The new england journal of
review article
From the Division of Geriatric Medicine
and Gerontology, Wesley Woods Center,
Center for Health in Aging, Emory Univer-
sity, and the Birmingham/Atlanta Veterans
Affairs Geriatric Research Education Clini-
cal Center — both in Atlanta. Address re-
print requests to Dr. Ouslander at the Wes-
ley Woods Center of Emory University, 1841
Clifton Rd., NE, Atlanta, GA 30329, or at
jouslan@emory.edu.
N Engl J Med 2004;350:786-99.
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786
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medicine
drug therapy
Alastair J.J. Wood, M.D., Editor
Management of Overactive Bladder
Joseph G. Ouslander, M.D.
o veractive bladder is a symptom complex that includes uri-
nary urgency with or without urge incontinence, urinary frequency (voiding
eight or more times in a 24-hour period), and nocturia (awakening two or
more times at night to void).1-3 The International Continence Society classifies over-
active bladder as a syndrome for which no precise cause has been identified, with local
abnormalities ruled out by diagnostic evaluation.4,5 This review extends beyond the In-
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
history have not been well studied.8 In a telephone survey of 16,776 adults who were 40
years of age or older in Europe, 16 percent of men and 17 percent of women reported
syndromes suggestive of overactive bladder. The prevalence was 3 percent among men
40 to 44 years of age, 9 percent among women 40 to 44 years of age, 42 percent among
men 75 years of age or older, and 31 percent among women 75 years of age or older.9
Similar data on the prevalence of overactive bladder have been reported in the United
States.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 is
associated with sleep disruption, which decreases the quality of life.11-14 Postmeno-
pausal women with urge incontinence have a substantially higher risk of falling and
sustaining a fracture than women without urge incontinence.15 The costs of overactive
bladder are probably high but have not been studied systematically. The total costs of
urinary 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
pathophy siology
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 urinary
tract; and the anatomical components of the lower urinary tract itself. Disorders of any
of these structures may contribute to the symptoms of overactive bladder. The normal
bladder functions like a compliant balloon as it fills, with pressure remaining lower
than 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 contractions
of 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-
n engl j med 350;8 www.nejm.org february 19, 2004
The New England Journal of Medicine
 drug therapy
sponse of the sphincter.17 Detrusor overactivity may
also have a myogenic origin.18 Detrusor contrac-
tions can be weak as a result of impaired contract-
ibility. Urodynamic testing indicates that up to half
of elderly patients with detrusor overactivity empty
less than one third of their bladder contents with
an involuntary bladder contraction19; incomplete
emptying can contribute to urinary frequency by
lowering the functional capacity of the bladder.
A variety of efferent and afferent neural pathways,
reflexes, and central and peripheral neurotransmit-
ters are involved in urine storage and bladder empty-
ing. The relation among these factors is incomplete-
ly understood. The role of central neurotransmitters
in the voiding cycle has been studied in animals.20-22
Glutamate is an excitatory neurotransmitter in path-
ways controlling the lower urinary tract. Serotoner-
gic activity facilitates urine storage by enhancing the
sympathetic reflex pathway and inhibiting the para-
sympathetic voiding pathway. Dopaminergic path-
ways may exert both inhibitory and facilitatory ef-
fects on voiding. Dopamine D1 receptors appear to
have a role in suppressing bladder activity, whereas
dopamine D2 receptors appear to facilitate voiding.
Other neurotransmitters, such as g-aminobutyric
acid and enkephalin, inhibit voiding in animals.
