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The new england journal of medicine Alastair J.J. Wood, M.D., Editor Management of Overactive Bladder Joseph G. Ouslander, M.D.
From the Division of Geriatric Medicine veractive bladder is a symptom complex that includes uri- and Gerontology, Wesley Woods Center, nary urgency with or without urge incontinence, urinary frequency (voiding Center for Health in Aging, Emory Univer- eight or more times in a 24-hour period), and nocturia (awakening two or sity, and the Birmingham/Atlanta VeteransAffairs Geriatric Research Education Clini- more times at night to void).1-3 The International Continence Society classifies over- cal Center — both in Atlanta. Address re- active bladder as a syndrome for which no precise cause has been identified, with local print requests to Dr. Ouslander at the Wes- abnormalities ruled out by diagnostic evaluation.4,5 This review extends beyond the In- ley Woods Center of Emory University, 1841Clifton Rd., NE, Atlanta, GA 30329, or at ternational Continence Society's current definition of overactive bladder, since a broad- er approach to this syndrome is essential for optimal management.6,7 Because overactive bladder is a recently defined syndrome, its prevalence and natural N Engl J Med 2004;350:786-99.
Copyright 2004 Massachusetts Medical Society. history have not been well studied. In a telephone survey of 16,776 adults who were 40years of age or older in Europe, 16 percent of men and 17 percent of women reportedsyndromes suggestive of overactive bladder. The prevalence was 3 percent among men40 to 44 years of age, 9 percent among women 40 to 44 years of age, 42 percent amongmen 75 years of age or older, and 31 percent among women 75 years of age or older.9Similar data on the prevalence of overactive bladder have been reported in the UnitedStates.10 Patients with symptoms of overactive bladder tend to curtail their participation in so- cial activities and to isolate themselves and are predisposed to depression. Nocturia isassociated with sleep disruption, which decreases the quality of life.11-14 Postmeno-pausal women with urge incontinence have a substantially higher risk of falling andsustaining a fracture than women without urge incontinence.15 The costs of overactivebladder are probably high but have not been studied systematically. The total costs ofurinary incontinence in the United States in 1995 were estimated to be approximately$26 billion. A substantial proportion of this cost is attributable to urge incontinence,one of the cardinal symptoms of overactive bladder.16 The symptoms of overactive bladder have many potential causes and contributing factors(Table 1).1-3 Urination involves the higher cortex of the brain; the pons; the spinal cord;the peripheral autonomic, somatic, and sensory afferent innervation of the lower urinarytract; and the anatomical components of the lower urinary tract itself. Disorders of anyof these structures may contribute to the symptoms of overactive bladder. The normalbladder functions like a compliant balloon as it fills, with pressure remaining lowerthan urethral resistance. With the initiation of normal urination, urethral resistance de-creases and a phasic contraction of the detrusor muscle empties the bladder (Fig. 1A).
The symptoms of overactive bladder are usually associated with involuntary contractionsof the detrusor muscle (Fig. 1B). Overactivity of the detrusor muscle, whether neuro-genic or idiopathic, can result in urgency or urge incontinence, depending on the re- february 19, 2004 Downloaded from www.nejm.org at BERKSHIRE MED CTR on August 21, 2006 . Copyright 2004 Massachusetts Medical Society. All rights reserved. sponse of the sphincter.17 Detrusor overactivity may Increasing attention has been paid to the role of also have a myogenic origin.18 Detrusor contrac- sensory afferent nerves in normal voiding and detru-tions can be weak as a result of impaired contract- sor overactivity.20-22,29 During bladder filling, affer-ibility. Urodynamic testing indicates that up to half ent activity from the bladder and urethra reaches theof elderly patients with detrusor overactivity empty spinal cord predominantly by means of the pelvicless than one third of their bladder contents with nerve. Sensory input during bladder filling resultsan involuntary bladder contraction19; incomplete in an increase in sympathetic tone, which inhibitsemptying can contribute to urinary frequency by bladder parasympathetic motor nerves, causinglowering the functional capacity of the bladder.
contraction of the bladder base and urethra. Adre- A variety of efferent and afferent neural pathways, nergic activity may also cause relaxation of the detru- reflexes, and central and peripheral neurotransmit- sor muscle through the stimulation of b -adrener- ters are involved in urine storage and bladder empty- gic receptors (Fig. 2).30 Myelinated A delta sensorying. The relation among these factors is incomplete- fibers respond to passive distention and actively understood. The role of central neurotransmitters contraction of the detrusor muscle. Unmyelinatedin the voiding cycle has been studied in animals.20-22 C sensory fibers have a higher mechanical thresholdGlutamate is an excitatory neurotransmitter in path- and respond to a variety of neurotransmitters (Fig.
