Pharmacologic Management of Overactive Bladder in Women

An Overview of Treatment Options

Matt T. Rosenberg, MD, Matthew A. Hazzard, BA

Matt T. Rosenberg is a practicing family physician and the Director of the Mid-Michigan Health Center in Jackson. Dr. Rosenberg has received grant/research support, served as a consultant for, and/or served on the speaker's bureaus of Ortho-McNeil Pharmaceuticals, GlaxoSmithKline, Esprit Pharmaceuticals, Inc, and Pfizer. Matthew A. Hazzard is a research assistant to Dr. Rosenberg.

Overactive bladder (OAB) is defined by the International Continence Society as a symptom syndrome comprising urgency, usually with frequency, and nocturia, with or without urge incontinence.^1,2 OAB symptoms are common in women and can have a pronounced negative effect on quality of life, as the condition disrupts the ability to work, sleep, and enjoy leisure activities and has detrimental effects on personal relationships.^3,4 Urge incontinence is especially bothersome to many patients and is associated with reduced quality of life, compared with OAB without urge incontinence.^5-7 Many cases of OAB remain undiagnosed, and patients often attempt to manage their symptoms on their own. The condition can be diagnosed based on symptoms, and effective treatments are available. Primary care clinicians should proactively seek to identify their patients with OAB and initiate treatment to reduce incontinence and related symptoms.^8,9

Prevalence

As many as 33 million Americans are thought to suffer from OAB.^5,10 The prevalence of OAB among adult women has been reported to be about 17% in both the United States (16.9% among women 18 or older) and Europe (17.4% among women 40 or older).^5,11 Although OAB and urge incontinence have in the past been considered problems primarily of elderly women, studies indicate that these conditions are common among middle-aged and younger women as well.^5,6 The prevalence of OAB does increase with age, from 10% to 15% in women ages 40 to 49 to more than 30% in women 75 and older.^5,12 Epidemiologic data indicate that the majority of women with OAB also experience urge incontinence. The National Overactive Bladder Evaluation program, a telephone survey of 5,204 English-speaking men and women in the US, found that among women, the prevalence of OAB with and without urge incontinence was 9.3% and 7.6%, respectively, indicating that about 55% of women with OAB have urge incontinence.⁵

Quality of life

As noted earlier, overactive bladder can have a substantial negative effect on quality of life, and urge incontinence may be particularly distressing.^5-7 Women with OAB may limit their activities and social contacts and may be preoccupied by plans for ensuring bathroom access and for concealing accidents.³ This is true for younger and middle-aged women as well as the elderly.^6,13 Depression and anxiety are often associated with OAB as a result of restricted daily functioning.^3,8 Women who have OAB with urge incontinence may also have impaired sexual functioning due to fear of urine loss during sex or to associated dyspareunia and vaginal dryness.^3,14,15 On several assessments of quality of life, patients who have OAB report lower scores across social, physical, functional, and psychological domains, compared with age-matched controls who do not have OAB.^3,5 Furthermore, patients with urge incontinence have lower scores for physical health than patients who have OAB without urge incontinence.⁵

Coping strategies

Women with OAB and urge incontinence use a variety of mechanisms to cope with their condition. The most common strategies are wearing pads "just in case" and always knowing the location of the nearest bathroom when away from home.^3,16,17 In addition, women may wear dark or baggy clothes or use deodorant powders or sprays to help conceal wetting accidents, and they may carry extra clothes with them wherever they go.³ Women with OAB may also limit their caffeine consumption or even limit fluid intake in an attempt to control their symptoms.^3,16 Several studies have found that women with OAB are more likely to use these frequently inconvenient and lifestyle-altering coping strategies than to seek treatment from a health care professional.^3,17

Management of OAB

Management goals

Overactive bladder is a chronic condition that requires effective management. Benchmark goals for the management of OAB include (1) proactively identifying patients with OAB by asking patients about urinary incontinence and letting them know that treatment options are available and (2) making a meaningful reduction in the symptoms of OAB to improve patients' quality of life.

