SUI with marginal success rates; this drug, although available in the United States for treatment of depression, is not approved for SUI. The search for newer and better pharmacologic options and novel therapies is on-going, fueled primarily by the high prevalence of bothersome incontinence and the tremendous number of health care dollars spent on current therapy. This review addresses pharmacologic options for treatment of urinary incontinence.

Key words::

• Antimuscarinics
• over-active bladder
• pharmacologic treatment
• stress urinary incontinence
• urgency urinary incontinence
• urinary incontinence

Abbreviations
5-HMT	=	5-hydroxymethyl tolterodine
ACh	=	acetylcholine
CYP	=	cytochrome P
DDAVP	=	desmopressin
DEO	=	N-desethyl-oxybutynin
ER	=	extended release
IR	=	immediate release
LUT	=	lower urinary tract
OAB	=	over-active bladder
OXY	=	oxybutynin
RCT	=	randomized controlled trial
SUI	=	stress urinary incontinence
TCA	=	tricyclic antidepressants
TDS	=	transdermal delivery system
TOLT	=	tolterodine
UI	=	urinary incontinence
UUI	=	urgency urinary incontinence

Key messages

• Several options exist for the pharmacologic treatment of urgency urinary incontinence, all resulting in moderate relief of symptoms at the expense of a moderate rate of side-effects.

• Few options exist for the pharmacologic treatment of stress urinary incontinence.

Introduction

Urinary incontinence (UI) is defined as ‘the involuntary loss of urine’ by the International Urogynecological Association/International Continence Society joint report (1). UI can be experienced by men and women of all age-groups with varying degrees of severity and bother. The specific type of UI can generally be elicited by thorough history and physical exam with complex clinical scenarios requiring urodynamic testing for definitive diagnosis. Urgency urinary incontinence (UUI) is preceded by urgency (defined as a sudden compelling desire to pass urine which is difficult to defer, often resulting in leakage en route to the toilet). UUI is generally accompanied by symptoms of over-active bladder (OAB) including frequency, urgency, and nocturia. The pathophysiology can be neurologic or idiopathic (2). Stress urinary incontinence (SUI) occurs with coughing, sneezing, laughing, or strenuous activity and is felt to be the result of a combination of impairment of the intrinsic urethral sphincter mechanism and pelvic support structures in women and only the former in men. UUI and SUI can occur together in the same patient, and this is referred to as mixed urinary incontinence. Pharmacologic therapy plays an integral role in the treatment of patients with OAB and UUI (3). Antimuscarinic agents produce symptomatic improvement by reducing urgency, UUI, and frequency, decreasing detrusor over-activity, and increasing bladder capacity (4). There are several drugs available for use today, with some variability based on country of residence. The efficacy of this class of medications is variable and associated with tolerability issues in many patients, resulting in overall poor patient compliance. This has driven the development of several newer agents looking to improve tolerability by offering once daily dosing, alternative routes of administration, and muscarinic subtype selectivity. Duloxetine, a serotonin–norepinephrine re-uptake inhibitor, was recently introduced in Europe as an alternative to surgical intervention for the treatment of SUI. Several trials have been conducted using this medication in the United States, but currently it is not approved for treatment of SUI. Several other agents have been tried with minimal success, and today SUI is best treated with pelvic floor muscle therapy and surgical intervention.

Mechanisms of continence

Risk factors for UUI include neurologic disease, inflammatory processes of the bladder, bladder outlet obstruction, aging, emotional stress, or it may be idiopathic. The most common pathology found in patients with UUI is detrusor over-activity (DO) (5). DO is the urodynamic observation of involuntary bladder contractions during bladder filling that are commonly associated with a corresponding sensation of urgency (2). DO may be the result of neurologic damage or disease or be idiopathic. Bladder compliance is a urodynamic measure calculated by dividing the change in bladder volume by a change in bladder pressure (2). Decreased compliance is usually the sequela of neurologic disease but may also result from any process that destroys the elastic or viscoelastic properties of the bladder wall. Impairment in compliance allows the pressure to increase in the bladder as it fills; this pressure rise can trigger a sensation of urgency and can also precipitate leakage of urine when the bladder pressure exceeds the urethral pressure. Heightened or altered sensation of the bladder may manifest as urgency in the absence of DO, impaired compliance, or leakage of urine. Previously this was referred to as sensory urgency, but the preferred terminology today is simply ‘urgency’.

Potential risk factors for SUI in women include parity, mode of delivery, hysterectomy, menopause, obesity, Caucasian race (6), and smoking (7). The primary risk factors for SUI in men is iatrogenic injury at the time of prostate surgery or radiation therapy (8). SUI can result from one of two deficiencies, intrinsic sphincter deficiency or urethral hypermobility (9). Intrinsic sphincter deficiency is the result of impairment in tonic closure pressure of the urethra (10). This decrease in outlet resistance may manifest from damage to the urethral sphincter mechanism secondary to surgical, obstetric, or other mechanical trauma, or from poor neurologic innervation with loss of neuronal mass secondary to neurologic disease, aging, or trauma (11). In addition, in women it may result from decreased pelvic floor support of the bladder outlet referred to as urethral hypermobility. This results from laxity of urethral support ligaments allowing mobility of the urethra out of the retropubic space and into the vagina with increases in intra-abdominal pressure (12). Ultimately, the rise in intra-abdominal pressure creates a corresponding rise in bladder pressure which is not matched by a rise in urethral pressure (since the urethra moved out of the pelvic cavity), and thereby a pressure differential exists where vesical pressure exceeds urethral pressure and leakage of urine occurs. Urethral hypermobility and intrinsic sphincter deficiency often coexist in the same patient.

Uro-pharmacology

Lower urinary tract (LUT) pharmacology, or uro-pharmacology, addresses the innervations and receptor contents of the bladder, urethra, and pelvic floor. The targets of pharmacologic intervention include not only these structures, but also the peripheral nerves and ganglia that supply these tissues, and the central nervous system (CNS) including the spinal cord and supraspinal areas. Specifically, pharmacologic targets include nerve terminals which alter the release of neurotransmitters, receptor subtypes, cellular second messenger systems, and ion channels. The autonomic nervous system assumes primary control over the two functions of the LUT (bladder filling/storage and bladder emptying); however, there are no pharmacologic agents that are purely selective for the LUT. Consequently, side-effects of treatment are common and are the result of collateral effects on organ systems that share some of the same neurophysiologic or pharmacologic characteristics as the bladder and urethra.