Acetylcholine, which interacts with muscarinic
receptors on the detrusor muscle, is the predomi-
nant peripheral neurotransmitter responsible for
bladder contraction. Of the five known muscarinic
subtypes (M1 through M5), M3 appears to be the
most clinically relevant in the human bladder.20 Ace-
tylcholine interacts with the M3 receptor, initiating
a cascade of events that results in contraction of the
detrusor muscle (Fig. 2). Data from studies of rat
bladders suggest that the M2 receptor may also fa-
cilitate bladder contraction by reducing intracellular
levels of cyclic adenosine monophosphate.23
Pathologic states can alter sensitivity to musca-
rinic stimulation. For example, bladder-outflow ob-
struction appears to enhance responsiveness to ace-
tylcholine, a phenomenon similar to denervation
suprasensitivity.20 Normally, only a small propor-
tion of the bladder contraction is resistant to atro-
pine, probably as a result of the interactions of ATP
with purinergic receptors. However, ATP may have
a more prominent role in bladder contraction in pa-
tients with overactive bladder.20-22 Anatomical cor-
relates of detrusor overactivity have also been de-
scribed. For example, the bladders of patients with
detrusor overactivity appear to have abnormal gap
junctions between smooth-muscle cells.24-28 Such
correlates require further study.
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Increasing attention has been paid to the role of
sensory afferent nerves in normal voiding and detru-
sor overactivity.20-22,29 During bladder filling, affer-
ent activity from the bladder and urethra reaches the
spinal cord predominantly by means of the pelvic
nerve. Sensory input during bladder filling results
in an increase in sympathetic tone, which inhibits
bladder parasympathetic motor nerves, causing
contraction of the bladder base and urethra. Adre-
nergic activity may also cause relaxation of the detru-
sor muscle through the stimulation of b3-adrener-
gic receptors (Fig. 2).30 Myelinated A delta sensory
fibers respond to passive distention and active
contraction of the detrusor muscle. Unmyelinated
C sensory fibers have a higher mechanical threshold
and respond to a variety of neurotransmitters (Fig.
3). C fibers are relatively inactive during normal void-
ing, but they may have a critical role in symptoms of
overactive bladder in patients with neurologic and
other disorders. Several types of receptors have been
identified on afferent nerves, including vanilloid re-
ceptors, which are activated by capsaicin and possi-
bly by endogenous anandamide; purinergic recep-
tors (P2X), which are activated by ATP; neurokinin
receptors, which respond to substance P and neuro-
kinin A; and receptors for nerve growth factor (trk-A
receptors).20,31 Other substances, including nitric
oxide, calcitonin gene–related protein, and brain-
derived neurotropic factor, may also have an impor-
tant role in modulating the sensory afferents in the
human detrusor.20-22 A better understanding of the
complex interplay among these various neurotrans-
mitters and other substances derived from uroepi-
thelium, detrusor-muscle cells, and afferent fibers
themselves should yield new and more specific tar-
gets for drug treatment of overactive bladder.
diagnostic evaluation
Effective treatment of patients with symptoms of
overactive bladder necessitates a targeted diagnostic
evaluation. Guidelines for the management of uri-
nary incontinence32 and benign prostatic hyper-
plasia33 are relevant to the evaluation of symptoms
of overactive bladder. A focused history that includes
information about past genitourinary disorders and
other conditions outlined in Table 1 should be elic-
ited from all patients. A symptom index for benign
prostatic hypertrophy (recommended by the Amer-
ican Urological Association) or a similar symptom
index is helpful to include as part of the evaluation
in older men.34,35 A variety of questionnaires re-
garding lower urinary tract symptoms have also
february 19, 2004 787
 The new england journal of medicine

