Management of Overactive Bladder and Urge Urinary Incontinence in the Elderly Patient

The American Journal of Medicine (2006) Vol 119 (3A), 29S–36S

Management of Overactive Bladder and Urge Urinary Incontinence in the Elderly Patient Nurum Erdem, MD, MPH,a Franklin M. Chu, MDb a

Division of Geriatric Medicine/Program on Aging, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA; and bSan Bernardino Urology Research Center, San Bernardino, California, USA ABSTRACT The symptoms of overactive bladder (OAB) and urge urinary incontinence may occur at any age but are particularly common among the elderly. These symptoms are associated with significant morbidity and often have a profound impact on patient quality of life. Urinary incontinence is an important contributor to the complications and economic cost of OAB for both community-dwelling and institutionalized elderly individuals. Many patients with OAB do not seek treatment because of embarrassment, fear of surgery, or the misperceptions that the problem is untreatable or is a normal and inevitable consequence of aging. Nonpharmacologic therapies improve bladder control by modifying lifestyle and behavior to prevent urine loss. This requires patient and caregiver motivation and can be time consuming. Improved results may be obtained by combining these strategies with pharmacotherapy or by means of pharmacotherapy alone. The most commonly used pharmacologic agents are the muscarinic receptor antagonists. These include oxybutynin, tolterodine, and three agents that have recently been approved for use in the United States: trospium, darifenacin, and solifenacin. In general, these therapies are well tolerated and safe; however, the selection of an optimal agent merits careful consideration. For elderly patients, important considerations include tolerability, absence of drug interactions, and the availability of a range of dosages to tailor treatment to individual patients. Primary care practitioners and geriatricians can have a key role in successful diagnosis and treatment of OAB. It is important for these physicians to realize that satisfactory outcomes may be achieved within the scope of a busy outpatient practice. © 2006 Elsevier Inc. All rights reserved. KEYWORDS: Elderly patients; Muscarinic receptor antagonists; Overactive bladder; Urge urinary incontinence

Overactive bladder (OAB) is characterized by urgency—a sudden compelling desire to pass urine that is difficult to defer. It is usually accompanied by frequency and nocturia, and it may occur with urge urinary incontinence (i.e., incontinence associated with urgency).1 Overall, OAB affects slightly ⬎16% of the adult population in the United States, or approximately 34 million individuals; the prevalence increases with advancing age (Figure 1).2-4 In fact, urinary incontinence is common in the elderly. In a large, community-based survey of Norwegian women, approximately 27% of those aged 65 to 69 years reported urinary incontinence and 35% to 40% of those

Requests for reprints should be addressed to Nurum Erdem, MD, MPH, Division of Geriatric Medicine, University of North Carolina School of Medicine, 141 MacNiderBuilding, CB#7550, Chapel Hill, North Carolina 27599. E-mail address: [email protected].

0002-9343/$ -see front matter © 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.amjmed.2005.12.014

ⱖ80 years of age were affected.4 A population-based US study of women enrolled in a large health maintenance organization suggests an even higher rate of urinary incontinence (⬎50%) among women aged 60 to 90 years. In this study, urge urinary incontinence was present in a majority of older women reporting urinary incontinence.5 The prevalence of urinary incontinence has also been estimated at ⱖ50% among residents of long-term care facilities.6,7 The total cost of OAB in 2000 was estimated at approximately $12 billion in the United States, with $9 billion of this cost incurred in the community.3 This includes the direct costs of routine care and treatment as well as consequence costs, such as those resulting from urinary tract infections and falls. In addition, informal (unpaid) caregiving to community-dwelling individuals likely increases the indirect costs.8 Intangible costs such as pain, suffering, and poor quality of life are not included in this estimate.

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Figure 1 The prevalence of overactive bladder increases with age among both men and women. (Adapted with permission from World J Urol.2 © 2003, Springer Science and Business Media.)

