Chapter 20 DRUG TREATMENT OF URINARY INCONTINENCE IN WOMEN

The lower urinary tract has two basic functions: the storage and emptying of urine. The physiology and pharmacology of micturition have been described by many qualified authors, each of whom has reported his or her own particular concept of the neuroanatomy, neurophysiology, and neuropharmacology of the smooth and striated muscle structures involved; of the peripheral, autonomic, and somatic neural factors; and of the spinal and supraspinal influences that are necessary for normal function.¹^–⁵ Although there are significant disagreements about the finer details, it is important to realize that exact agreement about neuromorphology, neurophysiology, and neuropharmacology is not necessary for an understanding of the pharmacologic principles and applications involved in drug-induced alterations of voiding function and dysfunction. Despite such disagreements, “experts” would agree that, for the purposes of description and teaching, urinary continence requires, first, accommodation of increasing volumes of urine at a low intravesical pressure and with appropriate sensation; second, a bladder outlet that is closed at rest and remains so during increases in intra-abdominal pressure; and third, absence of involuntary bladder contractions (IVCs), including non-neurogenic and neurogenic detrusor overactivity (DO).

As a result of advances in understanding of the neuropharmacology and neurophysiology of the lower urinary tract, effective pharmacologic therapy now exists for the management of urinary incontinence. Because of the number of drug therapies available along with the varying quality and quantity of studies performed using them, the International Consultation on Incontinence has assessed many of the available agents for voiding dysfunction and made recommendations regarding their use (Table 20-1).

Table 20-1 International Consultation on Incontinence Assessments of Pharmacotherapy for Voiding Dysfunction, 2004

Drug	Level^*	Grade^†
Antimuscarinics
Tolterodine	1	A
Trospium	1	A
Darifenacin	1	A
Solifenacin	1	A
Propantheline	2	B
Atropine, hyoscyamine	3	C
Drugs with mixed actions
Oxybutynin	1	A
Propiverine	1	A
Dicyclomine	3	C
Flavoxate	2	D
Antidepressants
Imipramine	3	C
Vasopressin analogues
Desmopressin	1	A
β-Adrenergic receptor agonists^‡	3	C
Baclofen	3	C
Capsaicin	2	C
Resiniferatoxin	2	C
Botulinum toxin	2	B

* Levels: 1—systematic reviews, meta-analyses, good-quality randomized controlled clinical trials; 2—randomized controlled trials, good-quality prospective cohort studies; 3—case-controlled studies, case series; 4—expert opinion.

† Grades: A—based on level 1 evidence (highly recommended); B—consistent level 2 or 3 evidence (recommended); C—level 4 studies or “majority evidence” (optional); D—evidence inconsistent or inconclusive (no recommendation possible).

‡ Class includes terbutaline, salbutamol, and clenbuterol.

This chapter summarizes the pharmacologic treatments available for female urinary incontinence within this functional classification. As an apology to others in the field whose works have not been specifically cited in this chapter, it should be noted that citations have generally been chosen primarily because of their review or informational content, or sometimes for their controversial nature, and not because of originality or initial publication on a particular subject.

CLINICAL UROPHARMACOLOGY OF THE LOWER URINARY TRACT

Some Useful Concepts

Clinical uropharmacology of the lower urinary tract is based primarily on an appreciation of the innervation and receptor content of the bladder and its related anatomic structures. The targets of pharmacologic intervention in the bladder body, base, or outlet include nerve terminals that alter the release of specific neurotransmitters, receptor subtypes, cellular second-messenger systems, and ion channels identified in the bladder and urethra. Peripheral nerves and ganglia, spinal cord, and supraspinal areas are also sites of action of some agents discussed. Because autonomic innervation and receptor content are ubiquitous throughout the human body’s organ systems, there are no agents in clinical use that are purely selective for action on the lower urinary tract. The majority of side effects attributed to drugs facilitating bladder storage or emptying are collateral effects on organ systems that share some of the same neurophysiologic or neuropharmacologic characteristics as the bladder.

Generally speaking, the simplest and least hazardous form of treatment should be tried first. A combination of therapeutic maneuvers or pharmacologic agents can sometimes be used to achieve a particular effect, especially if their mechanisms of action are different and their side effects are not synergistic. At the outset it should be noted that, in our experience, although great improvement often occurs with rational pharmacologic therapy, a perfect result (restoration to “normal” status) is seldom, if ever, achieved.

The pathophysiology of failure of the lower urinary tract to fill with or to store urine adequately may be secondary to problems related to the bladder, the outlet, or both.⁶ DO can be expressed as discrete IVCs or as reduced compliance with or without phasic contractions. It may manifest symptomatically as overactive bladder (OAB) syndrome, a syndrome of urgency that may be associated with frequency and nocturia. IVCs are most commonly associated with inflammatory or irritating processes in the bladder wall or with bladder outlet obstruction, or they may be idiopathic. Decreased compliance during filling may be secondary to the sequelae of neurologic injury or disease but may also result from any process that destroys the elastic or viscoelastic properties of the bladder wall. Purely sensory urgency may result from inflammatory, infectious, neurologic, or psychological factors, or it may be idiopathic. A fixed decrease in outlet resistance may result from degeneration of or damage to innervation of the structural elements of the smooth or striated sphincter or from neurologic disease or injury, surgical or other mechanical trauma, or aging. Classic stress urinary incontinence (SUI) or genuine SUI in women implies a failure of the normal transmission of increases in intra-abdominal pressure to the area of the bladder neck and proximal urethra due to changes in the anatomic position of the vesicourethral junction and proximal urethra during increases in intra-abdominal pressure (hypermobility). The pathophysiology of SUI may also involve a decrease in the reflex striated sphincter contraction, which occurs with a number of maneuvers that increase intra-abdominal pressure. Treatment of abnormalities related to the filling or storage phase of micturition are directed toward inhibiting bladder contractility, increasing bladder capacity, decreasing sensory input during filling, or increasing outlet resistance, either continuously or only during abdominal straining.