Treatment of incontinence

Failure of the LUT to adequately fill and store urine may be secondary to pathology in the bladder, the outlet, or both (13). Disruption in the filling and storing function of the bladder can, in theory, be improved by agents that increase bladder capacity, decrease detrusor activity, decrease sensory input, or increase outlet resistance (13). Treatment for UUI is aimed at increasing bladder capacity, decreasing bladder activity and contractility, and/or decreasing sensory (afferent) input. Specific treatment for SUI, though rarely effective, is aimed at increasing outlet resistance. In our experience, although great improvement can occur with rational pharmacologic therapy, a perfect result, i.e. the restoration to normal bladder or urethral function, is seldom achieved.

Treatment of UUI—decreasing bladder activity

Antimuscarinic agents. Physiologic bladder contractions are thought to be primarily triggered by acetylcholine (ACh)-induced stimulation of postganglionic parasympathetic muscarinic cholinergic receptor sites on bladder smooth muscle (14,15). Atropine and other antagonists of ACh which bind these receptor sites will depress normal bladder contractions and involuntary bladder contractions (15,16). In addition, these agents increase the volume to first involuntary bladder contractions and the total bladder capacity, and decrease the amplitude of the contraction (17).

The commonly held belief regarding antimuscarinic drugs is that they bind receptors on the detrusor that are stimulated by ACh, thereby decreasing the ability of the bladder to contract. However, during bladder filling and storage, there is no sacral parasympathetic outflow (18), raising the question, ‘why do antimuscarinics improve symptoms of frequency, urgency, and incontinence experienced during the filling/storage phase of the micturition cycle?’ The answer is probably related to the fact that muscarinic receptors are also present in bladder urothelium and suburothelium (19), and there is a basal ACh release in human detrusor muscle which may be produced, at least partly, by the urothelium and suburothelium (20). This suggests that detrusor tone may be affected by on-going ACh-mediated stimulation. There is now good direct experimental evidence that the antimuscarinics decrease activity in both C and A-delta afferent nerve fibers from the bladder during filling/storage (5,21).

ACh acts on two classes of receptors, nicotinic and muscarinic. Signal transduction between parasympathetic nerves and smooth muscle of the detrusor involves muscarinic receptors (22). At least five different muscarinic receptor subtypes exist, which are designated M₁–M₅. Although it appears that the majority of the muscarinic receptors in human smooth muscle are of the M₂ subtype, in-vitro data indicate that most smooth muscle contraction, including that of the bladder, is mediated by the M₃ receptor subtype. The muscarinic receptors are found not only on smooth muscle cells of the bladder but also on urothelial cells, suburothelial nerves, and on suburothelial structures such as interstitial cells with a M₂ and M₃ preponderance (19). Based on work in animals, the M₂ receptors have been implicated in the contraction of diseased bladders (21).

Antimuscarinics can be divided into tertiary and quaternary amines which differ in molecular size, molecular charge, and lipophilicity (22). Small molecular size with little charge and greater lipophilicity increases the passage through the blood–brain barrier with the theoretical potential of greater CNS side-effects. Tertiary compounds have higher lipophilicity and less molecular charge than quaternary agents. Quaternary compounds have greater molecular charge and less lipophilicity resulting in limited passage into the CNS and a theoretically lower incidence of CNS side-effects (23). Clinical data supporting these claims are lacking.

A recent meta-analysis on antimuscarinic agents found that these agents are more effective than placebo in improving continent days, mean voided volume, urgency episodes, and micturition frequency (3). The vast majority of agents studied provided improvement in health-related quality of life (HRQL). Across large patient samples, all of the currently available antimuscarinics appear to have comparable efficacy but do show some measurable differences in tolerability (24). Since the profiles of each drug and the dosing schedules differ, these things along with medical co-morbidities and concomitant medications should be considered when individualizing treatment for patients.

The currently available antimuscarinic drugs lack selectivity for the bladder and as a result produce side-effects on other organ systems. The most common adverse effects include dry mouth, blurred vision, pruritis, tachycardia, somnolence, impaired cognition, and headache. Constipation is reported as the most burdensome side-effect (3). This class of drug is contraindicated in patients with urinary retention, gastric retention and other severe decreased gastrointestinal motility conditions, and uncontrolled narrow-angle glaucoma.

As newer antimuscarinic agents have become available, some progress has been made, at least theoretically, in maximizing therapeutic efficacy while minimizing bothersome side-effects; however, the vast majority of patients (greater than 70%) discontinue therapy by one year, most of whom presumably are dissatisfied with the balance of efficacy and tolerability (25–27). Nevertheless, most physicians prescribe a trial of antimuscarinic therapy in addition to behavioral modification in patients with UUI, and, if it is not effective, a second trial using a different drug or formulation is often implemented. When these drugs fail, the side-effects become intolerable, or the category of drug is contraindicated, physicians have limited therapeutic options, including off-label use of other categories of drug or more invasive treatment options such as neuromodulatory agents or devices and major reconstructive surgery. Therefore, the demand for these agents, despite their nominal efficacy, remains high.

Antimuscarinic agents are considered first-line pharmacotherapy for UUI (28). Specific antimuscarinic drugs are listed below with available data on efficacy and comparative efficacy with other drugs in class. Table I lists the commonly prescribed antimuscarinics along with dosages and routes of administration that will be discussed below.

Table I. Commonly used antimuscarinic agents, formulations, and dosing regimens for the treatment of over-active bladder.

Agent	Formulation	Dosing regimen
Atropine (hyoscyamine)	0.125 mg sublingual tablet	1–2 tablets every 4 hours
	0.125 mg/1 mL oral drops, 0.125 mg/5 mg elixir	1–2 doses every 4 hours
	0.375 mg ER capsule	1–2 tablets twice daily
Belladonna + opium	16.2/30 mg, 16.2/60 mg suppository	once to twice daily
Darifenacin	7.5 mg, 15 mg tablet	daily
Fesoterodine	4 mg, 8 mg tablet	daily
Oxybutynin	5 mg tablet	2–4 times daily
	5 mg/5 mL syrup	2–4 times daily
	5, 10, 15 mg ER tablet	daily
	3.9 mg/day ER patch	twice weekly
	100 mg/1 g transdermal gel	daily
Solifenacin	5 mg, 10 mg tablet	daily
Tolterodine	1 mg, 2 mg tablet	twice daily
	2 mg, 4 mg ER capsule	daily
Trospium	20 mg tablet	twice daily
	60 mg ER capsule	daily

ER = extended release.