Table 1. Conditions That Can Cause or Contribute to Symptoms of Overactive Bladder.

Conditions Mechanisms or Effect Implications for Management
Lower urinary tract conditions
Both sexes
Urinary tract infection Inflammation with activation of sensory Treat infection before other interventions are con-
afferent innervation can result. sidered.
Obstruction 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
method).
Intermittent catheterization is helpful in selected
patients.
Bladder abnormalities or inflammation Intravesical abnormalities can precipitate Sterile hematuria and risk factors for bladder
(e.g., tumors, calculi, interstitial detrusor overactivity. cancer should prompt further evaluation.
cystitis)
Women
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.
Men
Prostate enlargement Benign or malignant prostate enlarge- Evaluation and treatment for prostate cancer
ment can contribute to detrusor should be considered.
overactivity. Alpha-adrenergic blockers may improve symptoms.
5a-Reductase inhibitors may reduce prostate size.
Surgical removal of obstructing prostate may be
indicated.
Neurologic conditions
Brain
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 detrusor overactivity. or both.
Spinal cord
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.
cord injury 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
can be helpful in determining the frequency, vol-
ume, and pattern of voiding, as well as providing
clues to underlying causes and contributing fac-
tors.37,38 All patients should undergo a focused
physical examination that includes genitourinary,
pelvic, and rectal examinations; a clean urine spec-
imen should be obtained to rule out hematuria and
infection.
Further evaluation should be considered in se-
lected patients. The presence of residual urine after
voiding should be determined in patients with risk
factors for urinary retention (diabetes, spinal cord
disease, and benign prostatic hypertrophy). This can
be accomplished by sterile in-and-out catheteriza-
tion. A portable ultrasonographic device is available
that permits noninvasive identification of clinically
significant residual urine (>100 ml), with an accu-
racy rate of more than 90 percent; it costs approxi-
mately $8,000.39 Patients with sterile hematuria or

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 drug therapy

Table 1. (Continued.)
Conditions Mechanisms or Effect Implications for Management
Systemic conditions
Congestive heart failure, venous Volume overload can contribute to urinary Proper timing of diuretics may ameliorate symptoms.
insufficiency frequency and nocturia when patient Use of leg elevation, support hose, and salt
is supine. restriction may be helpful.
Diabetes mellitus Poor blood glucose control can contribute Improved blood glucose control may ameliorate
to osmotic diuresis and polyuria. symptoms.
Sleep disorders (sleep apnea, periodic Sleep disorders can contribute to nocturia. Reports of sleep disruption or heavy snoring may
leg movements) 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;
polydipsia
Poor bowel habits and constipation
Impaired mobility (e.g., in patients with
degenerative joint disease, Par-
kinson’s disease, severe osteo-
porosis, or muscle weakness)
Psychological conditions
Side effects of medication
Diuretics, especially rapid-acting agents Diuretics cause a rapid increase in bladder
Anticholinergic agents, narcotics,
calcium-channel blockers
Cholinesterase inhibitors
Polyuria and urinary frequency can result.
Fecal impaction can contribute to symptoms. An appropriate bowel regimen will reduce the inci-
Impaired mobility can interfere with toilet- Treatment of underlying disorders, including physi-
ing ability and precipitate urge incon-
tinence.
Chronic anxiety and learned voiding dys-
function can cause symptoms of over-
active bladder.
volume, which may precipitate urgency
and detrusor overactivity.
These agents decrease bladder contractility
and may cause urinary retention, with a
decreased functional bladder capacity.
These agents could theoretically contribute
to detrusor overactivity by increasing
acetylcholine levels.
Modification of fluid intake is critical for successful
management.
dence of fecal impaction.
cal therapy, should be optimal; the use of urinals,
bedside commodes, and bedpans can be helpful.
The diagnosis should be considered on the basis of
a patient’s history and physical examination.
Changing to a longer-acting diuretic, altering the
timing of the dose, or discontinuing the drug,
if appropriate, can ameliorate symptoms.
Such drugs should be discontinued whenever
feasible.
No clinical studies have documented such effects,
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-
toscopy, and their urine should be sent for cytologic
analysis. Cystoscopy is also indicated in patients
with a history of recurrent urinary tract infection. Al-
though some urologists and gynecologists suggest
that all patients in whom symptoms of overactive
bladder develop should undergo cystoscopy to rule
out carcinoma in situ and other intravesical abnor-
malities, the cost effectiveness of this approach is
uncertain. Because early prostate cancer can cause
symptoms of overactive bladder, the possibility of
prostate cancer should be assessed.
The role of urodynamic testing in the evaluation
of patients with symptoms of overactive bladder is
controversial. A noninvasive determination of the
urinary flow rate, combined with a measurement of
residual urine after voiding, appears to be a sensitive
method of ruling out obstruction in older men.40
More complex urodynamic testing may be necessary
in patients with nonspecific symptoms and may be a
more accurate approach to the diagnosis of obstruc-
tion than less invasive testing. Because this test is
relatively expensive and invasive, it is recommend-
ed only to evaluate symptoms of overactive blad-
der in cases in which the findings will clearly influ-
ence treatment, such as after the failure of initial
therapy.1-3,7
therapy
Optimal therapy for overactive bladder depends on
a thorough evaluation, followed by treatment of all
the likely causes and contributing factors (Table 1).
The genesis of symptoms of overactive bladder is