ways controlling the lower urinary tract. Serotoner- 3). C fibers are relatively inactive during normal void-gic activity facilitates urine storage by enhancing the ing, but they may have a critical role in symptoms ofsympathetic reflex pathway and inhibiting the para- overactive bladder in patients with neurologic andsympathetic voiding pathway. Dopaminergic path- other disorders. Several types of receptors have beenways may exert both inhibitory and facilitatory ef- identified on afferent nerves, including vanilloid re-fects on voiding. Dopamine D1 receptors appear to ceptors, which are activated by capsaicin and possi-have a role in suppressing bladder activity, whereas bly by endogenous anandamide; purinergic recep-dopamine D2 receptors appear to facilitate voiding. tors (P2X), which are activated by ATP; neurokininOther neurotransmitters, such as g-aminobutyric receptors, which respond to substance P and neuro-acid and enkephalin, inhibit voiding in animals.
kinin A; and receptors for nerve growth factor (trk-A Acetylcholine, which interacts with muscarinic receptors).20,31 Other substances, including nitric receptors on the detrusor muscle, is the predomi- oxide, calcitonin gene–related protein, and brain-nant peripheral neurotransmitter responsible for derived neurotropic factor, may also have an impor-bladder contraction. Of the five known muscarinic tant role in modulating the sensory afferents in thesubtypes (M1 through M5), M3 appears to be the human detrusor.20-22 A better understanding of themost clinically relevant in the human bladder.20 Ace- complex interplay among these various neurotrans-tylcholine interacts with the M3 receptor, initiating mitters and other substances derived from uroepi-a cascade of events that results in contraction of the thelium, detrusor-muscle cells, and afferent fibersdetrusor muscle (Fig. 2). Data from studies of rat themselves should yield new and more specific tar-bladders suggest that the M2 receptor may also fa- gets for drug treatment of overactive bladder.
cilitate bladder contraction by reducing intracellularlevels of cyclic adenosine monophosphate.23 Pathologic states can alter sensitivity to musca- rinic stimulation. For example, bladder-outflow ob- Effective treatment of patients with symptoms ofstruction appears to enhance responsiveness to ace- overactive bladder necessitates a targeted diagnostictylcholine, a phenomenon similar to denervation evaluation. Guidelines for the management of uri-suprasensitivity.20 Normally, only a small propor- nary incontinence32 and benign prostatic hyper-tion of the bladder contraction is resistant to atro- plasia33 are relevant to the evaluation of symptomspine, probably as a result of the interactions of ATP of overactive bladder. A focused history that includeswith purinergic receptors. However, ATP may have information about past genitourinary disorders anda more prominent role in bladder contraction in pa- other conditions outlined in Table 1 should be elic-tients with overactive bladder.20-22 Anatomical cor- ited from all patients. A symptom index for benignrelates of detrusor overactivity have also been de- prostatic hypertrophy (recommended by the Amer-scribed. For example, the bladders of patients with ican Urological Association) or a similar symptomdetrusor overactivity appear to have abnormal gap index is helpful to include as part of the evaluationjunctions between smooth-muscle cells.24-28 Such in older men.34,35 A variety of questionnaires re-correlates require further study.
garding lower urinary tract symptoms have also n engl j med 350;8 february 19, 2004 Downloaded from www.nejm.org at BERKSHIRE MED CTR on August 21, 2006 . Copyright 2004 Massachusetts Medical Society. All rights reserved. The new england journal of medicine Table 1. Conditions That Can Cause or Contribute to Symptoms of Overactive Bladder.
Mechanisms or Effect
Implications for Management
Lower urinary tract conditions
Urinary tract infection Inflammation with activation of sensory Treat infection before other interventions are con- afferent innervation can result.
Obstruction can contribute to detrusor Consider surgical intervention.
overactivity and urinary retention.
Impaired bladder contractility Urinary retention and reduced functional Avoid drugs that decrease bladder contractility.
bladder capacity can result.
Teach patients to enhance voiding (e.g., Credé's Intermittent catheterization is helpful in selected Bladder abnormalities or inflammation Intravesical abnormalities can precipitate Sterile hematuria and risk factors for bladder (e.g., tumors, calculi, interstitial cancer should prompt further evaluation.
Estrogen deficiency Inflammation from atrophic vaginitis and Topical estrogen may ameliorate symptoms.
urethritis can contribute to symptoms.
Sphincter weakness Leakage of urine into proximal urethra Topical estrogen and pelvic-muscle exercises may may precipitate urgency.
help strengthen the sphincter.
Ability to inhibit detrusor by sphincter Periurethral injections or surgical procedures may contraction may be diminished.
be helpful in selected patients.
Prostate enlargement Benign or malignant prostate enlarge- Evaluation and treatment for prostate cancer ment can contribute to detrusor should be considered.
Alpha-adrenergic blockers may improve symptoms.
5a-Reductase inhibitors may reduce prostate size.
Surgical removal of obstructing prostate may be Stroke, Alzheimer's disease, multi- Higher cortical inhibition of the bladder Management must include a means of compensa- infarct dementia, other dementias, is impaired, causing neurogenic tion for impaired cognition, impaired mobility, Parkinson's disease, multiple sclerosis Multiple sclerosis, cervical or lumbar Neurogenic detrusor overactivity or urinary Presence of neurologic symptoms or signs may stenosis or disk herniation, spinal retention can result.
require further evaluation.