Oxybutynin. Oxybutynin (OXY) was brought to market in 1982 as a moderately potent antimuscarinic agent that had strong independent musculotropic relaxant activity as well as local anesthetic activity (that is likely only important during intravesical administration). It is a tertiary amine that is metabolized primarily by the cytochrome P (CYP) system into its primary metabolite, N-desethyl-oxybutynin (DEO) (29). The recommended oral adult dose for the immediate release (IR) formulation is 5 mg three or four times daily. An extended release (ER) once daily oral formulation as well as a transdermal delivery system (TDS) with twice weekly dosing, and a transdermal gel with once daily dosing are available. Side-effects are secondary to non-specific muscarinic receptor binding.

A meta-analysis summarizing 15 randomized controlled trials (RCTs) (n = 476) on OXY IR reported a 52% mean reduction in incontinence episodes, a 33% mean reduction in micturition frequency, and a mean overall improvement rate of 74%. This came at the expense of 70% of patients experiencing an adverse event (30). The therapeutic effect of OXY IR is associated with a high incidence of side-effects which are often dose-limiting (31). The ER form of OXY uses an osmotic system to release the active compound at a controlled rate over a period of 24 hours. As a result there is less absorption in the proximal portion of the gastrointestinal tract and less first-pass metabolism. By decreasing the liver metabolite DEO it was thought that fewer side-effects, especially dry mouth, would occur, thus improving patient compliance (32). Studies looking at salivary output showed markedly diminished production following administration of OXY IR with a gradual return to normal. In the OXY ER group salivary output was maintained at pre-dose levels throughout the day (33). OXY IR and ER have been compared in a multicenter, double-blind RCT of 106 patients, all of whom had previously responded to OXY IR (34). Interestingly, similar efficacy and similar side-effect profiles were noted for both formulations.

Three different doses of OXY ER (5, 10, and 15 mg) were compared in a RCT, and a significant dose–response relationship both for UUI episodes and dry mouth was found. Despite side-effects, the greatest patient satisfaction was with the 15 mg dose (35).

Transdermal administration of OXY (OXY-TDS) alters the metabolism of the drug, further reducing the production of DEO compared to OXY ER. The 3.9 mg daily dose patch decreased both micturition frequency and incontinence episodes while increasing mean voided volume (36). Dry mouth rate was similar to placebo. In a study comparing OXY-TDS to OXY IR similar reductions in incontinence episodes were found, but significantly less dry mouth was seen with OXY-TDS (38% versus 94% with OXY IR) (37). In a third study, OXY-TDS was compared to placebo and tolterodine (TOLT) ER (38). Both drugs had similarly significant reduced daily incontinence episodes and increased voided volume, but TOLT ER was associated with a higher rate of adverse events. The major side-effect for OXY-TDS was pruritus at the application site in 14% and erythema in 8.3%. In a review by Cartwright and Cardozo they concluded that the good balance between efficacy and tolerability with OXY-TDS was offset by the rate of local skin reaction (39).

Intravesical administration of OXY is a conceptually attractive form of drug delivery, especially for patients who already perform intermittent catheterization. A specific intravesical formulation of the drug is not available, and currently the oral formulation, either liquid or crushed tablet in solution, is delivered by periodic insertion through a catheter. Several uncontrolled studies have demonstrated efficacy of this therapy in a variety of patients with neurogenic bladders showing significant improvements in bladder capacity, compliance, and overall continence (40,41). In a study looking at the pharmacokinetics of intravesical OXY versus oral, it was found that plasma OXY levels following oral administration rose to 7.3 mg/mL within 2 hours then precipitously dropped to less than 2 mg/mL at 4 hours (42). In the intravesical group, plasma levels rose gradually to a peak of 6.2 mg/mL at 3.5 hours and remained between 3 and 4 mg/mL at 9 hours. From these data it is unclear whether the intravesically applied drug acted locally or systemically.

OXY topical gel is a new transdermal formulation which is applied once daily to the abdomen, thigh, shoulder, or upper arm area (43). Application of 1 gram of gel delivers approximately 4 mg of drug to the circulation with stable plasma concentrations. In a large multicenter trial (n = 789 patients; 89% women) patients with urgency predominant UI were randomized to OXY gel or placebo once daily for 12 weeks. Three-day voiding diaries showed a reduction in UUI by 3.0 episodes per day versus 2.5 in the placebo arm (P < 0.0001), and in urinary frequency by 2.7 episodes per day versus 2.0 episodes in the placebo arm (P = 0.0017). Voided volume increased by 21 mL versus 3.8 mL in the placebo group (P = 0.0018). Side-effects including dry mouth (reported in 6.9% of the treatment group versus 2.8% of the placebo group) and skin reaction at the application site (reported in 5.4% of the treatment group versus 1.0% in the placebo arm) were considered mild. The improved skin tolerability of the gel over the OXY TDS delivery system is likely the result of a lack of adhesive and skin occlusion. The gel dries rapidly upon application and leaves no residue; person-to-person transference via skin contact is largely eliminated if clothing is worn over the application site. Table I summarizes the available formulations of oxybutynin for the treatment of UUI.

Tolterodine. TOLT was brought to market in 1998 as a tertiary amine with a major active metabolite, 5-hydroxymethyl tolterodine (5-HMT), which significantly contributes to the therapeutic effect of the drug (44). Both TOLT and its metabolite have plasma half-lives of 2–3 hours, but their effects on the bladder seem to be more long-lasting. Whether this could be the result of urinary excretion of the drug with direct bladder mucosal effects remains unknown. TOLT does not have muscarinic subtype selectivity, but there is evidence in some experimental models that it has functional selectivity for the bladder over the salivary glands (45). TOLT is available in two formulations: an IR form prescribed as 2 mg twice daily, and an ER form prescribed as 2 or 4 mg once daily. There appears to be advantages in both efficacy and tolerability with the ER form (46). There appears to be a very low incidence of cognitive side-effects with TOLT which is likely due to the low lipophilicity of the drug and its metabolite, minimizing penetration into the central nervous system (47). A notable subset of patients, up to 10% of whites and up to 19% of blacks, lack the specific CYP enzyme, 2D6, that metabolizes TOLT to 5-HMT (48). In these patients a higher side-effect profile, specifically including sleep disturbance, is seen (49). Drugs that do not require CYP2D6 metabolism have the potential for less pharmacokinetic variability.

