Management of Urinary Incontinence
`
`George A. DeMaagd, PharmD, BCPS; and Timothy C. Davenport, MD
`
`DISEASE OVERVIEW
`Urinary incontinence (UI) may be defined as any involuntary or
`abnormal urine loss. UI is characterized by lower urinary tract
`symptoms (LUTS), which include both storage and voiding prob-
`lems. UI can be further defined by the patient’s presentations and
`symptoms. Urge urinary incontinence (UUI) is defined as invol-
`untary urine leakage associated with urgency. Stress urinary in-
`continence (SUI) is defined as involuntary urine leakage associated
`with specific activities (e.g., sneezing and coughing. Mixed urinary
`incontinence (MUI) includes features of both UUI and SUI.1–3
`Overflow incontinence (OFI) is caused by a hypotonic bladder,
`bladder outlet obstruction, or other forms of urinary retention. OFI
`may result in LUTS and in the loss of small amounts of urine; it most
`often occurs in men with benign prostatic hyperplasia (BPH).4
`The term overactive bladder (OAB) is often used to describe UI.
`OAB comprises a constellation of symptoms typically charac -
`terized by urgency, with or without UUI, accompanied by fre-
` quency and nocturia.1
`
`Epidemiology
`Approximately 10 million patients in the U.S. have UI, which is
`associated with significant morbidity and decreased quality of life.
`In 2007, it was estimated that more than 25 million people in the
`U.S. experienced episodes of UI. The prevalence of UI is higher
`in women than in men 80 years of age or younger, but both men
`and women are affected almost equally after age 80. UI may be
` associated with certain comorbidities, including hypertension
`and depression, although these associations are not fully under-
`stood.5,6 Among women, the incidence of UI is highest in
` Caucasians (7.3/100 person-years), followed by Asians (5.7/100
` person-years) and African-Americans (4.8/100 person-years).7
`As a result of the social stigma associated with UI or the as-
`sumption that UI is a normal part of aging, the prevalence of this
`disorder may be underestimated because of unreported cases.8 UI
`is also often undocumented upon hospital discharge; it is a
` neglected syndrome in nursing facilities; and it is underreported
`by health care professionals, who may view the condition as a
`symptom rather than as a medical problem.9,10
`UI is primarily associated with aging, affecting up to 30% of
` elderly people. It occurs in 85% of long-term-care patients and is
`often the reason for admission to these facilities.11,12 The prevalence
`of UI in nursing homes remains high, and the care of nursing-home
`residents with UI is the subject of clinical research.13,14 In addition,
`UI is one of the measures used by the Centers for Medicare and
`Medicaid Services (CMS) to assess quality of care.15–17
`Annual direct and indirect costs of managing UI in the U.S. is
`estimated at $25 billion for patients over 65 years of age.18,19 The
`direct costs of UI include diagnostic procedures and the various
`treatment options, including pharmacotherapy.20 Indirect costs
`include complications and disabilities, such as insomnia, falls,
`
`Dr. DeMaagd is Associate Dean of Academic Administration and Pro-
`fessor of Pharmacy at the Union University School of Pharmacy in
` Jackson, Tenn. Dr. Davenport is a Urologist at The Jackson Clinic in
` Jackson.
`
` depression, caregiving, and nursing-home placement.10,21 The
` indirect costs of UI are associated with a significant decrease in
`health-related quality of life, especially in women. Other “costs” of
`UI are difficult to measure but are significant. These include the
`consequences of social withdrawal or isolation resulting from the
`perceived stigma of UI or from the fear of leakage or odor.22–24
`
`Bladder Anatomy and Physiology
`The anatomy and physiology of the bladder are complex, but a
`basic understanding of these topics is essential in order to appre-
`ciate the various types of UI and their management.25,26 Figure 1
`illustrates the basic anatomic structures and nervous system
`“wiring” involved in bladder function, including the detrusor mus-
`cle, the internal and external sphincters (bladder neck and prox-
`imal urethra, respectively), and their neurological components.
