Pharmacolo gic

Ma nagement of
Urinar y Incontinence,
Voiding Dysfunction,
and Overactive Bladder
Emily K. Saks, MD*, LilyA. Arya, MD, MS

KEYWORDS
 Urinary incontinence  Overactive bladder  Female
 Medication  Treatment

The bladder and urethra comprise the female lower urinary tract and function in
concert to store and expel urine at the proper times. Urinary incontinence and voiding
dysfunction are the result of an inability to appropriately store or empty urine. The
capability of the female lower urinary tract to efficiently store urine and release it at
appropriate intervals requires an intact and functioning nervous system.
The female bladder and urethra are supplied by the somatic (pudenal) and auto-
nomic (sympathetic and parasympathetic) nerves (Fig. 1).1 The pudendal nerve, orig-
inating from the anterior horn of the second, third, and fourth sacral nerve roots,
supplies the external urethral sphincter and is under voluntary control. The parasym-
pathetic nerves are derived from dorsolateral ganglion of the second, third, and fourth
sacral segments of the spinal cord and have long preganglionic nerves that synapse
close to the bladder. The short postganglionic nerves end primarily on muscarinic
receptors of the detrusor muscle. Sympathetic nerve supply of the bladder is derived
from the thoracolumbar segments (T10–L2) of the spinal cord. The short preganglionic
fibers synapse in the sympathetic trunk and the long postganglionic fibers terminate in
adrenergic receptors of the urethra and the bladder neck. The pharmacologic treat-
ment of urinary incontinence and voiding dysfunction is focused on modulating
sphincter function or detrusor contractility through its effect on the nerve supply of
the lower urinary tract.

Division of Urogynecology and Pelvic Reconstructive Surgery, Department of Obstetrics and

Gynecology, University of Pennsylvania School of Medicine, 1000 Courtyard, Philadelphia,
PA 19104, USA
* Corresponding author.
E-mail address: emily.saks@uphs.upenn.edu (E.K. Saks).

Obstet Gynecol Clin N Am 36 (2009) 493–507

doi:10.1016/j.ogc.2009.08.001 obgyn.theclinics.com
0889-8545/09/$ – see front matter ª 2009 Elsevier Inc. All rights reserved.
494 Saks & Arya

Brain e
nerv
tric
ogas
hyp
etic
path M2 (80%)
Sym M3 (20%)
Bladder
T10–L2 M2
detrusor
smooth muscle
M3
e
ic nerv
tic pelv
mpathe Urethral smooth
Parasy muscle
M2
S2–S4 Striated urethral sphincter
Somatic pudendal nerve
Levator Ani
skeletal muscle

Urethral smooth muscle

Fig.1. Neurophysiology of the lower urinary tract. (Adapted from Wein AJ. Pharmacological
agents for the treatment of urinary incontinence due to overactive bladder. Expert Opin
Investig Drugs 2001;10(1):65–83; with permission. Data from Abrams P, Andersson KE,
Buccafusco JJ, et al. Muscarinic receptors: their distribution and function in body systems,
and the implications for treating overactive bladder. Br J Pharmacol 2006;148(5):565–78;
and Benson JT, Walters MD. Neurophysiology and pharmacology of the lower urinary tract.
In: Walters MD, Karram MM, editors. Urogynecology and reconstructive surgery. 3rd edition.
Philadelphia: Mosby and Elsevier; 2007. p. 33.).

