Overaktif Bladder

8/21/2019 Overaktif Bladder

1/14

review article

The new england journal of medicine

n engl j med 350;8

www.nejm.org february 19, 2004

786

drug therapy

Alastair J.J. Wood, M.D.,

Editor

Management of Overactive Bladder

Joseph G. Ouslander, M.D.

From the Division of Geriatric Medicineand Gerontology, Wesley Woods Center,Center for Health in Aging, Emory Univer-sity, and the Birmingham/Atlanta VeteransAffairs 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 [email protected].

N Engl J Med 2004;350:786-99.

Copyright © 2004 Massachusetts Medical Society.

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 ormore 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 reportedsyndromes 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 amongmen 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 UnitedStates.

10

Patients with symptoms of overactive bladder tend to curtail their participation in so-cial activities and to isolate themselves and are predisposed to depression. Nocturia isassociated with sleep disruption, which decreases the quality of life.

11-14

Postmeno-

pausal women with urge incontinence have a substantially higher risk of falling andsustaining a fracture than women without urge incontinence.

15

The costs of 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

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 lowerthan urethral resistance. With the initiation of normal urination, urethral resistance de-

creases and a phasic contraction of the detrusor muscle empties the bladder (Fig. 1A).The symptoms of overactive bladder are usually associated with involuntary 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-

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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 contraction

19

; incompleteemptying 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 neurotransmittersin the voiding cycle has been studied in animals.

20-22

Glutamate is an excitatory neurotransmitter in pathways controlling the lower urinary tract. Serotoner-

gic activity facilitates urine storage by enhancing thesympathetic reflex pathway and inhibiting the para-

sympathetic voiding pathway. Dopaminergic pathways may exert both inhibitory and facilitatory ef-fects on voiding. Dopamine D1

receptors appear to

have a role in suppressing bladder activity, whereasdopamine D2 receptors appear to facilitate voiding.

Other neurotransmitters, such as g

-aminobutyricacid 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 muscarinicsubtypes (M1 through M5), M3 appears to be the

most clinically relevant in the human bladder.

20

Ace-

tylcholine interacts with the M3 receptor, initiatinga 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 intracellularlevels 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 denervationsuprasensitivity.

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 havea 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.

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 pelvicnerve. Sensory input during bladder filling results

in an increase in sympathetic tone, which inhibitsbladder 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 b

3

-adrener-gic receptors (Fig. 2).

30

Myelinated A delta sensory fibers respond to passive distention and active

contraction of the detrusor muscle. UnmyelinatedC 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 beenidentified 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-Areceptors).

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 thehuman 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.

Effective treatment of patients with symptoms of overactive bladder necessitates a targeted diagnostic

evaluation. Guidelines for the management of uri-nary incontinence

32

and benign prostatic hyper-

plasia

33

are relevant to the evaluation of symptomsof overactive bladder. A focused history that includes

information about past genitourinary disorders andother 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 evaluationin older men.

34,35

A variety of questionnaires re-

garding lower urinary tract symptoms have also

diagnost ic eval u at ion





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been developed for women.

36 In addition, diariescan be helpful in determining the frequency, vol-

ume, and pattern of voiding, as well as providingclues to underlying causes and contributing fac-

tors.

37,38

All patients should undergo a focusedphysical examination that includes genitourinary,pelvic, and rectal examinations; a clean urine spec-

imen should be obtained to rule out hematuria andinfection.

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 corddisease, and benign prostatic hypertrophy). This can

be accomplished by sterile in-and-out catheteriza-tion. A portable ultrasonographic device is availablethat 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

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 sensoryafferent innervation can result.

Treat infection before other interventions are con-sidered.

Obstruction Obstruction can contribute to detrusoroveractivity and urinary retention.

Consider surgical intervention.

Impaired bladder contractility Urinary retention and reduced functionalbladder capacity can result.