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 The new england journal of medicine

mixed urge–stress incontinence. Educating patients

A about bladder function, appropriate fluid intake
Voluntary
voiding (avoidance of caffeine, maintenance of adequate hy-
Urgency
dration, and the timing of fluid intake), and manag-
Urethral
ing constipation is important for all patients with
resistance overactive bladder. Education may, in fact, underlie
Detrusor the prominent placebo effects (approximately 30
pressure percent improvement in symptoms) demonstrated
Striated sphincter-
repeatedly in drug trials for incontinence and over-
muscle activity active bladder. Several randomized, controlled trials,
largely involving middle-aged women and women
Bladder volume 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-
B vic-muscle exercises and “bladder training.”41-43
Involuntary
detrusor Approximately 70 percent of patients have a reduc-
contraction tion in the number of episodes of incontinence with-
Detrusor overactivity in two to three months. The long-term effectiveness
Urethral
resistance
of these interventions requires further study.
Many patients can be taught pelvic-muscle exer-
Detrusor
pressure cises during a pelvic or rectal examination or can
Striated sphincter-
learn them with the use of simple educational tools
muscle activity such as an audiotape or a booklet.42 A substantial
proportion of older patients benefit from biofeed-
back-assisted training. “Bladder training” generally
Bladder volume 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
of water) — substantially lower than urethral resistance pressure (Panel A). prompted voiding can be very helpful in the man-
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
bladder, involuntary bladder contractions can cause urgency and may precip- tive bladder that are refractory to proven behavioral
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
neurogenic or idiopathic and can be accompanied by urgency or be without refractory symptoms in order to maintain “social
sensation. continence” and good perineal hygiene.45,46 Only
limited evidence of efficacy is available regarding
more invasive interventions. Electrical stimulation
delivered by vaginal or rectal probes can be helpful
commonly multifactorial, and multimodal therapy in teaching some patients the proper use of pelvic
that includes nonpharmacologic as well as pharma- muscles (an approach similar to biofeedback), and
cologic interventions may be indicated. lower-frequency stimulation can inhibit bladder
contraction.47 Sacral neuromodulation by means of
nonpharmacologic interventions 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