Urodynamic testing is often indicated for diag- nostic purposes.
Peripheral innervation Diabetic neuropathy, nerve injury Urinary retention and low functional blad- History suggestive of nerve injury or neurologic der capacity can result.
signs require further evaluation.
been developed for women.36 In addition, diaries lected patients. The presence of residual urine aftercan be helpful in determining the frequency, vol- voiding should be determined in patients with riskume, and pattern of voiding, as well as providing factors for urinary retention (diabetes, spinal cordclues to underlying causes and contributing fac- disease, and benign prostatic hypertrophy). This cantors.37,38 All patients should undergo a focused be accomplished by sterile in-and-out catheteriza-physical examination that includes genitourinary, tion. A portable ultrasonographic device is availablepelvic, and rectal examinations; a clean urine spec- that permits noninvasive identification of clinicallyimen should be obtained to rule out hematuria and significant residual urine (>100 ml), with an accu-infection.
racy rate of more than 90 percent; it costs approxi- Further evaluation should be considered in se- mately $8,000.39 Patients with sterile hematuria or february 19, 2004 Downloaded from www.nejm.org at BERKSHIRE MED CTR on August 21, 2006 . Copyright 2004 Massachusetts Medical Society. All rights reserved. Table 1. (Continued.)
Mechanisms or Effect
Implications for Management
Congestive heart failure, venous Volume overload can contribute to urinary Proper timing of diuretics may ameliorate symptoms.
frequency and nocturia when patient Use of leg elevation, support hose, and salt restriction may be helpful.
Diabetes mellitus Poor blood glucose control can contribute Improved blood glucose control may ameliorate to osmotic diuresis and polyuria.
Sleep disorders (sleep apnea, periodic Sleep disorders can contribute to nocturia.
Reports of sleep disruption or heavy snoring may require further evaluation.
Abnormalities of arginine vasopressin Impaired secretion or action of vasopressin Carefully selected patients may benefit from desmo- may cause polyuria and nocturia.
pressin therapy.
Functional and behavioral conditions
Excess intake of caffeine, alcohol; Polyuria and urinary frequency can result.
Modification of fluid intake is critical for successful Poor bowel habits and constipation Fecal impaction can contribute to symptoms. An appropriate bowel regimen will reduce the inci- dence of fecal impaction.
Impaired mobility (e.g., in patients with Impaired mobility can interfere with toilet- Treatment of underlying disorders, including physi- degenerative joint disease, Par- ing ability and precipitate urge incon- cal therapy, should be optimal; the use of urinals, kinson's disease, severe osteo- bedside commodes, and bedpans can be helpful.
porosis, or muscle weakness) Psychological conditions Chronic anxiety and learned voiding dys- The diagnosis should be considered on the basis of function can cause symptoms of over- a patient's history and physical examination.
active bladder.
Side effects of medication
Diuretics, especially rapid-acting agents Diuretics cause a rapid increase in bladder Changing to a longer-acting diuretic, altering the volume, which may precipitate urgency timing of the dose, or discontinuing the drug, and detrusor overactivity.
if appropriate, can ameliorate symptoms.
Anticholinergic agents, narcotics, These agents decrease bladder contractility Such drugs should be discontinued whenever calcium-channel blockers and may cause urinary retention, with a decreased functional bladder capacity.
These agents could theoretically contribute No clinical studies have documented such effects, to detrusor overactivity by increasing but they should be considered in patients in whom symptoms develop after the initiation of one of these agents.
risk factors for bladder cancer should undergo cys- method of ruling out obstruction in older men.40toscopy, and their urine should be sent for cytologic More complex urodynamic testing may be necessaryanalysis. Cystoscopy is also indicated in patients in patients with nonspecific symptoms and may be awith a history of recurrent urinary tract infection. Al- more accurate approach to the diagnosis of obstruc-though some urologists and gynecologists suggest tion than less invasive testing. Because this test isthat all patients in whom symptoms of overactive relatively expensive and invasive, it is recommend-bladder develop should undergo cystoscopy to rule ed only to evaluate symptoms of overactive blad-out carcinoma in situ and other intravesical abnor- der in cases in which the findings will clearly influ-malities, the cost effectiveness of this approach is ence treatment, such as after the failure of initialuncertain. Because early prostate cancer can cause therapy.1-3,7symptoms of overactive bladder, the possibility ofprostate cancer should be assessed.
The role of urodynamic testing in the evaluation of patients with symptoms of overactive bladder is Optimal therapy for overactive bladder depends oncontroversial. A noninvasive determination of the a thorough evaluation, followed by treatment of allurinary flow rate, combined with a measurement of the likely causes and contributing factors (Table 1).
residual urine after voiding, appears to be a sensitive The genesis of symptoms of overactive bladder is n engl j med 350;8 february 19, 2004 Downloaded from www.nejm.org at BERKSHIRE MED CTR on August 21, 2006 . Copyright 2004 Massachusetts Medical Society. All rights reserved.

