Urinary Incontinence: Choices in Medical Therapy for the Overactive Bladder

ABSTRACT: Urge incontinence, also described as overactive bladder (OAB)-wet, affects millions of persons worldwide. The traditional therapy for this disease has been medical management, although refractory cases may be addressed with neuromodulation and augmentation cystoplasty. Recent advances in medical therapy include selective antimuscarinic agents that potentially decrease adverse effects and off-label botulinum toxin injection of the bladder. Nonsurgical modalities, including behavioral modification, pelvic floor muscle training, and biofeedback with or without electrical stimulation, can be used in conjunction with medication to optimize outcomes.

Urge incontinence, also referred to as overactive bladder (OAB)-wet, is the involuntary loss of urine accompanied by or immediately preceded by a sensation of urgency. It has a reported overall prevalence of 16.0% in men and 16.9% in women.¹ Currently, the mainstay of management for symptomatic urgency and OAB-wet is medical therapy.

In this article, we review the pathophysiology, evaluation, and different medical treatment options available for OAB-wet.

ETIOLOGY
Various causes for OAB and OAB-wet have been proposed. A neurogenic theory for the pathophysiology of OAB-wet is based on increased excitability of detrusor smooth muscle in the bladder.² This has been seen in several neurogenic disorders, including multiple sclerosis, stroke, spinal cord injury, transverse myelitis, and Parkinson disease. A myogenic theory attributes symptoms to alterations of the detrusor smooth muscle that lead to failure to store or failure to empty properly.³ The detrusor instability and overactivity lead to decreased compliance of the bladder secondary to structural and functional changes that may include infiltration of detrusor smooth muscle by elastin and collagen.⁴

Other proposed mechanisms for the pathophysiology of OAB-wet include inflammatory conditions and infection, or the condition may be idiopathic.⁵

EVALUATION
A detailed evaluation is essential before proceeding to treatment of patients with OAB-wet. History and physical examination should include assessment of comorbidities and concurrent medical conditions—such as multiple sclerosis or diabetes and history of urinary tract infections, previous pelvic surgery, and use of medications—and any evidence of vaginal atrophy or pelvic prolapse.

Review of the patient's medications is useful, because certain drugs, such as bethanechol and cisapride, can potentiate OAB-wet. Other agents (ie, α-blockers, benzodiazepines, and neuroleptics) can increase incontinence episodes by decreasing urethral resistance.⁶

A voiding diary is often helpful in assessing the degree of incontinence.⁷ Diaries include accounts of frequency, nocturia, and incontinence episodes; timing and amount of fluid intake; voids; and number of pads used per day; this information helps differentiate between frequency alone and high urine production with resultant frequency.

Patients in whom urodynamic studies may also be useful include those who present with mixed symptoms or underlying neurologic conditions or those in whom empiric medical therapy has failed. Important urodynamic parameters include bladder capacity, compliance, presence of detrusor overactivity with associated incontinence, and postvoid residual volumes (Figure).

In addition, cystoscopy to rule out bladder tumors or carcinoma in situ may be appropriate for a select group of patients.

TREATMENT
Medical therapy remains the standard for OAB and OAB-wet. Various nonsurgical modalities in addition to medications have been described, including behavioral modification, pelvic floor muscle training, and biofeedback with or without electrical stimulation. The latter options are often used in conjunction with medications to optimize outcomes.

Nonsurgical modalities. Behavioral modification is directed at improving voluntary control of bladder function to decrease urgency and may result in improvement rates in incontinence episodes in excess of 50%.^8,9 Pelvic floor muscle training has also been reported to help improve symptoms associated with bladder overactivity.¹⁰ There are subjective reports of improvement in patients with OAB-wet treated with biofeedback, with or without electrical stimulation. One study produced subjective improvement in 51.4% of patients treated with electrical stimulation and in 50% of those using biofeedback-assisted pelvic floor muscle training.^11,12

Medical therapy. Various medications have been used both exclusively and concomitantly with the aforementioned behavioral modifications. The foundation of medical therapy for OAB-wet remains the anticholinergic/antimuscarinic agents. Acetylcholine stimulates postganglionic muscarinic receptors in the bladder to initiate detrusor contraction and voiding. Five types of muscarinic receptors (M1-M5) mediate cognition, salivation, sympathetic output, ciliary muscle contraction in the eye, and GI motility. M2 and M3 receptors are the most pertinent receptors for bladder function. M2 receptors, which are most prevalent in the bladder, also mediate cardiac output; M3 receptors, which have the most selectivity for bladder contractions, are also present in the smooth muscle of the GI tract.¹³

Oxybutynin. The nonspecific muscarinic antagonists, or anticholinergics, act by antagonizing the muscarinic actions of acetylcholine on smooth muscle and by exerting a spasmolytic effect on the detrusor muscle.¹⁴ The most widely prescribed anticholinergic is oxybutynin, which is available in immediate-release, extended-release, and transdermal forms. In addition, off-label use has been described with intravesical oxybutynin.¹⁵

Oxybutynin is a nonselective tertiary amine ester that also provides local anesthetic properties. Cystometric studies have demonstrated that oxybutynin increases maximum bladder capacity and volume to first detrusor contraction.¹⁶ It also decreases urinary urgency and frequency of both incontinence episodes and voluntary urination.

