The

new england journal

of

medicine

review article

drug therapy
Alastair J.J. Wood, M.D., Editor

Management of Overactive Bladder

Joseph G. Ouslander, M.D.
From the Division of Geriatric Medicine
and Gerontology, Wesley Woods Center,
Center for Health in Aging, Emory University, and the Birmingham/Atlanta Veterans
Affairs Geriatric Research Education Clinical Center both in Atlanta. Address reprint requests to Dr. Ouslander at the Wesley 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.
Copyright 2004 Massachusetts Medical Society.

veractive bladder is a symptom complex that includes urinary 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 overactive 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 International Continence Societys current definition of overactive bladder, since a broader 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 social activities and to isolate themselves and are predisposed to depression. Nocturia is
associated with sleep disruption, which decreases the quality of life.11-14 Postmenopausal 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 decreases 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 neurogenic or idiopathic, can result in urgency or urge incontinence, depending on the re-

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drug therapy

sponse of the sphincter.17 Detrusor overactivity may

also have a myogenic origin.18 Detrusor contractions can be weak as a result of impaired contractibility. 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 neurotransmitters are involved in urine storage and bladder emptying. The relation among these factors is incompletely understood. The role of central neurotransmitters
in the voiding cycle has been studied in animals.20-22
Glutamate is an excitatory neurotransmitter in pathways controlling the lower urinary tract. Serotonergic activity facilitates urine storage by enhancing the
sympathetic reflex pathway and inhibiting the parasympathetic voiding pathway. Dopaminergic pathways may exert both inhibitory and facilitatory effects 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 predominant 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 Acetylcholine 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 facilitate bladder contraction by reducing intracellular
levels of cyclic adenosine monophosphate.23
Pathologic states can alter sensitivity to muscarinic stimulation. For example, bladder-outflow obstruction appears to enhance responsiveness to acetylcholine, a phenomenon similar to denervation
suprasensitivity.20 Normally, only a small proportion of the bladder contraction is resistant to atropine, probably as a result of the interactions of ATP
with purinergic receptors. However, ATP may have
a more prominent role in bladder contraction in patients with overactive bladder.20-22 Anatomical correlates of detrusor overactivity have also been described. 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.
n engl j med 350;8

Increasing attention has been paid to the role of

sensory afferent nerves in normal voiding and detrusor overactivity.20-22,29 During bladder filling, afferent 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. Adrenergic activity may also cause relaxation of the detrusor muscle through the stimulation of b3-adrenergic 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 voiding, 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 receptors, which are activated by capsaicin and possibly by endogenous anandamide; purinergic receptors (P2X), which are activated by ATP; neurokinin
receptors, which respond to substance P and neurokinin A; and receptors for nerve growth factor (trk-A
receptors).20,31 Other substances, including nitric
oxide, calcitonin generelated protein, and brainderived neurotropic factor, may also have an important role in modulating the sensory afferents in the
human detrusor.20-22 A better understanding of the
complex interplay among these various neurotransmitters and other substances derived from uroepithelium, detrusor-muscle cells, and afferent fibers
themselves should yield new and more specific targets 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 urinary incontinence32 and benign prostatic hyperplasia33 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 elicited from all patients. A symptom index for benign
prostatic hypertrophy (recommended by the American 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 regarding lower urinary tract symptoms have also

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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

afferent innervation can result.

Treat infection before other interventions are considered.

Obstruction

Obstruction can contribute to detrusor

overactivity and urinary retention.
Urinary retention and reduced functional
bladder capacity can result.

Consider surgical intervention.

Impaired bladder contractility

Bladder abnormalities or inflammation

(e.g., tumors, calculi, interstitial
cystitis)
Women
Estrogen deficiency
Sphincter weakness

Men
Prostate enlargement

Intravesical abnormalities can precipitate

detrusor overactivity.

Inflammation from atrophic vaginitis and Topical estrogen may ameliorate symptoms.
urethritis can contribute to symptoms.
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.
Benign or malignant prostate enlargement can contribute to detrusor
overactivity.

Neurologic conditions
Brain
Stroke, Alzheimers disease, multiHigher cortical inhibition of the bladder
infarct dementia, other dementias,
is impaired, causing neurogenic
Parkinsons disease, multiple sclerosis
detrusor overactivity.
Spinal cord
Multiple sclerosis, cervical or lumbar
Neurogenic detrusor overactivity or urinary
stenosis or disk herniation, spinal
retention can result.
cord injury
Peripheral innervation
Diabetic neuropathy, nerve injury

Urinary retention and low functional bladder capacity can result.

been developed for women.36 In addition, diaries

can be helpful in determining the frequency, volume, and pattern of voiding, as well as providing
clues to underlying causes and contributing factors.37,38 All patients should undergo a focused
physical examination that includes genitourinary,
pelvic, and rectal examinations; a clean urine specimen should be obtained to rule out hematuria and
infection.
Further evaluation should be considered in se-

788

Avoid drugs that decrease bladder contractility.

Teach patients to enhance voiding (e.g., Creds
method).
Intermittent catheterization is helpful in selected
patients.
Sterile hematuria and risk factors for bladder
cancer should prompt further evaluation.

n engl j med 350;8

Evaluation and treatment for prostate cancer

should be considered.
Alpha-adrenergic blockers may improve symptoms.
5a-Reductase inhibitors may reduce prostate size.
Surgical removal of obstructing prostate may be
indicated.

Management must include a means of compensation for impaired cognition, impaired mobility,
or both.
Presence of neurologic symptoms or signs may
require further evaluation.
Urodynamic testing is often indicated for diagnostic purposes.
History suggestive of nerve injury or neurologic
signs require further evaluation.

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 catheterization. A portable ultrasonographic device is available
that permits noninvasive identification of clinically
significant residual urine (>100 ml), with an accuracy rate of more than 90 percent; it costs approximately $8,000.39 Patients with sterile hematuria or

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drug therapy

Table 1. (Continued.)
Conditions
Systemic conditions
Congestive heart failure, venous
insufficiency
Diabetes mellitus
Sleep disorders (sleep apnea, periodic
leg movements)
Abnormalities of arginine vasopressin
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, Parkinsons disease, severe osteoporosis, or muscle weakness)
Psychological conditions

Mechanisms or Effect

Implications for Management

Volume overload can contribute to urinary

frequency and nocturia when patient
is supine.
Poor blood glucose control can contribute
to osmotic diuresis and polyuria.
Sleep disorders can contribute to nocturia.