OAB can have a negative impact on health, the ability to function, and quality of life.2,7,9 Elderly patients with urge incontinence are also more likely to be admitted to nursing homes. One study found a 2-fold and 3.2-fold increase in risk of admission to a nursing facility for women and men with incontinence, respectively.10 Episodes of urge urinary incontinence may result in anxiety, negative self-perception, and social isolation. Urge urinary incontinence is comorbid with depression11 and a risk of suicide exceeding that associated with many other conditions, including congestive heart failure, chronic obstructive pulmonary disease, and moderate pain.12 OAB puts patients at risk for other forms of morbidity as well. For example, fracture risk, already high among the elderly, is further increased in patients who experience urgency. In a study of 6,049 elderly women with urge incontinence, 55% reported falling and 8.5% reported fractures during an average follow-up of 3 years.13 In this study, urge urinary incontinence episodes occurring weekly or more frequently were associated with a 26% increase in the risk of falls and a 34% increase in the risk of fractures. Other common problems associated with OAB include skin ulceration and urinary tract infection.14 Nocturia, defined as waking up at night ⱖ1 time to void, is a common symptom of OAB syndrome, particularly among elderly individuals,15 and it is among the most bothersome of lower urinary tract symptoms.16 In addition to sleep interruptions and the resulting daytime fatigue, decreased vitality, and reduced productivity,15,17 patients with nocturia may be especially likely to suffer from falls and fractures,18 which are associated with high morbidity in elderly patients: 33% of patients do not survive beyond 1 year after a hip fracture.19 Together, the immediate consequences and comorbidities of OAB and urge urinary incontinence have an important negative influence on quality of life, particularly among the elderly. The impact of OAB is apparent from the results of the National Overactive Bladder Evaluation (NOBLE)

study. In this study, OAB was associated with significantly lower 36-item Short Form (SF-36) quality-of-life scores, higher scores on measures of depression, and poorer quality sleep when compared with controls.3 Although the prevalence of OAB and urge urinary incontinence increases with age, it should not be considered a normal consequence of aging by patients or physicians. Primary care practitioners and geriatricians have an important role at the first line of evaluation and treatment. Evaluation can be performed quickly and accurately even in the setting of a busy outpatient practice. In the majority of patients, treatment can be initiated effectively without referral to a specialist. By using a systematic approach to diagnosing OAB and instituting appropriate therapy, primary care practitioners and geriatricians can substantially improve the health and quality of life of elderly patients with OAB.

PHYSIOLOGY OF THE BLADDER Normal bladder function involves a complex interplay between the urinary tract and nervous system. During filling, the healthy bladder functions like a compliant balloon, with pressure in the bladder remaining lower than urethral resistance. Normal urination is initiated by a decrease in urethral resistance and rhythmic contractions of the detrusor muscle. Symptoms of OAB are frequently attributable to overactivity of the detrusor muscle causing uninhibited contractions, which can result from neurogenic or idiopathic alterations in bladder physiology; alterations in the properties of the smooth muscle itself may also result in OAB.20 In contrast, weak detrusor contractility may lead to incomplete emptying and increased urinary frequency due to decreased functional capacity of the bladder.21 A detailed discussion of the pathophysiology of OAB appears in the article by Chu and Dmochowski elsewhere in this supplement.22 Acetylcholine, by acting on muscarinic receptors within the detrusor muscle, is the primary neurotransmitter respon-

Erdem and Chu

Management of Overactive Bladder and Urge Urinary Incontinence in the Elderly Patient

sible for bladder contraction. There are 5 known muscarinic subtypes (M1 to M5) that are widely distributed throughout the body.23 In general, the muscarinic receptor subtypes are located in smooth muscle (bladder), exocrine glands, the nervous system, and the heart.24 M2 receptors are the predominant subtype within the detrusor muscle of the healthy bladder; activation of M2 receptors inhibits sympathetically mediated detrusor relaxation. They are also located in the heart and central nervous system (CNS). M3 receptors are responsible for detrusor smooth muscle contraction and also have an exocrine function in the salivary glands.24,25 The muscarinic receptor antagonists used to treat OAB stimulate some or all of these receptors to varying degrees; the use of muscarinic receptor antagonists is therefore associated with a wide spectrum of outcomes in terms of both efficacy and side-effect profile.