`Reduced activation of the sympathetic nervous system (SNS)
`results in relaxation of the detrusor muscle, closure of the sphinc-
`ter, and bladder filling. When the volume of urine in the bladder
`reaches 200 to 400 mL, the sensation of urge to void is relayed via
`the spinal cord to the brain centers. Voluntary voiding (micturition)
`involves the parasympathetic nervous system and the voluntary
`somatic nervous system. Influences from these systems cause
` contractions of the detrusor muscle and corresponding somatic
`nervous activity, leading to sphincter relaxation.26–31
`
`Etiology and Risk Factors
`Multiple factors, including age-related physiological changes,
`may result in or contribute to the various syndromes of UI. Both
`genitourinary and non-genitourinary factors may contribute to
`incontinence in aging patients. Age-related functional changes in
`the urinary tract (detrusor overactivity, impaired bladder con-
`tractility, decreased pressure in urethra closure, atrophy of ure-
`thral areas, and prostatic hypertrophy) may contribute to UI.32 In
`women, risk factors for these genitourinary changes include mul-
`tiple or complex vaginal deliveries, high infant birth weight, a his-
`tory of hysterectomy, and physiological changes related to the tran-
`sition to postmenopause. Smoking, a high body mass index, and
`constipation are also associated with an increased risk of UI.33–37
`Pathophysiological causes of UI include lesions in higher mic-
`turition centers, in the sacral spinal cord, and in other neurologi-
`cal areas as well. UI may also be associated with numerous
` comorbidities, such as Parkinson’s disease, Alzheimer’s disease,
`
`Key Abbreviations
`
`benign prostatic hyperplasia
`lower urinary tract symptoms
`mixed urinary incontinence
`overactive bladder
`overflow incontinence
`stress urinary incontinence
`urinary incontinence
`urinary tract infection
`urge urinary incontinence
`
`BPH
`LUTS
`MUI
`OAB
`OFI
`SUI
`UI
`UTI
`UUI
`
`Accepted for publication January 23, 2012.
`
`Disclosure: The authors report that they have no financial, com-
`mercial, or industrial relationships in regard to this article.
`
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`Management of Urinary Incontinence
`
`cerebrovascular disease, diabetes, hypertension, obstructive sleep
`apnea, and normal-pressure hydrocephalus. Functional factors, in-
`cluding mobility and dexterity, along with reaction time and lack
`of access to a bathroom facility, may also contribute to UI.33–37
`Reversible causes of UI, often described by the mnemonic
` DIAPPERS, include urinary-tract infections (UTIs), stool impaction,
`and drugs (Table 1).35–44 Incontinence in older adults may or may
`not be associated with the genitourinary system. Pharmacological
`causes and contributors should be considered in patients with UI,
`especially if they are taking multiple medications (Table 2).32,38–44
`Primary care providers and specialists should work as a team to
`manage patients with UI and to evaluate the broad spectrum of fac-
`tors that may contribute to incontinence in older adults.32,38,40
`
`Diagnosis and Evaluation
`Patients with signs and symptoms of UI should undergo a com-
`plete medical evaluation to rule out reversible causes of the dis-
`order. Formulating an accurate diagnosis may require the partic-
`ipation of clinicians with specialized training in urology. Clinically,
`patients with UI present with a variety of symptoms, depending on
`the type and severity of the condition. Patients with UUI usually
`experience urgency episodes that result in loss of urine. Women
`with SUI usually experience small amounts of leakage related to
`external stimuli, such as coughing or sneezing. Men with OFI sec-
`
`ondary to BPH usually experience LUTS, including difficulty ini-
`tiating a urine stream, the presence of a weak stream, a sense of
`incomplete emptying, nocturia, and dribbling.1,4,25,38 The impor-
`tance of a correct diagnosis cannot be overemphasized. A complete
`review of the patient’s history, including comorbidities, is neces-
`sary for the development of an appropriate treatment plan.47,48
`Urodynamic studies assist clinicians in determining the precise
`cause of UI and are an important part of the diagnostic process.