Proper timing of diuretics may ameliorate symptoms.

Use of leg elevation, support hose, and salt
restriction may be helpful.
Improved blood glucose control may ameliorate
symptoms.
Reports of sleep disruption or heavy snoring may
require further evaluation.
Carefully selected patients may benefit from desmopressin therapy.

Impaired secretion or action of vasopressin

may cause polyuria and nocturia.

Polyuria and urinary frequency can result.

Modification of fluid intake is critical for successful

management.
Fecal impaction can contribute to symptoms. An appropriate bowel regimen will reduce the incidence of fecal impaction.
Impaired mobility can interfere with toiletTreatment of underlying disorders, including physiing ability and precipitate urge inconcal therapy, should be optimal; the use of urinals,
tinence.
bedside commodes, and bedpans can be helpful.
Chronic anxiety and learned voiding dysfunction can cause symptoms of overactive bladder.

Side effects of medication

Diuretics, especially rapid-acting agents Diuretics cause a rapid increase in bladder
volume, which may precipitate urgency
and detrusor overactivity.
Anticholinergic agents, narcotics,
These agents decrease bladder contractility
calcium-channel blockers
and may cause urinary retention, with a
decreased functional bladder capacity.
Cholinesterase inhibitors
These agents could theoretically contribute
to detrusor overactivity by increasing
acetylcholine levels.

risk factors for bladder cancer should undergo cystoscopy, and their urine should be sent for cytologic
analysis. Cystoscopy is also indicated in patients
with a history of recurrent urinary tract infection. Although 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 abnormalities, 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

n engl j med 350;8

The diagnosis should be considered on the basis of

a patients 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.

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 obstruction than less invasive testing. Because this test is
relatively expensive and invasive, it is recommended only to evaluate symptoms of overactive bladder in cases in which the findings will clearly influence 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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A
Urgency

new england journal

Voluntary
voiding

Urethral
resistance
Detrusor
pressure
Striated sphinctermuscle activity
Bladder volume

Involuntary
detrusor
contraction
Detrusor overactivity
Urethral
resistance
Detrusor
pressure

Striated sphinctermuscle activity

Bladder volume
Figure 1. Normal Voiding Physiology (Panel A) and Involuntary Detrusor Contraction Commonly Associated with Symptoms of Overactive Bladder (Panel B).
Normally, as bladder volume increases, the detrusor muscle functions like a
compliant balloon and maintains a low intravesicular pressure (less than 10 cm
of water) substantially lower than urethral resistance pressure (Panel A).
As bladder volume continues to increase, the activity of the striated muscles
of the urethral sphincter increases. At the time of normal voluntary voiding,
which generally occurs at a urinary volume of 300 to 400 ml, muscle activity in
the sphincter ceases, urethral resistance decreases, and a phasic detrusor
contraction empties the bladder. In patients with symptomatic overactive
bladder, involuntary bladder contractions can cause urgency and may precipitate urine loss, depending on the response of the sphincter (Panel B). Involuntary contractions may occur at any bladder volume, but they commonly occur at volumes of less than 200 ml. The sphincter-muscle activity depicted in
Panel B is a response to the involuntary contraction of the detrusor muscle
(as opposed to detrusorsphincter dyssynergy). Detrusor overactivity can be
neurogenic or idiopathic and can be accompanied by urgency or be without
sensation.

commonly multifactorial, and multimodal therapy

that includes nonpharmacologic as well as pharmacologic interventions may be indicated.
nonpharmacologic interventions

Various clinical trials suggest that behavioral interventions are efficacious for managing urge and

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mixed urgestress incontinence. Educating patients

about bladder function, appropriate fluid intake
(avoidance of caffeine, maintenance of adequate hydration, and the timing of fluid intake), and managing constipation is important for all patients with
overactive bladder. Education may, in fact, underlie
the prominent placebo effects (approximately 30
percent improvement in symptoms) demonstrated
repeatedly in drug trials for incontinence and overactive 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 pelvic-muscle exercises and bladder training.41-43
Approximately 70 percent of patients have a reduction in the number of episodes of incontinence within two to three months. The long-term effectiveness
of these interventions requires further study.
Many patients can be taught pelvic-muscle exercises during a pelvic or rectal examination or can
learn them with the use of simple educational tools
such as an audiotape or a booklet.42 A substantial
proportion of older patients benefit from biofeedback-assisted training. Bladder training generally
refers to a combination of patient education, scheduled voiding and urge-suppression techniques, and
pelvic-muscle exercises.41 For some patients with
cognitive impairment, limited mobility, or both,
the use of toileting-assistance protocols such as
prompted voiding can be very helpful in the management of overactive bladder.44 All these behavioral interventions can also be effective adjuncts to
drug therapy.
Some patients with severe symptoms of overactive bladder that are refractory to proven behavioral
treatment may benefit from other nonpharmacologic interventions. A wide variety of highly absorbent pads and undergarments are available that can
be effective and acceptable in selected patients with
refractory symptoms in order to maintain social
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
in teaching some patients the proper use of pelvic
muscles (an approach similar to biofeedback), and
lower-frequency stimulation can inhibit bladder
contraction.47 Sacral neuromodulation by means of
implantable stimulators is used in selected patients
with severe neurogenic detrusor overactivity.48 Magnetic stimulation has also been approved for the

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drug therapy

treatment of incontinence, but this requires multiple visits to a facility that has the stimulation equipment. Surgical procedures, including motor-nerve
ablation and augmentation cystoplasty, are used
only in patients with the most severe symptoms.49,50

