Overactive Bladder: When and How to Treat and When to Refer

Overactive bladder is a common, debilitating condition. Patients often feel uncomfortable or unwilling to mention the symptoms, and physicians should ask relevant questions to elicit the history of patients at risk. The most important part of the evaluation is the medical history, which is used to identify any of the numerous conditions that can cause overactive bladder or contribute to the symptoms. Anticholinergic medications are the cornerstone of therapy, with the newer, extended-release formulations generally having fewer side effects. Behavioral therapy to modify abnormal voiding patterns is a valuable therapeutic adjunct.

David Mobley, MD, FACS, Chair, Section of Urology, Memorial City Hospital, Houston, Tex; Neil Baum, MD, Clinical Associate Professor of Urology, Tulane University Medical School, New Orleans, La

Few medical conditions are as disabling and detrimental to a patient's quality of life as overactive bladder (OAB). As one patient put it so succinctly, "OveraOctober 11, 2005ctive bladder doesn't take your life, it just steals it from you." In this article, we review the prevalence of this condition, provide a brief discussion of pathophysiology, and outline the approach to evaluation and treatment and when to refer to a urologist.

The International Continence Society defines OAB as urinary urgency, with or without urge incontinence, usually with urinary frequency and nocturia.¹ Urgency, the primary symptom, is defined as a sudden and compelling desire to eliminate urine that is hard to defer.¹ OAB is difficult to measure objectively because there are no universally accepted scales for symptoms such as urgency.

The National Overactive Bladder Evaluation (NOBLE) program surveyed more than 5000 individuals in the United States and found a 16% prevalence of OAB among men and a 17% prevalence among women, which constitutes approximately 33.3 million adults.² A similar prevalence was reported in an evaluation of 16,000 patients, in which almost 17% of individuals older than 40 years had OAB.³ One third were women who had OAB with incontinence ("OAB wet"), which consists of at least 3 episodes of urinary incontinence in the preceding 4 weeks that could not be attributed to stress incontinence. Two thirds were men who had OAB without incontinence ("OAB dry"), defined as at least 4 episodes of urgency in the preceding 4 weeks and either more than 8 voids per day or the use of 1 or more coping behaviors to control bladder function.³

Although it is a very prevalent condition, many people with symptoms of OAB will not seek medical attention and will suffer in silence, because of a perceived embarrassment or their erroneous belief that nothing can be done to help them.

Impact of OAB on Quality of Life

Those who suffer from OAB report negative effects on their quality of life, including daily activities, such as work, travel, social interactions, physical activity, sexual function, or sleep. The consequences can be significant.

Recent studies using validated questionnaires have confirmed that OAB, even without incontinence, also erodes quality of life. In one study, patients with OAB were found to have a lower quality of life in social and functional domains than those with diabetes.⁴ Data from the NOBLE studies showed that men and women with OAB, with or without incontinence, had clinically, and statistically significant, lower quality of life, increased depression, and poorer sleep quality than controls after adjusting for comorbid conditions.⁵

In 2000, direct and indirect costs associated with urinary incontinence in the United States were $19.5 billion and with OAB, $12.6 billion.⁶ These costs are expected to increase with the aging of the baby boomers.

Comorbidities

Not only do OAB and associated incontinence diminish overall quality of life, they can create additional health problems. Urinary urgency and urge incontinence are predictors of recurrent falls and fractures in the elderly. In a study of 6000 women, the odds ratio of a hip fracture in elderly women with urge incontinence was twice that of the general population.⁷ Women with weekly urge incontinence had a 26% greater risk of sustaining a fall and a 34% greater risk of fracture.

Patients with nocturia may report lack of energy, chronic fatigue, or difficulty performing daily activities. Nocturia has been shown to correlate with reduced quality of life, disturbed sleep, and poor health.⁸

There is also a strong association between depression and urge incontinence. In a study of 115 patients, the prevalence of depression was greatest among those with idiopathic urge incontinence (60%) or mixed incontinence (44%) compared with controls (17%), those with stress incontinence (14%), or those with urge incontinence associated with neurologic disease (8%) or bladder outlet obstruction (33%).⁹ Patients with urge incontinence were more likely to have depression than controls, and the association with depression was the most marked in patients with idiopathic urge incontinence.