DECREASING BLADDER CONTRACTILITY

Anticholinergic Agents

Physiologic bladder contractions are thought to be primarily triggered by acetylcholine-induced stimulation of postganglionic parasympathetic muscarinic cholinergic receptor sites on bladder smooth muscle.^1,⁵ Atropine and atropine-like agents should depress normal bladder contractions and IVCs of any cause.⁶^–⁸ In patients taking such agents, the volume accumulated before the first IVC is generally increased, the amplitude of the IVC is decreased, and the maximum bladder capacity is increased. However, although the volume and pressure thresholds at which an IVC is elicited may increase, the “warning time” (the time between perception of an IVC about to occur and its occurrence) and the ability to suppress an IVC are not increased. Therefore, urgency and incontinence still occur unless such therapy is combined with a regimen of timed voiding or toileting. McGuire and Savastano⁹ reported that atropine increased both the compliance and the capacity of the neurologically decentralized primate bladder.¹⁰ However, the effect of pure antimuscarinics in those who exhibit only decreased compliance has not been well studied. Outlet resistance, at least as reflected by urethral pressure measurements, does not seem to be clinically affected by anticholinergic therapy.

Although antimuscarinic agents can produce significant clinical improvement in patients with IVCs and associated symptoms, only partial inhibition results. In many animal models, atropine only partially antagonizes the response of the whole bladder to pelvic nerve stimulation and of bladder strips to field stimulation, although it does completely inhibit the response of bladder smooth muscle to exogenous cholinergic stimulation. Of the theories proposed to explain this phenomenon, termed atropine resistance, the most attractive and most commonly cited is the idea that a portion of the neurotransmission involved in the final common pathway of bladder contraction is nonadrenergic noncholinergic (NANC)—that is, it occurs secondary to a release of a transmitter other than acetylcholine or noradrenaline.^1,^2,⁵ Although the existence of atropine resistance in human bladder muscle is by no means agreed on, this concept is the most common hypothesis invoked to explain clinical difficulty in abolishing IVCs with anticholinergic agents alone, and it is also used to support the rationale of treatment of such types of bladder activity with agents that have different mechanisms of action. Brading^11,¹² and Andersson⁵ both discussed the difficulty of evaluating apparently conflicting data in the literature with respect to atropine resistance. Brading¹² stated that the size of the atropine-resistant component varies markedly among species and, in a given preparation, also depends on the frequency of nerve stimulation. Andersson⁵ stated that “most probably normal human detrusor muscle exhibits little atropine resistance,” but that this does not exclude its existence in morphologically or functionally abnormal bladders.

At least five different genetically established muscarinic subtypes (M₁ through M₅) exist, as determined by cloning experiments ¹³; the cholinergic muscarinic receptor genes are designated CHRM1 through CHRM5. The protein products of the M₁ through M₄ subtypes have been defined pharmacologically with the use of receptor subtype agonists and antagonists.^5,^14,¹⁵ A physiologic role for the product of the M₅ coding region remains undefined.¹⁵ Pirenzepine (a selective muscarinic blocker) was originally used to subdivide muscarinic receptors into M₁ and M₂ categories; using this subclassification, detrusor muscarinic receptors were classified as the M₂ type.^5,^16,¹⁷ On further analysis of the M₂ receptor population, a small proportion of glandular M₂ receptors were found which could represent the pharmacologic type responsible for muscarinic agonist-induced contractions. This subtype is now called the M₃ receptor.^5,¹⁴ Although it appears that the majority of the muscarinic receptors in human smooth muscle, including bladder, are of the M₂ subtype,¹⁸ in vitro data indicate that most smooth muscle contraction, including that of the urinary bladder, is mediated by the M₃ receptor subtype.^18,¹⁹ Muscarinic receptor subtyping becomes important when considering the possibility of pharmacologically selecting (and blocking) those receptors responsible for urinary bladder smooth muscle contraction while minimally affecting other muscarinic receptor sites throughout the body. Ideally, this approach would effectively treat the underlying problem (DO) while eliminating the unpleasant systemic side effects of most nonspecific antimuscarinic agents (e.g., dry mouth, constipation, blurred vision), which, in many cases, are worse than the problem they are treating and result in patient noncompliance.

Specific Drugs

Propantheline bromide is the classically described oral agent used for producing an antimuscarinic effect in the lower urinary tract. The usual adult oral dose is 15 to 30 mg every 4 to 6 hours, although higher doses are often necessary. Propantheline is a quaternary ammonium compound that is poorly absorbed after oral administration. No available oral drug has a direct in vitro antimuscarinic binding potential that is closer to that of atropine than propantheline bromide.^20,²¹ There is a surprising lack of valuable data on the effectiveness of propantheline for the treatment of bladder overactivity. As Andersson pointed out,⁸ anticholinergic drugs in general have been reported to have both great and poor efficacy for this indication. Zorzitto and colleagues²² concluded that propantheline bromide administered orally in doses of 30 mg four times a day to a group of institutionalized incontinent geriatric patients had marginal benefits that were outweighed by the side effects. Blaivas and colleagues,⁷ on the other hand, increased the dose of propantheline (up to 60 mg four times a day) until incontinence was eliminated or side effects precluded further use and obtained a complete response in 25 of 26 patients with IVCs. Differences in bioavailability, selective drug delivery, receptor selectivity, receptor density, atropine resistance, pathophysiology, susceptibility to dose-limiting side effects, and mental status are all potential factors that could explain such disparate results. The Agency for Health Care Policy and Research (AHCPR) Clinical Practice Guidelines²³ listed five randomized controlled trials for propantheline, in which 82% of the patients were women. The percentage of cure was listed as ranging from zero to 5%, reduction in urge incontinence from zero to 53%, side effects from zero to 50%, and dropouts from zero to 9% (all figures refer to overall percentage minus percentage on placebo).

Atropine is reported to be available in a 0.5-mg tablet, although we have yet to find it. Atropine and all related belladonna alkaloids are well absorbed from the gastrointestinal tract. Atropine is said to have almost no detectable central nervous system (CNS) effects at clinically used doses.²⁴ It has a half-life of about 4 hours.

Scopolamine is another belladonna alkaloid marketed as a soluble salt. It has prominent central depressive effects at low doses, probably because of its greater penetration (compared with atropine) through the blood-brain barrier. Transdermal scopolamine has been used for treatment of IVCs.²⁵ The “patch” provides continuous delivery of 0.5 mg daily to the circulation for 3 days. Cornella and associates,²⁶ however, reported poor results with this dosage in 10 patients with DO: only 2 patients showed a positive response; 1 showed a slight improvement, and the drug was discontinued in 8 patients because of side effects. Side effects were related to the CNS (ataxia, dizziness) and included blurred vision and dry mouth. A double-blind placebo-controlled study using transdermal scopolamine was performed on 20 patients with DO: after a 14-day treatment period, the 10 patients randomized to transdermal scopolamine treatment showed statistically significant improvements in frequency, nocturia, urgency, and urge incontinence compared with the placebo group; no adverse effects of the therapy were reported.²⁷ A double-blind placebo study on the effects of transdermal scopolamine in patients who had undergone suprapubic prostatectomy was performed to investigate its use in the treatment or prevention of pain, IVCs, urgency, and bladder pressure rises of 15 cm H₂O. No statistical differences were found.²⁸ In our experience of treating IVCs with this method, results were very erratic, and skin irritation with the patch was a problem for some patients. Because of the fixed dose, caution should be exercised in the use of the patch in elderly and young patients.