The efficacy of TOLT has been documented by several double-blind RCTs on patients with UUI. In the IMPACT (Improvement in Patients: Assessing symptomatic control with TOLT ER) study, the efficacy of TOLT in improving patients’ most bothersome bladder symptoms was assessed (50). It found significant reduction in incontinence, urgency episodes, and micturition frequency. Dry mouth occurred in 10% of patients and constipation in 4%. Comparative effectiveness between OXY and TOLT has been assessed, but no clear winner emerged (51–53). Conflicting data exist on the concomitant use of TOLT and pelvic floor muscle training. In a prospective, open study of 139 women with OAB, who were randomized to TOLT, bladder training, or both, combination therapy was found to be most effective (54). Similarly, a multicenter, single-blind study of 505 patients comparing TOLT alone to TOLT plus bladder training concluded that the effectiveness of TOLT can be augmented with the addition of a bladder training regimen (55). However, a similar multinational RCT including 480 patients concluded that no additional benefit was seen with the addition of pelvic floor muscle exercises to TOLT (56).

Trospium. Trospium was brought to market in 2004 as a hydrophilic, quaternary amine with limited ability to cross the blood–brain barrier. This, in theory at least, should result in minimal cognitive related dysfunction (57). Trospium does not have muscarinic subtype selectivity, and is not metabolized by the CYP enzyme system. It is mainly eliminated unchanged in the urine by renal tubular secretion and, as a result, may affect the urothelial mucosal signaling system as has been shown in the rat (58). Whether this contributes to clinical efficacy in humans remains unknown at this time.

The effectiveness of trospium in the treatment of UUI has been well documented (59–61). A long-term tolerability and efficacy study comparing trospium 20 mg twice daily and OXY 5 mg twice daily in 358 patients with OAB undergoing treatment for 52 weeks was performed (62). Urodynamics and patient-recorded voiding diaries were performed at base-line, 26 weeks, and 52 weeks. Mean maximum cystometric capacity increased in the trospium group by 92 mL at 26 weeks and by 115 mL at 52 weeks. The micturition diaries indicated a reduction in micturition frequency, incontinence frequency, and a reduction in urgency episodes in both treatment groups. At least one adverse event occurred in the majority of patients: 64.8% in the trospium group and 76.6% in the OXY group. The most common side-effect in both groups was dry mouth. Overall, both drugs were comparable in the efficacy in improving urinary symptoms, but trospium had a better benefit–risk ratio than OXY due to better tolerability.

An ER formulation of trospium, 60 mg once daily, has been shown in RCTs to have similar efficacy and side-effects as the twice daily preparation (63).

Intravesical installation of trospium was studied with a single-center, single-blind RCT with 84 patients (64). Since intravesical trospium does not seem to be absorbed, an opportunity exists for treatment with minimal systemic antimuscarinic effects (65). Compared to placebo, intravesical trospium produced a significant increase in maximum bladder capacity and a decrease in detrusor pressure. No improvement in uninhibited bladder contractions was seen. No adverse events were reported, but an increase in residual urine was noted.

Solifenacin. Solifenacin was brought to market in 2005 as a tertiary amine with modest selectivity for the M₃ receptor over the M₂ and marginal selectivity over the M₁ receptors (22,66). It is a once-a-day antimuscarinic with 5 mg and 10 mg doses. It is extensively metabolized by the liver via CYP3A4 with less than 15% excreted unchanged in the urine. There have been several large trials examining the effects of solifenacin (67). Cardozo and colleagues performed a multinational RCT comparing solifenacin 5 and 10 mg daily to placebo in 857 patients (68). Both doses significantly improved micturition frequency, urgency, volume voided, and incontinence episodes compared to placebo as determined by 3-day micturition diaries. Of patients who reported any incontinence at base-line, 50% achieved continence after treatment with solifenacin compared with 27.9% after placebo. Dry mouth was reported in 7.7% of patients taking solifenacin 5 mg, 23.1% in solifenacin 10 mg, and 2.3% in the placebo arm. Only a small percentage of patients (2%–4%) did not complete the study due to adverse events, and this was comparable in all groups.

The STAR (Solifenacin and Tolterodine as an Active comparator in a Randomized) trial was a prospective double-blind, parallel group 12-week study comparing solifenacin 5 and 10 mg once daily to TOLT ER 4 mg once daily (69). After 4 weeks of treatment patients were given the option to increase medication dosage. However, only those on solifenacin actually received the dose increase. The results showed non-inferiority of solifenacin's flexible dosing regimen compared to TOLT ER for voiding frequency. Solifenacin showed increased efficacy in decreasing urgency episodes, incontinence, and pad usage compared with TOLT ER. Additionally, more solifenacin patients achieved dryness, as documented by 3-day voiding diary, by the end of the study (59% versus 49%). However, these symptomatic improvements were accompanied by an increase in adverse events with dry mouth and constipation occurring in 30% and 6.4% of the solifenacin group, respectively, versus 23% and 2.5% in the TOLT group. The discontinuation rate was comparably low in both groups.

Darifenacin. Darifenacin was brought to market in 2005 as a tertiary amine with moderate lipophilicity and is a relatively selective M₃ receptor antagonist. At least theoretically, darifenacin's advantage is the ability to relatively selectively block the M₃ receptor which, although less prevalent than the M₂ receptor, appears to be more important in bladder contraction. This selectivity is expected to increase efficacy in patients with OAB/UUI while reducing the adverse events related to the blockade of other muscarinic subtypes (70). Darifenacin has been developed as a controlled release formulation to allow daily dosing and is available at 7.5 and 15 mg per day. Several RCTs have documented the clinical effectiveness of the drug (71,72). Significant dose-related improvements in number of incontinence episodes per week were seen: 8.8 less episodes per week with the 7.5 mg dose and 10.6 less episodes per week with the 15 mg dose. Improvements in micturition frequency, bladder capacity, and severity of urgency were also seen. The most common side-effects were dry mouth and constipation.

The effects of darifenacin on cognitive function in elderly volunteers was tested in a randomized, double-blind, three-period cross-over study with 129 patients 65 years of age or older (73). After 2 weeks of treatment no effect on cognitive function compared with base-line was found. The authors hypothesized that this was related to its M₃ receptor selectivity.