`Urodynamic assessments include a variety of measures that
` evaluate urine flow, including flow rate, post-void residual urine,
`filling cystometry, bladder pressure, and urethral pressure. These
` assessments provide an extensive description of lower urinary
`tract function and are helpful in determining the appropriate man-
`agement strategy or in evaluating treatment failures.1,49–51
`Because UI in older adults is associated with a high risk of
` institutionalization and comorbidities, including depression and
`UTIs, appropriate assessment of transient UI is essential. Transient
`UI may have an abrupt onset and may last less than 6 months. Be-
`cause caregivers and health care professionals may erroneously
`consider UI an inevitable consequence of aging, failure to identify
`transient forms of the disorder may result in a permanent diag-
`nosis and poor patient outcomes. Various tools, including bladder
`diaries and the mnemonic described in Table 1, should be helpful
`in identifying and treating underlying causes of transient UI.
`
`Brain (micturition center)
`
`Sympathetic nervous system (SNS)
`(beta-adrenergic receptors)
`
`SNS
`inhibition
`
`Spinal cord
`(thoracic and
`lumbar regions)
`
`Detrusor muscle
`
`Bladder
`
`Parasympathetic
`nervous system (PNS)
`(cholinergic receptors)
`
`Internal
`sphincter
`(alpha-adrenergic
`receptors)
`
`External
`sphincter
`
`Somatic (pudendal) nerve
`
`Urethra
`
`(Sacral region)
`
`Figure 1 Bladder anatomy and physiology.
`
`Illustration by Alison Schroeer
`
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`Petitioner Amerigen Pharmaceuticals Ltd.
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`Management of Urinary Incontinence
`
`Initial questions for patients suspected of having UI may include
`“Have you ever leaked urine?” or “Have you lost bladder control?”
`Bladder diaries may be used to assess patterns of voiding, fre-
`quency, and volume. Questionnaires may also be helpful, although
`they depend on the patient’s or the caregiver’s memory.45–49
`Because only approximately 20% of women with UI seek med-
`ical attention, and because there is the misconception that urinary
`leakage is a normal part of aging, health care practitioners should
`aim discussions at identifying women who are experiencing UI and
`need further evaluation.7,41,51,52 Pharmacists should have a thor-
`ough understanding of UI and its pharmacotherapeutic manage-
`ment. A comprehensive understanding of UI is necessary to opti-
`mize pharmacotherapy and to allow the pharmacist to review the
`patient’s medical profile for medications that might be causing or
`exacerbating the disorder.33,34,25,42 Because many patients with UI
`are older, it is often necessary to make dosage adjustments in their
`medications. Because of changes in both pharmacokinetics and
`pharmacodynamics in elderly populations, additional monitoring
`to avoid drug-related adverse events is required.52
`
`Nonpharmacological Management:
`Conservative Measures and Exercises
`The management of UI should include an evaluation of poten-
`tial reversible contributors and trials of nonpharmacological inter -
`ventions, which depend on the type of UI identified. Clinical stud-
`ies support proper nutrition, the avoidance of constipation, weight
`loss, and physical activity as beneficial in improving symptoms.53–
`61 A study of weight loss in overweight women reported a clinically
`relevant reduction in the frequency of both stress and urge in-
`continence episodes.58 Women who are able to engage in regular
`daily exercise of moderate intensity are reported to have a lower
`incidence of UI than sedentary women, although the ability to ex-
`ercise may be limited by physical disabilities in elderly women.
`Other non-drug interventions for UI include prompted or timed
`voiding, habit retraining, and praises for appropriate toileting. Suc-
`cess with these interventions requires the patient’s awareness of
`the need to void and the ability to delay voiding if necessary. These
`interventions, along with exercise, are associated with modest
`
`Table 1 Reversible Causes of Urinary Incontinence
`(DIAPPERS)
`
`D
`
`I
`
`A
`
`P
`
`P
`
`E
`
`R
`
`S
`
`Delirium
`
`Infection (urinary tract)
`
`Atrophic
`
`Pharmacological
`
`Psychological
`
`Endocrine/excess urine output
`
`Restricted mobility
`
`Stool impaction
`
`Data adapted from references 38–46.