Identifying patients with OAB: overcoming barriers

Despite experiencing symptoms for many years, women who have OAB often do not consult a clinician regarding their condition.^3,18 Among incontinent women in general, the rate of treatment seeking has been reported to be as low as 6% to 27%.^19,20 Even among patients who experience daily large-volume loss of urine, or whose lives are substantially affected, only about 60% have consulted a physician regarding their symptoms.^11,12 There are a variety of reasons why women may avoid seeking medical care for OAB, including embarrassment, a belief that the symptoms are part of normal aging or not a valid medical condition, lack of awareness that effective treatments are available, and fear of invasive procedures.^3,18,20,21

Given these patient barriers, it may be helpful for clinicians to initiate discussion of urinary health with patients during routine visits or at a minimum during annual physical examinations. This can be done with a simple question such as, "Do you have problems with urination?" A positive response would lead the health care provider to more in-depth questions. Table 1 presents a list of key questions that may help in the early identification of patients with OAB.²²

Diagnosis

The diagnosis of OAB is primarily symptom based.²³ Evaluation of the patient with possible OAB should begin with a history to assess medical, neurologic, and genitourinary symptoms. A physical examination should be performed, including a general examination, assessment of any neurologic abnormalities, and an abdominal, pelvic, and rectal examination.^23,24 Laboratory tests should include urinalysis, and possibly urine culture and urine cytology.²³ If the symptoms suggest primarily urge incontinence, a challenge test for stress incontinence (such as checking for leakage during a Valsalva's maneuver while the patient is squatting) may not be necessary.²³ Postvoid residual volume assessment is not considered necessary in all cases. ^9,23,24 The need for urodynamic measurements is a subject of debate but is not required as part of the initial evaluation. Patients should complete a voiding diary to help establish the frequency and severity of their symptoms.

Once a diagnosis has been established, OAB may be treated with a simple, straightforward approach. Therapeutic options include nonpharmacologic and pharmacologic approaches, which may be used separately or in combination. In a patient with symptoms and no evidence of bacteriuria, hematuria, or other physical findings suggestive of known pathologies, it is reasonable to empirically initiate pharmacologic treatment.²³

Therapeutic Options

Nonpharmacologic

Nonpharmacologic intervention may be of some help in the management of OAB. This includes bladder training and pelvic floor muscle rehabilitation through exercises or biofeedback.²⁵ Bladder training involves voiding on a preset schedule and then gradually increasing the intervals between voids; it requires the patient to ignore or suppress the urge to urinate during these intervals.⁴ Bladder training is thought to act by increasing cortical inhibition over the sacral micturition reflex.^4,25 Pelvic floor rehabilitation (Kegel exercises) may be helpful to increase pelvic support and urethral resistance. ^4,25

Behavior modifications such as these may require considerable commitment on the part of both the patient and health care professional,⁴ which may not be an option for the primary care provider. It may be helpful to designate a nurse in the office to help patients with this training. Bladder training and pelvic floor exercises may provide some benefit to patients, but few patients with OAB can achieve complete symptom relief through these approaches alone.^25,26 Approximately 70% of patients may experience a reduction in incontinence episodes with these techniques; however, on average, less than 15% of patients will achieve continence.^25,26 Behavior modifications may be of greatest benefit when combined with pharmacologic approaches.^4,23

Pharmacologic

Anticholinergic/antimuscarinic drugs are the mainstay of pharmacologic therapy for OAB.¹ These drugs are thought to act by inhibiting the muscarinic (M) receptors that are present in the smooth muscle of the bladder, thus controlling the involuntary bladder contractions associated with OAB.⁸ The M3 receptor subtype is thought to be primarily responsible for bladder contraction.¹

Anticholinergic agents available for the treatment of OAB are listed in Table 2 (below), along with recommended dosage regimens.^27-34 With the exception of the oxybutynin patch, all are available in oral formulations. As a class, anticholinergic agents are associated with a range of side effects, including dry mouth (the most common), constipation, blurred vision, urinary retention, and cognitive impairment.¹ All anticholinergic agents indicated for the treatment of OAB are contraindicated in patients with urinary or gastric retention or uncontrolled narrow-angle glaucoma, and in patients who have demonstrated hypersensitivity to the active agent or any other component of the product.