The new england journal of medicine mixed urge–stress incontinence. Educating patients about bladder function, appropriate fluid intake (avoidance of caffeine, maintenance of adequate hy- dration, and the timing of fluid intake), and manag-ing constipation is important for all patients with overactive bladder. Education may, in fact, underlie the prominent placebo effects (approximately 30 percent improvement in symptoms) demonstratedrepeatedly in drug trials for incontinence and over- Striated sphincter- active bladder. Several randomized, controlled trials,largely involving middle-aged women and women under 75 years of age who had urge or mixed urge–stress incontinence, suggest that cognitively intact,motivated patients have a positive response to pel- vic-muscle exercises and "bladder training."41-43 Approximately 70 percent of patients have a reduc- tion in the number of episodes of incontinence with- Detrusor overactivity in two to three months. The long-term effectiveness of these interventions requires further study. Many patients can be taught pelvic-muscle exer- cises during a pelvic or rectal examination or can learn them with the use of simple educational tools Striated sphincter- such as an audiotape or a booklet.42 A substantialproportion of older patients benefit from biofeed-back-assisted training. "Bladder training" generally refers to a combination of patient education, sched-uled voiding and urge-suppression techniques, and Figure 1. Normal Voiding Physiology (Panel A) and Involuntary Detrusor Con-
pelvic-muscle exercises.41 For some patients with traction Commonly Associated with Symptoms of Overactive Bladder (Panel B).
cognitive impairment, limited mobility, or both, Normally, as bladder volume increases, the detrusor muscle functions like a the use of toileting-assistance protocols such as compliant balloon and maintains a low intravesicular pressure (less than 10 cm prompted voiding can be very helpful in the man- of water) — substantially lower than urethral resistance pressure (Panel A). As bladder volume continues to increase, the activity of the striated muscles agement of overactive bladder.44 All these behav- of the urethral sphincter increases. At the time of normal voluntary voiding, ioral interventions can also be effective adjuncts to which generally occurs at a urinary volume of 300 to 400 ml, muscle activity in drug therapy.
the sphincter ceases, urethral resistance decreases, and a phasic detrusor Some patients with severe symptoms of overac- contraction empties the bladder. In patients with symptomatic overactive tive bladder that are refractory to proven behavioral bladder, involuntary bladder contractions can cause urgency and may precip-itate urine loss, depending on the response of the sphincter (Panel B). Invol- treatment may benefit from other nonpharmaco- untary contractions may occur at any bladder volume, but they commonly oc- logic interventions. A wide variety of highly absor- cur at volumes of less than 200 ml. The sphincter-muscle activity depicted in bent pads and undergarments are available that can Panel B is a response to the involuntary contraction of the detrusor muscle be effective and acceptable in selected patients with (as opposed to detrusor–sphincter dyssynergy). Detrusor overactivity can be refractory symptoms in order to maintain "social neurogenic or idiopathic and can be accompanied by urgency or be without sensation.
continence" and good perineal hygiene.45,46 Onlylimited evidence of efficacy is available regardingmore invasive interventions. Electrical stimulationdelivered by vaginal or rectal probes can be helpful commonly multifactorial, and multimodal therapy in teaching some patients the proper use of pelvicthat includes nonpharmacologic as well as pharma- muscles (an approach similar to biofeedback), andcologic interventions may be indicated.
lower-frequency stimulation can inhibit bladdercontraction.47 Sacral neuromodulation by means of implantable stimulators is used in selected patients Various clinical trials suggest that behavioral inter- with severe neurogenic detrusor overactivity.48 Mag-ventions are efficacious for managing urge and netic stimulation has also been approved for the february 19, 2004 Downloaded from www.nejm.org at BERKSHIRE MED CTR on August 21, 2006 . Copyright 2004 Massachusetts Medical Society. All rights reserved.

treatment of incontinence, but this requires multi-ple visits to a facility that has the stimulation equip-ment. Surgical procedures, including motor-nerve ablation and augmentation cystoplasty, are usedonly in patients with the most severe symptoms.49,50 Many classes of drugs have been studied or pro-posed for the treatment of symptoms of overactive bladder.1-3,20-22,51 The majority of clinical trials have targeted the symptoms of urinary incontinence, though more recent trials have specifically includedsubjects with overactive bladder. Several pitfalls lim- it the quality of many studies. Expert groups have proposed methodologic standards that should im-prove the science underlying drug therapy of over-active bladder.52-54 Table 2 lists drugs currently used to treat symp- toms of overactive bladder and notes both evidence of efficacy and recommendations based on the In- ternational Consultation on Urological Diseases.7A recent review summarizes the efficacy of anticho- Contraction of bladder
Relaxation of bladder
linergic drugs for the treatment of overactive blad- smooth muscle
der as reported in 32 placebo-controlled trials thatincluded 6800 subjects, over 70 percent of whom Figure 2. Current Concepts of Autonomic Efferent Innervation Contributing
to Bladder Contraction and Urine Storage.