`
`and short-term improvements in daytime UI. Absorbent products
`or pads may also be helpful to some patients; the use of these prod-
`ucts should be based on the needs of the patient rather than on the
`convenience of the caregiver or facility staff. The drugs listed in
`Table 2 are often problematic in these patients and may contribute
`to or exacerbate UI; thus, evaluation may be necessary.62–68
`Pelvic floor (Kegel) muscle training and bladder training have
`been beneficial in resolving or improving UI.69,70 Kegel exercises
` involve strengthening and retraining the detrusor bladder muscle to
`regain some control of urinary function. Evidence supports the use
`of this behavioral intervention in the treatment of UUI, SUI, and MUI.
`Choi et al. suggested that these exercises might be most effective
`in younger women with predominantly stress-related incontinence.71
`The training process involved in learning these exercises may
`be complex for some patients, especially older adults with mem-
`ory disorders.69–71 Comparisons of various conservative tech-
`niques, using a device that monitors compliance and the per-
`formance of exercises, showed that pelvic floor exercises, alone
`or in combination with biofeedback or electrical stimulation, may
`be beneficial for patients with SUI or MUI.53,54,56,72
`The treatment of UI in older adults living in the community is
`
`Table 2 Medications That Can Cause or Exacerbate Urinary Incontinence
`
`Classification
`
`Medication
`
`Activity
`
`Alpha-adrenergic agonists
`
`Nasal decongestants
`
`Alpha-adrenergic antagonists
`
`Prazosin, terazosin, doxazosin, silodosin, alfuzosin
`
`Urinary retention in men with overflow
` incontinence related to BPH
`
`Urethral relaxation; may cause or exacerbate
`stress incontinence in women
`
`Anticholinergic drugs
`
`Antihistamines, tricyclic antidepressants, some
` antipsychotics
`
`Anticholinergic actions; urinary retention in
` overflow incontinence or impaction
`
`Antineoplastic drugs
`
`Vincristine
`
`Urinary retention
`
`Calcium-channel blockers
`
`Dihydropyridines (e.g., nifedipine)
`
`Diuretics
`
`Furosemide, bumetanide
`
`Narcotic analgesics
`
`Opiates
`
`Sedatives/hypnotics
`
`Long-acting benzodiazepines (e.g., diazepam,
` flurazepam)
`
`BPH = benign prostatic hyperplasia.
`Data adapted from references 25, 33, 34, and 42–46.
`
`Urinary retention; nocturnal diuresis resulting
`from fluid retention
`
`Polyuria; frequency; urgency
`
`Urinary retention; sedation
`
`Sedation; delirium; immobility
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`Management of Urinary Incontinence
`
`often overlooked, but if the disorder is identified in these individ-
`uals, it can be successfully managed with conservative measures.