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 drug therapy
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 used
only in patients with the most severe symptoms.49,50
drug therapy
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 included
subjects 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.7
A recent review summarizes the efficacy of anticho-
linergic drugs for the treatment of overactive blad-
der as reported in 32 placebo-controlled trials that
included 6800 subjects, over 70 percent of whom
were women.57
All anticholinergic drugs can have bothersome
side effects. Although dry mouth is the most com-
mon, constipation, gastroesophageal reflux, blurry
vision, urinary retention, and cognitive side effects
can also occur. Both overactive bladder and demen-
tia are common in older patients. Since various
forms of dementia are routinely treated with cholin-
esterase inhibitors, the potential for adverse cog-
nitive effects and delirium due to antimuscarinic
drugs is a particular concern in this population.58,59
Although these drugs have not had major effects
on cognition in clinical trials involving relatively
healthy older adults, more subtle but functionally
important changes could occur. Quantitative elec-
troencephalographic data suggest that oxybutynin
has more central nervous system effects than tros-
pium or tolterodine.60 Long-acting anticholinergic
agents and newer, more selective antimuscarinic
agents should be tested for clinically important cog-
nitive side effects, especially in older patients.
Among the anticholinergic agents, only oxybuty-
nin, propiverine, tolterodine, and trospium (Table 2)
have the highest level of clinical recommendation
and evidence of efficacy; oxybutynin and tolterodine
have been studied most extensively. Oxybutynin is a
nonselective antimuscarinic agent that relaxes blad-
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Parasympathetic Sympathetic
nerve nerve
ATP
Acetylcholine M2 Norepinephrine
receptor
M3
receptor
P2X1
G protein receptor b3-adrenergic
receptor
Phospholipase C
Adenylate
Inositol cyclase
triphosphate
Cyclic AMP
Contraction of bladder Relaxation of bladder
smooth muscle smooth muscle
Figure 2. Current Concepts of Autonomic Efferent Innervation Contributing
to Bladder Contraction and Urine Storage.
In the normal human bladder, acetylcholine is the predominant neurotrans-
mitter that causes bladder contraction. Acetylcholine interacts with M3 mus-
carinic receptors and activates phospholipase C through coupling with G pro-
teins, which generates inositol triphosphate, which in turn causes the release
of calcium from the sarcoplasmic reticulum and the contraction of bladder
smooth muscle. M2 receptors may contribute to bladder contraction by inhib-
iting adenylate cyclase activity and decreasing intracellular cyclic adenosine
monophosphate (AMP) levels, which mediate bladder relaxation. In the nor-
mal human bladder, only a small proportion of muscle contraction is resistant
to atropine. Resistance to atropine most likely results from the interaction of
ATP with purinergic receptors, including P2X1 receptors. ATP and other non-
cholinergically mediated processes may have a more important role in disor-
ders that cause overactive bladder. Stimulation of b3-adrenergic receptors
may also lead to relaxation of bladder smooth muscle. Plus signs indicate ac-
tivation, and minus signs inhibition. Data are from Morrison et al.,20
Yoshimura and Chancellor,21 and Andersson and Hedlund.22
der muscles and has local anesthetic activity. It is
available in immediate and extended-release forms,
as well as in a transdermal patch. Immediate-release
oxybutynin (usual adult dosage, 5 mg thrice daily)
appears to be efficacious for the treatment of neu-
rogenic and non-neurogenic overactivity of the de-
trusor muscle with urge incontinence. Given in this
formulation, oxybutynin has led to a clinically sig-
nificant improvement, defined as a reduction in
incontinence episodes by more than 50 percent,
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 The new england journal of medicine

Uroepithelial cell
Nerve
Anandamide? ATP
growth Neurokinin A
factor Substance P

Vanilloid P2X2 or P2X3

receptor receptor
trk-A
receptor
Neurokinin
receptor

C sensory fiber

Detrusor
smooth-
C sensory
muscle cell
fibers
A delta
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 (P2X2 and P2X3), 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 approximately

jects.21,32,51,61 The efficacy of immediate-release
oxybutynin has been limited by antimuscarinic side
effects of the parent drug and its active metabolite
(N-desethyloxybutynin); dry mouth, for example, is
reported in up to two thirds of subjects in some clin-
ical trials. Generic immediate-release oxybutynin is
relatively inexpensive and may be useful for patients
whose symptoms are best managed by a short-act-
ing drug (e.g., symptoms that are bothersome only
when the patient is away from home or at night).
A once-daily controlled-release formulation of
oxybutynin appears to have the same beneficial ef-
fects as immediate-release oxybutynin, with fewer
side effects — a benefit ascribed to the more con-
stant levels of the parent drug and, possibly, a lower
rate of conversion to the active metabolite in the
stomach and small intestine.62 Most studies of con-
trolled-release oxybutynin have reported a reduction
70 percent.43,63-66 A transdermal oxybutynin patch
is also available that is as efficacious as immediate-
release oxybutynin but with half the incidence of
dry mouth.67,68 In one placebo-controlled trial, the
patch caused local skin erythema in more than half
the subjects (3 percent of cases were severe) and
was associated with pruritus in up to 17 percent.68
Tolterodine is a muscarinic antagonist that is
available in short-acting (twice-daily) and long-act-
ing (once-daily) preparations. Both forms have had
statistically and clinically significant effects on
symptoms of overactive bladder in multiple, ran-
domized, controlled clinical trials.69-77 Side effects
are similar to those of short-acting oxybutynin, with
dry mouth in 20 to 25 percent of patients, and the
rates of discontinuation due to side effects are sim-
ilar to those for placebo (5 to 6 percent). Tolterodine
appears to be equally efficacious in old and young