Fesoterodine. Fesoterodine was brought to market in 2007 as an antimuscarinic drug that is metabolized rapidly and extensively to 5-hydroxymethyl tolterodine (5-HMT), the same active metabolite of tolterodine (TOLT) (74). Unlike TOLT, fesoterodine does not use the CYP2D6 enzyme for conversion but rather relies on non-specific esterases that produce a rapid and complete conversion with little pharmacokinetic variability. Like TOLT, this compound is a non-subtype-selective muscarinic receptor antagonist (75). 5-HMT is metabolized in the liver, but there is significant renal excretion without additional metabolism, raising the possibility that 5-HMT could also work from the luminal side of the bladder (76). Fesoterodine is indicated for the treatment of UUI at doses of 4 and 8 mg daily.

In a multicenter RCT with TOLT ER the 4 mg and 8 mg doses of fesoterodine were effective in improving symptoms of OAB, with the 8 mg dose having greater effect at the expense of a higher rate of dry mouth (74). The dose–response relationship was confirmed in another study that pooled data from two phase III RCTs (77). Fesoterodine 8 mg performed better than the 4 mg dose in improving urgency and UUI as recorded by 3-day bladder diary, offering the possibility of dose titration. A study on the effect of fesoterodine on health-related quality of life in patients with OAB confirmed improvement for both the 4 and the 8 mg doses of the drug (78).

Atropine. Atropine has been available for many years and, along with hyoscyamine and scopolamine, is an active belladonna alkaloid derived from the toxic belladonna plant with anticholinergic properties (5). Atropine has significant systemic side-effects including ventricular fibrillation, tachycardia, dizziness, nausea, blurred vision, loss of balance, dilated pupils, photophobia, extreme confusion, and dissociative hallucinations which limit its oral use for the treatment of OAB. Its mention in this chapter is more of a historic one. Belladonna and opium suppositories are available in two strengths, 16.2 mg/30 mg and 16.2 mg/60 mg, and can be used one to two times daily per rectum. Despite lacking clinical efficacy data they remain in use today primarily in the management of postoperative patients who are unable to absorb oral medications. Hyoscyamine is a pharmacologically active antimuscarinic component of atropine that is reported to have similar actions and side-effects (5). Few clinical studies are available to evaluate efficacy in the treatment of UUI (79).

Antimuscarinic drugs are proven efficacious and safe and are the mainstay of treatment for UUI (3). Head-to-head studies comparing these agents are not available, and therefore no ‘best-in-class’ recommendation can be given. The continuous evolution and development of newer agents stems from the fact that the ideal agent has yet to be found—one that is LUT selective, easily administered, and relatively inexpensive. This search continues, and therapies with different mechanisms of action are currently being studied with great promise.

Three specific clinical concerns with the use of antimuscarinic medication deserve special mention: urinary retention, cognitive impairment, and glaucoma. In the past there was universal concern regarding the risk of urinary retention when prescribing antimuscarinic drugs. However, these drugs are usually competitive antagonists which imply that when there is massive release of ACh during voiding, the effect of the drug should be diminished (21). If this did not occur, urinary retention would result from inability of the bladder to contract. And, in fact, at high doses urinary retention can occur, but this is uncommon at the doses typically prescribed (21). Current understanding regarding the dose range used for beneficial effects in OAB, and those needed to produce a significant reduction in the voiding contraction, suggests safety of these medications at standard doses. Monitoring post void residual urine volumes in patients with prostatic enlargement or incomplete bladder emptying is still recommended; however, these diagnoses should not be considered as absolute contraindications to the use of antimuscarinics in such patients with OAB.

More recently, concern over the association of anticholinergics and cognitive impairment has prompted several studies evaluating reaction time, memory, confusion, and other cognitive decrements. In a longitudinal cohort study involving 372 adults aged > 60 years without dementia at recruitment, the effects of continuous anticholinergic drug use on cognition was assessed (80). A total of 80% of anticholinergic users were classified as having mild cognitive impairment compared with only 35% of non-users. There was no difference between users and non-users in the risk of developing dementia after 8 years of follow-up. Other studies in continent elderly volunteers have shown no significant effects on cognition (73). There are few data available on the cognitive consequences of anticholinergics in patients with dementia. However, cholinesterase inhibitors which are often used to improve cognition in Alzheimer's disease have been shown to precipitate urinary incontinence (81).

Patients with OAB and glaucoma present another therapeutic dilemma for urologists. Both conditions increase in prevalence with age, and it has been estimated that the conditions coexist in approximately 11.6% of female patients (in Japan) (82). The distinction between open-angle and narrow-angle glaucoma is an important one, and when the answer is unknown referral to an ophthalmologist is imperative. A Japanese study reported that in approximately 75% of patients with glaucoma and OAB, the glaucoma is open-angle, and this was felt to confer no additional risk to therapeutic intervention with anticholinergic medication. In the remaining 25% with narrow-angle glaucoma, risk was felt to be elevated only if iridotomy had not been performed or had not successfully controlled the disease, reducing the true contraindication rate to approximately 8.3% of patients with OAB. Interestingly, the same study found that 33% of patients did not report glaucoma on their medical intake form. Under-estimating the risk of glaucoma can result in blindness, albeit rarely, while over-estimating (which often occurs out of fear) can result in denial of the most effective oral agents for the treatment of OAB. Complaints of eye pain, headache, or visual loss following initiation of anticholinergic therapy should be taken seriously, and prompt medical advice should be sought (83).

Antidepressants

Several antidepressants have been said, in largely uncontrolled or anecdotal trials, to have beneficial effects in patients with UUI (14). These effects include facilitating urine storage by decreasing bladder contractility and increasing outlet resistance. In general, these agents have two major pharmacologic actions. They have anticholinergic effects both centrally and peripherally, and they block the re-uptake of serotonin and noradrenaline (84). The most common side-effects include: nausea, followed by dry mouth, dizziness, constipation, insomnia, and fatigue. Tricyclic antidepressants (TCA) can have cardiotoxic side-effects, as well as CNS effects including weakness, Parkinsonian effects, fine tremor, manic or schizophrenic picture, and sedation (84). In general, the doses given for the treatment of urgency incontinence are much lower than those prescribed for depression. Whether the same toxicity profile exists for these drugs at the lower dose remains to be seen.