Parasympathetic
nerve

Sympathetic
nerve

ATP

drug therapy

Many classes of drugs have been studied or proposed 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 limit the quality of many studies. Expert groups have
proposed methodologic standards that should improve the science underlying drug therapy of overactive bladder.52-54
Table 2 lists drugs currently used to treat symptoms of overactive bladder and notes both evidence
of efficacy and recommendations based on the International Consultation on Urological Diseases.7
A recent review summarizes the efficacy of anticholinergic drugs for the treatment of overactive bladder 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 common, constipation, gastroesophageal reflux, blurry
vision, urinary retention, and cognitive side effects
can also occur. Both overactive bladder and dementia are common in older patients. Since various
forms of dementia are routinely treated with cholinesterase inhibitors, the potential for adverse cognitive 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 electroencephalographic data suggest that oxybutynin
has more central nervous system effects than trospium or tolterodine.60 Long-acting anticholinergic
agents and newer, more selective antimuscarinic
agents should be tested for clinically important cognitive side effects, especially in older patients.
Among the anticholinergic agents, only oxybutynin, 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-

n engl j med 350;8

Acetylcholine
M3
receptor

M2
receptor

G protein

Norepinephrine

P2X1
receptor

b3-adrenergic
receptor

Phospholipase C
Inositol
triphosphate

Adenylate
cyclase
Cyclic AMP

Contraction of bladder
smooth muscle

Relaxation of bladder
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 neurotransmitter that causes bladder contraction. Acetylcholine interacts with M3 muscarinic receptors and activates phospholipase C through coupling with G proteins, 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 inhibiting adenylate cyclase activity and decreasing intracellular cyclic adenosine
monophosphate (AMP) levels, which mediate bladder relaxation. In the normal 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 noncholinergically mediated processes may have a more important role in disorders that cause overactive bladder. Stimulation of b3-adrenergic receptors
may also lead to relaxation of bladder smooth muscle. Plus signs indicate activation, 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 neurogenic and non-neurogenic overactivity of the detrusor muscle with urge incontinence. Given in this
formulation, oxybutynin has led to a clinically significant improvement, defined as a reduction in
incontinence episodes by more than 50 percent,

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Uroepithelial cell
Nerve
growth
factor

Anandamide?

trk-A
receptor

ATP

Neurokinin A
Substance P

Vanilloid P2X2 or P2X3

receptor
receptor
Neurokinin
receptor

C sensory fiber

Detrusor
smoothmuscle cell

C sensory
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 bladder 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, detrusor 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 subjects.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 clinical trials. Generic immediate-release oxybutynin is
relatively inexpensive and may be useful for patients
whose symptoms are best managed by a short-acting 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 effects as immediate-release oxybutynin, with fewer
side effects a benefit ascribed to the more constant 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 controlled-release oxybutynin have reported a reduction

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in episodes of urge incontinence by approximately

70 percent.43,63-66 A transdermal oxybutynin patch
is also available that is as efficacious as immediaterelease 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-acting (once-daily) preparations. Both forms have had
statistically and clinically significant effects on
symptoms of overactive bladder in multiple, randomized, 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 similar 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.*

Drug

Level of
Evidence/Grade of
Recommendation

Usual Adult Dose

Comments

Drugs with predominantly

anticholinergic or antimuscarinic effects
Hyoscyamine

0.375 mg twice daily orally

2/D

The drug is also available in sublingual and

elixir forms; it has prominent anticholinergic side effects.

Oxybutynin

2.55.0 mg thrice daily orally (short-acting)

530 mg daily orally (long-acting)
3.9 mg over a 96-hr period (transdermal)

1/A

Long-acting and transdermal preparations

have fewer side effects than short-acting
preparations.
The transdermal patch can cause local skin
irritation in some patients.

Propantheline

1530 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 currently available in the United States.

Tolterodine

12 mg twice daily orally (short-acting)

4 mg daily orally (long-acting)

1/A

The long-acting and short-acting preparations

have similar efficacy.

Trospium

20 mg twice daily orally

1/A

The agent is a quaternary ammonium compound, 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.

Approximately 0.5 g cream applied topically

nightly for 2 wk, then twice per week
Estradiol ring, replaced every 90 days
Estradiol, 1 tablet daily for 2 wk, then 1 tablet
twice a week

4/D

Local vaginal preparations are probably more

effective than oral estrogen, but definitive
data on effectiveness are lacking.

2.5 mg thrice daily orally

116 mg daily orally
110 mg twice daily orally
0.40.8 mg daily orally
110 mg orally each day at bedtime

4/D

These agents are useful in men with benign

prostatic enlargement.
Postural hypotension can be a serious side
effect.
Doses must be increased gradually to facilitate
tolerance.

Estrogen (for women)

Vaginal estrogen
preparations

Alpha-adrenergic antagonists
(for men)
Alfuzosin
Doxazosin
Prazosin
Tamsulosin
Terazosin
Other drugs
Imipramine

1025 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

2040 g of intranasal spray daily at bedtime

0.10.4 mg orally 2 hr before bedtime

1/B

The intranasal spray is used for primary nocturnal enuresis in children; hyponatremia
occurs commonly in older adults, and serum 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 casecontrol studies; and a score of 4 evidence 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, controlled 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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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 medical practices were randomized,77 and in the other,
women (mean age, 60 years) were randomly assigned 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 effective when combined with various types of behavioral interventions.78,80-82
Randomized, controlled trials indicate that
propiverine and trospium are effective for the treatment of urge incontinence and have fewer side effects than short-acting oxybutynin.83-86 Neither
drug is currently available in the United States (trospium is being evaluated in clinical trials in the United States). Though hyoscyamine, like short-acting
oxybutynin, may be useful for some patients with intermittent symptoms or under specific circumstances, 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 multiple daily doses and the relatively high incidence of
side effects are drawbacks. Imipramine, a tricyclic
antidepressant with both anticholinergic and alphaadrenergic effects and, possibly, a central effect on
voiding reflexes, has been recommended for mixed
urgestress incontinence, which is common among
older women with overactive bladder. Imipramine
can cause postural hypotension and cardiac-conduction abnormalities and thus must be used carefully.
Postmenopausal women with symptoms of overactive bladder are commonly treated with oral or
topical estrogen, but few data document the efficacy 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 bladder depends on several factors, such as the degree
to which specific symptoms bother the patient, the
patients preferences, evaluation of the riskbenefit
ratio, and the physicians bias. Treatment decisions
are further complicated by the fact that complex
urodynamic studies are required to rule out bladder-outlet obstruction as a cause. Men with isolated
symptoms of overactive bladder in whom prostate 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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the efficacy of these drugs for overactive bladder, because 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 alphablockers can cause postural hypotension, they require 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 surgical intervention may benefit from a trial of an anticholinergic agent, provided they are carefully monitored 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 therapy 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 combination of these conditions.104,105 Nocturia that is
primarily related to detrusor overactivity can be treated with an anticholinergic agent. Nocturnal polyuria related to volume overload (e.g., venous insufficiency or congestive heart failure with peripheral
edema) may respond to a small dose of a rapid-acting diuretic taken in the late afternoon. Oral and intranasal preparations of desmopressin are approved
for use in children with nocturnal enuresis.
Data supporting an association among nocturnal polyuria, nocturia, abnormal diurnal responsiveness to vasopressin, and levels of endogenous
arginine vasopressin in adults are limited and conflicting.106-109 However, two randomized, controlled trials suggest that orally administered desmopressin 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 desmopressin 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 episodes (as compared with 3 percent of patients in
the placebo group) and a significant increase in the