STRESS URINARY INCONTINENCE

Numerous drugs have been investigated as potential treatments for stress urinary
incontinence, but unfortunately few have made significant impact. This is likely
because the main underlying cause of stress urinary incontinence is mechanical
displacement of the bladder neck and urethra.2 Pharmacologic therapies for stress
urinary incontinence are targeted toward improving urethral muscle tone by stimula-
tion of adrenergic receptors at the urethra and bladder neck, where a-adrenoceptors
predominate over b-adrenoceptors.3
Adrenergic agonists, such as pseudoephedrine and ephedrine, have long been
used off-label for stress urinary incontinence with some beneficial results in uncon-
trolled studies.4 A recent Cochrane review5 concluded that the potential of serious
side effects, such as hypertension, arrhythmias, and cardiovascular events, severely
limits the use of these medications for stress urinary incontinence.
Imipramine inhibits reuptake of norepinephrine and serotonin and is thought to
improve contraction of urethral smooth muscle. Imipramine may also have some
benefit in the treatment of detrusor hyperactivity because it exerts weak antimuscar-
inic properties in the bladder. There are no well-conducted studies proving efficacy of
the drug in stress or urge incontinence.6–8 Additionally, there is concern regarding
associated side effects including peripheral antimuscarinic effects, hypertension,
and orthostatic hypotension, especially in older adults.
Duloxetine, an antidepressant, inhibits presynaptic reuptake of serotonin and
norepinephrine in the sacral spinal cord, which leads to increased activity of the
urethral striated sphincter. Duloxetine may also reduce detrusor overactivity and
increase bladder capacity through a central mechanism.9 Although randomized
clinical trials have shown overall decreases in the frequency of stress and urge incon-
tinence episodes and improvements in quality of life, it remains unclear whether these
effects are sustainable.10–12 High rates of nausea lead to significant dropout (over
 Pharmacologic Management of Urinary Incontinence 495

50%) in the clinical trials.13 The drug is not approved for urinary incontinence in the
United States and carries a black box warning regarding suicidal tendencies during
early use.
Because of the limited efficacy of medications in women with stress urinary incon-
tinence, pharmacotherapy should be used in conjunction with behavioral therapies.
Behavioral treatments and surgical procedures remain the mainstay of treatment for
stress urinary incontinence.

URGE URINARY INCONTINENCE AND OVERACTIVE BLADDER

Antimuscarinic medications serve as the foundation of therapy for urge urinary incon-
tinence and overactive bladder and have been used for several decades. Recently,
with the development of slow-release and transdermal formulations, and novel anti-
muscarinic medications, a variety of treatment options have emerged. Multiple studies
have established their safety and tolerability. Although these drugs produced signifi-
cant improvements in symptoms and quality of life as compared with placebo,14 the
overall cure rate (ie, the number of patients reporting no urinary leakage) is low.
Acetylcholine, the main contractile neurotransmitter of the detrusor muscle, acts by
stimulation of the muscarinic receptors.15 Antimuscarinic agents act during the filling-
storage phase of the micturition cycle by inhibiting afferent (sensory) input from the
bladder, and directly inhibiting smooth muscle contractility. Clinically, antimuscarinic
agents reduce urinary frequency, urgency, and the number of incontinence episodes,
while increasing the warning time to get to the bathroom and the volume of each void.
Antimuscarinic medications may be prescribed for overactive bladder when behav-
ioral measures, such as caffeine restriction, fluid manipulation, bladder retraining,
and pelvic physical therapy, have failed to control symptoms.
Five subtypes of muscarinic receptors are found throughout the human body
including the central nervous system, salivary glands, heart, and bowel.16 Urinary
smooth muscle and urothelium contain mainly M2 and M3 receptors. Although M2
receptors account for 80% of the receptors in the urinary tract, M3 receptors are
primarily responsible for bladder contraction. Unfortunately, M2 and M3 receptors
are also present in other tissues of the body (eg, M3 in bowel, salivary glands, and
eye; M2 in cardiac smooth muscle), making it difficult to develop purely uroselective
drugs. Most of the current antimuscarinic medications used in the treatment of urge
incontinence produce varying degrees of common antimuscarinic side effects, such
as dry mouth, blurred vision, confusion, constipation, and rarely increased heart
rate. Although these medications have varying selectivity for the different subtypes
of muscarinic receptors, it is unclear whether this results in clinically significant differ-
ences in efficacy and tolerability.
Historical antimuscarinics, such as urospas, propiverine, and flavoxate, are no
longer recommended because of lack of efficacy. Data on the efficacy of tricyclic anti-
depressants, a-adrenergic agonists, afferent nerve inhibitors, prostaglandin antago-
nists, b-adrenergic agonists, and calcium channel blockers for overactive bladder
are lacking and are generally not used.17 Currently, six main anticholinergic drugs
are available in the United States for the treatment of urge urinary incontinence and
overactive bladder. The receptor selectivity, dose, and pharmacodynamics of these
drugs are listed in Table 1.
Oxybutynin18 is one of the earliest medications used for the treatment of overactive
bladder and has a combination of antimuscarinic, antispasmodic, and local anesthetic
properties.19 The drug seems to have the greatest affinity for M1 and M3 receptors,
but may have more selectivity for salivary gland tissue than bladder smooth muscle20
 496
Saks & Arya
Table 1
Dose, receptor selectivity, and pharmacodynamics of antimuscarinic medications