Oxybutynin

Oxybutynin is a nonselective antimuscarinic agent that competi!= tively blocks the effects of acetylcholine, resulting in relaxation of the bladder.¹ Oxybutynin is available in three forms: immediate-release (IR), extended-release (ER), and a transdermal patch.^28,30,31 The ER formulation was designed to maintain efficacy and minimize adverse effects in comparison with the older IR form of the drug. Oxybutynin-ER uses osmotic pressure to deliver oxybutynin at a controlled rate over a 24-hour dosing period.^28,35,36

Oxybutynin-ER is initially administered at once-daily doses ofÜ 5 or 10 mg and may be titrated up to 30 mg at 5-mg increments.²⁸ This wide range of available doses allows therapy to be tailored to individual patient tolerability and desire for symptom relief. Oxybutynin is metabolized by the cytochrome P-450 (CYP450) enzyme system, in particular by the CYP3A4 isoenzyme.²⁸ In clinical trials, oxybutynin-ER has produced clinically significant reductions in the symptoms of OAB, including reductions in weekly urge incontinence episodes of more than 70% at the 10 mg/d dose.^28,37,38 Adverse events associated with oxybutynin-ER were typical of anticholinergic agents and included dry mouth, constipation, headache, and somnolence. The most common adverse event was dry mouth, which was reported in 29% of patients receiving 10 mg/d oxybutynin-ER and was generally mild.²⁸

Transdermal oxybutynin has been shown to be as effective as oxybutynin-IR and tolterodine-ER in reducing incontinence symptoms, with fewer anticholinergic side effects for some patients.^39,40 Disadvantages associated with this mode of administration include problems with application or adhesion, as well as adverse dermatologic events such as erythema and pruritus.^1,31 Application-site reactions were severe in 5% to 6% of patients.³¹ Approximately 11% of patients discontinued transdermal oxybutynin therapy due to adverse events, most due to application-site reactions.³¹

Tolterodine

Tolterodine is a nonselective competitive muscarinic receptor antagonist and, like oxybutynin, is available in both IR and ER formulations.^27,29 Tolterodine-ER is composed of slow-release beads in a gelatin capsule.³⁶ Tolterodine is metabolized in the liver via the CYP450 isoenzyme CYP2D6.²⁹ Both forms of tolterodine have been shown to produce clinically significant reductions in OAB symptoms in randomized controlled clinical trials.^41,42 Tolterodine-ER at a dose of 4 mg qd reduced weekly urge incontinence episodes by 53%.²⁹ Common adverse events associated with tolterodine-ER included dry mouth (23% of patients), constipation, headache, fatigue, and dizziness.²⁹

Trospium

Trospium is a competitive muscarinic inhibitor. Because it is a quaternary amine, its ability to cross the blood-brain barrier may be limited, thus reducing its potential for adverse cognitive effects.^34,43 The drug is minimally metabolized by the CYP450 system. Trospium is dosed at 20 mg twice daily and must be taken on an empty stomach. In clinical trials, trospium was associated with 56% to 60% reductions in weekly urge incontinence epiodes.³⁴ Adverse events associated with trospium include dry mouth (20%), constipation, abdominal pain, and headache.³⁴

Solifenacin

Solifenacin is a competitive muscarinic receptor antagonist. The recommended dosage of solifenacin is 5 mg/d, which may be titrated to 10 mg/d if the lower dose is tolerated.³² Solifenacin is metabolized through the CYP450 system, primarily by CYP3A4. Clinical trials enrolled populations with relatively mild OAB.^44-46 In a pooled analysis, 5 mg/d solifenacin produced a mean reduction in daily urinary incontinence episodes of 60%.⁴⁶ In separate trials, 10 mg/d solifenacin was associated with incontinence episode reductions of 57% to 69%. ³² Common adverse events associated with solifenacin included dry mouth (11% at 5 mg/d and 28% at 10 mg/d), constipation, nausea, and blurred vision. ³²