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drug therapy

duration of sleep before their first nighttime voiding

during the three-week double-blind phase. Side effects were mild; hyponatremia occurred in approximately 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 overactive bladder, but data from randomized, controlled clinical trials are lacking. Such drug classes
include calcium-channel blockers, prostaglandinsynthesis inhibitors, dopamine D1receptor agonists, 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 Parkinsons disease and lower
urinary tract symptoms, and baclofen, a GABA ago-

nist, has been used in patients with the detrusor hyperreflexia associated with spinal cord disorders.
Direct injection of botulinum toxin into the detrusor muscle, which inhibits acetylcholine at the presynaptic 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 (Table 3). At least two antimuscarinic drugs (darifenacin 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 instilled intravesicularly through a catheter to treat severe 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.*
Examples Studied
in Humans

Drug Classes and Actions

Drugs used for other conditions
Calcium-channel blockers

Inhibitors of prostaglandin synthesis

Diltiazem
Nifedipine
Verapamil
Flurbiprofen

g-Aminobutyric acidreceptor agonists

Neuromuscular-junction inhibition
of acetylcholine release
Drugs in development
Antimuscarinic agents more selective
for M3 receptors than other antimuscarinic agents
Potassium-channel openers

Baclofen
Botulinum toxin

Serotonergic agonists

Duloxetine

Vanilloids and other afferent-nerve

inhibitors
Dopamine-D1receptor agonists
Nerve growth factor inhibitors

Capsaicin
Resiniferatoxin
Pergolide

Enkephalins

Comments
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.
Prostaglandins may increase the contraction of bladder smooth muscle;
no currently available agents have proven efficacy.
Stimulation of g-aminobutyric acid receptors inhibits the voiding reflex.
Botulinum toxin A injections have been used for refractory symptoms.

Darifenacin
Solifenacin
Cromakalim
Pinacidil

These agents decrease spontaneous detrusor-muscle contractions and can

have clinically significant effects on blood pressure; potassium-channel
gene therapy has also been studied.
The central serotonergic effects of these agents increase urethral striated
sphincter-muscle tone.
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 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 clinical trials are published.

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verse consequences such as injurious falls. The

symptoms may be caused by myriad factors, including disorders of the lower urinary tract, neurologic
conditions, behavioral factors such as caffeine intake, and a variety of commonly prescribed drugs.
The pathophysiologic process in an individual patient is often multifactorial. Diagnostic evaluation
includes a focused history taking, targeted physical examination, and urinalysis. Selected patients
should have a post-void residual determination, and
some should undergo cystoscopy (such as those
with hematuria) or complex urodynamic testing
(such as those with urinary retention or neurologic
disorders).
Patients with overactive bladder often benefit
from supportive measures such as education,
changes in fluid intake, and the use of bedside commodes or urinals, especially at night. Behavioral
treatments such as pelvic-muscle exercises and
bladder training are efficacious and can enhance the
benefits of drug therapy. The mainstay of drug therapy is antimuscarinic agents. The two best-studied
agents are oxybutynin and tolterodine; both have
well-proven efficacy in short- and long-acting
forms. The extended-release formulations and the
oxybutynin skin patch are generally well tolerated,
but all antimuscarinic drugs can have bothersome
anticholinergic side effects. The effects of these
agents on cognitive function are a particular concern
in older adults. Men with symptoms of overactive
bladder in association with benign prostatic hyperplasia may benefit from treatment with alpha-blockers. Promising future directions in drug therapy
include the development of more specific antisummary
muscarinic agents, new drug-delivery systems, and
Symptoms of overactive bladder are common, can drugs that affect the sensory innervation of the lowbe distressing, and are associated with serious ad- er urinary tract.

bladder pump is being developed that can deliver a

constant dose of intravesicular oxybutynin for up
to 30 days.21 Such a device may make this method
of drug delivery more practical and acceptable and
may result in fewer systemic anticholinergic side
effects.
Drugs that act by means of potassium-channel
transporters to hyperpolarize smooth muscle and
decrease spontaneous bladder contractions may be
useful for suppressing involuntary bladder contractions without interfering with normal voiding.115
However, first-generation agents in this class have
had effects on vascular smooth muscle and can
cause hypotension. Duloxetine is an inhibitor of serotonin and norepinephrine that appears to act centrally, increasing tone in the striated smooth muscle
of the external urethral sphincter.116 Although it is
being studied primarily for the treatment of stress
incontinence, duloxetine may also have therapeutic
benefits in patients with mixed stressurge incontinence. Drugs that act on sensory afferent pathways
are also being developed and hold promise when
used either alone or in combination with other
drugs. Capsaicin and resiniferatoxin desensitize
C-fiber afferents and have been administered experimentally by the intravesicular route. Resiniferatoxin appears to be more potent and less irritating
than capsaicin and may be more useful clinically.55,117,118 Other drugs that block receptors on sensory afferents, such as neurokinin-receptor antagonists (Fig. 3), might not cause urinary retention,
which can occur with antimuscarinic agents.

refer enc es
1. Abrams P, Wein AJ, eds. The Overactive

Bladder: From Basic Science to Clinical Management Consensus Conference. Urology

1997;50:Suppl:1-114.
2. Idem. Overactive Bladder and Its Treatments Consensus Conference. Urology
2000;55:Suppl:1-84.
3. Staskin DR, Wein AJ, eds. New perspectives on the overactive bladder. Urology 2002;
60:Suppl:1-104.
4. Abrams P, Cardozo L, Fall M, et al. The
standardisation of terminology of lower urinary tract function: report from the Standardisation Sub-committee of the International
Continence Society. Neurourol Urodyn 2002;
21:167-78.
5. van Kerrebroeck P, Abrams P, Chaikin