Avoid drugs that decrease bladder contractility.Teach patients to enhance voiding (e.g., Credé’s

method).Intermittent catheterization is helpful in selected

patients.

Bladder abnormalities or inflammation(e.g., tumors, calculi, interstitialcystitis)

Intravesical abnormalities can precipitatedetrusor overactivity.

Sterile hematuria and risk factors for bladdercancer should prompt further evaluation.

Women

Estrogen deficiency Inflammation from atrophic vaginitis andurethritis can contribute to symptoms.

Topical estrogen may ameliorate symptoms.

Sphincter weakness Leakage of urine into proximal urethramay precipitate urgency.

Ability to inhibit detrusor by sphinctercontraction may be diminished.

Topical estrogen and pelvic-muscle exercises mayhelp strengthen the sphincter.

Periurethral injections or surgical procedures maybe helpful in selected patients.

Men

Prostate enlargement Benign or malignant prostate enlarge-ment can contribute to detrusoroveractivity.

Evaluation and treatment for prostate cancershould be considered.

Alpha-adrenergic blockers may improve symptoms.5

a

-Reductase inhibitors may reduce prostate size.Surgical removal of obstructing prostate may be

indicated.

Neurologic conditions

Brain

Stroke, Alzheimer’s disease, multi-infarct dementia, other dementias,Parkinson’s disease, multiple sclerosis

Higher cortical inhibition of the bladderis impaired, causing neurogenicdetrusor overactivity.

Management must include a means of compensa-tion for impaired cognition, impaired mobility,or both.

Spinal cord

Multiple sclerosis, cervical or lumbarstenosis or disk herniation, spinalcord injury

Neurogenic detrusor overactivity or urinaryretention can result.

Presence of neurologic symptoms or signs mayrequire further evaluation.

Urodynamic testing is often indicated for diag-nostic purposes.

Peripheral innervation

Diabetic neuropathy, nerve injury Urinary retention and low functional blad-der capacity can result.

History suggestive of nerve injury or neurologicsigns require further evaluation.





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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 overactivebladder 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 causesymptoms 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 theurinary 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 amore accurate approach to the diagnosis of obstruc-

tion than less invasive testing. Because this test isrelatively 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

Optimal therapy for overactive bladder depends on

a thorough evaluation, followed by treatment of allthe likely causes and contributing factors (Table 1).

The genesis of symptoms of overactive bladder is

t h er apy

Table 1. (Continued.)

Conditions Mechanisms or Effect Implications for Management

Systemic conditions

Congestive heart failure, venousinsufficiency

Volume overload can contribute to urinaryfrequency and nocturia when patientis supine.

Proper timing of diuretics may ameliorate symptoms.Use of leg elevation, support hose, and salt

restriction may be helpful.

Diabetes mellitus Poor blood glucose control can contributeto osmotic diuresis and polyuria.

Improved blood glucose control may amelioratesymptoms.

Sleep disorders (sleep apnea, periodicleg movements)

Sleep disorders can contribute to nocturia. Reports of sleep disruption or heavy snoring mayrequire further evaluation.

Abnormalities of arginine vasopressin Impaired secretion or action of vasopressinmay cause polyuria and nocturia.

Carefully selected patients may benefit from desmo-pressin therapy.

Functional and behavioral conditions

Excess intake of caffeine, alcohol;polydipsia

Polyuria and urinary frequency can result. Modification of fluid intake is critical for successfulmanagement.

Poor bowel habits and constipation Fecal impaction can contribute to symptoms. An appropriate bowel regimen will reduce the inci-dence of fecal impaction.

Impaired mobility (e.g., in patients withdegenerative joint disease, Par-kinson’s disease, severe osteo-

porosis, or muscle weakness)

Impaired mobility can interfere with toilet-ing ability and precipitate urge incon-tinence.

Treatment of underlying disorders, including physi-cal therapy, should be optimal; the use of urinals,bedside commodes, and bedpans can be helpful.