Duloxetine. Duloxetine is a combined serotonin–norepinephrine re-uptake inhibitor which has been shown to increase both bladder capacity and sphincteric muscle activity during filling and storage in the cat (85). The data to support its role in increasing outlet resistance will be presented later. A RCT on 306 women with OAB looked at the effects of duloxetine 80 mg daily for 4 weeks, followed by 120 mg daily for 8 weeks (86). The duloxetine group showed significant improvement in number of voids and incontinence episodes, voiding interval, and HRQL. No urodynamic indices showed improvement. The product information for this drug contains a black box warning due to increased suicidal thinking and behavior in those taking the drug for psychiatric disorders.

Imipramine. Imipramine is a TCA that has been widely used clinically to treat UUI despite a lack of good-quality RCTs to document its effects. Imipramine has prominent systemic anticholinergic effects but only a weak antimuscarinic effect on bladder smooth muscle (87). The effect of imipramine on noradrenaline re-uptake is non-selective, and direct evidence suggesting it occurs in the LUT as well as the brain has been provided (88).

Clinically, imipramine seems to be effective in decreasing bladder contractility and increasing outlet resistance. In a study of elderly patients with OAB, imipramine 25 mg nightly was given and increased by 25 mg every 3 days until either the patient was continent, had side-effects, or a dose of 150 mg was reached (89). Six of ten patients became continent. In those patients who underwent repeated cystometry, bladder capacity increased by a mean of 105 mL, and bladder pressure at capacity decreased by a mean of 18 cmH₂O. In our experience, the effects of imipramine on the LUT are often additive to those of antimuscarinic agents; however, it should be noted that the anticholinergic side-effects may also be additive. A combination of low-dose imipramine and an antimuscarinic or an antispasmodic has been reported as useful for decreasing bladder contractility and detrusor pressure in some neurogenic patients (90). However, serious toxic side-effects can occur with therapeutic doses of imipramine, including orthostatic hypotension, ventricular arrhythmias, and prolongation of the QT interval. A proper risk–benefit analysis of imipramine in a good-quality clinical trial has not been performed.

Estrogen

Estrogen has been used for decades to treat OAB, UUI, and SUI, yet much of the evidence to support this use has come from uncontrolled observational studies utilizing a wide range of estrogen preparations, doses, and routes of administration. The role of systemic estrogen replacement in postmenopausal women with incontinence was considered in the secondary analyses of three large observational studies (91–93). All three found an increase in the incidence of UI as well as deterioration in symptoms in women who had UI at base-line. In the Nurses’ Health Study (NHS), subgroup post-hoc analysis determined that women taking estrogen were at greater risk of UI than women not taking estrogen (oral estrogen RR 1.54, 95% CI 1.44–1.65; transdermal estrogen RR 1.68, 95% CI 1.41–2.00) (92). However, the annual incidence of UI was 1.6%, proving to be a small risk, a risk that appeared reversible with discontinuation of therapy (92). Similarly, post-hoc analysis of the Heart and Estrogen/progestin Replacement Study (HERS), specifically looking at the subgroup of women who at base-line had one episode or more of incontinence weekly, found that daily oral hormone replacement was associated with increased symptoms of both SUI and UUI (91). The risk was small and translated to an increase in incontinence episodes of approximately one per week (91). This certainly did not suggest a protective effect of estrogen against urinary incontinence. The Women's Health Initiative (WHI) trial showed greater incident urinary incontinence, both SUI and UUI, among women taking hormone therapy (HT) (94). Highest risk was reported for SUI (RR 2.15; 95% CI 1.77–2.62), followed by mixed urinary incontinence (RR 1.79; 95% CI 1.26–2.53), and UUI (RR 1.32; 95% CI 1.10–1.68). Women taking estrogen reported a greater frequency of incontinence episodes (RR 1.38; 95% CI 1.28–1.49 and RR 1.47; 95% CI 1.35–1.61, respectively), increased volume of leakage (RR 1.20; 95% CI 1.06–1.76 and RR 1.59; 95% CI 1.39–1.82, respectively), and a greater degree of bother (RR 1.18; 95% CI 1.06–1.32 and RR 1.29; 95% CI 1.15–1.45, respectively) than a similar cohort of women not taking estrogen. The findings of these three large observational studies contributed new evidence to the body of literature composed primarily of anecdotal reports that estrogen therapy improved symptoms of UI. Skepticism arose, however, due to the fact that these large trials were not designed to address incontinence and therefore lacked a-priori power analysis and proper randomized trial design to answer this question. Evidence from double-blind placebo-controlled studies was available, but the results were contradictory. A cross-over study of 34 postmenopausal women using 3 mg daily of oral estriol found a subjective and clinically significant improvement in urgency and mixed urinary incontinence over placebo (95). A subsequent study using the same dose and preparation of estrogen failed to show a difference in subjective or objective lower urinary tract function in women with UUI (96). Two RCTs of the estradiol vaginal tablet showed improvements in subjective urinary urgency (97,98); one trial, though limited since it was not designed to look at the impact of vaginal estrogen on urinary symptoms, showed statistically significant improvements in ‘urologic symptoms’ at 2 and 12 weeks of treatment (98). At 2 weeks, 60.5% of women reported improvement in ‘urologic symptoms’ compared to 35.3% in the placebo group (P < 0.02). At 12 weeks, 62.8% of the treatment group reported improvement compared to 32.4% in the placebo group (P < 0.001).

To clarify the role of oral versus vaginal estrogen in OAB/UUI, a meta-analysis of eleven RCTs (n = 430) utilizing estrogen for the treatment of OAB symptoms was performed (99). Six voiding parameters felt to be important in OAB were improved in the estrogen treatment groups. Urinary frequency improved in eight out of ten study groups (P = 0.001), urgency improved in four out of six study groups (P = 0.043), nocturia improved in six out of nine study groups (P = 0.037), UUI improved in eight out of ten study groups (P = 0.0002), and urodynamic parameters, including first sensation to void and bladder capacity, improved in ten out of ten (P = 0.0001) and seven out of ten (P = 0.002) study groups, respectively. Local estrogen administration provided greater symptomatic relief of urinary symptoms than systemic administration and essentially accounted for the differences seen in the meta-analysis. Systemic estrogen only improved first sensation to void and reduced incontinence episodes compared to placebo. A Cochrane review also found that local estrogen therapy produced improvement in OAB symptoms (100). A decrease in urinary frequency of one to two times per day and a decrease in nocturia of one to two times per night were reported in this review. Too few data were available to comment on the reduction in incontinence episodes. Long et al. proposed that vaginal estrogen provided enhanced symptoms relief over that of oral estrogen as a result of enhanced blood-flow to the urethra and bladder neck area with improvement in atrophy of the urogenital tissues (101). The superiority of local estrogen over systemic for the treatment of OAB has not itself been tested in a RCT. The 4th International Consultation on Incontinence gave estrogen a grade C recommendation based on a level of evidence of 2 for OAB and concluded that there is no solid evidence to support the use of HT for the treatment of UUI (5).