Pathophysiology of the Lower Urinary Tract

The proper function of the lower urinary tract is based on a complex mechanism that begins centrally and is mediated through muscarinic receptors in the detrusor muscle. Cognition, brain centers, and an intact sacral neurologic pathway are all necessary for normal functioning of the urinary tract. Pathology in any of these areas can cause OAB, but ultimately the function of the bladder is mediated by muscarinic pathways activated through the sacral spinal cord.

It is believed that OAB occurs with upregulation of muscarinic receptors in the bladder, stimulated by acetylcholine released from parasympathetic nerves. Muscarinic receptors are distributed throughout the body. Five subtypes, M1 to M5, have been identified; these are distributed in the brain (M1-M5), the glands (M1, M3), the sympathetic ganglia (M1), the heart (M2), smooth muscles (M2, M3), and in the eyes (M5).¹⁰ None of these receptors has been identified as specific to bladder function only.

The muscarinic receptors in the bladder are of the M2 and M3 subtypes, with M2 predominating. Despite the predominance of M2 in the human bladder, the M3 receptors are the mediators for normal bladder function. The widespread presence of these subtypes explains many of the side effects seen with the use of antimuscarinic medications (ie, constipation, dry mouth, visual changes, and mental changes).

Evaluation of a Patient with OAB Symptoms

The single most important aspect in evaluating patients who may have OAB is to establish that no other potentially treatable cause of the symptoms exists (Table 1). This is indeed inherent in the definition of this condition. At a minimum, a thorough history, physical examination, and urinalysis are required before medical therapy can be initiated.

Routine laboratory testing can rule out some of the other possible conditions, and urinalysis is used to determine the presence of bacteria in the urine, glycosuria, or hematuria.¹¹

The physical examination should include checking for abdominal scars, masses, or hernias, and an inspection of the back for surgical scars or other abnormalities. The diagnostic algorithm (Figure) outlines the accepted approach to the evaluation. Genitourinary examination is important for determining mucosal integrity and urethral mobility.¹¹

Diagnostic strategies need to be individualized to the specific patient; depending on the physician's familiarity with the diagnosis of this condition, cases requiring the use of radiologic imaging of the upper and lower urinary tract, uroflowmetry, postvoid residual assessment, or urodynamic testing may need to be referred to or consulted with a urologist.

In the primary care setting, some modalities are useful in assessing the nature and severity of OAB symptoms. A validated questionnaire, such as the Detrusor Instability Score (DIS), can help differentiate stress incontinence from urge incontinence. The following questions are helpful in the identification of OAB¹¹:

• Do you ever have the sudden urge to urinate and feel you can barely make it to the bathroom?
• Do you try to find out where the bathroom is located when you go out?
• How often do you get up to go to the bathroom after going to sleep?
• Do you ever leak urine during sex?

In addition, a voiding diary spanning a 48-to 72- hour period can be helpful in determining micturition frequency, number and type of incontinent episodes, and total urinary volume. The diary and the DIS questionnaire are helpful not only in dictating appropriate therapy but also as a treatment outcome tool.

Pharmacotherapy: The Anticholinergic Drugs

Because the mediation of bladder activity is through the muscarinic receptors, the mainstay of OAB therapy is the use of antimuscarinic (ie, anticholinergic) medications. In addition, behavior modification and sacral nerve modulation have been shown to be very effective.

A number of anticholinergic agents have been approved by the US Food and Drug Administration (FDA) for the treatment of OAB (Table 2), with 3 of these agents having been approved in the past year only. The efficacy and side-effect profiles of all these medications are remarkably similar, thus deciding which agent to use is not easy.

As with any class of medications, there will be individual responses to a specific medication. Thus, if a patient does not respond to one agent, or has unacceptable side effects, do not assume that another medication in this class might not be effective. Try another agent until you find the one appropriate for the individual patient.