Hyoscyamine and hyoscyamine sulphate are reported to have anticholinergic actions and side effects similar to those of other belladonna alkaloids. Hyoscyamine sulphate is available as a sublingual formulation, a theoretical advantage, but controlled studies of its effects on bladder overactivity are lacking. Glycopyrrolate is a synthetic quaternary ammonium compound that is a potent inhibitor of both M₁ and M₂ receptors but has a preference for the M₂ subtype.²⁹ It is available in both oral and parenteral preparations; the latter is commonly used as an antisialagogue during anesthesia. An anticholinergic agent with a significant ganglionic-blocking action as well as such action at the peripheral receptor level might be more effective in suppressing bladder contractility. Although methantheline has a higher ratio of ganglionic blocking to antimuscarinic activity than does propantheline, the latter drug seems to be at least as potent in each respect, clinical dose for dose. Methantheline does have similar effects on the lower urinary tract, and some clinicians still prefer it over other anticholinergic agents. Few solid data are available regarding its efficacy.

The potential side effects of all antimuscarinic agents include inhibition of salivary secretion (dry mouth), blockade of the ciliary muscle of the lens to cholinergic stimulation (blurred vision for near objects), tachycardia, drowsiness, and inhibition of gut motility. Those agents that possess some ganglionic-blocking activity may also cause orthostatic hypotension and erectile dysfunction at high doses (at which nicotinic activity becomes manifest). Antimuscarinic agents are contraindicated in patients with narrow-angle glaucoma and should be used with caution in patients with significant bladder outlet obstruction, because complete urinary retention may be precipitated.

A lack of selectivity is a major problem with all antimuscarinic compounds, because they tend to affect parasympathetically innervated organs in the same order; in general, larger doses are required to inhibit bladder activity than to affect salivary, bronchial, nasopharyngeal, and sweat secretions. Several new receptor antagonists with varying degrees of specificity for the lower urinary tract show some promise in decreasing the side effect profiles of this class of medications without compromising efficacy.

Tolterodine and its primary metabolite, PNU-200577,³⁰ have shown some selectivity for bladder tissue over salivary tissue in in vitro and in vivo studies in the anesthetized cat.^31,³² These tissue-selective effects do not appear to be related to muscarinic receptor subtype selectivity^30,³¹ but may be the result of differential affinities of the receptors in the salivary gland and detrusor muscle for tolterodine compared with oxybutynin. Although it appears that the binding affinity of tolterodine and oxybutynin to muscarinic receptors in the urinary bladder (in the guinea pig) are very similar, the affinity of tolterodine for muscarinic receptors in the parotid gland is eight times lower than that of oxybutynin.³³ Tolterodine is available in two formulations: an immediate-release (IR) form (2 mg twice daily) and an extended-release (ER) form (2 mg or 4 mg once daily).

In a pilot study in 12 healthy men, tolterodine was shown to have a greater objective and subjective effect on bladder function than on salivation.³⁴ Jonas and colleagues³⁵ looked at the urodynamic effects of tolterodine in a multicenter, randomized, double-blind, placebo-controlled study: 242 patients were enrolled and treated over a 4-week period with 1 or 2 mg tolterodine or placebo twice daily. Compared with placebo, 2 mg tolterodine (but not 1 mg) produced statistically significant improvements in mean volume to first IVC (from 141 to 230 mL in the 2-mg group, 142 to 210 mL in the 1-mg group, and 140 to 181 mL in the placebo group), mean maximal strength of IVC (52 to 37 cm H₂O, 41 to 35 cm H₂O, and 47 to 40 cm H₂O in the three groups, respectively), and maximal cystometric capacity (272 to 316 mL, 276 to 294 mL, and 264 to 268 mL, respectively). The proportion of adverse effects in the treated groups, compared with placebo, was not statistically significant; however, dry mouth, the most common event, was reported in 9% of treated patients, significantly less than the 50% incidence reported in the literature for other commonly used anticholinergic preparations.³⁶ Furthermore, the dry mouth was classified as “severe” by only 1% of patients. At higher doses, the incidence of side effects of tolterodine may be more significant and may approach that of other commonly used anticholinergic drugs.

Rentzhog and colleagues ³⁷ noted that, at a dose of 2 mg or less, the incidence of adverse effects (including dry mouth) due to tolterodine was comparable to that of placebo (2/13 patients in the placebo group versus 9/51 patients in the tolterodine group reported dry mouth); however, when the dose of tolterodine was increased to 4 mg, a substantial increase in the incidence of dry mouth occurred (9/16 patients). Overall, it appears that tolterodine is safe and efficacious for the treatment of DO. A favorable side-effect profile exists at lower doses (less effect on salivary glands), which may diminish in a dose-dependent fashion.

There have been have been several randomized controlled studies documenting the effectiveness of tolterodine in reducing micturition frequency and incontinence episodes.^38,³⁹ There have also been comparative trials comparing it to other agents.

The Overactive Bladder: Judging Effective Control and Treatment (OBJECT) trial performed by Appell and colleagues ⁴⁰ compared tolterodine IR 2 mg twice daily to oxybutynin ER 10 mg daily. This was a randomized, double blind, parallel-group study that included 378 patients with OAB. Patients were treated for 12 weeks. The outcome measures included number of episodes of urge incontinence, total incontinence, and micturition frequency. The study showed oxybutynin ER to be significantly more effective than tolterodine in each of the outcome measures when adjusted for baseline. The most common adverse event was dry mouth, which was reported by 28% and 33% of those taking oxybutynin ER and tolterodine IR, respectively. Rates of other adverse events including CNS side effects were generally low and comparable between the two groups.