Psychological conditions Chronic anxiety and learned voiding dys-function can cause symptoms of over-active bladder.

The diagnosis should be considered on the basis ofa patient’s history and physical examination.

Side effects of medication

Diuretics, especially rapid-acting agents Diuretics cause a rapid increase in bladdervolume, which may precipitate urgencyand detrusor overactivity.

Changing to a longer-acting diuretic, altering thetiming of the dose, or discontinuing the drug,if appropriate, can ameliorate symptoms.

Anticholinergic agents, narcotics,calcium-channel blockers

These agents decrease bladder contractilityand may cause urinary retention, with adecreased functional bladder capacity.

Such drugs should be discontinued wheneverfeasible.

Cholinesterase inhibitors These agents could theoretically contributeto detrusor overactivity by increasingacetylcholine levels.

No clinical studies have documented such effects,but they should be considered in patients inwhom symptoms develop after the initiationof one of these agents.





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commonly multifactorial, and multimodal therapy that includes nonpharmacologic as well as pharma-cologic interventions may be indicated.

nonpharmacologic interventions

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

mixed urge–stress incontinence. Educating patients

about bladder function, appropriate fluid intake(avoidance of caffeine, maintenance of adequate hy-dration, and the timing of fluid intake), and manag-

ing constipation is important for all patients withoveractive bladder. Education may, in fact, underlie

the prominent placebo effects (approximately 30percent improvement in symptoms) demonstrated

repeatedly in drug trials for incontinence and over-active bladder. Several randomized, controlled trials,

largely involving middle-aged women and womenunder 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 reduc-tion in the number of episodes of incontinence with-

in two to three months. The long-term effectivenessof these interventions requires further study.

Many patients can be taught pelvic-muscle exer-cises during a pelvic or rectal examination or canlearn them with the use of simple educational tools

such as an audiotape or a booklet.

42

A substantialproportion of older patients benefit from biofeed-

back-assisted training. “Bladder training” generally refers to a combination of patient education, sched-uled voiding and urge-suppression techniques, and

pelvic-muscle exercises.

41

For some patients withcognitive impairment, limited mobility, or both,

the use of toileting-assistance protocols such asprompted voiding can be very helpful in the man-

agement of overactive bladder.

44

All these behav-

ioral interventions can also be effective adjuncts todrug therapy.

Some patients with severe symptoms of overac-tive bladder that are refractory to proven behavioral

treatment may benefit from other nonpharmaco-logic interventions. A wide variety of highly absor-

bent pads and undergarments are available that canbe effective and acceptable in selected patients withrefractory 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 stimulationdelivered by vaginal or rectal probes can be helpful

in teaching some patients the proper use of pelvicmuscles (an approach similar to biofeedback), andlower-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

Mag-netic stimulation has also been approved for the

Figure 1. Normal Voiding Physiology (Panel A) and Involuntary Detrusor Con-

traction Commonly Associated with Symptoms of Overactive Bladder (Panel B).

Normally, as bladder volume increases, the detrusor muscle functions like acompliant 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 detrusorcontraction empties the bladder. In patients with symptomatic overactive

bladder, involuntary bladder contractions can cause urgency and may precip-

itate urine loss, depending on the response of the sphincter (Panel B). Invol-

untary contractions may occur at any bladder volume, but they commonly oc-cur 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 detrusor–sphincter dyssynergy). Detrusor overactivity can beneurogenic or idiopathic and can be accompanied by urgency or be without

sensation.

Urgency

Bladder volume

Urethralresistance

Detrusorpressure

Urethralresistance

Detrusorpressure

Striated sphincter-muscle activity

Striated sphincter-muscle activity

A

B

Voluntaryvoiding

Involuntarydetrusor

contractionDetrusor overactivity

Bladder volume





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treatment of incontinence, but this requires multi-

ple visits to a facility that has the stimulation equip-ment. Surgical procedures, including motor-nerveablation 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 overactivebladder.