`The use of nonpharmacological interventions, including Kegel
` exercises and bladder retraining, can be effective even in frail older
`adults, especially with caregiver assistance. Medications may be
`necessary in some patients, however, and treatment outcomes may
`be less successful in patients with advanced age and severe UI.73
`
`Pharmacotherapy: Estrogen Replacement
`The loss of estrogen during menopause has multiple effects on
`postmenopausal women, including atrophic tissue changes in the
`urogenital tract. These physiological changes may result in dry-
`ness, burning, itching, dyspareunia, and infections along with
` additional LUTS, including frequency and urgency.74–77 Hormone
`therapy (HT) has always been considered a therapeutic option for
`the management of postmenopausal symptoms. HT offers signif-
`icant benefits in the management non-urogenital features, such as
`hot flashes, and may relieve the vaginal dryness associated with
`menopause. In addition, HT has been used to improve LUTS be-
`cause of its effect on estrogen receptors in the urogenital area.78,79
`During the past decade, the use of exogenous estrogen in post-
`menopausal women has become controversial because of con-
`cerns about increased rates of breast cancer and the risk of vascular
`disease–related morbidity (e.g., clotting and stroke).80 The role of
`estrogen in the management of UI is also contro versial because data
`have suggested that HT provides only minimal benefit in UI and
`may even exacerbate the disorder.81–85 The basis for the assump-
`tion that estrogen would be beneficial in UI is the presence of es-
`trogen and progesterone receptors throughout the genital tract,
`bladder, and vaginal epithelium. The presence of these receptors
`led investigators to theorize that HT could be a useful treatment for
`UI, especially stress urinary incontinence (SUI).74–77,85–92
`Some clinical trials, however, have not supported the use of oral
`HT for managing UI.84,93 In a meta-analysis of 28 clinical studies of
`approximately 3,000 women with UI and in controlled trials of
` estrogen in more than 700 women with features of UUI and SUI,
`greater improvement of symptoms was reported for estrogen-
`treated patients with UUI than for the control groups; however, no
`beneficial effects were observed among patients with SUI.94
`Other controlled studies showed that the use of estrogen alone
`or in combination with progestin may contribute to or increase the
`incidence of UI, especially SUI, in postmenopausal women.95–102
`The Nurse Health Study reported an increased risk of UI associ-
`ated with the use of estrogen, with or without progestin therapy,
`in younger postmenopausal women (37–54 years of age).95
` Additional retrospective data from this study suggested an
` association between the use of oral contraceptives and UI in
` premenopausal women.96
`The Women’s Health Initiative (WHI), a randomized controlled
`trial involving more than 23,000 postmenopausal women 50 to 79
`years of age, reported that HT increased the incidence of UI at
`1 year; the highest incidence was in women with SUI. Estrogen
`alone or taken with progestin increased the risk of UI among con-
`tinent women and worsened the features of UI among symptomatic
`women after 1 year.97–100 The Heart Estrogen/Progestin Replace-
`ment Study (HERS), a randomized, placebo-controlled, double-
`blinded trial, evaluated conjugated estrogen plus progestin for
`the secondar y prevention of heart disease in 1,200 women.
` Estrogen plus progestin increased the risk of UUI and SUI within
`4 months after initiation of treatment.101,102
`These trials showed that conjugated estrogen alone and in com-
`bination with progestin increased the risk of UI and exacerbated
`
`348 P&T® • June 2012 • Vol. 37 No. 6
`
`existing UI in postmenopausal women. HT, therefore, should not
`be used for the prevention or treatment of UI. Additional associa-
`tions between HT and cerebrovascular disease and breast cancer
`in postmenopausal women should further increase the reluctance
`to use HT in postmenopausal women with UI.103,104
`The role of topical estrogens in the management of UI is unclear;
`more study is needed to investigate these formulations in UI.78,105
`Evidence supports the use of topical or localized estrogen in treat-
`ing UUI caused by postmenopausal atrophic changes, which result
`in the loss of urethral support and in symptoms of UI.74,106 Topical
`estrogen formulations may include creams or estradiol-impreg-
`nated vaginal rings. The mechanisms of topical estrogen in this set-
`ting may include an increased blood supply and increased mucosal
`thickness, resulting in improved function of the lower urogenital
`system. Although these benefits have been reported in elderly
`women with atrophic changes and concurrent OAB, they have not
`been reported in women with SUI.107–109
`
`Classification and Treatment
`Urinary incontinence is usually classified in the format de-
`scribed in Table 3, although many patients may experience symp-
`toms that suggest a mixed disorder. An overview of the various
`types of UI is presented in Table 3.3,4,30,31,110–112 The next sections
`discuss urge UI, stress UI, overflow incontinence, and mixed UI.