In the Overactive Bladder: Performance of Extended Release Agents (OPERA) study, Diokno and colleagues ⁴¹ compared tolterodine ER 4 mg daily to oxybutynin ER 10 mg daily in 790 women with OAB symptoms. This too was a randomized, double-blind study with a duration of 12 weeks. Patients kept 24-hour voiding diaries to document the number of incontinence episodes (primary outcome), total incontinence, and micturition frequency at weeks 2, 4, 8, and 12. Improvements in weekly urge incontinence episodes were similar between the two treatment groups. Oxybutynin ER was more effective in reducing micturition frequency, and 23.0% of women taking it reported no episodes of urinary incontinence, compared with to 16.8% of women taking tolterodine ER. Dry mouth was more common in the oxybutynin ER group, with both groups having similar discontinuation rates. The conclusions were that the two drugs had similar reductions in weekly urge incontinence and total incontinence episodes. Those taking oxybutynin ER had more dry mouth, but the tolerability between the two drugs was comparable.

In the Antimuscarinic Clinical Effectiveness Trial (ACET), Sussman and Garely ⁴² performed an open-label trial in patients with OAB comparing tolterodine ER 2 mg or 4 mg to oxybutynin ER 5 mg or 10 mg. A total of 1289 subjects participated in the study. After 8 weeks, 70% of patients taking tolterodine ER 4 mg perceived an improved bladder condition, compared with about 60% in the other groups. There were fewer withdrawals from the study in the tolterodine ER 4 mg group (12%) than in either the oxybutynin ER 5 mg group (19%) or the oxybutynin 10 mg group (21%). Patients taking tolterodine ER 4 mg reported significantly less dry mouth than those taking oxybutynin ER 10 mg. Although the findings suggest that tolterodine ER 4 mg may have improved clinical efficacy and tolerability compared with oxybutynin ER 10 mg, the open-label design of this study makes for a less convincing conclusion.

Zinner and colleagues ⁴³ performed a 12-week randomized, double-blind, placebo-controlled study to evaluate the efficacy, safety, and tolerability of tolterodine ER in treating OAB symptoms in older (≥65 years) and younger (<65 years) patients. Objective measures by micturition diaries as well as subjective measures were evaluated. There were significant improvements among patients taking tolterodine ER in micturition chart variables, compared with placebo. There were no age-related differences. Dry mouth was the most common adverse event in both arms. No CNS or cardiac events were seen. Tolterodine ER appeared to be well tolerated by both age groups.

Freeman et al ⁴⁴ presented a secondary analysis of a double-blind, placebo-controlled study looking at the effects of tolterodine ER 4 mg on the symptoms of urinary urgency in patients with OAB. A total of 772 patients with eight or more micturitions per 24 hours and urge incontinence (≥5/week) were randomized to drug or placebo therapy and treated for 12 weeks. Efficacy was assessed by using patient perception evaluations. Patients taking tolterodine ER 4 mg had a greater improvement in urgency (44% versus 32%) and bladder symptoms (62% versus 48%) than those taking placebo. Patients taking tolterodine ER 4 mg were also significantly more likely to hold their urine after experiencing urgency.

Recently, several pharmacologic agents have been approved by the Food and Drug Administration (FDA) for use in the United States. Darifenacin, a tertiary amine, is a selective muscarinic M₃ receptor antagonist. Its theoretical advantage is its ability to selectively block the M₃ receptor, which is the most important subtype in bladder contraction, and thereby decrease the adverse events related to blockade of other muscarinic subtypes.

Darifenacin has been studied in several randomized controlled studies. Haab and colleagues performed a multicenter, randomized, double-blind, placebo-controlled study comparing darifenacin 3.75 mg, 7.5 mg, 15 mg, and placebo once daily.⁴⁵ The treatment period was 12 weeks. Using an electronic voiding diary, patients recorded daily incontinence episodes, micturition frequency, volume voided, frequency and severity of urgency, incontinence episodes necessitating a change of clothing or pads, and nocturnal awakenings due to bladder symptoms. The 7.5- and 15-mg doses of darifenacin had a quick onset of action, with significant improvements over placebo being seen at week 2. The clinical parameters in which the treatment arm were significantly better than placebo included improvements in micturition frequency, bladder capacity, frequency of urgency, severity of urgency, and number of incontinence episodes. No significant change occurred in nocturnal awakening due to bladder symptoms. The most common side effects seen were mild-tomoderate dry mouth and constipation. No patients withdrew from the study due to dry mouth, and the discontinuation rate due to constipation was rare (0.9% for darifenacin versus 0.6% for placebo). The CNS and safety profile were similar for darifenacin and placebo.

An analysis of the pooled data from phase 3 trials was performed by Chapple and associates.⁴⁶ A total of 1059 patients (85% female) with symptoms of urgency, urge incontinence, and frequency were randomized to into three arms: darifenacin 7.5 mg, darifenacin 15 mg, or placebo daily for 12 weeks. Once again, patient voiding diaries were maintained electronically. The parameters monitored included incontinence episodes, frequency and severity of urgency, micturition frequency, and volume voided. Compared to baseline, there was a significant dose-related decrease in the number of incontinence episodes per week, with darifenacin 7.5 mg reducing episodes by 8.8, and darifenacin 15 mg reducing episodes by 10.6 per week. Significant decreases in the frequency and severity of urgency, micturition frequency, and number of incontinent episodes requiring a change of clothing or pads were seen, as well as an increase in bladder capacity. Although the most common side effect was dry mouth, this led to few discontinuations (darifenacin 7.5 mg, 0.5%; darifenacin, 15 mg, 2.1%; placebo, 0.3%), and the incidence of CNS and cardiovascular adverse events was similar to placebo.

Cardozo and colleagues ⁴⁷ performed a study to determine the effects of darifenacin on “warning time,” or the ability of the medication to allow patients to postpone micturition once urge was sensed. This was a multicenter, randomized, double-blind, placebo-controlled study with a 2-week treatment phase of darifenacin 30 mg daily or placebo. Darifenacin treatment resulted in a significant increase in the mean warning time (median increase, 4.3 minutes) compared with placebo. Overall, 47% of darifenacin-treated subjects and 20% of those receiving placebo achieved a greater than 30% increase in mean warning time. Although this study used a higher than usual dose of therapeutic agent and the treatment period was short, it was the first to evaluate changes in warning time. This effect may be particularly germane to patients with severe symptoms of urgency and urge incontinence.