1-3,20-22,51

The majority of clinical trials have

targeted the symptoms of urinary incontinence,though more recent trials have specifically includedsubjects with overactive bladder. Several pitfalls lim-

it the quality of many studies. Expert groups haveproposed 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 effectscan 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 antimuscarinicdrugs is a particular concern in this population.

58,59

Although these drugs have not had major effectson 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 antimuscarinicagents 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 recommendationand evidence of efficacy; oxybutynin and tolterodine

have been studied most extensively. Oxybutynin is anonselective antimuscarinic agent that relaxes blad-

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 thisformulation, oxybutynin has led to a clinically sig-

nificant improvement, defined as a reduction inincontinence episodes by more than 50 percent,

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 ofATP with purinergic receptors, including P2X

1

receptors. ATP and other non-

cholinergically mediated processes may have a more important role in disor-

ders that cause overactive bladder. Stimulation of b

3

-adrenergic receptorsmay 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

Parasympatheticnerve

Sympatheticnerve

Acetylcholine

M3receptor

M2receptor

G protein

Phospholipase C

Contraction of bladder smooth muscle

Relaxation of bladder smooth muscle

Cyclic AMP

AdenylatecyclaseInositol

triphosphate

P2X1receptor

Norepinephrine

ATP

b3-adrenergicreceptor





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in approximately 60 to 80 percent of study sub-

jects.

21,32,51,61

The efficacy of immediate-releaseoxybutynin 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 isrelatively 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 fewerside effects — a benefit ascribed to the more con-

stant levels of the parent drug and, possibly, a lowerrate of conversion to the active metabolite in the

stomach and small intestine.

62

Most studies of con-trolled-release oxybutynin have reported a reduction

in episodes of urge incontinence by approximately

70 percent.

43,63-66

A transdermal oxybutynin patchis 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 isavailable in short-acting (twice-daily) and long-act-

ing (once-daily) preparations. Both forms have hadstatistically and clinically significant effects on

symptoms of overactive bladder in multiple, ran-domized, controlled clinical trials.

69-77

Side effectsare similar to those of short-acting oxybutynin, with

dry mouth in 20 to 25 percent of patients, and therates of discontinuation due to side effects are sim-

ilar to those for placebo (5 to 6 percent). Tolterodineappears to be equally efficacious in old and young

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 bycapsaicin and, possibly, endogenous anandamide; purinergic receptors (P2X

2

and P2X

3

), 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

Yoshimuraand Chancellor,

21

and Andersson and Hedlund.

22

Uroepithelial cell

Detrusorsmooth-

muscle cellC sensory

fibers

Nervegrowtfactor

Anandamide?

trk-Areceptor

C sensory fiber

anilloireceptor

P2X2 or P2 3receptor

Neurokinin ASubstance P

Neurokininreceptor

ATP

A deltasensory fiber





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* 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 Consultationon Urological Diseases

7

: 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.

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

Drug Usual Adult Dose

Level ofEvidence/Grade ofRecommendation† Comments

Drugs with predominantlyanticholinergic or anti-

muscarinic effects

Hyoscyamine 0.375 mg twice daily orally 2/D The drug is also available in sublingual andelixir forms; it has prominent anticho-linergic side effects.

Oxybutynin 2.5–5.0 mg thrice daily orally (short-acting)5–30 mg daily orally (long-acting)3.9 mg over a 96-hr period (transdermal)

1/A Long-acting and transdermal preparationshave fewer side effects than short-actingpreparations.

The transdermal patch can cause local skinirritation in some patients.

Propantheline 15–30 mg 4 times daily orally 2/B The drug has prominent anticholinergic sideeffects.

Propiverine 15 mg thrice daily orally 1/A The drug has complex pharmacokinetics withseveral active metabolites; it is not current-ly available in the United States.

Tolterodine 1–2 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 com-pound, which does not cross the blood–brain barrier and may have fewer cognitiveside effects than other anticholinergicagents; it is not currently available in theUnited States.