`
`URGE URINARY INCONTINENCE
`Urge (urgency) urinary incontinence (UUI) is a common cause
`of incontinence in elderly people. It is characterized by urgency,
`followed by involuntary loss of urine. UUI is sometimes referred
`to as OAB. However, the terms are not inter changeable, because
`about two-thirds of patients with OAB do not have UI.1,31
`UUI occurs primarily as a result of detrusor muscle over activity,
`resulting in uninhibited or involuntary muscle contractions.26–28
`Patients with UUI describe a sudden desire to urinate that is dif-
`ficult to defer, resulting in leakage of urine. These episodes may
`occur at various times during the day or night.31,114 The primary
`causes of UUI (see Table 3) include idiopathic detrusor overac-
`tivity (resulting from UTIs) and neurogenic detrusor overactivity
`(resulting from stroke, trauma, neurological diseases, or medica-
`tions).25–28,43–46,112 The severity of age-related volumetric changes in
`the brain’s white matter may be associated with urinary urgency,
`and this process may have impli cations for future UI therapies.115,116
`
`Nonpharmacological Management
`The nonpharmacological management of UUI includes bladder
`training, behavioral treatments; pelvic floor exercises; the avoid-
`ance of caffeine; the use of pads for temporary bladder support;
`and, in some cases, surgery.117,118 Behavioral therapy in combina-
`tion with drug therapy has produced variable results. Behavioral
`interventions, including educational brochures with verbal rein-
`forcement, were beneficial in UUI patients who were dissatisfied
`with anticholinergic drug therapy.118 Behavioral training, includ-
`ing Kegel exercises and urge-suppression techniques, was found
`to be ineffective in improving outcomes in women with UUI.53,54,119
`
`Pharmacotherapy
`Anticholinergic (Antimuscarinic) Agents
`The current focus of pharmacotherapy for UUI is control of de-
`trusor muscle overactivity through the inhibition of M2 and M3
`muscarinic (acetylcholine) receptors on the bladder.120–122 Nu-
`merous drugs that act as acetylcholine antagonists (anticholiner-
`gic agents) are available for the treatment of UUI and can reduce
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`Management of Urinary Incontinence
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`symptoms of urgency and improve bladder control. Because mus-
`carinic receptors are located in other organ systems throughout
`the body, their inhibition can have a variety of physiological and
`adverse effects.
`The five most commonly used types of muscarinic receptors,
`their anatomic locations, and the adverse effects that can result
`from their inhibition are presented in Table 4. Table 5 lists the avail-
`able antimuscarinic (anticholinergic) agents used to treat UUI.
`Each of these agents is discussed on the following pages.123–126
`Antimuscarinic side effects are associated with both central
`and peripheral adverse reactions (see Table 4). Central adverse
`
` effects include delirium, confusion, and exacerbation of existing
`memory loss; these effects are especially concerning in elderly
` patients. Peripheral adverse effects include constipation, dry eye,
`and urinary retention.25,120,127,128
`Contraindications to the use of anticholinergic agents include
` uncontrolled narrow-angle glaucoma, a risk of urinary or gastric
`retention, the presence of underlying delirium or dementia, and
`a hypersensitivity to these drugs. Cautious use of anticholinergic
`drugs is recommended in patients with myasthenia gravis and with
`some gastrointestinal (GI) disorders, such as ulcerative colitis,
` intestinal atony, and gastroesophageal reflux disease.129–134
`
`Table 3 Causes, Symptoms, and Treatment of Urinary Incontinence
`
`Type of Incontinence
`
`Common Causes
`
`Common Symptoms
`
`Treatment Options
`
`Urge urinary incontinence (UUI)
`
`Idiopathic detrusor overactivity Urinary tract infections
`
`Neurogenic detrusor
`overactivity
`
`• Neurological disorders
`• Parkinson’s disease
`• Alzheimer’s disease
`• Cerebrovascular accidents
`(e.g., stroke)
`• Trauma
`• Medications
`
`Urgency and frequency,
`day or night
`
`• Anticholinergic drugs
`• Oxybutynin
`• Tolterodine
`• Surgery
`• Intravesical Botox
`• Sacral nerve stimulation
`
`Stress urinary incontinence (SUI)
`
`Stress incontinence
`(outlet incompetence)
`
`• Pelvic surgery
`• Parity (childbirth)
`• Constipation
`
`Small volumes of urine
`loss with coughing or
`sneezing
`
`• Weight loss
`• Kegel (pelvic floor) exercises with