All anticholinergic drugs can have bothersome In the normal human bladder, acetylcholine is the predominant neurotrans- side effects. Although dry mouth is the most com- mitter that causes bladder contraction. Acetylcholine interacts with M3 mus- mon, constipation, gastroesophageal reflux, blurry carinic receptors and activates phospholipase C through coupling with G pro-teins, which generates inositol triphosphate, which in turn causes the release vision, urinary retention, and cognitive side effects of calcium from the sarcoplasmic reticulum and the contraction of bladder can also occur. Both overactive bladder and demen- smooth muscle. M2 receptors may contribute to bladder contraction by inhib- tia are common in older patients. Since various iting adenylate cyclase activity and decreasing intracellular cyclic adenosine forms of dementia are routinely treated with cholin- monophosphate (AMP) levels, which mediate bladder relaxation. In the nor- esterase inhibitors, the potential for adverse cog- mal human bladder, only a small proportion of muscle contraction is resistant to atropine. Resistance to atropine most likely results from the interaction of nitive effects and delirium due to antimuscarinic ATP with purinergic receptors, including P2X receptors. ATP and other non- drugs is a particular concern in this population.58,59 cholinergically mediated processes may have a more important role in disor- Although these drugs have not had major effects ders that cause overactive bladder. Stimulation of b -adrenergic receptors on cognition in clinical trials involving relatively may also lead to relaxation of bladder smooth muscle. Plus signs indicate ac- healthy older adults, more subtle but functionally tivation, and minus signs inhibition. Data are from Morrison et al., Yoshimura and Chancellor,21 and Andersson and Hedlund.22 important changes could occur. Quantitative elec-troencephalographic data suggest that oxybutyninhas more central nervous system effects than tros-pium or tolterodine.60 Long-acting anticholinergic der muscles and has local anesthetic activity. It isagents and newer, more selective antimuscarinic available in immediate and extended-release forms,agents should be tested for clinically important cog- as well as in a transdermal patch. Immediate-releasenitive side effects, especially in older patients.
oxybutynin (usual adult dosage, 5 mg thrice daily) Among the anticholinergic agents, only oxybuty- appears to be efficacious for the treatment of neu- nin, propiverine, tolterodine, and trospium (Table 2) rogenic and non-neurogenic overactivity of the de-have the highest level of clinical recommendation trusor muscle with urge incontinence. Given in thisand evidence of efficacy; oxybutynin and tolterodine formulation, oxybutynin has led to a clinically sig-have been studied most extensively. Oxybutynin is a nificant improvement, defined as a reduction innonselective antimuscarinic agent that relaxes blad- incontinence episodes by more than 50 percent, n engl j med 350;8 february 19, 2004 Downloaded from www.nejm.org at BERKSHIRE MED CTR on August 21, 2006 . Copyright 2004 Massachusetts Medical Society. All rights reserved.

The new england journal of medicine Uroepithelial cell Vanilloid P2X2 or P2X3 C sensory fiber
Figure 3. Current Concepts of Sensory Innervation of the Bladder.
Myelinated A delta sensory fibers respond predominantly to mechanical stretching of detrusor muscle cells during blad-der filling. Unmyelinated C sensory fibers may help trigger the symptoms of overactive bladder in pathologic conditions. C fibers have receptors for a variety of neurotransmitters and substances that can be released from afferent nerves, de-trusor smooth muscle, and the uroepithelium. These receptors include vanilloid receptors, which can be stimulated by capsaicin and, possibly, endogenous anandamide; purinergic receptors (P2X and P2X ), which are activated by ATP; neurokinin receptors, which are activated by neurokinin A and substance P; and trk-A receptors for nerve growth factor. The nerve growth factor produced by muscle cells, as well as nitrous oxide produced by the uroepithelium, may play key roles in modulating the responsiveness of afferent innervation in the bladder. Data are from Morrison et al.,20 Yoshimura and Chancellor,21 and Andersson and Hedlund.22 in approximately 60 to 80 percent of study sub- in episodes of urge incontinence by approximatelyjects.21,32,51,61 The efficacy of immediate-release 70 percent.43,63-66 A transdermal oxybutynin patchoxybutynin has been limited by antimuscarinic side is also available that is as efficacious as immediate-effects of the parent drug and its active metabolite release oxybutynin but with half the incidence of(N-desethyloxybutynin); dry mouth, for example, is dry mouth.67,68 In one placebo-controlled trial, thereported in up to two thirds of subjects in some clin- patch caused local skin erythema in more than halfical trials. Generic immediate-release oxybutynin is the subjects (3 percent of cases were severe) andrelatively inexpensive and may be useful for patients was associated with pruritus in up to 17 percent.68whose symptoms are best managed by a short-act- Tolterodine is a muscarinic antagonist that is ing drug (e.g., symptoms that are bothersome only available in short-acting (twice-daily) and long-act-when the patient is away from home or at night).