Estrogen (for women)

Vaginal estrogenpreparations

Approximately 0.5 g cream applied topicallynightly for 2 wk, then twice per week

Estradiol ring, replaced every 90 daysEstradiol, 1 tablet daily for 2 wk, then 1 tablet

twice a week

4/D Local vaginal preparations are probably moreeffective than oral estrogen, but definitivedata on effectiveness are lacking.

Alpha-adrenergic antagonists(for men)

AlfuzosinDoxazosinPrazosinTamsulosinTerazosin

2.5 mg thrice daily orally1–16 mg daily orally1–10 mg twice daily orally0.4–0.8 mg daily orally1–10 mg orally each day at bedtime

4/D‡ These agents are useful in men with benignprostatic enlargement.

Postural hypotension can be a serious sideeffect.

Doses must be increased gradually to facilitatetolerance.

Other drugs

Imipramine 10–25 mg thrice daily orally 2/C This agent may be useful for mixed urge–stress incontinence; it can cause posturalhypotension and bundle-branch block.

Desmopressin 20–40 µg of intranasal spray daily at bed-time

0.1–0.4 mg orally 2 hr before bedtime

1/B The intranasal spray is used for primary noc-turnal enuresis in children; hyponatremiaoccurs commonly in older adults, and se-rum sodium levels must be monitoredclosely.





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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 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 drugshave 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-actingoxybutynin, 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 mixedurge–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 benignprostatic hypertrophy.

93-95

In clinical practice, theapproach to men with symptoms of overactive blad-

der depends on several factors, such as the degreeto 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 complexurodynamic 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-adrenergicblockers (alpha-blockers). It is difficult to determine

the efficacy of these drugs for overactive bladder, be-

cause the outcomes of most clinical trials have beenbased on composite scores that include symptomsof 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 beused carefully, especially in patients who are already

taking antihypertensive agents.

93,100-102

Men who neither tolerate nor have a response toalpha-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 underlyingcause or causes — detrusor overactivity, nocturnal

polyuria, a primary sleep disorder, or some combi-nation of these conditions.104,105 Nocturia that isprimarily 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 peripheraledema) 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 approvedfor use in children with nocturnal enuresis.

Data supporting an association among noctur-nal polyuria, nocturia, abnormal diurnal respon-

siveness to vasopressin, and levels of endogenousarginine 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 (0.1to 0.4 mg), during which approximately one third

of the patients were excluded. Among patients withsome 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 inthe placebo group) and a significant increase in the





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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 inEurope, 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 classesinclude calcium-channel blockers, prostaglandin-

synthesis inhibitors, dopamine D1–receptor ago-nists, beta-adrenergic (particularly b3) agonists, andg -aminobutyric acid (GABA) agonists (Table 3).20-22

For example, pergolide, a D1-receptor agonist, may

benefit patients with Parkinson’s disease and lowerurinary 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 amelioratedetrusor hyperreflexia in patients with spinal cord

injury 112,113

; it may have some therapeutic value inselected patients with severe refractory symptoms

of overactive bladder. Although currently availablebeta-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 availableagents are being studied. Oxybutynin has been in-

stilled intravesicularly through a catheter to treat severe overactivity of the detrusor muscle,114 and a

* 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.

Table 3. Examples of Classes of Drugs under Investigation for the Treatment of Symptoms of Overactive Bladder.*

Drug Classes and ActionsExamples Studied

in Humans Comments

Drugs used for other conditions

Calcium-channel blockers DiltiazemNifedipineVerapamil

Agents inhibit bladder contraction by decreasing calcium available forsmooth-muscle contraction; there is no evidence that these agentsare effective for symptoms of overactive bladder.

Inhibitors of prostaglandin synthesis Flurbiprofen Prostaglandins may increase the contraction of bladder smooth muscle;no currently available agents have proven efficacy.

g -Aminobutyric acid–receptor agonists Baclofen Stimulation of g -aminobutyric acid receptors inhibits the voiding reflex.