Peak Plasma Elimination

Generic Name Brand Name Subtype of Muscarinic Blockade20 Dose Levela Half-Lifea
Darifenacin Enablex Relatively selective for M3 7.5–15 mg daily 7h 13–19 h
Fesoterodine Toviaz Similar block of M3 and M2 4–8 mg daily 3–8 h 45–68 h
Oxybutinin IR Ditropanb Relatively selective for M3 and M1 5 mg two to four times daily 1h 2–3 h
Oxybutinin ER Ditropan XLb Relatively selective for M3 and M1 5–30 mg daily 4–6 h 13 h
Oxybutinin transdermal Oxytrol Relatively selective for M3 and M1 One patch every 3–4 d 10 h 7–8 h
patch
Oxybutinin transdermal gel Gelnique Relatively selective for M3 and M1 1g gel daily 7–8 h 64 h
Solifenacin Vesicare Relatively selective for M3 and M1 5–10 mg daily 3–8 h 45–68 h
Tolterodine IR Detrol Similar block of M3 and M2, 1–2 mg twice a day 0.5–2 h 2.4 h
relatively nonselective
Tolterodine ER Detrol LA Similar block of M3 and M2, 2–4 mg daily 2–6 h 7–9 h
relatively nonselective
Tropsium IR Sanctura Similar block of M3 and M2, 20 mg twice a day 5–6 h 20 h
relatively nonselective
Tropsium ER Sanctura XR Similar block of M3 and M2, 60 mg daily 4–5 h 35 h
relatively nonselective
a
Pharmacodynamic data obtained from drug prescribing information.
b
Generic form also available.
 Pharmacologic Management of Urinary Incontinence 497

as reflected in the significantly high rates of dry mouth. Most of the side-effects of oxy-
butynin are caused by its active metabolite, N-desethyloxyloxybutynin, produced
through the extensive first-pass metabolism in the gut.21 Alternate formulations of oxy-
butynin, such as an extended-release formulation,22 a transdermal patch,23 and a new
transdermal gel,24 produce lower levels of N-desethyloxyloxybutynin by reducing the
first-pass effect. They have similar efficacy rates with fewer side effects than the
immediate-release oral preparation. The transdermal patches have been associated
with local skin irritation, such as pruritis and erythema.23 Because of its local anes-
thetic properties, oxybutynin may be of some benefit in patients with urgency,
frequency, and bladder pain.25
Tolterodine26 was the first drug to be developed specifically for treatment of over-
active bladder. It is a relatively nonselective muscarinic receptor antagonist, but
may have more affinity for the receptors of the bladder than of the salivary gland, likely
contributing to the reports of significantly less dry mouth than oxybutynin.20 The
extended-release formulation was developed to reduce side effects. In clinical trials,
the extended-release formulation was 18% more effective and had a 27% decrease
in the rate of dry mouth than the immediate-release formulation.22
Trospium27 was approved for use in the United States in 2004 but has been
approved in Europe for over 25 years. In contrast to other antimuscarinics, which
are negatively charged tertiary amines, tropsium is a positively charged, hydrophilic,
quaternary amine.28 This structure results in impaired absorption from the gut that
is even worse if taken with food. It does not cross the blood-brain barrier and very
few effects on the central nervous system have been reported in clinical trials. It is
the only drug, other than fesoterodine, not metabolized by the liver and has lower
potential for side effects. Because it is excreted by the kidneys, there is concern for
toxicity in patients with renal impairment.28 It does not seem, however, that the
dose needs to be adjusted in elderly patients.29 The drug binds to all muscarinic
receptors with similar affinity and the extended-release formulation has fewer side
effects than the immediate-release drug.
Solifenacin30 primarily blocks M1 and M3 receptors and may be more selective for
M3 receptors on bladder smooth muscle cells than for salivary gland tissue, explaining
the low rate of dry mouth in clinical trials.31 As compared with placebo, there is
a reduction in the mean number of voids and daily incontinence episodes and an
increase in the mean voided volume. As compared with tolterodine extended-release,
slightly improved efficacy, fewer side effects, and lower drug discontinuation rates
were observed with solifenacin.32
Darifenacin33 is a relatively selective M3 muscarinic receptor antagonist. Consis-
tent with its low relative affinity for M1 and M2 receptors, it has few effects on cogni-
tive function or the cardiovascular system. Darifenacin is metabolized by the liver and
is not recommended for patients with severe liver impairment.34 It is unclear if
improved M3 selectivity of darifenacin correlates with improved efficacy and
tolerability.
Festoterodine,35 the newest antimuscarinic compound for the treatment of overac-
tive bladder and urge urinary incontinence, was approved by the Food and Drug
Administration in October of 2008. It is a prodrug of tolterodine that is nonhepatically
metabolized and has demonstrated acceptable efficacy and safety with both the 4-
and 8-mg doses in two recent, placebo-controlled, phase three trials.35,36 Fesotero-
dine was found to be superior to placebo in decreasing the number of voids, number
of incontinence, and urgency episodes in a 24-hour period and increasing mean
voided volume. Side effects of fesoterodine are similar to that of other antimuscarinic
medications.
498 Saks & Arya