EVALUATION OF ELDERLY PATIENTS WITH OVERACTIVE BLADDER Patients with OAB can be successfully managed by geriatricians and primary care physicians. The first step is to discuss symptoms of frequency, urgency, and incontinence. Appropriate queries may include “How often do you get up at night to urinate?” and “Do you ever lose urine when you don’t want to?”26 Unfortunately, many patients with OAB do not seek treatment because of embarrassment or the misconceptions that the problem is an inevitable consequence of aging and treatment options are limited.27,28 Patients who screen positive should undergo a basic evaluation that includes a history and physical examination. The history should focus on medical, neurologic, and genitourinary symptoms. Neurologic problems such as stroke, Alzheimer disease, or Parkinson disease may affect cortical inhibitory function, which can cause or contribute to OAB. Pathology affecting the spinal cord may also disrupt normal micturition reflexes, resulting in OAB. Any conditions causing increased urine production (diabetes mellitus, congestive heart failure) or affecting lower urinary tract function (atrophic vaginitis, fecal impaction) may also lead to OAB. Table 126 details conditions that may cause or contribute to symptoms of OAB. When considering these conditions, it is important to identify reversible causes and appropriate management in each case. Fluid intake, voiding patterns, and symptoms should be reviewed. This can be achieved most accurately with a patientcompleted voiding diary, in which the patient logs information for ⱖ24 hours (Table 2).29 OAB is frequently described by patients as an uncontrollable sudden urge to urinate with largevolume urine loss (urge urinary incontinence). This is in contrast to stress urinary incontinence, which is characterized by small-volume urine loss accompanying laughing or coughing or other exertions that cause an increase in intra-abdominal pressure. Medications should be reviewed for drugs that may affect urinary function (Table 3). Diuretics have the potential to mimic symptoms of OAB by increasing urinary frequency. Anticholinergic agents, narcotics, and calcium channel block-

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ers may decrease bladder contractility and exacerbate OAB symptoms.30 Sedatives may lead to immobility and functional urge incontinence. Physical examination should include the general examination with attention to abdominal, genitourinary, rectal, and neurologic organ systems. Abdominal examination should include bladder palpation, genitourinary examination with pelvic examination in women to rule out atrophic vaginitis or urethritis, and rectal examination to rule out impaction and to assess the prostate in males. Neurologic examination should focus on mental status and lumbar/ sacral reflexes to ensure that the spinal cord is intact. Regarding laboratory assessment, urinalysis is essential to exclude hematuria, glucosuria, proteinuria, and urinary tract infection. Blood work is necessary if compromised renal function is suspected or if polyuria is present. Obstruction can sometimes be detected by palpation of the bladder. If obstruction is a concern, postvoid residual volume should be measured with a bladder scanner, which uses ultrasound to measure the volume of urine remaining in the bladder. Clinic nurses are usually able to perform straight catheterization to assess postvoid residual volume if a bladder scanner is not available. Although the majority of OAB cases can be successfully treated by the geriatrician or primary care physician, some patients do require referral to a urologist. Red flags for referral include treatment failure, history of frequent urinary tract infections, hesitancy, postvoid residual volume ⬎200 mL, evidence of stricture on physical examination, or evidence of hematuria on urinalysis.7 Previous pelvic surgery, radiation therapy, and prolapse are also reasons for referral.

TREATMENT OF THE ELDERLY PATIENT WITH OVERACTIVE BLADDER Nonpharmacologic Intervention: Behavioral Therapy Behavioral therapy (discussed in greater depth in “Management of Incontinence for Family Practice Physicians” elsewhere in this supplement31) includes techniques such as bladder training, timed/prompted voiding, pelvic muscle exercises, and biofeedback. Behavioral therapy may improve bladder control by changing the incontinent patient’s voiding habits and teaching skills for preventing urine loss.7 The use of behavioral therapy in 1 study resulted in elimination of symptoms in 82% of patients32; in another, a randomized clinical trial, bladder training resulted in a 57% reduction in incontinence episode frequency.33 Although most patients who receive behavioral treatment achieve some improvement, most do not become completely dry. Moreover, behavioral therapy may be challenging to implement effectively in elderly patients with dementia or other debilitating conditions. In long-term care settings, behavioral treatment requires increased nursing time; however, prompted voiding has been reported to be effective in 40% of patients.34 Optimal results may be

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The American Journal of Medicine, Vol 119 (3A), March 2006

Table 1

Conditions that may cause or contribute to symptoms of overactive bladder

Condition

Management

Impaired ability or willingness to reach a toilet Delirium Chronic illness, injury, or restraint that interferes with mobility Psychological condition Increased urine production Metabolic disorder Hyperglycemia Hypercalcemia Excess fluid intake Volume overload Venous insufficiency with edema Congestive heart failure Conditions affecting the lower urinary tract Urinary tract infection Atrophic vaginitis/urethritis Stool impaction