796

D, et al. The standardisation of terminology

in nocturia: report from the Standardisation
Sub-committee of the International Continence Society. Neurourol Urodyn 2002;21:
179-83.
6. Blaivas JG. Overactive bladder revisited.
Neurourol Urodyn 2002;21:523.
7. Abrams P, Cardozo L, Khoury S, Wein A,
eds. Incontinence. 2nd ed. Plymouth, England: Health Publications, 2002.
8. Garnett S, Abrams P. The natural history
of the overactive bladder and detrusor overactivity: a review of the evidence regarding
the long-term outcome of the overactive
bladder. J Urol 2003;169:843-8.
9. Milson I, Abrams P, Cardozo L, Roberts
RG, Thuroff J, Wein AJ. How widespread are

n engl j med 350;8

www.nejm.org

the symptoms of an overactive bladder and

how are they managed? A population-based
prevalence study. BJU Int 2001;87:760-6.
[Erratum, BJU Int 2001;88:807.]
10. Stewart W, Herzog R, Wein A, et al. Prevalence and impact of overactive bladder in
the US: results for the NOBLE program. Neurourol Urodyn 2001;20:406. abstract.
11. Kobelt G. Economic considerations and
outcome measurement in urge incontinence.
Urology 1997;50:Suppl:100-10.
12. Brown JS, Posner SF, Stewart AL. Urge
incontinence: new health-related quality of
life measures. J Am Geriatr Soc 1999;47:
980-8.
13. DuBeau CE, Kiely DK, Resnick NM.
Quality of life impact of urge incontinence

february 19, 2004

The New England Journal of Medicine

Downloaded from nejm.org on November 18, 2013. For personal use only. No other uses without permission.
Copyright 2004 Massachusetts Medical Society. All rights reserved.

drug therapy

in older persons: a new measure and conceptual structure. J Am Geriatr Soc 1999;47:
989-94.
14. Dugan E, Cohen SJ, Bland DR, et al. The
association of depressive symptoms and
urinary incontinence among older adults.
J Am Geriatr Soc 2000;48:413-6.
15. Brown JS, Vittinghoff E, Wyman JF, et al.
Urinary incontinence: does it increase risk
for falls and fractures? Study of Osteoporotic Fractures Research Group. J Am Geriatr
Soc 2000;48:721-5.
16. Hu T-W. Moore K, Subak L, et al. Economics of incontinence. In: Abrams P, Cardozo L, Khoury S, Wein A, eds. Incontinence.
2nd ed. Plymouth, England: Health Publications, 2002:3-20.
17. Fisser AJ, Walmsley K, Blaivas JG. Urodynamic classification of patients with symptoms of overactive bladder. J Urol 2003;169:
529-34.
18. Brading AF. A myogenic basis for the
overactive bladder. Urology 1997;50:Suppl:
57-73.
19. Resnick NM, Yalla SV. Detrusor hyperactivity with impaired contractile function:
an unrecognized but common cause of incontinence in elderly patients. JAMA 1987;
257:3076-81.
20. Morrison J, Steers WD, Brading AF, et al.
Neurophysiology and neuropharmacology.
In: Abrams P, Cardoza L, Khoury S, Wein A,
eds. Incontinence. 2nd ed. Plymouth, England: Health Publications, 2002:86-163.
21. Yoshimura N, Chancellor MB. Current
and future pharmacological treatment for
overactive bladder. J Urol 2002;168:1897913.
22. Andersson KE, Hedlund P. Pharmacologic perspective on the physiology of the
lower urinary tract. Urology 2002;605:Suppl
1:13-21.
23. Hedge S, Choppin A, Bonhaus D, et al.
Functional role of M2 and M3 muscarinic
receptors in the urinary bladder of rats in vitro and in vivo. Br J Pharmacol 1997;120:
1409-18.
24. Elbadawi A, Hailemariam S, Yalla SV,
Resnick NM. Structural basis of geriatric
voiding dysfunction. VI. Validation and update of diagnostic criteria in 71 detrusor biopsies. J Urol 1997;157:1802-13.
25. Idem. Structural basis of geriatric voiding dysfunction. VII. Prospective ultrastructural/urodynamic evaluation of its natural
evolution. J Urol 1997;157:1814-22.
26. Elbadawi A, Yalla SV, Resnick NM.
Structural basis of geriatric voiding dysfunction. I. Methods of a prospective ultrastructural/urodynamic study and an overview of
the findings. J Urol 1993;150:1650-6.
27. Idem. Structural basis of geriatric voiding dysfunction. II. Aging detrusor: normal
versus impaired contractility. J Urol 1993;
150:1657-67.
28. Tse V, Wills E, Szonyi G, Khadra MH.
The application of ultrastructural studies in
the diagnosis of bladder dysfunction in a
clinical setting. J Urol 2000;163:535-9.

29. Jung SY, Fraser MO, Ozawa H, et al. Ure-

thral afferent nerve activity affects the micturition reflex: implication for the relationship
between stress incontinence and detrusor
instability. J Urol 1999;162:204-12.
30. Igawa Y, Yamazaki Y, Takeda H, et al.
Functional and molecular biological evidence for a possible beta3-adrenoceptor in
the human detrusor muscle. Br J Pharmacol
1999;126:819-25.
31. OReilly BA, Kosaka AH, Knight GF, et
al. P2X receptors and their role in female idiopathic detrusor instability. J Urol 2002;
167:157-64.
32. Fantl JA, Newman DK, Colling J, et al.
Urinary incontinence in adults: acute and
chronic management. Clinical practice
guideline. No. 2. 1996 update. Rockville,
Md.: Agency for Health Care Policy and Research, March 1996. (AHCPR publication
no. 96-0682.)
33. McConnell JD, Barry MJ, Bruskewitz
RC, et al. Benign prostatic hyperplasia: diagnosis and treatment. Clinical practice guide.
No. 8. Rockville, Md.: Agency for Health
Care Policy and Research, February 1994.
(AHCPR publication no. 94-0582.)
34. Barry MJ, Fowler FJ Jr, OLeary MP, et al.
The American Urological Association symptom index for benign prostatic hyperplasia.
J Urol 1992;148:1549-57, 1564.
35. Peters TJ, Donovan JL, Kay HE, et al. The
International Continence Society Benign
Prostatic Hyperplasia Study: the bothersomeness of urinary symptoms. J Urol 1997;
157:885-9.
36. Graham CW, Dmochowki RR. Questionnaires for women with urinary symptoms. Neurourol Urodyn 2002;21:473-81.
37. Wyman JF, Choi SC, Harkins SW, Wilson MS, Fantl JA. The urinary diary in evaluation of incontinent women: a test-retest
analysis. Obstet Gynecol 1988;71:812-7.
38. Locher JL, Goode PS, Roth DL, Worrell
RL, Burgio KL. Reliability assessment of the
bladder diary for urinary incontinence in
older women. J Gerontol A Biol Sci Med Sci
2001;56:M32-M35.
39. Marks LS, Dorey FJ, Macairan ML, Park
C, deKernion JB. Three-dimensional ultrasound device for rapid determination of
bladder volume. Urology 1997;50:341-8.
40. DuBeau CE, Yalla SV, Resnick NM. Improving the utility of urine flow rate to exclude outlet obstruction in men with voiding
symptoms. J Am Geriatr Soc 1998;46:111824.
41. Fantl JA, Wyman JF, McClish DK, et al.
Efficacy of bladder training in older women
with urinary incontinence. JAMA 1991;265:
609-13.
42. Burgio KL, Goode PS, Locher JL, et al.
Behavioral training with and without biofeedback in the treatment of urge incontinence in older women: a randomized controlled trial. JAMA 2002;288:2293-9.
43. Burgio KL, Locher JL, Goode PS, et al.
Behavioral vs drug treatment for urge urinary incontinence in older women: a ran-