ing (once-daily) preparations. Both forms have had A once-daily controlled-release formulation of statistically and clinically significant effects on oxybutynin appears to have the same beneficial ef- symptoms of overactive bladder in multiple, ran-fects as immediate-release oxybutynin, with fewer domized, controlled clinical trials.69-77 Side effectsside effects — a benefit ascribed to the more con- are similar to those of short-acting oxybutynin, withstant levels of the parent drug and, possibly, a lower dry mouth in 20 to 25 percent of patients, and therate of conversion to the active metabolite in the rates of discontinuation due to side effects are sim-stomach and small intestine.62 Most studies of con- ilar to those for placebo (5 to 6 percent). Tolterodinetrolled-release oxybutynin have reported a reduction appears to be equally efficacious in old and young february 19, 2004 Downloaded from www.nejm.org at BERKSHIRE MED CTR on August 21, 2006 . Copyright 2004 Massachusetts Medical Society. All rights reserved. Table 2. Drugs Used to Treat Symptoms of Overactive Bladder.*
Evidence/Grade of
Usual Adult Dose
Drugs with predominantly
anticholinergic or anti-
muscarinic effects
0.375 mg twice daily orally The drug is also available in sublingual and elixir forms; it has prominent anticho-linergic side effects.
2.5–5.0 mg thrice daily orally (short-acting) Long-acting and transdermal preparations 5–30 mg daily orally (long-acting) have fewer side effects than short-acting 3.9 mg over a 96-hr period (transdermal) The transdermal patch can cause local skin irritation in some patients.
15–30 mg 4 times daily orally The drug has prominent anticholinergic side 15 mg thrice daily orally The drug has complex pharmacokinetics with several active metabolites; it is not current-ly available in the United States.
1–2 mg twice daily orally (short-acting) The long-acting and short-acting preparations 4 mg daily orally (long-acting) have similar efficacy.
20 mg twice daily orally The agent is a quaternary ammonium com- pound, which does not cross the blood–brain barrier and may have fewer cognitive side effects than other anticholinergic agents; it is not currently available in the United States.
Estrogen (for women)
Approximately 0.5 g cream applied topically Local vaginal preparations are probably more nightly for 2 wk, then twice per week effective than oral estrogen, but definitive Estradiol ring, replaced every 90 days data on effectiveness are lacking.
Estradiol, 1 tablet daily for 2 wk, then 1 tablet Alpha-adrenergic antagonists
(for men)
2.5 mg thrice daily orally These agents are useful in men with benign 1–16 mg daily orally 1–10 mg twice daily orally Postural hypotension can be a serious side 0.4–0.8 mg daily orally 1–10 mg orally each day at bedtime Doses must be increased gradually to facilitate Other drugs
10–25 mg thrice daily orally This agent may be useful for mixed urge– stress incontinence; it can cause postural hypotension and bundle-branch block.
20–40 µg of intranasal spray daily at bed- The intranasal spray is used for primary noc- turnal enuresis in children; hyponatremia 0.1–0.4 mg orally 2 hr before bedtime occurs commonly in older adults, and se-rum sodium levels must be monitored closely.
* Not all drugs listed in this table have proven efficacy specifically for symptoms of overactive bladder.
† Levels of evidence are based on the Oxford System: a score of 1 indicates evidence from randomized, controlled trials; a score of 2 evidence from good-quality prospective cohort studies; a score of 3 evidence from good-quality retrospective case–control studies; and a score of 4 ev-idence from good-quality case series.55,56 The grade of recommendations is based on the definitions used by the International Consultation on Urological Diseases7: A indicates consistent level 1 evidence; B consistent level 2 or 3 evidence or major evidence from randomized, con-trolled trials; C level 4 evidence or major evidence from level 2 or 3 studies or expert opinion based on the Delphi method; and D inconclusive, inconsistent, or nonexistent evidence or evidence based on expert opinion only.
‡ The rating is for symptoms of overactive bladder, not for overall symptoms of benign prostatic hyperplasia.
n engl j med 350;8 february 19, 2004 Downloaded from www.nejm.org at BERKSHIRE MED CTR on August 21, 2006 . Copyright 2004 Massachusetts Medical Society. All rights reserved. The new england journal of medicine subjects and was well tolerated in one trial involving the efficacy of these drugs for overactive bladder, be-patients who were living in nursing homes.75,76,78 cause the outcomes of most clinical trials have beenTwo published studies, both industry-sponsored, based on composite scores that include symptomshave compared the long-acting forms of oxybutynin of both overactive bladder and obstruction.96-102and tolterodine. In one study, participating medi- Symptoms of overactive bladder tend to decreasecal practices were randomized,77 and in the other, with alpha-blocker therapy, but less so than dowomen (mean age, 60 years) were randomly as- symptoms of obstruction.102,103 Because alpha-signed to receive one or the other of these agents.79 blockers can cause postural hypotension, they re-The results of both trials suggest that the drugs quire a gradual titration of the dose and must behave similar efficacy and effectiveness. In addition, used carefully, especially in patients who are alreadyboth oxybutynin and tolterodine appear to be effec- taking antihypertensive agents.93,100-102tive when combined with various types of behavior- Men who neither tolerate nor have a response to alpha-blockers and who are not candidates for sur- Randomized, controlled trials indicate that gical intervention may benefit from a trial of an anti- propiverine and trospium are effective for the treat- cholinergic agent, provided they are carefully mon-ment of urge incontinence and have fewer side ef- itored for the development of urinary retention.