Solifenacin (YM-905) is a tertiary amine, once-daily antimuscarinic. It is well absorbed from the gastrointestinal tract and undergoes significant hepatic metabolism by the cytochrome P450 enzyme system. There have been several large trials examining the effects of solifenacin.

Chapple and colleagues performed a multinational study comparing various does of solifenacin (2.5, 5, 10, and 20 mg) to tolterodine IR 2 mg twice daily and placebo ⁴⁸ in patients with OAB. A total of 225 patients were treated for 4 weeks and monitored for an additional 2 weeks. To be included in the study, all patients had to have at least eight micturitions in 24 hours and one episode of incontinence or one episode of urgency daily, as recorded by a 3-day voiding diary. Micturition frequency was the primary outcome. In patients treated with solifenacin, there was a statistically significant reduction in micturition frequency for those taking 5, 10, or 20 mg. This was not seen in the other two arms of the study. Additionally, these doses of solifenacin, when compared with placebo, resulted in a significant increase in volume voided and a reduction in episodes of frequency and incontinence. The onset of action was rapid, occurring at 2 weeks, the earliest follow-up point in the study. Discontinuation rates were similar among the various treatments except for solifenacin 20 mg, which was higher. The 5- and 10-mg doses of solifenacin had a lower rate of dry mouth than tolterodine did.

Another dose-ranging, placebo-controlled study of solifenacin 2.5 to 20 mg, was performed by Smith and colleagues in the United States.⁴⁹ The treatment duration was 4 weeks, with 2 weeks of follow-up. There was a significant reduction in micturition frequency in the solifenacin 10-mg and 20-mg groups, compared with placebo. The onset of efficacy was seen at 7 days, with continued improvement at 28 days. Significant increases in volume voided were seen in those taking 5, 10, or 20 mg of solifenacin. The 10 mg solifenacin dose also had a significant decrease in incontinent episodes.

There were four phase 3 trials to evaluate efficacy, safety, and tolerability of solifenacin in adult patients with OAB. The primary outcome in all the studies was 24-hour micturition frequency. Secondary outcomes included change in number of urgency and incontinence episodes and mean volume voided.

Chapple and colleagues ⁵⁰ performed a multicenter, randomized, placebo-controlled and tolterodine-controlled study. Subjects were treated for 12 weeks with solifenacin 5 mg daily, solifenacin 10 mg daily, tolterodine IR 2 mg twice daily, or placebo. Both doses of solifenacin resulted in a significant decrease in urgency episodes at 24 hours, compared with placebo, but tolterodine did not. In the solifenacin group, there was a significant decrease in incontinence episodes; and the mean number of voids in 24 hours was significantly lower in all three active treatment arms. As with most antimuscarinics, the most common side effect was dry mouth, occurring in 14% in the solifenacin 5 mg group and in 21.3% of the solifenacin 10 mg group.

Cardozo and colleagues ⁵¹ performed a multicenter randomized, placebo-controlled study comparing solifenacin 5 mg and 10 mg once daily with placebo. They found that both of the doses significantly improved frequency compared with placebo. Solifenacin was also better than placebo in improving urgency, increasing volume voided, and decreasing incontinence episodes over 24 hours. The reduction in urgency was slightly greater than 50% for both doses of solifenacin, whereas placebo resulted in a reduction of 33%. The percentage increases in voided volume per micturition were 25.4%, 29.7%, and 11% for solifenacin 5 mg, 10 mg, and placebo, respectively. The percentage decreases in overall incontinence episodes were 60.7%, 51.9%, and 27.9%, respectively. Only a small percentage of patients (2% to 4%) did not complete the study due to adverse events, which were comparable in all groups. The incidence of dry mouth was 2.3%, 7.7%, and 23.1% in placebo, solifenacin 10 mg, and solifenacin 20 mg groups, respectively. There were no changes in electrocardiographic parameters.

Two double-blind trials of solifenacin were performed ⁵² in the United States, in which a total of 1208 patients participated. Findings included a reduction in the number of micturitions per 24 hours, a decrease in the number of incontinence and urgency episodes per 24 hours, and an increase in the volume voided per micturition. Among patients who were incontinent at baseline, a significant percentage of those taking solifenacin became continent, compared to those taking placebo (53% versus 31%, respectively).

Musculotropic Relaxants

Musculotropic relaxants affect smooth muscle directly at a site that is metabolically distal to the cholinergic or other contractile receptor mechanism. Although the agents discussed in this section do relax smooth muscle in vitro by papaverine-like (direct) action, all have also been found to possess variable anticholinergic and local-anesthetic properties. There is still some uncertainty about how much of their clinical efficacy is due only to their atropine-like effect. If, in fact, any of these agents do exert a clinically significant inhibitory effect that is independent of antimuscarinic action, a therapeutic rationale exists for combining them with a relatively pure anticholinergic agent.

Oxybutynin chloride is a moderately potent anticholinergic agent that has strong independent musculotropic relaxant activity as well as local-anesthetic activity. The recommended oral adult dose is 5 mg three or four times a day; side effects are antimuscarinic and dose-related. Initial reports documented success in depressing neurogenic DO,⁵³ and subsequent reports documented success in inhibiting other types of bladder overactivity as well.⁸ A randomized double-blind, placebo-controlled study comparing 5 mg oxybutynin three times a day with placebo in 30 patients with DO was carried out by Moisey and colleagues: 17 of 23 patients who completed the study with oxybutynin had symptomatic improvement, and 9 showed evidence of urodynamic improvement, mainly an increase in maximum bladder capacity.⁵⁴ Hehir and Fitzpatrick⁵⁵ reported that 16 of 24 patients with neuropathic voiding dysfunction secondary to myelomeningocele were cured or improved (17% dry, 50% improved) with oxybutynin treatment; average bladder capacity increased from 197 to 299 mL with oxybutynin compared to 218 mL with placebo, and maximum bladder filling pressure decreased from 47 to 37 cm H₂O with oxybutynin versus 45 cm H₂O with placebo. In a prospective randomized study of 34 patients with voiding dysfunction secondary to multiple sclerosis, Gajewski and Awad⁵⁶ found that 5 mg oral oxybutynin three times a day produced a good response more frequently than 15 mg propantheline three times a day; they concluded that oxybutynin was more effective in the treatment of neurogenic DO secondary to multiple sclerosis. Holmes and associates⁵⁷ compared the results of oxybutynin and propantheline in a small group of women with DO. The experimental design was a randomized crossover trial with a patient-regulated variable-dose regimen. This kind of dosetitration study allows the patient to increase the drug dose to whatever she perceives to be the optimum ratio between clinical improvement and side effects—an interesting way of comparing two drugs while minimizing differences in oral absorption. Of the 23 women in the trial, 14 reported subjective improvement with oxybutynin as opposed to 11 with propantheline. Both drugs significantly increased the maximum cystometric capacity and reduced the maximum detrusor pressure on filling. The only significant objective difference was a greater increase in the maximum cystometric capacity with oxybutynin. The mean total daily dose of oxybutynin tolerated was 15 mg (range, 7.5 to 30 mg), and that of propantheline was 90 mg (range, 45 to 145 mg).