All the following medications are currently available in the United States and have been shown to be effective in clinical trials. The older agents have been determined to be beneficial in the treatment of OAB by the Third International Consultation of Incontinence 2004.¹⁰

Oxybutynin chloride (Ditropan)

N

. The oldest agent in this category, oxybutynin chloride has been available for more than 30 years; it is one of the most prescribed drugs for OAB in this country and is available in several formulations. Oxybutynin chloride is a tertiary amine that is metabolized by the cytochrome (CY) P3A4 enzyme system. Its metabolite, -desethyloxybutynin, is thought to be the active component responsible for its desired effects as well as for its adverse events.¹²

The oral formulations can be used in doses up to 30 mg/day. The efficacy of the transdermal patch (Oxytrol) is comparable to the oral preparations of either oxybutynin or tolterodine, but it has fewer antimuscarinic side effects. Skin irritation has been reported in up to 28% of patients.^13,14

Tolterodine tartrate (Detrol)

. Like oxybutynin, tolterodine tartrate is metabolized through the CYP450 enzyme system. Its main metabolite appears to be responsible for its beneficial effects.¹⁵ Tolterodine tartrate is also available in several formulations. Oxybutynin and tolterodine are the 2 older anticholinergic agents and have therefore been in clinical use for a longer period.

Comparisons of oxybutynin and tolterodine.

Several clinical trials have compared the efficacy and safety of the 2 agents in head-to-head studies. The Overactive bladder: Performance of Extended-Release Agents (OPERA) trial compared the efficacy of extended-release oxybutynin, 10 mg/day, with extended-release tolterodine, 4 mg/day.¹⁶ A total of 790 women participated in this 12-week trial. Demographics and incontinence histories were essentially identical in both groups. Efficacy results were very similar, with a mean reduction in urgency and urge incontinence episodes at week 12 of about 10 fewer per week, slightly (but not significantly) favoring oxybutynin across all time points. The proportion of patients with no incontinence episodes at week 12 was 23% with oxybutynin, 17% with tolterodine. Tolerability was similar in both groups, and dry mouth was the most common side effect (30% in the oxybutynin group, 22% in the tolterodine group). Other anticholinergic side effects (ie, constipation, blurred vision) occurred with equal frequency in both groups.

The Overactive Bladder: Judging Effective Control and Treatment (OBJECT) trial compared extended-release oxybutynin, 10 mg/day, with immediate-release tolterodine, 2 mg twice daily. Results were similar to those of the OPERA trial, favoring oxybutynin slightly in efficacy and favoring tolterodine slightly in terms of side effects.¹⁷

Trospium chloride (Sanctura)

has been available in Europe for more than a decade; the FDA approved it for use in this country in May 2004. Trospium is a quaternary amine and is therefore expected to cross the blood-brain barrier to a very limited extent.¹⁸ As a result, it appears to have no negative effects on cognition.¹⁸ Trospium must be taken on an empty stomach for maximal effectiveness.¹⁹

A summary of US clinical trials with trospium chloride showed that urinary frequency and urge incontinence episodes decreased in a significant manner compared with placebo, while volume per void increased. These results were similar to those seen with oxybutynin and with tolterodine extended-release formulations. Side effects were as expected in this class, with 20% of patients experiencing dry mouth and 10% having constipation.¹⁹ Clinical experience with trospium is naturally limited so far, but clinical trials data show a good efficacy and safety profile similar to that of the older agents.

Darifenacin (Enablex).

The second agent that received FDA approval in the past year is darifenacin, which was approved by the FDA in December 2004. It is a tertiary amine that is metabolized extensively through the CYP3A4 pathway and is a selective M3- receptor antagonist. Although darifenacin is recommended in doses of 7.5 or 15 mg/day, in patients using potent CYP3A4 inhibitors, such as ketoconazole (Nizoral), tadalafil (Cialis), or erythromycin (Ery-Tab), the maximum recommended dose is 7.5 mg/day.

In a multicenter trial involving 561 patients, darifenacin, in 7.5 or 15 mg/day doses, was superior to placebo in reducing incontinence episodes, frequency, and urgency.²⁰ Dry mouth and constipation were the most common side effects, but no patient discontinued treatment because of dry mouth. Less than 1% of patients discontinued secondary to constipation.