n engl j med 350;8

www.nejm.org

domized controlled trial. JAMA 1998;280:

1995-2000.
44. Ouslander JG, Schnelle JF, Uman G, et
al. Predictors of successful prompted voiding among incontinent nursing home residents. JAMA 1995;273:1366-70.
45. Johnson TM II, Kincade JE, Bernard SL,
Busby-Whitehead J, DeFriese GH. Self-care
practices used by older men and women to
manage urinary incontinence: results from
the National Follow-up Survey on Self-Care
and Aging. J Am Geriatr Soc 2000;48:894902.
46. Johnson TM, Ouslander JG, Uman GC,
Schnelle JF. Urinary incontinence treatment
preferences in long-term care. J Am Geriatr
Soc 2001;49:710-8.
47. Brubaker L. Electrical stimulation in
overactive bladder. Urology 2000;55:Suppl:
17-23, 31-2.
48. Hohenfellner M, Dahms SE, Matzel K,
Thuroff JW. Sacral neuromodulation for
treatment of lower urinary tract dysfunction.
BJU Int 2000;85:Suppl 3:10-9, 22-3.
49. Madersbacher H. Denervation techniques. BJU Int 2000;85:Suppl 3:1-6, 8-9.
50. Atala A. New methods of bladder augmentation. BJU Int 2000;85:Suppl 3:24-34,
36.
51. Anderson K-E, Appell R, Awad S, et al.
Pharmacologic treatment of urinary incontinence. In: Abrams P, Cardozo L, Khoury S,
Wein A, eds. Incontinence. 2nd ed. Plymouth, England: Health Publications, 2002:
481-511.
52. Blaivas JG, Appell RA, Fantl JA, et al.
Standards of efficacy for evaluation of
treatment outcomes in urinary incontinence: recommendations of the Urodynamic Society. Neurourol Urodyn 1997;16:
145-7.
53. Fonda D, Resnick NM, Colling J, et al.
Outcome measures for research of lower
urinary tract dysfunction in frail older people. Neurourol Urodyn 1998;17:273-81.
54. Payne C, van Kerrebroeck P, Blaivas JG,
et al. Research methodology in urinary incontinence. In: Abrams P, Cardozo L,
Khoury S, Wein A, eds. Incontinence. 2nd
ed. Plymouth, England: Health Publications, 2002:1047-77.
55. De Ridder D, Chandiramani V, Dasgupta P, Van Poppel H, Baert L, Fowler C. Intravesical capsaicin as a treatment for refractory detrusor hyperreflexia: a dual center study
with long-term followup. J Urol 1997;158:
2087-92.
56. Levels of evidence and grades of recommendation. Oxford, England: Centre for Evidence-Based Medicine. (Accessed January
27, 2004, at http://www.cebm.net/levels_ of_
evidence.asp.)
57. Herbison P, Hay-Smith J, Ellis G, Moore
K. Effectiveness of anticholinergic drugs
compared with placebo in the treatment of
overactive bladder: systematic review. BMJ
2003;326:841-4.
58. Edwards KR, OConnor JT. Risk of delirium with concomitant use of tolterodine

february 19, 2004

The New England Journal of Medicine

Downloaded from nejm.org on November 18, 2013. For personal use only. No other uses without permission.
Copyright 2004 Massachusetts Medical Society. All rights reserved.

797

The

new england journal

and acetylcholinesterase inhibitors. J Am

Geriatr Soc 2002;50:1165-6.
59. Katz IR, Sands LP, Bilker W, DiFillipo S,
Boyce A, DAngelo K. Identification of medications that cause cognitive impairment in
older people: the case of oxybutynin chloride. J Am Geriatr Soc 1998;46:8-13.
60. Todorova A, Vonderheid-Guth B, Dimpfel W. Effects of tolterodine, trospium chloride, and oxybutynin on the central nervous
system. J Clin Pharmacol 2001;41:636-44.
61. Yarker YE, Goa KL, Fitton A. Oxybutynin: a review of its pharmacodynamic and
pharmacokinetic properties, and its therapeutic use in detrusor instability. Drugs Aging 1995;6:243-62.
62. Gupta SK, Sathyan G. Pharmacokinetics of an oral once-a-day controlled-release
oxybutynin formulation compared with immediate-release oxybutynin. J Clin Pharmacol 1999;39:289-96.
63. Anderson RU, Mobley D, Blank B,
Saltzstein D, Susset J, Brown JS. Once daily
controlled versus immediate release oxybutynin chloride for urge urinary incontinence. J Urol 1999;161:1809-12.
64. Gleason DM, Susset J, White C, Munoz
DR, Sand PK. Evaluation of a new once-daily
formulation of oxybutynin for the treatment
of urinary urge incontinence. Urology 1999;
54:420-3.
65. Birns J, Lukkari E, Malone-Lee JG.
A randomized controlled trial comparing
the efficacy of controlled-release oxybutynin
tablets (10 mg once daily) with conventional
oxybutynin tablets (5 mg twice daily) in patients whose symptoms were stabilized on
5 mg twice daily of oxybutynin. BJU Int 2000;
85:793-8.
66. Appell RA, Sand P, Dmochowski R, et
al. Prospective randomized controlled trial
of extended-release oxybutynin chloride and
tolterodine tartrate in the treatment of overactive bladder: results of the OBJECT Study.
Mayo Clin Proc 2001;76:358-63.
67. Davila GW, Daugherty CA, Sanders SW.
A short-term, multicenter, randomized double-blind dose titration study of the efficacy
and anticholinergic side effects of transdermal compared to immediate release oral oxybutynin treatment of patients with urge urinary incontinence. J Urol 2001;166:140-5.
68. Dmochowski RR, Davila GW, Zinner
NR, et al. Efficacy and safety of transdermal
oxybutynin in patients with urge and mixed
urinary incontinence. J Urol 2002;168:580-6.
69. Abrams P, Freeman R, Anderstrom C,
Mattiasson A. Tolterodine, a new antimuscarinic agent: as effective but better tolerated than oxybutynin in patients with an overactive bladder. Br J Urol 1998;81:801-10.
70. Jonas U, Hofner K, Madersbacher H,
Holmdahl TH. Efficacy and safety of two
doses of tolterodine versus placebo in patients with detrusor overactivity and symptoms of frequency, urge incontinence, and
urgency: urodynamic evaluation. World
J Urol 1997;15:144-51. [Erratum, World
J Urol 1997;15:210.]