`or without biofeedback
`• Sling procedures
`• Transurethral collagen
`denaturation (Renessa
`procedure)
`• Transurethral bulking agents
`
`Mixed urinary incontinence (MUI)
`
`Mixed UUI and SUI
`
`• Pelvic surgery
`• Parity (childbirth)
`• Constipation
`
`Symptoms may include
`urge and stress features
`
`Treatment depends on predomi-
`nant symptoms
`
`Overflow incontinence (OFI)
`
`Overflow incontinence
`
`• Benign prostatic hyperplasia
`(BPH)
`• Bladder outlet obstruction
`• Fecal impaction
`• Hypotonic/neurogenic bladder
`• Urethral stricture disease
`
`Poor stream, incomplete
`emptying, and dribbling
`
`• Alpha-adrenergic blockers
`• 5-alpha-reductase inhibitors
`• Intermittent catheterization
`• Surgical options
`
`Other types of incontinence
`
`Post-prostatectomy
`incontinence
`
`Disruption or denervation of pelvic
`floor muscle fibers
`
`Stress incontinence and
`dribbling
`
`• Kegel pelvic floor exercises
`• Male urethral sling
`• Artificial urinary sphincter
`
`Fistula (e.g., colovesical or
`vesicovaginal)
`
`Functional incontinence
`
`• Postsurgical complications
`• Crohn’s disease
`• Diverticulitis
`• Cancer
`
`• Limited mobility
`• Change in mental status
`
`Data compiled from references 1–4, 30, and 110–112.
`
`Continuous, steady
`incontinence
`
`Surgical repair
`
`Symptoms vary
`
`Eliminate causes
`
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`Management of Urinary Incontinence
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`Gopal et al. reported high discontinuation rates for anti -
`cholinergic drugs that were used to treat LUTS in women.135 The
`study authors estimated overall and drug-specific discontinuation
`rates for nine agents in approximately 30,000 women over a
`6-month period. Discontinuation rates were high for all anti -
`cholinergic drugs regardless of class. The overall dis continuation
`rate was 60%; oxybutynin (Ditropan, Janssen) and extended- release
`(ER) tolterodine (Detrol LA, Pfizer) were discontinued at rates of
`71% and 54%, respectively. Some limitations of the study included
`diagnoses based on electronic medical data and a lack of data
`about why patients stopped therapy. The results suggest a need for
`more effective and tolerable therapies for UUI, including more
` vigilant use of nonpharmacological interventions, such as fluid
`modification, pelvic floor rehabilitation, and bladder training.135
`Anticholinergics have the potential to interact with other med-
`ications that have the same side-effect profile and with other cen-
`trally acting drugs.120 The concomitant use of acetylcholinesterase
`inhibitors for dementia and anticholinergic drugs may exacerbate
`cognitive decline and should be avoided if possible.136
`As shown in Table 5, all of the anticholinergic agents used to treat
`UI, except trospium chloride (Sanctura, Allergan/Esprit/
`Indevus), are metabolized by hepatic cytochrome P450 (CYP)
` enzymes; inhibitors of these enzymes, therefore, may potentiate the
`adverse effect of anticholinergic drugs. Clinicians should monitor
`patients with UUI, especially older adults and those taking multiple
`medications, for adverse effects, drug interactions, and potential
` contraindications during treatment with anticholin ergics.25,120,137
`Older drugs, such as propantheline (Pro-Banthine, Shire),
` dicyclomine (Bentyl, Axcan Pharma), and flavoxate (Urispas,
`Ortho-McNeil), are still available, but they are rarely used because
`of their questionable efficacy and side-effect profiles. The tricyclic
` antidepressant imipramine (Tofranil, Mallinckrodt) has been used
`to treat patients with UUI and may have a role in MUI because of
`its dual anticholinergic and alpha-adrenergic properties.120, 128,138–141
`Currently, the anticholinergic drugs most commonly used in
`clinical practice for the treatment of UUI include transdermal
` oxybutynin (Oxytrol, Watson Pharma), oxybutynin gel (Gelnique,
`Watson Pharma), tolterodine (Detrol and Detrol LA, Pfizer),
` trospium chloride, darifenacin (Enablex, Novartis), solifenacin
`(VESIcare, Astellas/GlaxoSmithKline), and ER fesoterodine
`(Toviaz, Pfizer) (see Table 5).138–141
`As mentioned, several anticholinergic agents are available in var-
`ious doses, formulations, and routes of administration, providing
`clinicians with several treatment options for with UUI.128,132,137,138,141
`
`These drugs are usually used to treat UUI and OAB in patients who
`have not achieved symptom relief and improved quality of life
`with conservative nonpharmacological interventions.