Solifenacin (Vesicare)

received FDA approval in January 2005. Like darifenacin, solifenacin is a tertiary amine that is metabolized extensively through the CYP3A4 pathway, and is a selective M3-receptor antagonist. It was evaluated in a 12-week multicenter trial of 827 men and women with OAB.²¹ A significant decrease in micturition frequency and incontinence episodes was seen with both the 5-and 10-mg doses compared with placebo. Episodes of nocturia diminished, and 50% of patients became fully continent. Solifenacin was well tolerated, with dry mouth being the most common side effect?7.7% with the 5-mg dosage and 23% with the 10-mg dosage.

Choosing the Medication

Obviously, the older agents have a longer track record and are therefore more frequently prescribed. However, in time the new agents may prove just as effective, and in some cases even more effective, depending on the specific clinical situation. Data from clinical trials show these new agents have good safety and efficacy profiles. Currently, the most frequently prescribed agent is the extended-release (long-acting) tolterodine formulation at a dose of 4 mg, once daily. However, all the anticholinergic medications with antimuscarinic properties are as effective for the management of OAB.

It is hard to recommend one or the other, but empiric preference may be useful. The only caveat at this point concerns the use of oxybutynin for elderly patients. Because of its potential to cross the blood-brain barrier and produce cognitive disorders in elderly patients,¹⁸ oxybutynin is not recommended for this patient population, since other agents are now available that do not cross the blood-brain barrier.

Behavior Modification

Behavior modification techniques include timed voiding, bladder-retraining drills, dietary modification, and pelvic floor (ie, Kegel) exercises. These modalities have the advantages of safety, low cost, and an absence of side effects. Unfortunately, most patients are not motivated to continue with behavior modification because a response is not evident for up to 4 to 6 months. However, significant improvement is seen when behavior therapy is combined with drug therapy.²²

Surgical Treatment: Neuromodulation

The only widespread surgical treatment for OAB is sacral neuromodulation. Bladder enhancement with the intestine is rarely used. A patient requiring this modality would normally be referred to a urologist.

Results of a multicenter trial of the implant in patients with urge incontinence showed that 79% had a reduction of incontinence episodes by at least 50%, and 45% of patients were rendered completely dry.²³ In patients with symptoms of urgency and frequency, the number of episodes decreased significantly, and voided volumes increased.

Indications for Urologic Referral

Our experience shows that pharmacotherapy is effective in more than two thirds of patients. This is further supported by the medical literature, which shows a 65% to 75% reduction in incontinence episodes with any of the anticholinergic agents.

Patients who do not respond to drug treatment require additional workup and should be referred to a urologist or a gynecologist who specializes in OAB and urinary incontinence. Also refer patients with:

• Hematuria.
• Pelvic pain or painful urination.
• Significant anatomic defect, such as prolapse of the bladder, uterus, or rectum.

Conclusion

OAB affects millions of Americans and, with the aging of the baby boomers, the number is destined to increase. With appropriate treatment, most patients with this incapacitating condition can be helped, and some can even be cured.

Disclosure statement

Dr Mobley is on the Speaker's Bureau of Lilly, Pfizer, Yamanouchi, and GlaxoSmithKline; he receives research grants from Norvartis, Lilly, Pfizer, Yamanouchi, and Merck. Dr Baum is on the Speaker's Bureau of Indevus, Ortho- McNeil, and Pfizer.

SELF-ASSESSMENT TEST

1. Which of these statements about OAB is NOT true?

• It increases the risk of falls in the elderly
• Most affected persons do not seek treatment

2. All these conditions are associated with OAB, except:

• Impaired mobility
• Estrogen deficiency

3. Which of these signs and symptoms is NOT suggestive of OAB?

• Feeling you can barely make it to the bathroom
• Checking to see where the bathroom is in an unfamiliar place

4. Which of these statements about pharmacotherapy for OAB is NOT true?

• Oxybutynin is slightly more effective than tolterodine
• Tolterodine must be taken on an empty stomach

5. All these are recommended dosages, except:

• Darifenacin, 7.5-15 mg/d
• Solifenacin, 5 to 10 mg/d

(Answers at end of reference list)

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Answers:

1. A; 2. C; 3. A; 4. D; 5. C