Botulinum toxin

Botulinum toxin (BTX) is a neurotoxin produced by Clostridium botulinum and is a potent presynaptic inhibitor of acetylcholine release at the neuromuscular junction of muscle. It is applied directly by cystoscopic injection into the urothelium, suburothelium, or detrusor muscle, producing a chemical denervation which is reversible after approximately 6 months. Intravesical administration allows for high bladder concentrations with minimal systemic effects and minimal effects on surrounding organs. BTX is not approved by the FDA for treatment of UUI, but many consider it an option for second-line therapy in patients who are refractory to conventional oral antimuscarinic therapy or who do not tolerate it due to systemic side-effects.

Several dose and injection protocols for BTX have been described in the literature with corresponding data to support their use. In the initial description, 300 units of BTX were diluted in normal saline to a concentration of 10 U/mL. Under direct cystoscopic visualization using a 6F injection needle, 30 injections of 1 mL each were administered to the bladder wall in 30 different locations above the trigone (102). Since that description, several other authors have described varying doses, dilutions, number of sites, and locations (trigone, suburothelial space).

A large multicenter, non-controlled trial including 231 neurogenic patients, most with spinal cord injury, was conducted in Europe (103). A total of 300 units of BTX was injected in 30 different locations. Follow-up was available on 200 patients and revealed marked improvement with respect to continence in all patients. Urodynamic evaluation 12 weeks after injection revealed significant increases in maximum cystometric capacity, post void residual urine volume, and compliance. These changes were observed up to 36 weeks after injection. No injection-related complications or toxin side-effects were reported. Several other non-controlled studies have been published confirming these observations (104). In a double-blind RCT including 34 patients with idiopathic OAB refractory to antimuscarinics, 200 units of BTX was studied (105). Significant improvements in maximum cystometric capacity, frequency, and incontinence episodes were seen at 4 and 12 weeks. Despite clinical improvement, six patients (37.5%) required intermittent catheterization to empty the bladder.

The onset of BTX effects is seen within the first 2 weeks after injection (104). Urgency, nocturia, and frequency have been shown to improve as early as 2 days after BTX injection in neurogenic patients (106). The reported duration of BTX following the first injection was 6 to 9 months (104), and duration of effect along with beneficial clinical effect after subsequent injections is maintained (107).

Urinary retention requiring intermittent catheterization is an important concern in non-neurogenic patients who are not already committed to catheterization. Dose reductions studies looking at 100 units have been performed in hopes of maintaining symptomatic efficacy and decreasing the risk of urinary retention. In a prospective, non-randomized study including 100 men and women, 100 units of BTX was injected in 30 locations (108). At 4 and 12 weeks’ follow-up, 88% of patients showed significant improvement in bladder function in regard to subjective symptoms, urodynamic parameters, and HRQL. There were four cases of urinary retention amounting to a 2% risk. Side-effects of intravesical BTX include: elevated post void residual urine, urinary retention, and urinary tract infection (109).

BTX appears to produce moderate symptom relief for neurogenic and idiopathic OAB/UUI. Further studies are underway addressing where this treatment fits in the algorithm of care for OAB/UUI as well as the optimum dose, locations, and methods of injection. The case for use in neurogenic patients who are already on Clean Intermittent Catheterization (CIC) and are bothered by leakage between catheterizations seems more clear than use in patients with idiopathic symptoms, in whom urinary retention would require learning and initiating intermittent self-catheterization.

Treatment of SUI—increasing outlet resistance

Alpha-adrenergic agonists

The bladder neck and proximal urethra contain a preponderance of α-adrenergic receptor sites, which, when stimulated, produce smooth muscle contraction and an increase in maximal urethral pressure and maximal urethral closure pressure (14). α-Adrenergic stimulation generally increases outlet resistance to a variable degree but is most often limited by the potential side-effects including blood pressure elevation, anxiety, insomnia, headache, tremor, weakness, palpitations, cardiac arrhythmia, and respiratory difficulties. These agents should be used with caution in patients with hypertension, cardiovascular disease, and hyperthyroidism (110).

Ephedrine. The use of ephedrine to treat SUI was mentioned as early as 1948 (110). This is a non-catecholamine sympathomimetic agent that enhances release of noradrenaline from sympathetic neurons and directly stimulates both α- and β-adrenergic receptors. The oral adult dosage is 25–50 mg four times daily (111). In 38 patients with sphincteric incontinence treated with ephedrine sulfate, 27 reported ‘good to excellent’ results. The beneficial effects were most often achieved in those with minimal to moderate incontinence symptoms; little benefit was achieved in patients with severe SUI (111).

Pseudoephedrine. Pseudoephedrine, a stereoisomer of ephedrine, is used for similar indications and carries similar precautions. The adult dosage is 30–60 mg four times a day, and the 30 mg dose is available in the United States without prescription.

A recent Cochrane review evaluated randomized and quasi-RCTs in adults with SUI treated in at least one arm of the trial with an adrenergic agonist drug (112). A total of 22 eligible trials were identified involving 1,099 women (there were no controlled trials reporting on the use of these drugs in men). The authors concluded: ‘there was weak evidence to suggest that use of an adrenergic agonist was better than placebo treatment’. They also reported a similar adverse events profile for adrenergic agonists and placebo.

Antidepressants

Duloxetine. Duloxetine, as mentioned above, is a combined serotonin–norepinephrine re-uptake inhibitor which is approved by the Federal Drug Administration for the treatment of depression, diabetic neuropathic pain, and generalized anxiety disorder and licensed in the European Union for the treatment of SUI. It has been shown to increase sphincteric muscle activity during the filling and storage phase of micturition with no effect on sphincter function during voiding in a cat model (85). It was also noted that duloxetine increased bladder capacity, probably through a central nervous system effect. The effects on the sphincter were reversed by α₁-adrenergic and 5HT₂-serotonergic antagonism, while the effects on the bladder were provoked by serotonin and noradrenaline in the synaptic cleft (113). There have been several RCTs documenting the effects of duloxetine in the treatment of SUI. Dmochowski and colleagues enrolled 683 patients in a double-blind RCT comparing duloxetine 40 mg twice daily to placebo (114). There was a 50% decrease in incontinence episodes in the duloxetine group compared to 27% in the placebo group; a significant improvement in HRQL was also seen in the duloxetine group. The improvements with duloxetine were associated with significant increases in the voiding interval (20 minutes versus 2 minutes) compared to placebo. The discontinuation rate was higher in the duloxetine group (24%) than placebo (4%), most frequently due to nausea which was usually transient.