798

of

medicine

71. Drutz HP, Appell RA, Gleason D, Klim-

berg I, Radomski S. Clinical efficacy and

safety of tolterodine compared to oxybutynin and placebo in patients with overactive
bladder. Int Urogynecol J Pelvic Floor Dysfunct 1999;10:283-9.
72. Freedman S, Mitcheson HD, Antoci J,
Primus G, Chancellor MF, Wein A. Tolterodine, an effective and well tolerated treatment for urge incontinence and other overactive bladder symptoms. Clin Drug Invest
2000;19:83-91.
73. Van Kerrebroeck P, Kreder K, Jonas U,
Zinner N, Wein A. Tolterodine once-daily:
superior efficacy and tolerability in the treatment of the overactive bladder. Urology
2001;57:414-21.
74. Malone-Lee J, Shaffu B, Anand C, Powell C. Tolterodine: superior tolerability than
and comparable efficacy to oxybutynin in individuals 50 years old or older with overactive bladder: a randomized controlled trial.
J Urol 2001;165:1452-6.
75. Malone-Lee JG, Walsh JB, Maugourd
MF. Tolterodine: a safe and effective treatment for older patients with overactive bladder. J Am Geriatr Soc 2001;49:700-5.
76. Zinner NR, Mattiasson A, Stanton SL.
Efficacy, safety, and tolerability of extendedrelease once-daily tolterodine treatment for
overactive bladder in older versus younger
patients. J Am Geriatr Soc 2002;50:799-807.
77. Sussman D, Garely A. Treatment of
overactive bladder with once-daily extended-release tolterodine or oxybutynin: the
Antimuscarinic Clinical Effectiveness Trial
(ACET). Curr Med Res Opin 2002;18:17784.
78. Ouslander J, Maloney C, Grasela T, Rogers L, Walawander C. Implementation of a
nursing home urinary incontinence management program with and without tolterodine. J Am Med Dir Assoc 2001;2:207-14.
79. Diokno AC, Appell RA, Sand PK, et al.
Prospective, randomized, double-blind
study of the efficacy and tolerability of the
extended-release formulations of oxybutynin and tolterodine for overactive bladder:
results of the OPERA trial. Mayo Clin Proc
2003;78:687-95.
80. Burgio KL, Locher JL, Goode PS. Combined behavioral and drug therapy for urge
incontinence in older women. J Am Geriatr
Soc 2000;48:370-4.
81. Ouslander JG, Schnelle JF, Uman G, et
al. Does oxybutynin add to the effectiveness
of prompted voiding for urinary incontinence
among nursing home residents? A placebocontrolled trial. J Am Geriatr Soc 1995;43:
610-7.
82. Mattiasson A, Blaakaer J, Hye K, Wein
AJ, Tolterodine Scandinavian Study Group.
Simplified bladder training augments the
effectiveness of tolterodine in patients with
an overactive bladder. BJU Int 2003;91:54-60.
83. Mazur D, Wehnert J, Dorschner W,
Schubert G, Herfurth G, Alken RG. Clinical
and urodynamic effects of propiverine in patients suffering from urgency and urge in-

n engl j med 350;8

www.nejm.org

continence: a multicentre dose-optimizing

study. Scand J Urol Nephrol 1995;29:289-94.
84. Madersbacher H, Halaska M, Voigt R,
Alloussi S, Hofner K. A placebo-controlled,
multicentre study comparing the tolerability
and efficacy of propiverine and oxybutynin
in patients with urgency and urge incontinence. BJU Int 1999;84:646-51.
85. Madersbacher H, Murtz G. Efficacy, tolerability and safety profile in propiverine in
the treatment of the overactive bladder (nonneurogenic and neurogenic). World J Urol
2001;19:324-35.
86. Madersbacher H, Stohrer M, Richter R,
Burgdorfer H, Hachen HJ, Murtz G. Trospium chloride versus oxybutynin: a randomized, double-blind, multicentre trial in the
treatment of detrusor hyper-reflexia. Br
J Urol 1995;75:452-6.
87. Holmes DM, Montz FJ, Stanton SL.
Oxybutynin versus propantheline in the management of detrusor instability: a patientregulated variable dose trial. Br J Obstet Gynaecol 1989;96:607-12.
88. Thuroff J, Bunke B, Ebner A, et al. Randomized, double-blind, multicenter trial on
treatment of frequency, urgency and incontinence related to detrusor hyperactivity:
oxybutynin versus propantheline versus placebo. J Urol 1991;145:813-7.
89. Fantl JA, Cardozo L, McClish DK. Estrogen therapy in the management of urinary
incontinence in postmenopausal women:
a meta-analysis: first report of the Hormones
and Urogenital Therapy Committee. Obstet
Gynecol 1994;83:12-8.
90. Sultana CJ, Walters MD. Estrogen and
urinary incontinence in women. Maturitas
1994;20:129-38.
91. Fantl JA, Bump RC, Robinson D, McClish DK, Wyman JF. Efficacy of estrogen
supplementation in the treatment of urinary
incontinence: the Continence Program for
Women Research Group. Obstet Gynecol
1996;88:745-9.
92. Ouslander JG, Greendale GA, Uman G,
Lee C, Paul W, Schnele J. Effects of oral estrogen and progestin on the lower urinary
tract among female nursing home residents.
J Am Geriatr Soc 2001;49:803-7.
93. Oesterling JE. Benign prostatic hyperplasia: medical and minimally invasive treatment options. N Engl J Med 1995;332:99109.
94. DuBeau CE, Yalla SV, Resnick NM. Implications of the most bothersome prostatism symptom for clinical care and outcomes
research. J Am Geriatr Soc 1995;43:985-92.
95. Thomas AW, Abrams P. Lower urinary
tract symptoms, benign prostatic obstruction and the overactive bladder. BJU Int
2000;85:Suppl 3:57-68, 70-1.
96. Debruyne FM, Witjes WP, Fitzpatrick J,
Kirby R, Kirk D, Prezioso D. The international terazosin trial: a multicentre study of
the long-term efficacy and safety of terazosin
in the treatment of benign prostatic hyperplasia. Eur Urol 1996;30:369-76. [Erratum,
Eur Urol 1997;31:458.]