Diagnosis and treatment of underlying causes of acute confusional state Regular toileting, use of toilet substitutes, environmental alterations Removal of restraints (if feasible); appropriate pharmacologic/nonpharmacologic management Improved control of diabetes mellitus Correction of the underlying disorder Reduction of intake of diuretic fluids (e.g., caffeinated beverages) Support stockings, leg elevation, sodium restriction, diuretic therapy Medical therapy Antimicrobial therapy Oral or topical estrogen (if risk–benefit ratio is appropriate) Disimpaction and use of stool softeners, bulk-forming agents, and laxatives

Adapted with permission from Rev Urol.26 © 2002, Med Reviews, LLC. All rights reserved.

Table 2

A sample voiding diary form

Name: ________________________________________________

Date: _____________________

Instructions: Place a check in the appropriate column next to the time you urinated in the toilet or when a leak occurred. Note the amount of and reason for the leak, and describe your liquid intake (for example: coffee, water) and estimate the amount of your liquid intake (for example: 1 cup) Time Interval

Urinated in Toilet

Leaked Urine

Amount Leaked

Reason for Incontinence Episode

Type and Amount of Liquid Intake

6–8 AM 8–10 AM 10 AM–12 PM 12–2 PM 2–4 PM 4–6 PM 6–8 PM 8–10 PM 10 PM–midnight Overnight Number of pads used on this date: __________________ Number of episodes: __________________ Comments:

obtained by combining behavioral and pharmacologic interventions.35,36

Considerations for Pharmacologic Intervention The muscarinic receptor antagonists are the mainstay of pharmacologic treatment for OAB. These drugs act by blocking acetylcholine from stimulating the muscarinic receptor on the detrusor muscle. Treatment with these agents results in fewer and less forceful uninhibited bladder contractions, allowing improved bladder filling and reduced urgency and urge incontinence.24,25

The use of muscarinic receptor antagonists is associated with certain bothersome anticholinergic side effects, including dry mouth, constipation, sedation, impaired or disturbed cognitive function, tachycardia, and blurred vision. The primary adverse effect seen with the use of muscarinic receptor antagonists is dry mouth; initial studies of the newer M3 selective muscarinic receptor antagonists have also noted increased incidence of constipation. The use of these medications is contraindicated in patients with narrow-angle glaucoma, urinary retention, or gastric retention. Caution should be used in prescribing these medications to elderly patients with gastroesophageal

Erdem and Chu Table 3

Management of Overactive Bladder and Urge Urinary Incontinence in the Elderly Patient

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Drugs potentially affecting urinary function

Drug Class

Side Effects

Alcohol ␣-agonists (nonprescription cold medicines) ␣-blockers ACE inhibitors Anticholinergic agents Antidepressants Antiparkinsonian medications Antipsychotics ␤-agonists Caffeine Calcium channel blockers Diuretics Sedatives

Polyuria, frequency, urgency, sedation, delirium Urinary retention Urethral relaxation Diuresis, cough with relaxation of pelvic floor Urinary retention, overflow urge incontinence, stool impaction Anticholinergic side effects, sedation, rigidity Urinary urgency, constipation Anticholinergic side effects, sedation, rigidity Urinary retention Aggravation or precipitation of urge incontinence Urinary retention Polyuria, frequency, urgency Sedation, delirium, immobility

ACE ⫽ angiontensin-converting enzyme.

reflux, constipation, memory loss, or dementia.37,38 Older patients who may be susceptible to memory loss and dementia should undergo baseline cognitive assessment and be monitored closely.38 It is crucial to remain alert to the potential for drug interactions. This poses a particular problem in elderly patients, who are subject to polypharmacy for treatment of multiple conditions. Established drug regimens should be carefully assessed to guide selection of appropriate pharmacologic therapy for OAB.