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 drug therapy

Table 2. Drugs Used to Treat Symptoms of Overactive Bladder.*

Level of
Evidence/Grade of
Drug Usual Adult Dose Recommendation† Comments
Drugs with predominantly
anticholinergic or anti-
muscarinic effects
Hyoscyamine 0.375 mg twice daily orally 2/D The drug is also available in sublingual and
elixir forms; it has prominent anticho-
linergic side effects.
Oxybutynin 2.5–5.0 mg thrice daily orally (short-acting) 1/A 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) preparations.
The transdermal patch can cause local skin
irritation in some patients.
Propantheline 15–30 mg 4 times daily orally 2/B The drug has prominent anticholinergic side
effects.
Propiverine 15 mg thrice daily orally 1/A The drug has complex pharmacokinetics with
several active metabolites; it is not current-
ly available in the United States.
Tolterodine 1–2 mg twice daily orally (short-acting) 1/A The long-acting and short-acting preparations
4 mg daily orally (long-acting) have similar efficacy.
Trospium 20 mg twice daily orally 1/A 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)
Vaginal estrogen Approximately 0.5 g cream applied topically 4/D Local vaginal preparations are probably more
preparations 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
twice a week
Alpha-adrenergic antagonists
(for men)
Alfuzosin 2.5 mg thrice daily orally 4/D‡ These agents are useful in men with benign
Doxazosin 1–16 mg daily orally prostatic enlargement.
Prazosin 1–10 mg twice daily orally Postural hypotension can be a serious side
Tamsulosin 0.4–0.8 mg daily orally effect.
Terazosin 1–10 mg orally each day at bedtime Doses must be increased gradually to facilitate
tolerance.
Other drugs
Imipramine 10–25 mg thrice daily orally 2/C This agent may be useful for mixed urge–
stress incontinence; it can cause postural
hypotension and bundle-branch block.
Desmopressin 20–40 µg of intranasal spray daily at bed- 1/B The intranasal spray is used for primary noc-
time 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.