february 19, 2004

The New England Journal of Medicine

Downloaded from nejm.org on November 18, 2013. For personal use only. No other uses without permission.
Copyright 2004 Massachusetts Medical Society. All rights reserved.

drug therapy

97. Lepor H, Williford WO, Barry MJ, et al.

The efficacy of terazosin, finasteride, or

both in benign prostatic hyperplasia. N Engl
J Med 1996;335:533-9.
98. Lepor H, Kaplan SA, Klimberg I, et al.
Doxazosin for benign prostatic hyperplasia:
long-term efficacy and safety in hypertensive and normotensive patients. J Urol 1997;
157:525-30.
99. Lepor H. Phase III multicenter placebocontrolled study of tamsulosin in benign
prostatic hyperplasia. Urology 1998;51:
892-900.
100. Lepor H, Williford WO, Barry MJ,
Haakenson C, Jones K. The impact of medical therapy on bother due to symptoms,
quality of life and global outcome, and factors predicting response. J Urol 1998;160:
1358-67.
101. Roehrborn CG, Van Kerrebroeck P,
Nordling J. Safety and efficacy of alfuzosin
10 mg once-daily in the treatment of lower
urinary tract symptoms and clinical benign
prostatic hyperplasia: a pooled analysis of
three double-blind, placebo-controlled
studies. BJU Int 2003;92:257-61.
102. Boyle P, Robertson C, Manski R, Padley RJ, Roehrborn CG. Meta-analysis of randomized trials of terazosin in the treatment
of benign prostatic hyperplasia. Urology
2001;58:717-22.
103. Johnson TM II, Jones K, Williford WO,
Kutner MH, Issa MM, Lepor H. Changes in
nocturia from medical treatment of benign
prostatic hyperplasia: secondary analysis of

the Department of Veterans Affairs Cooperative Study Trial. J Urol 2003;170:145-8.

104. Weiss JP, Blaivas JG. Nocturia. J Urol
2000;163:5-12.
105. Miller M. Nocturnal polyuria in older
people: pathophysiology and clinical implications. J Am Geriatr Soc 2000;48:1321-9.
106. Asplund R, Aberg H. Diurnal variation
in the levels of antidiuretic hormone in the
elderly. J Intern Med 1991;229:131-4.
107. Idem. Desmopressin in elderly subjects
with increased nocturnal diuresis: a twomonth treatment study. Scand J Urol Nephrol 1993;27:77-82.
108. Ouslander JG, Nasr SZ, Miller M, et al.
Arginine vasopressin levels in nursing home
residents with nighttime urinary incontinence. J Am Geriatr Soc 1998;46:1274-9.
[Erratum, J Am Geriatr Soc 1999;47:481.]
109. Johnson TM II, Miller M, Pillion DJ,
Ouslander JG. Arginine vasopressin and
nocturnal polyuria in older adults with frequent nighttime voiding. J Urol 2003;170:
480-4.
110. Lose G, Lalos O, Freedman RM, van
Kerrebroeck P, Nocturia Study Group. Efficacy of desmopressin (Minirin) in the treatment of nocturia: a double-blind placebocontrolled study in women. Am J Obstet
Gynecol 2003;189:1106-13.
111. Mattiasson A, Abrams P, Van Kerrebroeck P, Walter S, Weiss J. Efficacy of desmopressin in the treatment of nocturia: a double-blind placebo-controlled study in men.
BJU Int 2002;89:855-62.

112. Smith CP, Franks ME, Phelan MW, et

al. Botulinum toxin A: physiologic and clinical effects on the lower urinary tract. J Urol
2001;165:Suppl:37. abstract.
113. Schurch B, Stohrer M, Kramer G,
Schmid D, Gaul G, Hauri D. Botulinum-A
toxin for treating detrusor hyperreflexia in
spinal cord injured patients: a new alternative to anticholinergic drugs? Preliminary
results. J Urol 2000;164:692-7.
114. Brendler CB, Radebaugh LC, Mohler
JL. Topical oxybutynin chloride for relaxation of dysfunctional bladders. J Urol 1989;
141:1350-2.
115. Martin SW, Radley SC, Chess-Williams
R, Korstanje C, Chapple CR. Relaxant effects of potassium-channel openers on normal and hyper-reflexic detrusor muscle. Br J
Urol 1997;80:405-13.
116. Sharma A, Goldberg MJ, Cerimele BJ.
Pharmacokinetics and safety of duloxetine,
a dual-serotonin and norepinephrine reuptake inhibitor. J Clin Pharmacol 2000;40:
161-7.
117. Chancellor MB, de Groat WC. Intravesical capsaicin and resiniferatoxin therapy: spicing up the ways to treat the overactive bladder. J Urol 1999;162:3-11.
118. Silva C, Ribeiro MJ, Cruz F. The effect
of intravesical resiniferatoxin in patients
with idiopathic detrusor instability suggests
that involuntary detrusor contractions are
triggered by C-fiber input. J Urol 2002;168:
575-9.
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