Pharmacologic Treatment of OAB Multiple agents are available for the pharmacologic management of OAB (Table 4). Older agents include propantheline, hyoscyamine, and imipramine. Propantheline bromide, a quaternary ammonium compound, is a nonselective muscarinic receptor antagonist with low and varying biologic availability.39 Given the availability of more selective agents with less frequent dosing and a smaller side-effect burden, it should not be considered a first-line agent for the treatment of OAB.7 Hyoscyamine sulfate, a muscarinic receptor antagonist, may be useful in patients with intermittent symptoms; however, it is associated with prominent anticholinergic side effects.40 Imipramine, a tricyclic antidepressant, may be useful for stress incontinence or mixed urge–stress incontinence, particularly when used in combination with an antimuscarinic agent, but is not recommended for treatment of isolated OAB. Imipramine is also associated with potentially serious CNS effects and cardiotoxicity.7,39 The most frequently prescribed antimuscarinic agents for the treatment of OAB are oxybutynin and tolterodine. Three additional drugs were approved by the US Food and Drug Administration (FDA) in 2004 to treat the symptoms of OAB: trospium, which has been used in Europe for the treatment of OAB for ⬎20 years,41 darifenacin, and solifenacin (Table 4).

Established Agents. Oxybutynin is a relatively nonselective muscarinic receptor antagonist. The efficacy of immediate-release oxybutynin (oxybutinin-IR) has been demonstrated in several large trials and it has been used for approximately 30 years for the management of OAB. Currently, oxybutynin is available in 3 formulations: immediate-release (taken twice daily), extended-release (taken once daily), and transdermal (applied once every 3 days). Each of these formulations has unique benefits that allow treatment to be tailored to the patient’s needs. For example, once nocturnal polyuria is ruled out, short-acting oxybutynin-IR may be useful as a single dose in the evening for patients with nocturia who are troubled by interrupted sleep. Once-daily, extended-release oxybutynin (oxybutininER) has also been demonstrated to be efficacious in several large trials. In addition to less frequent dosing, oxybutynin-ER is better tolerated than oxybutinin-IR particularly with respect to the incidence and severity of dry mouth. Among antimuscarinic agents, oxybutynin-ER has the widest FDA-approved dosing range (5 mg to 30 mg), which may facilitate achievement of the optimum balance between efficacy and tolerability. The recommended starting dose is 5 or 10 mg/day. Oxybutynin is also available in a transdermal formulation.42 Because transdermal oxybutynin does not undergo first-pass metabolism in the liver, much lower concentrations of N-desethyloxybutynin are observed. This is the active metabolite of oxybutynin hypothesized to be primarily responsible for its anticholinergic side effects.43 Twiceweekly transdermal oxybutynin should also be considered in patients who are unlikely to remain adherent to oral therapy or who dislike multiple-dose daily regimens. In clinical studies, transdermal oxybutynin has been associated with a relatively low risk of side effects; the most frequently seen side effects were application-site reactions. These can be minimized by application of topical corticosteroid or antihistamine to the site.

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Table 4

Drugs used for the treatment of overactive bladder (OAB)

Drug

Dosage(s)

Comments

Propantheline Hyoscyamine

15–30 mg qid 0.375 mg bid

Imipramine Oxybutynin Immediate-release Extended-release

10–25 mg tid

Frequent dosing and high side-effect burden Not proved to be effective in randomized controlled trials; may be useful in some patients with intermittent symptoms Primarily useful in patients with stress or mixed urge–stress incontinence

Transdermal

2.5–5.0 mg tid 5, 10, 15, 20, 25, 30 mg qd 3.9 mg over a 96-hr period

Tolterodine Immediate-release Extended-release

1–2 mg bid 2 or 4 mg qd

Trospium

20 mg bid

Darifenacin Solifenacin

7.5 or 15 mg qd 5 or 10 mg qd

Appropriate in patients with nocturia Lower side-effect burden and greater efficacy than immediate release formulation; wide dose range Lower propensity for drug interactions; consider in older patients taking multiple medications Appropriate in patients with nocturia Lower side-effect burden and greater efficacy than immediate-release formulation Side-effect burden similar to extended release oxybutynin and tolterodine; no known drug interactions Constipation is frequent compared with other antimuscarinic agents Efficacy proved only in patients with mild-to-moderate OAB