`
`Clinical Efficacy
`Efficacy data for anticholinergic drugs in patients with UUI have
`been obtained from a number of meta-analyses and head-to-head
`trials. Two large meta-analyses reported similar clinical efficacy
`among the available anticholinergic agents, as measured by
` reductions in episodes of urgency and incontinence, frequency,
`daily micturition, nocturnal awakenings, increased volume per
`void, patient satisfaction, and quality of life.141,142 Another meta-
`analysis included data from 50 randomized controlled trials and
`three pooled analyses that included various formulations and doses
`of anticholinergic agents. This study reported advantages with ER
` formulations in terms of efficacy and safety. Dose escalations with
` immediate-release (IR) formulations provided some improvement
`in efficacy but with an increased risk of adverse events.143
`Head-to-head trials with anticholinergic agents have reported
`similar efficacy or insignificant differences among the various
`drugs. Tolerability differences were evident in some studies,
` especially when other drugs were compared with IR oxybutynin.
`One report described the available anticholinergic agents as equiv-
`alent first choices, except for oral oxybutynin administered at
`dosages of more than 10 mg/day, which were associated with a
`higher rate of adverse effects.144 The study data showed a smaller
`treatment effect with anticholinergics compared with placebo than
`what might be expected in clinical practice. This difference might
`have been due to the use of concurrent bladder training in some
`patients who were prescribed these drugs in the clinical setting,
`compared with the absence of this intervention in clinical trials. The
`literature is devoid of direct comparisons between anticholinergic
`drugs and bladder-training interventions.53,54,142–147
`Oxybutynin (Ditropan, Oxytrol). Oxybutynin is the oldest of
`the agents currently used to treat UUI. It is available in IR and ER
`oral formulations (Ditropan and Ditropan XL, Janssen), along
`with a dermal patch and topical gel formulations (see Table 5).
`Oxybutynin is considered the gold standard with which other
`agents in the class are compared. Trial data indicate that the effi-
`cacy of oxybutynin is similar to that of other anticholinergic drugs.
`The significance of its proposed muscle-relaxant properties is
` unclear.148 The ER tablet, dermal patch, and topical gel may offer
`improved tolerability because of reduced levels of the active
`metabolite, N-desethyloxybutynin.149–153
`
`Table 4 Muscarinic Receptor Subtypes and Adverse Effects of Receptor Inhibition
`
`Organ System
`
`Receptor Subtype
`
`Adverse Effects of Inhibition (Anticholinergic Effects)
`
`Bladder (detrusor muscle)
`
`Cardiac tissue
`
`M2, M3
`
`M2
`
`Decreased contractions; urinary retention
`
`Tachycardia; palpitations
`
`Central nervous system and brain
`(cortex and hippocampus)
`
`M1, M2, M3, M4, M5
`
`Effects on memory, cognition, and psychomotor speed; confusion;
`delirium; sedation; hallucinations; sleep disruption
`
`Eyes (ciliary muscle and iris)
`
`M3, M5
`
`Dry eyes; blurred vision; mydriasis (dilation of the pupil)
`
`Gastrointestinal tract
`
`M1, M2, M3
`
`Sl