Thuroff and colleagues ⁵⁸ compared oxybutynin with propantheline and placebo in a group of patients with symptoms of instability and either neurogenic and non-neurogenic DO. Oxybutynin (5 mg three times a day) performed best, but propantheline was used at a relatively low dose (15 mg three times a day). The incidence of side effects was higher for oxybutynin at approximately the level of clinical and urodynamic improvement. The mean grade of improvement on a visual analogue scale was higher for oxybutynin (58.2%) than for propantheline (44.7%) or placebo (43.4%). Urodynamic volume at the first IVC increased more with oxybutynin (51 mL, versus 11.2 mL for propantheline and 9.7 mL for placebo), as did the change in maximum cystometric capacity (80.1, 48.9, and 22.5 mL, respectively). Residual urine volume also increased more (27.0, 2.2, and 1.9 mL, respectively). The authors further subdivided their overall results into the categories of excellent (>75% improvement), good (50% to 74%), fair (25% to 49%), and poor (<25%). Results for treatment with oxybutynin were 42% excellent, 25% good, 15% fair, and 18% poor. The authors concluded that their 67% rate of good or excellent results compared favorably with those reported in seven other oxybutynin series in the literature (some admittedly poorer studies included), which ranged from 61% to 86%. The results of propantheline treatment generally ranked between those of oxybutynin and placebo but did not reach significant levels over placebo in any variable. Subdivision of propantheline results into excellent, good, fair, and poor categories yielded percentages of 20%, 30%, 14%, and 36%, respectively. The 50% ratio of good or excellent results were consistent with those achieved in six other propantheline studies reported in the literature (30% to 57%). Although this study was better than most in the literature, it did have drawbacks, and anyone using it in a meta-analysis would be well advised to read it and the other cited studies very carefully.

Zeegers and colleagues ⁵⁹ reported on a double-blind, prospective, crossover study comparing oxybutynin, flavoxate, emepronium, and placebo. Although there was a high dropout rate (19 of 60 patients) and the entry criteria were vague (frequency, urgency, urge incontinence), the results, scored as 5 (excellent overall effect) to 1 (no improvement) by both patient and physician, were combined into a single number. The percentages of results in categories 3 to 5 for the agents used were oxybutynin, 61%; placebo, 41%; emepronium, 34%; and flavoxate, 31%. The results of the first treatment gave corresponding percentages of only 63%, 29%, 18% (probably reflecting eight dropouts due to side effects), and 44%, respectively.

Ambulatory urodynamic monitoring and pad weighing were used to assess the effects of oxybutynin on DO by Von Doorn and Zwiers.⁶⁰ The 24-hour average frequency of IVCs decreased from 8.7 to 3.4; the maximum contraction amplitude decreased from 32 to 22 cm H₂O, and the duration of the average IVC decreased from 90 to 60 seconds. However, the daily micturition frequency did not change (11 to 10), nor did the amount of urine lost—findings the authors tried to minimize by pointing out that some patients also had sphincteric incontinence and that, during treatment, there may have been a higher fluid intake.

The AHCPR guidelines ²³ list six randomized controlled trials for oxybutynin; 90% of patients were women. The percentage of cure was listed as ranging from 28% to 44%, reduction in urge incontinence from 9% to 56%, side effects from 2% and 66%, and dropouts from 3% to 45% (all figures refer to overall percentage minus percentage on placebo). There were some negative reports on the efficacy of oxybutynin. Zorzitto and colleagues⁶¹ came to conclusions similar to those resulting from their study of propantheline in a double-blind placebo-controlled trial conducted in 24 incontinent geriatric institutionalized patients: oxybutynin 5 mg twice a day was no more effective than placebo with scheduled toileting in treating incontinence in this type of population with DO. An incontinence profile was used to assess results, and the only significant difference noted was an increase in residual urine volume (from 159 to 92 mL). Ouslander and colleagues ⁶² reported similar conclusions in a smaller study of geriatric patients, and in an accompanying article they concluded simply that the drug is safe for use in the elderly at doses of 2.5 to 5 mg three times a day.^62,⁶³

An ER form of oxybutynin is available that releases the active compound over a period of 24 hours. Aside from the ease of once-daily administration, the potential benefit of the ER formulation is that stabilization of serum levels throughout the day should lower the incidence of side effects.⁶⁴ Another theoretical advantage may be that less absorption occurs in the proximal portion of the gastrointestinal tract which drains into the portal system, so there is less first-pass metabolism.

IR and ER oxybutynin were compared in a multicenter randomized, double-blind trial of 106 patients, all of whom had previously responded to IR oxybutynin.⁶⁵ For patients currently taking anticholinergic therapy, after a 1-week washout period, a dose-titration schedule was used to reach the maximum allowable dose (20 mg IR or 30 mg ER daily), or to the dose at which no urge urinary incontinence (UUI) episodes occurred over the course of 2 days (as measured from a diary) or until a dose was reached with intolerable side effects (at which point, the final dose was decreased by 5 mg). Thirteen patients discontinued therapy during the trial, four because of anticholinergic events. Overall, similar efficacy was noted for both formulations of oxybutynin in overall number of episodes (27.4 to 4.8 for ER and 23.4 to 3.1 for IR), in the percentage decrease in weekly UUI episodes (84% for ER and 88% for IR), and in overall incontinence episodes (urge, stress, and mixed). The number and proportion of patients achieving continence was also similar between the groups (41% for ER, and 40% for IR). Curiously, voiding frequency increased in both groups, with a statistically significant percentage increase of voiding frequency in patients receiving the ER compared with those receiving the IR formulation (54% versus 17%; P < .001). Anticholinergic side effects were noted in both groups. Dry mouth was the most frequent symptom, occurring in a majority of patients. Dry mouth was reported as moderate or severe by 25% and 46% of patients receiving the ER and IR formulations, respectively (P = .03). Other anticholinergic side effects were reported with similar frequency in the ER and IR groups: somnolence (38% versus 40%), blurred vision (28% versus 17%), constipation (30% versus 31%), dizziness (28% versus 38%), impaired urination (25% versus 29%), nervousness (25% versus 23 %), and nausea (19% versus 17%).