Like oxybutynin, tolterodine is available in short-acting (twice-daily) and long-acting (once-daily) formulations. Both formulations have demonstrated statistically significant effects on the symptoms of OAB in several large-scale, randomized, controlled trials. Similar to oxybutynin, the extended-release formulation of tolterodine is better tolerated and more effective than the immediate-release formulation.44 In a randomized controlled trial of extended-release tolterodine (tolterodine ER) 4 mg/day in patients with urge incontinence and urinary frequency, no differences were found for efficacy, tolerability, or safety between older and younger patients.45 In a second trial there was a small, but statistically significant, decrease in the efficacy of tolterodine with age.46 Tolterodine-ER is available in 2- and 4-mg doses; the recommended dose is 4 mg once daily. Although the dose may be decreased to 2 mg daily based on individual response, limited efficacy data are available for the lower dosage. The Overactive Bladder: Performance of Extended-Release Agents (OPERA) trial was a head-to-head study comparing oxybutynin-ER and extended-release tolterodine (tolterodine-ER).47 In this study, reductions in the frequency of incontinence episodes were similar in the oxybutynin-ER and tolterodine-ER groups. However, micturition frequency was reduced to a significantly greater extent in the oxybutynin-ER group than in the tolterodine-ER group. Moreover, more patients in the oxybutynin-ER group achieved complete continence. In a follow-up study using the same data, the CNS tolerability profiles of oxybutynin-ER and tolterodine-ER were compared.48 The incidence of CNS adverse events was 9.0% in the oxybutynin-ER group and 8.3% in the tolterodine-ER treatment groups (P ⫽ 0.8). All CNS adverse events were judged to be mild or moderate.

Newer Agents. Trospium chloride, a quaternary ammonium compound, was recently approved by the FDA for the treatment of OAB. It is available in a single 20-mg dose for twice-daily use. Trospium has efficacy equivalent to twicedaily oxybutynin-IR and a lower incidence of dry mouth.49 Trospium may have a low risk of CNS side effects because of its low propensity to cross the blood– brain barrier, and it is not metabolized by the cytochrome P450 system.50 Thus, despite a limited dose range and twice-daily dosing, this agent may theoretically be considered favorable in patients who are elderly and receiving multiple concomitant medications. The newest additions to the range of agents available for the treatment of OAB are darifenacin and solifenacin, both of which have proven efficacy and are available in oncedaily formulations.51,52 Currently, darifenacin is available in 7.5-mg/day and 15-mg/day formulations; the recommended starting dosage is 7.5 mg once daily. The recommended starting dosage of solifenacin is 5 mg once daily; dosing can be increased to 10 mg once daily if desired. These M3selective receptor antagonists may have increased bladder specificity and reduced propensity for anticholinergic side effects, although, as anticholinergic agents, they should be used with caution in patients with narrow-angle glaucoma, decreased gastrointestinal motility, or clinically significant bladder outflow obstruction. M3-selective agents are associated with relatively high rates of constipation; rates of 9.1% and 14.4% have been reported for solifenacin 10 mg daily and darifenacin 7.5 mg daily, respectively.51,52 Solifenacin should be used with caution in patients with reduced hepatic or renal function. Darifenacin is not recommended for use in patients with severe hepatic impairment, but the 7.5-mg dose can be used with caution in patients with moderate hepatic impairment and there are no dosing adjustments for patients with mild hepatic impairment. For

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Management of Overactive Bladder and Urge Urinary Incontinence in the Elderly Patient

darifenacin, no dose adjustment is necessary for elderly patients and no differences in safety and efficacy have been observed between older and younger patients. Solifenacin likewise has similar efficacy and safety in older and younger patients; therefore these drugs should be considered for treatment of elderly patients. Direct comparisons among newer and older treatments are lacking at present.

SUMMARY OAB, frequently seen in the elderly population, has a significant impact on patient health and quality of life. As the first line of patient care, geriatricians and primary care providers can play a major role in improving quality of life by ensuring that elderly patients are assessed for OAB and treated appropriately. Nonpharmacologic therapy should be considered initially, but combination therapy or drug therapy alone should be considered if the desired results are not achieved. In the majority of elderly patients, treatment with a muscarinic receptor antagonist should provide substantial benefit with relatively little risk when the proper agent and optimal dose are selected. With a variety of agents, delivery systems, and doses available, a well-informed care provider can optimize OAB treatment for elderly patients.

ACKNOWLEDGMENT The authors thank Jan Busby-Whitehead, MD, for her thoughtful review of and contributions to this article.

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