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 The new england journal
subjects and was well tolerated in one trial involving
patients who were living in nursing homes.75,76,78
Two published studies, both industry-sponsored,
have compared the long-acting forms of oxybutynin
and tolterodine. In one study, participating medi-
cal practices were randomized,77 and in the other,
women (mean age, 60 years) were randomly as-
signed to receive one or the other of these agents.79
The results of both trials suggest that the drugs
have similar efficacy and effectiveness. In addition,
both oxybutynin and tolterodine appear to be effec-
tive when combined with various types of behavior-
al interventions.78,80-82
Randomized, controlled trials indicate that
propiverine and trospium are effective for the treat-
ment of urge incontinence and have fewer side ef-
fects than short-acting oxybutynin.83-86 Neither
drug is currently available in the United States (tros-
pium is being evaluated in clinical trials in the Unit-
ed States). Though hyoscyamine, like short-acting
oxybutynin, may be useful for some patients with in-
termittent symptoms or under specific circumstanc-
es, it can be associated with prominent side effects.
Propantheline has proven efficacy for the treatment
of urge incontinence,32,87,88 but the need for mul-
tiple daily doses and the relatively high incidence of
side effects are drawbacks. Imipramine, a tricyclic
antidepressant with both anticholinergic and alpha-
adrenergic effects and, possibly, a central effect on
voiding reflexes, has been recommended for mixed
urge–stress incontinence, which is common among
older women with overactive bladder. Imipramine
can cause postural hypotension and cardiac-conduc-
tion abnormalities and thus must be used carefully.
Postmenopausal women with symptoms of over-
active bladder are commonly treated with oral or
topical estrogen, but few data document the effica-
cy of these agents.89-92 Among men, symptoms of
overactive bladder overlap with those of benign
prostatic hypertrophy.93-95 In clinical practice, the
approach to men with symptoms of overactive blad-
der depends on several factors, such as the degree
to which specific symptoms bother the patient, the
patient’s preferences, evaluation of the risk–benefit
ratio, and the physician’s bias. Treatment decisions
are further complicated by the fact that complex
urodynamic studies are required to rule out blad-
der-outlet obstruction as a cause. Men with isolated
symptoms of overactive bladder — in whom pros-
tate cancer and obstruction have been ruled out —
are often treated initially with alpha-adrenergic
blockers (alpha-blockers). It is difficult to determine
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Copyright © 2004 Massachusetts Medical Society. All rights reserved.
of medicine
the efficacy of these drugs for overactive bladder, be-
cause the outcomes of most clinical trials have been
based on composite scores that include symptoms
of both overactive bladder and obstruction.96-102
Symptoms of overactive bladder tend to decrease
with alpha-blocker therapy, but less so than do
symptoms of obstruction.102,103 Because alpha-
blockers can cause postural hypotension, they re-
quire a gradual titration of the dose and must be
used carefully, especially in patients who are already
taking antihypertensive agents.93,100-102
Men who neither tolerate nor have a response to
alpha-blockers and who are not candidates for sur-
gical intervention may benefit from a trial of an anti-
cholinergic agent, provided they are carefully mon-
itored for the development of urinary retention.
Further research is needed to determine the optimal
use of alpha-blockers and anticholinergic drugs —
alone, together, or combined with behavioral ther-
apy — as a treatment for overactive bladder in men.
Treatment of nocturia, the most bothersome
symptom of overactive bladder for many patients
of both sexes, depends on the primary underlying
cause or causes — detrusor overactivity, nocturnal
polyuria, a primary sleep disorder, or some combi-
nation of these conditions.104,105 Nocturia that is
primarily related to detrusor overactivity can be treat-
ed with an anticholinergic agent. Nocturnal polyu-
ria related to volume overload (e.g., venous insuffi-
ciency or congestive heart failure with peripheral
edema) may respond to a small dose of a rapid-act-
ing diuretic taken in the late afternoon. Oral and in-
tranasal preparations of desmopressin are approved
for use in children with nocturnal enuresis.
Data supporting an association among noctur-
nal polyuria, nocturia, abnormal diurnal respon-
siveness to vasopressin, and levels of endogenous
arginine vasopressin in adults are limited and con-
flicting.106-109 However, two randomized, con-
trolled trials suggest that orally administered des-
mopressin can reduce nocturia in both women
(mean age, approximately 57 years)110 and men
(mean age, approximately 65 years).111 Both trials
used a three-week run-in dose-titration design (0.1
to 0.4 mg), during which approximately one third
of the patients were excluded. Among patients with
some responsiveness and ability to tolerate desmo-
pressin during the dose-titration phase, one third
of the women and the men had at least a 50 percent
reduction in the number of nighttime voiding epi-
sodes (as compared with 3 percent of patients in
the placebo group) and a significant increase in the
february 19 , 2004
 drug therapy