A Cochrane review of the effects of duloxetine on SUI summarizes data from 9 RCTs totaling 3,060 women (115). Cure rate in the duloxetine 40 mg twice daily group was higher than in the placebo group (10.8% versus 7.7%; P = 0.04). Significant reductions in incontinence episodes and improvement in HRQL and patient global impression of improvement were seen (RR for better health status 1.24; 95% CI 1.14–1.36; P < 0.00001). However, no data were available on sustainability of treatment. The estimated absolute size of effect showed that for every 100 patients treated, 3 patients were cured. Only one trial reported objective cure data and showed no clear difference between drug and placebo. Adverse events were common (71% versus 59% in placebo) but were not considered serious. The authors conclude that more research is needed to determine whether duloxetine is clinically effective and cost-effective compared to the other minimally invasive or more invasive treatment options available.

Imipramine. The actions of imipramine have been discussed in further detail above. On a theoretical basis, an increase in urethral resistance might be expected if an enhanced α-adrenergic effect at this level resulted from an inhibition of noradrenaline re-uptake. However, imipramine also causes α-adrenergic blocking effects, at least in vascular smooth muscle. Many clinicians have noted improvement in patients treated with imipramine primarily for OAB/UUI but who had in addition some component of sphincteric incontinence. In a study of 30 women with SUI who were treated with imipramine 75 mg daily for 4 weeks, 21 women reported continence; the mean maximal urethral closure pressure for the group increased from 34.06 to 48.23 cmH₂O (116). There are no RCTs on the use of imipramine for SUI. The safety issues are potentially significant and are listed above.

Estrogen

In 1994 the Hormones and Urogenital Therapy Committee completed a meta-analysis of 166 articles on incontinence published in English between 1969 and 1992; of these 6 were controlled trials, and 17 were uncontrolled series. In the RCTs, subjective improvement in incontinence ranged from 64% to 75% (versus 10%–56% in placebo) while in the uncontrolled studies it ranged from 8% to 89% (117). The Committee concluded that estrogen therapy significantly improved subjective urinary incontinence in postmenopausal women. They also found significant improvement in the subset of patients with pure SUI and reported a significant rise in maximal urethral closure pressure in the estrogen group. However, no change in volume of urine loss was seen.

A subsequent review of 22 prospective studies, 8 controlled and 14 uncontrolled, found that estrogen therapy was not efficacious for the treatment of SUI but may be useful for urgency, frequency, and UUI (118). Two subsequent RCTs looked specifically at the impact of oral estrogen replacement in postmenopausal women with urodynamic SUI. Neither estrogen alone nor combination therapy significantly improved subjective or objective outcomes (119,120).

More recently, in 2003, a meta-analysis on the subject concluded that current evidence does not support the use of estrogen for the treatment of SUI (121). Today, few clinicians even consider estrogen a part of the treatment armamentarium for SUI. The 4th International Consultation on Incontinence gave estrogen a grade D recommendation based on a level of evidence of 2 for SUI (5). This translates to ‘no recommendation possible’ due to inadequate and conflicting evidence.

Circumventing the problem

Antidiuretic agents

Endogenous production of antidiuretic hormone serves two purposes: stimulation of water reabsorption in the renal medulla and contraction of vascular smooth muscle. A relative lack of hormone is believed to be important in polyuria, specifically nocturnal polyuria (122).

Desmopressin. The synthetic Antidiuretic Hormone (ADH) analog, desmopressin (DDAVP), has been used for the symptomatic relief of refractory nocturnal enuresis in children and adults (123). More recently it has been explored for the treatment of OAB and incontinence. The drug can be administered by oral, parenteral, or intranasal spray and effectively suppresses urine production for 7–10 hours. Several small controlled studies on patients with multiple sclerosis and nocturia have consistently reported efficacy of DDAVP at the risk of asymptomatic or minimally symptomatic hyponatremia (124). Further studies in non-neurologic patients have confirmed the efficacy and determined effective dose regimens for the treatment of nocturia (125). In a phase IIb study on the use of oral DDAVP in the treatment of OAB symptoms a decrease in frequency and urgency episodes was observed. Patients also reported an improvement in HRQL with only mild side-effects including headache. No hyponatremia was reported (126). Given the safety concerns over hyponatremia, it is recommended that the drug not be given in patients older than 79 years of age or to those with 24-hour urine volumes greater than 28 mL/kg. It is also recommended that serum sodium levels be checked at base-line and at 3 days and 7 days after starting treatment or changing dose (127). General precautions including limiting fluid intake from 1 hour before the dose until 8 hours after, periodic blood pressure measurements, and weight measurements to monitor for fluid overload should be instituted (128). Further studies on DDAVP for the treatment of OAB and incontinence are needed.

Conclusions

UI is a prevalent condition with tremendous impact on quality of life and health care resources. Proper diagnosis of UUI and SUI is critical as the two conditions have very different treatment options. With recent advances in the science of incontinence through both laboratory and clinical research, it has become clear that the function and dysfunction of the urinary bladder and urethra are much more complex than previously appreciated. Pharmacologic therapy is the mainstay of treatment for UUI with several antimuscarinic drugs available, all with moderate efficacy. New drug development has produced time release options with once daily dosing, muscarinic receptor selectivity, and alternative drug delivery systems. Whether these newer agents contribute a real advantage in terms of therapeutic efficacy or adverse event profile over the previously available agents is still a matter of debate, as head-to-head comparisons are rare. There has been little success in the development of pharmacologic agents to treat SUI. Continued drug development focusing on alternative and complementary mechanisms of action as well as bladder and urethra selectivity is needed to address this prevalent, bothersome problem.

Declaration of interest: A J Wein is a consultant for Allergan, Astellas, Endo, Medtronic, Novartis, Pfizer, and Serenity. A L Smith declares no conflicts of interest.