Darifenacin

Darifenacin is an M3-selective anticholinergic agent. It is taken once daily at a dose of 7.5 or 15 mg. Darifenacin is metabolized through the liver by the enzymes CYP2D6 and CYP3A4. In clinical trials, median reductions in weekly urinary incontinence episodes were 55% to 58% in patients treated with the 7.5-mg/d dosage and 60% to 70% in patients who received 15-mg/d.³³ Common adverse events associated with darifenacin use included dry mouth (20% and 35% in the 7.5-mg and 15-mg dosing groups, respectively) and constipation (15% and 21% in the 7.5-mg and 15-mg dosing groups).³³

Selecting appropriate therapy

Only one trial has been conducted to directly compare anticholinergic agents for the treatment of OAB. The Overactive bladder: Performance of Extended Release Agents (OPERA) trial compared the ER formulations of oxybutynin and tolterodine.³⁸ This randomized, double-blind clinical trial enrolled 790 women who had 21 to 60 urge incontinence episodes per week and 10 or more voids per 24-hour period. This population therefore comprised patients who had severe OAB. Participants were randomized to receive either oxybutynin-ER 10 mg/d (n = 391) or tolterodine-ER 4 mg/d (n = 399). The main efficacy outcomes of weekly urge incontinence episodes, total incontinence, and micturition frequency were recorded in 24-hour urinary diaries at baseline and at the time of subsequent evaluations.

Oxybutynin-ER and tolterodine-ER reduced the mean number of urge incontinence episodes per week by 72% and 70%, respectively, a nonsignificant difference (Table 3, above).³⁸ Other end points were also not significantly different, with the exception of micturition frequency (mean reduction 28% vs 25%, respectively; P = .003) and the proportion of patients who had no incontinence episodes (23% vs 17%, respectively; P = .03).³⁸ Dry mouth was the most common adverse event in each group and was slightly more common in the oxybutynin-ER group than in the tolterodine-ER group (30% vs 22%, respectively; P = .02). The rates of other adverse events, including diarrhea, constipation, headache, and urinary tract infections, ranged from 3% to 8% and were also similar for both drugs (Table 4, below).³⁸ The rates of discontinuation due to adverse events were similar for both drugs--about 5% for each agent. Dry mouth was cited as the reason for discontinuation by seven patients in the oxybutynin group and by four patients in the tolterodine group.³⁸

Further analysis was conducted using combined data from OPERA and the Overactive Bladder: Judging Effective Control and Treatment (OBJECT) trial. The OBJECT trial included 378 patients with seven to 50 urge incontinence episodes per week and at least 10 voids in a 24-hour period; patients were randomized to receive oxybutynin-ER 10 mg/day or tolterodine-IR 2 mg twice daily. There were 559 patients who received oxybutynin-ER in either trial and who had at least one efficacy assessment. ⁴⁷ Those patients who completed the studies (n = 496) achieved at least a 50% reduction in incontinence episodes at two weeks of treatment, and at 12 weeks of treatment they achieved a 70% or greater reduction in incontinence episodes [data on file, Ortho-McNeil Pharmaceutical].^38,47 In contrast, the patients who dropped out (n = 63) did not reach a similar level of incontinence reduction, suggesting that achieving a certain level of symptom reduction may be important for patient persistence on therapy.

Conclusion

In summary, there are many anticholinergic agents currently available for the treatment of OAB. A head-to-head trial found that oxybutynin-ER and tolterodine-ER reduced the number of urge incontinence episodes to a similar degree, although oxybutynin-ER was superior on some measures (eg, the proportion of patients with no episodes). Tolerability profiles of the different agents are largely similar across the most commonly prescribed doses. Unlike other anticholinergic agents, trospium is minimally metabolized through the CYP450 system and thus may be a drug of choice for patients with hepatic impairment. The oxybutynin patch is a nonoral product that is administered twice a week, although there are concerns with adverse effects at the site of administration.

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