fects than short-acting oxybutynin.83-86 Neither Further research is needed to determine the optimaldrug is currently available in the United States (tros- use of alpha-blockers and anticholinergic drugs —pium is being evaluated in clinical trials in the Unit- alone, together, or combined with behavioral ther-ed States). Though hyoscyamine, like short-acting apy — as a treatment for overactive bladder in men.
oxybutynin, may be useful for some patients with in- Treatment of nocturia, the most bothersome termittent symptoms or under specific circumstanc- symptom of overactive bladder for many patientses, it can be associated with prominent side effects. of both sexes, depends on the primary underlyingPropantheline has proven efficacy for the treatment cause or causes — detrusor overactivity, nocturnalof urge incontinence,32,87,88 but the need for mul- polyuria, a primary sleep disorder, or some combi-tiple daily doses and the relatively high incidence of nation of these conditions.104,105 Nocturia that isside effects are drawbacks. Imipramine, a tricyclic primarily related to detrusor overactivity can be treat-antidepressant with both anticholinergic and alpha- ed with an anticholinergic agent. Nocturnal polyu-adrenergic effects and, possibly, a central effect on ria related to volume overload (e.g., venous insuffi-voiding reflexes, has been recommended for mixed ciency or congestive heart failure with peripheralurge–stress incontinence, which is common among edema) may respond to a small dose of a rapid-act-older women with overactive bladder. Imipramine ing diuretic taken in the late afternoon. Oral and in-can cause postural hypotension and cardiac-conduc- tranasal preparations of desmopressin are approvedtion abnormalities and thus must be used carefully. for use in children with nocturnal enuresis. Postmenopausal women with symptoms of over- Data supporting an association among noctur- active bladder are commonly treated with oral or nal polyuria, nocturia, abnormal diurnal respon-topical estrogen, but few data document the effica- siveness to vasopressin, and levels of endogenouscy of these agents.89-92 Among men, symptoms of arginine vasopressin in adults are limited and con-overactive bladder overlap with those of benign flicting.106-109 However, two randomized, con-prostatic hypertrophy.93-95 In clinical practice, the trolled trials suggest that orally administered des-approach to men with symptoms of overactive blad- mopressin can reduce nocturia in both womender depends on several factors, such as the degree (mean age, approximately 57 years)110 and mento which specific symptoms bother the patient, the (mean age, approximately 65 years).111 Both trialspatient's preferences, evaluation of the risk–benefit used a three-week run-in dose-titration design (0.1ratio, and the physician's bias. Treatment decisions to 0.4 mg), during which approximately one thirdare further complicated by the fact that complex of the patients were excluded. Among patients withurodynamic studies are required to rule out blad- some responsiveness and ability to tolerate desmo-der-outlet obstruction as a cause. Men with isolated pressin during the dose-titration phase, one thirdsymptoms of overactive bladder — in whom pros- of the women and the men had at least a 50 percenttate cancer and obstruction have been ruled out — reduction in the number of nighttime voiding epi-are often treated initially with alpha-adrenergic sodes (as compared with 3 percent of patients inblockers (alpha-blockers). It is difficult to determine the placebo group) and a significant increase in the february 19, 2004 Downloaded from www.nejm.org at BERKSHIRE MED CTR on August 21, 2006 . Copyright 2004 Massachusetts Medical Society. All rights reserved. duration of sleep before their first nighttime voiding nist, has been used in patients with the detrusor hy-during the three-week double-blind phase. Side ef- perreflexia associated with spinal cord disorders.
fects were mild; hyponatremia occurred in approx- Direct injection of botulinum toxin into the detru-imately 5 percent of patients but only during the sor muscle, which inhibits acetylcholine at the pre-three-week dose-titration phase. On the basis of synaptic cholinergic junction, appears to amelioratethese data, oral desmopressin has been approved detrusor hyperreflexia in patients with spinal cordfor the treatment of nocturia in several countries in injury112,113; it may have some therapeutic value inEurope, but it is not yet approved for this indication selected patients with severe refractory symptomsin the United States.
of overactive bladder. Although currently available Because of their mechanisms of action, several beta-agonists have not been shown to be useful for classes of drugs used for other conditions are of overactive bladder, more selective b -agonists may potential therapeutic value for patients with over- have therapeutic value.
active bladder, but data from randomized, con- There are several promising directions for the trolled clinical trials are lacking. Such drug classes development of drugs to treat overactive bladder (Ta-include calcium-channel blockers, prostaglandin- ble 3). At least two antimuscarinic drugs (darifena-synthesis inhibitors, dopamine D1–receptor ago- cin and solifenacin) with selective M3-receptor–nists, beta-adrenergic (particularly b ) agonists, and antagonist actions and, theoretically, fewer systemic g-aminobutyric acid (GABA) agonists (Table 3).20-22 anticholinergic side effects than currently availableFor example, pergolide, a D1-receptor agonist, may agents are being studied. Oxybutynin has been in-benefit patients with Parkinson's disease and lower stilled intravesicularly through a catheter to treat se-urinary tract symptoms, and baclofen, a GABA ago- vere overactivity of the detrusor muscle,114 and a Table 3. Examples of Classes of Drugs under Investigation for the Treatment of Symptoms of Overactive Bladder.*
Drug Classes and Actions
in Humans
Drugs used for other conditions
Calcium-channel blockers Agents inhibit bladder contraction by decreasing calcium available for smooth-muscle contraction; there is no evidence that these agents are effective for symptoms of overactive bladder.