In an open-label trial ⁶⁶ with 256 patients (23.4 % of whom were taking an anti-incontinence medication at baseline and switched over to oxybutynin ER for the study), oxybutynin ER reduced the number of incontinence episodes per week from 18.8 at baseline to 2.8 at the end of the study (83.1% reduction); 31% of patients remained free of UUI throughout the study. A 14.7% reduction in voiding frequency was noted on therapy compared with baseline, as measured from the voiding diary. Dry mouth was reported by 58.6% of patients; 23.0% reported moderate or severe dry mouth. Only 1.6% of patients discontinued therapy because of dry mouth. Overall, 7.8% of patients discontinued therapy because of adverse events, of which nausea, dry mouth, and somnolence were most frequent.

Topical application of oxybutynin and other agents to normal or unstable bladders has been suggested and implemented.⁶⁷ This conceptually attractive form of alternative drug administration, delivered by periodic intravesical instillation of either liquid or timed-released pellets, awaits further clinical trials and the development of preparations specifically formulated for this purpose. Several nonrandomized, unblinded and non–placebo-controlled studies have demonstrated the efficacy of this therapy in a variety of patients with neurogenic bladders, showing statistically significant improvements in cystometric capacity, volume at first IVC, bladder compliance, and overall continence.⁶⁸^–⁷⁰

Madersbacher and Jilg reviewed the intravesical usage of 5 mg of oxybutynin dissolved in 30 mL distilled water in 13 patients with complete suprasacral cord lesions who were on clean intermittent catheterization.⁷¹ Of the 10 patients who were incontinent, 9 remained dry for 6 hours. For the group, the changes in bladder capacity and maximum detrusor pressure were statistically significant. Some of the more interesting data were given in a figure showing plasma oxybutynin levels for a group of patients in whom administration was intravesical or oral. The level achieved after an oral dose rose to 7.3 mg/mL within 2 hours and then precipitously dropped to slightly less than 2 mg/mL at 4 hours. After intravesical administration, the level rose gradually to a peak of about 6.2 mg/mL at 3.5 hours, but at 6 hours it was still greater than 4 mg/mL and at 9 hours it was still between 3 and 4 mg/mL. From these data, it is unclear whether the intravesically applied drug acted locally or systemically.

In a later study, Madersbacher and Knoll ⁷² administered oxybutynin intravesically and then, 1 week later, gave oxybutynin orally to six patients with neurogenic bladders in order to study the pharmacokinetics of the drug and investigate the pharmacologic properties responsible for its clinical effects. Serum drug levels were correlated with urodynamic effects 20 minutes and 2 hours after administration of the drug. The authors concluded that the main effect of intravesical oxybutynin was a result of systemic absorption; however, a secondary direct local effect (smooth muscle relaxation or topical anesthetic effect) could not be excluded.

Weese and colleagues ⁷³ reported use of a similar dose of oxybutynin (5 mg in 30 mL sterile water) to treat 42 patients with IVCs for whom oral anticholinergic therapy had failed (11 patients) or who had intolerable side effects (31 patients): 20 had neurogenic DO, 19 had non-neurogenic DO, and 3 had bowel or DO after augmentation. The drug was instilled two or three times each day for 10 minutes by catheter. Nine patients (21%) withdrew from the study because they were unable to tolerate clean intermittent catheterization or to retain the solution properly, but there were no reported side effects. Of the patients (33) who were able to follow the protocol, 18 (55%) reported at least a moderate subjective improvement in incontinence and urgency. Nine patients became totally continent and experienced complete resolution of their symptoms; 18 patients improved and experienced a decrease of 2.5 pads per day. There were no urodynamic data. Follow-up ranged from 5 to 35 months (mean, 18.4 months).

The lack of side effects prompted some speculation about the mechanism of drug action: one possibility was simply a more prolonged rate of absorption; another was a decreased pass through the liver and therefore a decrease in metabolites, the hypothesis being that perhaps the metabolites and not the primary compound are responsible for the side effects.

Enzelsberger and associates ⁷⁴ reported on the use of intravesical oxybutynin in the treatment of DO in 52 women. In the only published randomized, double-blind, placebo-controlled study of this intravesical administration, patients received once-daily intravesical oxybutynin (20 mg in 40 mL sterile water) or placebo for 12 days. The results revealed statistically significant differences in first desire to void (from 95 mL before treatment to 150 mL after treatment), cystometric capacity (205 to 310 mL), maximal pressure during filling (16 to 9 cm H₂O), daytime frequency (7.5 to 4), and nocturia (5.1 to 1.8). Side effects were similar in the treated and placebo groups (17% versus 10%, respectively). For unexplained reasons, 19 of 23 patients in the treated group continued to have symptomatic relief after termination of the study.

In an increasing effort to maintain or improve the efficacy of oxybutynin while minimizing its side effects, the use of transdermal oxybutynin has been investigated. In one study,⁷⁵ the daily-dose patch significantly reduced the number of weekly incontinence episodes while reducing average daily urinary frequency by increasing the average voided volume. Dry mouth rates were similar to those reported with placebo (7% versus 8.3%). A recent study⁷⁶ comparing transdermal oxybutynin and oxybutynin IR demonstrated equivalent reduction in incontinent episodes but significantly less dry mouth with the patch (38% versus 94%). In a third study,⁷⁷ transdermal oxybutynin was compared to placebo and tolterodine ER. The two drugs had similarly significant reduced daily incontinence episodes and increased voided volume, but tolterodine ER was associated with a higher rate of antimuscarinic adverse events. The major side effect for transdermal oxybutynin was pruritus at the application site in 14% and erythema in 8.3% of patients.

Dicyclomine hydrochloride is also reported to exert a direct relaxant effect on smooth muscle in addition to an antimuscarinic action.⁷⁸ An oral dose of 20 mg three times a day in adults has been reported to increase bladder capacity in patients with neurogenic DO.⁷⁹ Beck and coworkers⁸⁰ compared the use of 10 mg dicyclomine, 15 mg propantheline, and placebo three times a day in patients with DO⁸¹: the rates of cure or improvement were 62%, 73%, and 20%, respectively. Awad and associates⁸² reported that 20 mg dicyclomine three times a day caused resolution or significant improvement in 24 of 27 patients with IVCs.