duration of sleep before their first nighttime voiding
during the three-week double-blind phase. Side ef-
fects were mild; hyponatremia occurred in approx-
imately 5 percent of patients but only during the
three-week dose-titration phase. On the basis of
these data, oral desmopressin has been approved
for the treatment of nocturia in several countries in
Europe, but it is not yet approved for this indication
in the United States.
Because of their mechanisms of action, several
classes of drugs used for other conditions are of
potential therapeutic value for patients with over-
active bladder, but data from randomized, con-
trolled clinical trials are lacking. Such drug classes
include calcium-channel blockers, prostaglandin-
synthesis inhibitors, dopamine D1–receptor ago-
nists, beta-adrenergic (particularly b3) agonists, and
g-aminobutyric acid (GABA) agonists (Table 3).20-22
For example, pergolide, a D1-receptor agonist, may
benefit patients with Parkinson’s disease and lower
urinary tract symptoms, and baclofen, a GABA ago-
nist, has been used in patients with the detrusor hy-
perreflexia associated with spinal cord disorders.
Direct injection of botulinum toxin into the detru-
sor muscle, which inhibits acetylcholine at the pre-
synaptic cholinergic junction, appears to ameliorate
detrusor hyperreflexia in patients with spinal cord
injury112,113; it may have some therapeutic value in
selected patients with severe refractory symptoms
of overactive bladder. Although currently available
beta-agonists have not been shown to be useful for
overactive bladder, more selective b3-agonists may
have therapeutic value.
There are several promising directions for the
development of drugs to treat overactive bladder (Ta-
ble 3). At least two antimuscarinic drugs (darifena-
cin and solifenacin) with selective M3-receptor–
antagonist actions and, theoretically, fewer systemic
anticholinergic side effects than currently available
agents are being studied. Oxybutynin has been in-
stilled intravesicularly through a catheter to treat se-
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
Drugs used for other conditions
Calcium-channel blockers
Inhibitors of prostaglandin synthesis
g-Aminobutyric acid–receptor agonists
Neuromuscular-junction inhibition
of acetylcholine release
Drugs in development
Antimuscarinic agents more selective
for M3 receptors than other anti-
muscarinic agents
Potassium-channel openers
Serotonergic agonists
Vanilloids and other afferent-nerve
inhibitors
Dopamine-D1–receptor agonists
Nerve growth factor inhibitors
Enkephalins
Examples Studied
in Humans Comments
Diltiazem Agents inhibit bladder contraction by decreasing calcium available for
Nifedipine smooth-muscle contraction; there is no evidence that these agents
Verapamil are effective for symptoms of overactive bladder.
Flurbiprofen Prostaglandins may increase the contraction of bladder smooth muscle;
no currently available agents have proven efficacy.
Baclofen Stimulation of g-aminobutyric acid receptors inhibits the voiding reflex.
Botulinum toxin Botulinum toxin A injections have been used for refractory symptoms.
Darifenacin
Solifenacin
Cromakalim These agents decrease spontaneous detrusor-muscle contractions and can
Pinacidil have clinically significant effects on blood pressure; potassium-channel
gene therapy has also been studied.
Duloxetine The central serotonergic effects of these agents increase urethral striated
sphincter-muscle tone.
Capsaicin These agents cause desensitization of unmyelinated C fibers; other
Resiniferatoxin afferent-nerve inhibitors may be useful.
Pergolide D1-receptor stimulation inhibits the voiding reflex.
— 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.

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 The new england journal of medicine

bladder pump is being developed that can deliver a verse consequences such as injurious falls. The
constant 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, neurologic
of 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 patients
useful for suppressing involuntary bladder contrac- should have a post-void residual determination, and
tions without interfering with normal voiding.115 some should undergo cystoscopy (such as those
However, first-generation agents in this class have with hematuria) or complex urodynamic testing
had effects on vascular smooth muscle and can (such as those with urinary retention or neurologic
cause hypotension. Duloxetine is an inhibitor of se-disorders).
rotonin and norepinephrine that appears to act cen- Patients with overactive bladder often benefit
from supportive measures such as education,
trally, increasing tone in the striated smooth muscle
changes in fluid intake, and the use of bedside com-
of the external urethral sphincter.116 Although it is
being studied primarily for the treatment of stress modes or urinals, especially at night. Behavioral
incontinence, duloxetine may also have therapeutic treatments such as pelvic-muscle exercises and
benefits in patients with mixed stress–urge inconti-bladder training are efficacious and can enhance the
nence. 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-studied
used either alone or in combination with other agents are oxybutynin and tolterodine; both have
drugs. Capsaicin and resiniferatoxin desensitize well-proven efficacy in short- and long-acting
C-fiber afferents and have been administered ex- forms. The extended-release formulations and the
perimentally by the intravesicular route. Resinifer-oxybutynin skin patch are generally well tolerated,
atoxin appears to be more potent and less irritatingbut all antimuscarinic drugs can have bothersome
than capsaicin and may be more useful clinical- anticholinergic side effects. The effects of these
agents on cognitive function are a particular concern
ly.55,117,118 Other drugs that block receptors on sen-
sory afferents, such as neurokinin-receptor antago- in older adults. Men with symptoms of overactive
nists (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 therapy
summary include 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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