Adverse effects associated with antimuscarinic agents are dose-related and include dry mouth, constipation, drowsiness, and blurred vision. The adverse effects associated with oxybutynin are thought to be related to the metabolite N-desethyloxybutynin, which is rendered via the cytochrome P-450 system.

The extended-release formulation of oxybutynin was developed to reduce the first-pass metabolism and rate of absorption.¹⁷ The decreased rate of absorption allows the medication to reach the colon, where cytochrome P-450-mediated oxidation is less extensive than in the small intestine. The incidence of dry mouth with extended-release oxybutynin was reduced by about 50% when compared with the immediate-release formulation, but the efficacy was comparable to immediate-release oxybutynin.^14,18,19

The transdermal system delivers oxybutynin continuously over a 3- to 4-day interval. Oxybutynin is transported across intact skin into the systemic circulation by passive diffusion across the stratum corneum. The average daily dose of oxybutynin absorbed from the 39-cm² transdermal oxybutynin system is 3.9 mg.²⁰ The transdermal route also bypasses first-pass metabolism, reducing the formation of the N-desethyloxybutynin metabolite.²¹

Contraindications to use of all formulations of oxybutynin include narrow-angle glaucoma, urinary or gastric retention, myasthenia gravis, or ulcerative colitis or other obstructive GI tract disease.

Tolterodine. Tolterodine is another competitive muscarinic receptor antagonist that demonstrates high affinity for muscarinic receptors without muscarinic receptor subtype selectivity. However, it has been shown to produce "bladder selectivity" by producing a more pronounced effect on acetylcholine-induced bladder contraction than on salivation.²²

Therapeutic efficacy of tolterodine has been reported to be equivalent to oxybutynin in that frequency and OAB-wet episodes were decreased and voided volume increased to a similar extent.²³

Tolterodine is also available in an extended-release formulation that provides sustained release of the drug for 24 hours. It therefore produces a flatter serum concentration-time profile than the immediate-release tablet formulation, which gives a time to peak concentration of 4 to 6 hours. Various studies have reported that the extended-release formulation is better tolerated than the immediate-release formulation, with a lower frequency of dry mouth.²⁴ In a large randomized, placebo-controlled study, 50% of patients treated with extended-release tolterodine had a greater than 71% reduction in incontinence.²⁵

The drug is metabolized hepatically via the cytochrome P-450 CYP2D6 and CYP3A4 subtypes to produce the active metabolite 5-hydroxymethyl. Approximately 7% of the US population have a deficiency of CYP2D6 and are poor metabolizers of tolterodine. Patients who have hepatic dysfunction should be treated with the lowest effective dose. Contraindications are similar to those of oxybutynin, including narrow-angle glaucoma, urinary or gastric retention, myasthenia gravis, or ulcerative colitis or other obstructive GI tract disease.

Solifenacin. Solifenacin succinate, which is given once daily, is a competitive muscarinic receptor antagonist with higher affinity for the M3 receptor subtype. Similar to the other anticholinergics, it is metabolized primarily by the liver, producing the active metabolite 4R-hydroxy solifenacin. The drug has an elimination half-life of approximately 50 hours (range, 45 to 68 hours). Phase 3 trials showed that solifenacin reduced urgency, incontinence, and frequency. It also increased mean bladder capacity by approximately 30% from baseline.²⁶

A prospective double-blind study that compared the efficacy and safety of solifenacin with tolterodine extended-release also showed greater efficacy in decreasing OAB, OAB-wet, and pad use and increasing the volume voided.²⁷ Adverse-effect profile and contraindications are similar to those of oxybutynin and tolterodine. Caution is encouraged when solifenacin is used with certain medications known to prolong the QT interval, such as quinidine, sotalol, and procainamide.

Trospium chloride. Trospium chloride is a quaternary amine muscarinic receptor antagonist that is given twice daily. It is predominantly a peripheral nonselective antimuscarinic that is not associated with CNS side effects because of its molecular structure, which does not permit the drug to cross the blood-brain barrier.²⁸ This is particularly appealing in elderly patients because of the decreased risk of cognitive impairment. There is slow absorption from the GI tract, with 80% of the drug excreted unchanged in the urine. Because only 15% is hepatically metabolized, there is no significant difference in pharmacokinetics in patients with hepatic impairment; thus, it can be administered to patients with liver disease. However, adjustment to once-daily dosing is required for patients with a creatinine clearance of less than 30 mL/min.