Flavoxate hydrochloride has a direct inhibitory action on smooth muscle but very weak anticholinergic properties.^8,⁸³ In cats, at least, there is some evidence that flavoxate may also have central effects on the inhibition of the micturition reflex in addition to its effects on the relaxation of smooth muscle.⁸⁴ Clinical studies addressing the efficacy of flavoxate in the treatment of DO have been mixed. Milani and colleagues⁸⁵ performed a double-blind, crossover study comparing flavoxate 1200 mg/day with oxybutynin 15 mg daily in 41 women with idiopathic motor or sensory urgency, using clinical and urodynamic criteria. The two drugs had similar efficacy, with flavoxate having fewer side effects. However, Briggs and colleagues⁸⁶ reported that this drug had essentially no effect on non-neurogenic DO in an elderly population, an experience that coincides with the laboratory effects obtained by Benson and associates.⁸⁷ There were few reported side effects. Although the efficacy of flavoxate compared with other agents in this group has not been proven, a short clinical trial may be worthwhile.

Trospium and propiverine are classified as predominantly antispasmodic agents (smooth muscle relaxants) with some anticholinergic effects as well. Although both drugs have been used in Europe for years, trospium chloride has been recently approved by the FDA and is now available for use in the United States. It is a quaternary amine and has limited ability to cross the blood-brain barrier, therefore in theory leading to minimal cognitive dysfunction.⁸⁸^–⁹⁰ Trospium has no selectivity for a muscarinic subtype.

Several randomized controlled trials have shown the beneficial effects of trospium ^91,⁹² in both neurogenic and non-neurogenic DO.⁹³^–⁹⁷ Stohrer and colleagues performed a multicenter, placebo controlled, double-blind study to determine the effects of trospium on urodynamic parameters in patients with neurogenic DO secondary to spinal cord injury.⁹¹ Patients were randomized to either trospium 20 mg twice daily or placebo for 3 weeks. The treatment group showed an increase in maximum cystometric capacity, decreased maximal detrusor pressure, and increased compliance. No such effects were seen in the placebo group. A similar study by Madersbacher and coworkers⁹² compared the use of trospium and oxybutynin in the treatment of neurogenic DO. The two medications appeared to have equal effects, but those patients taking trospium had fewer side effects.

The effectiveness of trospium in the treatment of non-neurogenic DO has also been well documented. Allouis and colleagues ⁹³ performed a randomized, double-blind, placebo-controlled study in 309 patients with non-neurogenic DO. The treatment group received trospium 20 mg twice daily, and the study length was 3 weeks. They found a significant increase over placebo in volume at first involuntary detrusor contraction and in maximum bladder capacity. Cardozo and colleagues⁹⁴ also performed a randomized, placebo-controlled, double-blind study in patients with non-neurogenic DO. A total of 208 patients participated in the study and were given placebo or trospium 20 mg twice daily for 2 weeks. They similarly found an increase in volume at which the first involuntary detrusor contraction took place as well as an increase in maximum cystometric capacity.

In a study comparing the efficacy of trospium 20 mg twice daily with tolterodine 2 mg twice daily and placebo in patients with urodynamically proven DO, Junemann and colleagues found trospium to be significantly more effective in decreasing the frequency of micturition than either tolterodine or placebo.⁹⁵ Trospium was also found to cause a greater reduction in the number of incontinence episodes and produced similar rates of dry mouth as tolterodine.

Halaska and associates ⁹⁶ performed a long-term tolerability and efficacy study comparing trospium 20 mg twice daily and oxybutynin 5 mg twice daily in patients with DO. Patients were treated for 52 weeks. Urodynamic studies were performed at baseline, 26 weeks, and 52 weeks, and patient voiding diaries were also kept at baseline, 2, 26, and 52 weeks. A significant increase in mean maximum cystometric capacity was found, with 92 mL at 26 weeks and 115 mL at 52 weeks in the trospium group. No other significant difference in urodynamic parameters was noted between the two treatment groups. Voiding diaries revealed a decrease in frequency, frequency of incontinence, and urgency episodes in both groups. At least one adverse event occurred in patients (64.8% and 76.6% in the trospium and oxybutynin groups, respectively). The most common side effect in both groups was dry mouth. Overall, the two drugs were comparable in efficacy in improving urinary symptoms, but trospium had a better benefit-risk ratio than oxybutynin due to better tolerability.

In a large multicenter, placebo controlled, randomized, parallel study, Zinner and colleagues, from the Trospium Study Group,⁹⁷ compared the effects of trospium 20 mg twice daily and placebo in patients with OAB and urge incontinence. The study length was 12 weeks, with the primary end points being a change in the mean number of voids and a change in urge incontinent episodes in a 24-hour period. Other variables, such as mean volume per void, urge severity, diurnal and nocturnal micturition episodes, and onset of action, were also examined. Compared with placebo, trospium produced a significant reduction in the mean frequency of toilet voids and in urge incontinent episodes. A significant increase in volume voided and decrease in urge severity and diurnal frequency were also seen. The effects were seen after 1 week of treatment and were maintained throughout the remainder of the study. Once again, the most common side effect was dry mouth, occurring in 21.8% of patients, followed by constipation in 9.5% and headache in 6.5%. Similar results were confirmed by Rudy and colleagues⁹⁸ in a large multicenter study in the United States that included 658 patients.

Propiverine is a musculotropic smooth muscle relaxant with anticholinergic activity. It is rapidly absorbed and has a high first-pass metabolism.⁹⁹ Thuroff and associates¹⁰⁰ reviewed nine randomized studies on a total of 230 patients and found reductions in frequency and micturitions per 24 hours of 30% and 17%, respectively. There was a 77% subjective improvement, and side effects were found in 14% of the patients. In a study by Stohrer and colleagues,¹⁰¹ superiority of propiverine over placebo was documented in patients with neurogenic DO. In controlled trials comparing propiverine, flavoxate, and placebo or propiverine, oxybutynin, and placebo,¹⁰² they confirmed the efficacy of propiverine and suggested that the drug may have equal efficacy and fewer side effects than oxybutynin.

Madersbacher and colleagues ¹⁰³

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