Inhibitors of prostaglandin synthesis Prostaglandins may increase the contraction of bladder smooth muscle; no currently available agents have proven efficacy.
g-Aminobutyric acid–receptor agonists Stimulation of g-aminobutyric acid receptors inhibits the voiding reflex.
Neuromuscular-junction inhibition Botulinum toxin A injections have been used for refractory symptoms.
of acetylcholine release Drugs in development
Antimuscarinic agents more selective for M3 receptors than other anti- muscarinic agents These agents decrease spontaneous detrusor-muscle contractions and can have clinically significant effects on blood pressure; potassium-channel gene therapy has also been studied.
Serotonergic agonists The central serotonergic effects of these agents increase urethral striated Vanilloids and other afferent-nerve These agents cause desensitization of unmyelinated C fibers; other afferent-nerve inhibitors may be useful.
D1-receptor stimulation inhibits the voiding reflex.
Nerve growth factor inhibitors Nerve growth factor modulates sensory afferent function; antibody-based gene therapy to suppress nerve growth factor has also been studied.
Opioid peptides, including enkephalin, suppress the voiding reflex; therapy with the herpes simplex virus proenkephalin gene has been studied.
* Drugs listed in this table do not have proven efficacy in the treatment of overactive bladder and should not be prescribed until data from clin- ical trials are published.
n engl j med 350;8 february 19, 2004 Downloaded from www.nejm.org at BERKSHIRE MED CTR on August 21, 2006 . Copyright 2004 Massachusetts Medical Society. All rights reserved. The new england journal of medicine bladder pump is being developed that can deliver a verse consequences such as injurious falls. Theconstant dose of intravesicular oxybutynin for up symptoms may be caused by myriad factors, includ-to 30 days.21 Such a device may make this method ing disorders of the lower urinary tract, neurologicof drug delivery more practical and acceptable and conditions, behavioral factors such as caffeine in-may result in fewer systemic anticholinergic side take, and a variety of commonly prescribed drugs.
effects.
The pathophysiologic process in an individual pa- Drugs that act by means of potassium-channel tient is often multifactorial. Diagnostic evaluation transporters to hyperpolarize smooth muscle and includes a focused history taking, targeted physi-decrease spontaneous bladder contractions may be cal examination, and urinalysis. Selected patientsuseful for suppressing involuntary bladder contrac- should have a post-void residual determination, andtions without interfering with normal voiding.115 some should undergo cystoscopy (such as thoseHowever, first-generation agents in this class have with hematuria) or complex urodynamic testinghad effects on vascular smooth muscle and can (such as those with urinary retention or neurologiccause hypotension. Duloxetine is an inhibitor of se- disorders).
rotonin and norepinephrine that appears to act cen- Patients with overactive bladder often benefit trally, increasing tone in the striated smooth muscle from supportive measures such as education,of the external urethral sphincter.116 Although it is changes in fluid intake, and the use of bedside com-being studied primarily for the treatment of stress modes or urinals, especially at night. Behavioralincontinence, duloxetine may also have therapeutic treatments such as pelvic-muscle exercises andbenefits in patients with mixed stress–urge inconti- bladder training are efficacious and can enhance thenence. Drugs that act on sensory afferent pathways benefits of drug therapy. The mainstay of drug ther-are also being developed and hold promise when apy is antimuscarinic agents. The two best-studiedused either alone or in combination with other agents are oxybutynin and tolterodine; both havedrugs. Capsaicin and resiniferatoxin desensitize well-proven efficacy in short- and long-actingC-fiber afferents and have been administered ex- forms. The extended-release formulations and theperimentally by the intravesicular route. Resinifer- oxybutynin skin patch are generally well tolerated,atoxin appears to be more potent and less irritating but all antimuscarinic drugs can have bothersomethan capsaicin and may be more useful clinical- anticholinergic side effects. The effects of thesely.55,117,118 Other drugs that block receptors on sen- agents on cognitive function are a particular concernsory afferents, such as neurokinin-receptor antago- in older adults. Men with symptoms of overactivenists (Fig. 3), might not cause urinary retention, bladder in association with benign prostatic hyper-which can occur with antimuscarinic agents.
plasia may benefit from treatment with alpha-block-ers. Promising future directions in drug therapyinclude the development of more specific anti- muscarinic agents, new drug-delivery systems, and Symptoms of overactive bladder are common, can drugs that affect the sensory innervation of the low-be distressing, and are associated with serious ad- er urinary tract.
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