No drug-drug interactions have been reported.^29,30 One randomized placebo-controlled trial demonstrated a significant decrease in frequency of voids and OAB-wet episodes, as well as increased volume voided and decreased daytime and nighttime frequency compared with placebo.²⁸

Darifenacin. Darifenacin is a relatively new selective M3 receptor antagonist. It has a 59-fold selectivity for the M3 receptor that is most selective for bladder contraction. Darifenacin is well absorbed from the GI tract, and less than 2% of the drug is recovered in the feces. One randomized placebo-controlled trial demonstrated reduction in incontinence episodes of approximately 70% compared with placebo, as well as increase in bladder capacity, decrease in frequency and urgency episodes, and decrease in severity of urgency compared with placebo.³¹ Because of its receptor selectivity, darifenacin is associated with lower rates of blurred vision, cognitive impairment, and cardiac effects.³²

In another multicenter, double-blind, placebo-controlled trial that evaluated the efficacy, tolerability, safety, and flexible dose titration of darifenacin, Steers and colleagues³³ noted significantly lower rates of incontinence episodes with darifenacin than with placebo (262.9% and 248.1%, respectively). They also found significant improvement in frequency episodes and bladder capacity, with mild to moderate adverse effects similar to those of other antimuscarinic agents.³³ In addition, analysis of pooled data from three phase 3, multicenter, double-blind clinical trials showed that when patients increased the dose from 7.5 mg to 15 mg, they had an increase in efficacy but not an increase in side effects.³⁴

Tricyclic antidepressants. Tricyclic antidepressants, such as imipramine hydrochloride, have long been used in the management of OAB-wet. While the precise mechanism of action is unknown, it is thought to block norepinephrine reuptake (thereby increasing the amount available to stimulate α-adrenergic receptors), which increases bladder outlet resistance at the bladder neck. Its activity is also unique in that it has anticholinergic effects, which decrease bladder contractility, as well as local anesthetic effects.

Adverse effects may include cardiac dysrhythmias, sedation, weight gain, bloating, constipation, dizziness, headache, blurred vision, urinary retention, impotence, and possible psychiatric disturbances. Contraindications include concomitant use with monoamine oxidase inhibitors and use in patients who are recovering from acute myocardial infarction because of the risk of cardiac dysrhythmia.³⁵ Nevertheless, in the properly selected patient, tricyclic antidepressants are an excellent first-line option for management of mixed incontinence.

Propantheline. Propantheline is a synthetic quaternary ammonium compound that may be used as second-line therapy for management of OAB. One study of 42 patients evaluated cystometric changes with propantheline and showed a 79% positive response to propantheline that included elimination of uninhibited bladder contractions and increase in bladder capacity, although urinary retention occurred in half of the patients.³⁶ Contraindications to use include narrow-angle glaucoma, urinary or gastric retention, myasthenia gravis, ulcerative colitis or other obstructive GI tract disease, and unstable cardiac status in acute hemorrhage.³⁵

Hyoscyamine. Hyoscyamine is an anticholinergic with antispasmodic properties, and it is available in immediate-release, extended-release, and sublingual formulations. It also inhibits the muscarinic action of acetylcholine at parasympathetic sites in smooth muscle, secretory glands, and the CNS and may have vagolytic effects, including tachycardia.³⁵ Contraindications are similar to those of other anticholinergics.

Dicyclomine. Dicyclomine is an anticholinergic that is used primarily for irritable bowel syndrome. Because of its smooth muscle relaxant properties, there has been reported subjective improvement in urgency and OAB-wet.³⁵

Flavoxate. Bladder relaxation drugs or antispasmodics have also been used in the management of OAB. Flavoxate is a tertiary amine with antispasmodic activity similar to that of propantheline. It produces an increase in bladder capacity in patients with bladder spasticity, possibly as a result of direct spasmolytic effect on the detrusor muscle. It exerts smooth muscle relaxation via phosphodiesterase inhibition and possibly by calcium antagonistic activity.³⁷ Contraindications are similar to those of other anticholinergics and also include achalasia, GI hemorrhage, and pyloric or duodenal obstruction.³⁵

Botulinum toxin A. Botulinum toxin A has recently gained popularity in the management of refractory OAB-wet. While the toxin is not self-administered, it has proved effective in off-label management of OAB. It acts by blocking neuromuscular conduction by binding to receptor sites on motor nerve terminals, entering the nerve terminals, and inhibiting the release of acetylcholine. When injected intravesically into detrusor muscle, it produces a localized chemical denervation to the muscle.

Detrusor injections of botulinum toxin have been found to increase cystometric bladder capacity and decrease detrusor pressure.^38,39 Cystoscopic injections are given at a dose of 200 to 300 IU per session in 20 to 30 injections. Patients typically require repeated treatments. The durability is variable, but the agent appears to be a viable treatment option in patients with otherwise refractory urgency and OAB-wet. Contraindications to use include documented hypersensitivity and infection at the site of injection.³⁵ In addition, patients must be cautioned that botulinum toxin for OAB-wet is an off-label use of the agent.

Off-label drugs. Several medications that are not FDA-approved for OAB-wet have shown some effectiveness in managing symptoms associated with bladder overactivity. These include calcium antagonists such as nifedipine and anticonvulsants such as gabapentin. Medications such as potassium channel openers and prostaglandin inhibitors; estrogens, both topically and orally administered; atropine; and scopolamine have also shown some benefit in managing symptoms associated with OAB-wet—although they are currently not considered first-line therapy.