Neuromuscular-junction inhibitionof acetylcholine release

Botulinum toxin Botulinum toxin A injections have been used for refractory symptoms.

Drugs in development

Antimuscarinic agents more selectivefor M3 receptors than other anti-muscarinic agents

DarifenacinSolifenacin

Potassium-channel openers CromakalimPinacidil

These agents decrease spontaneous detrusor-muscle contractions and canhave clinically significant effects on blood pressure; potassium-channelgene therapy has also been studied.

Serotonergic agonists Duloxetine The central serotonergic effects of these agents increase urethral striatedsphincter-muscle tone.

Vanilloids and other afferent-nerveinhibitors

CapsaicinResiniferatoxin

These agents cause desensitization of unmyelinated C fibers; otherafferent-nerve inhibitors may be useful.

Dopamine-D1–receptor agonists Pergolide D1-receptor stimulation inhibits the voiding reflex.Nerve growth factor inhibitors — Nerve growth factor modulates sensory afferent function; antibody-based

gene therapy to suppress nerve growth factor has also been studied.

Enkephalins — Opioid peptides, including enkephalin, suppress the voiding reflex; therapywith the herpes simplex virus proenkephalin gene has been studied.





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bladder pump is being developed that can deliver a

constant dose of intravesicular oxybutynin for upto 30 days.21 Such a device may make this methodof drug delivery more practical and acceptable and

may result in fewer systemic anticholinergic sideeffects.

Drugs that act by means of potassium-channeltransporters to hyperpolarize smooth muscle and

decrease spontaneous bladder contractions may beuseful for suppressing involuntary bladder contrac-

tions without interfering with normal voiding.115

However, first-generation agents in this class havehad effects on vascular smooth muscle and can

cause hypotension. Duloxetine is an inhibitor of se-rotonin and norepinephrine that appears to act cen-

trally, increasing tone in the striated smooth muscleof the external urethral sphincter.116 Although it is

being studied primarily for the treatment of stressincontinence, duloxetine may also have therapeutic

benefits in patients with mixed stress–urge inconti-nence. Drugs that act on sensory afferent pathwaysare also being developed and hold promise when

used either alone or in combination with otherdrugs. Capsaicin and resiniferatoxin desensitize

C-fiber afferents and have been administered ex-perimentally by the intravesicular route. Resinifer-atoxin appears to be more potent and less irritating

than capsaicin and may be more useful clinical-ly.55,117,118 Other drugs that block receptors on sen-

sory afferents, such as neurokinin-receptor antago-nists (Fig. 3), might not cause urinary retention,

which can occur with antimuscarinic agents.

Symptoms of overactive bladder are common, can

be distressing, and are associated with serious ad-

verse consequences such as injurious falls. The

symptoms may be caused by myriad factors, includ-ing disorders of the lower urinary tract, neurologicconditions, behavioral factors such as caffeine in-

take, and a variety of commonly prescribed drugs.The pathophysiologic process in an individual pa-

tient is often multifactorial. Diagnostic evaluationincludes a focused history taking, targeted physi-

cal examination, and urinalysis. Selected patientsshould 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 com-

modes or urinals, especially at night. Behavioraltreatments such as pelvic-muscle exercises and

bladder training are efficacious and can enhance thebenefits of drug therapy. The mainstay of drug ther-apy 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 theoxybutynin skin patch are generally well tolerated,but all antimuscarinic drugs can have bothersome

anticholinergic side effects. The effects of theseagents on cognitive function are a particular concern

in older adults. Men with symptoms of overactivebladder in association with benign prostatic hyper-

plasia may benefit from treatment with alpha-block-

ers. Promising future directions in drug therapy include the development of more specific anti-

muscarinic agents, new drug-delivery systems, anddrugs that affect the sensory innervation of the low-

er urinary tract.

summary

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