INTERPRETATION OF CLINICAL TRIAL DATA

Most clinical trials on antimuscarinic medications assess efficacy by using objective

measures, such as pad counts, pad weights, voiding diary variables, and urodynamic
parameters. It is clear that improvements in some of these objective measures may
not correspond to the patient’s perception of improvement in symptoms or address
the most disabling aspects of urinary incontinence. Currently, few clinical trials include
patient-reported outcomes and there are insufficient data to compare the effects of
individual antimuscarinic medications on health-related quality of life.37 Future well-
designed clinical trials should routinely include validated instruments to measure
symptomatic improvements and treatment-related enhancement in quality of life.

COMPLIANCE

Although numerous well-performed studies have demonstrated the efficacy of anti-

muscarinic medications, their effectiveness in real life is limited by poor adherence.
Because overactive bladder is a symptom-based disease, adherence may be an over-
all marker of the efficacy/side effect ratio, with women likely to continue the drug if they
experience significant improvement. Studies have reported discontinuation rates of up
to 80% at 1 year.38–40 Side effects along with patient perception of inadequate relief of
symptoms may be contributing factors to high discontinuation rates.41

WHICH ANTIMUSCARINIC?

To help guide clinicians in their choice of antimuscarinic drugs, a Cochrane review42

analyzed 49 randomized clinical trials that compared two formulations of antimuscar-
inic medications or one antimuscarinic drug with another and concluded that overall
efficacies of the varied antimuscarinic drugs are similar. Chapple and coworkers43
recommended that if one drug does not seem to provide satisfactory relief of symp-
toms, the clinician should choose an alternate drug. The initial choice of antimuscar-
inic agent should be based on its side effect profile. Major studies comparing different
antimuscarinic medications are summarized in Table 2.

CONSIDERATIONS IN THE ELDERLY

Although the prevalence of overactive bladder increases with age, there are relatively
little data on the safety and the efficacy of antimuscarinic medications in older women.
In a community-based study in women 65 years and older, side effects were similar to
those observed in younger women with no increase in serious adverse events.44
Although drug absorption is generally unchanged with aging, drug distribution may
change because of decreased muscle mass with decreased water content and renal
impairment. These factors become particularly important in the frail elderly, and in
women with comorbidities or on multiple medications. When prescribing antimuscar-
inic medications to older women, care should be taken regarding the overall antimus-
carinic burden because several other medications used in older women (eg, those for
Parkinson’s disease or dementia) also have antimuscarinic effects. There is significant
concern for cognitive side effects with antimuscarinics in older women and studies
have shown impaired memory recall and immediate learning with oxybutynin.45 Dar-
fenicin, transdermal oxybutynin, tolterodine,46 and solifenacin47 have been shown to
have relatively few cognitive side effects in clinical studies of older women. Close
monitoring is required when these medications are prescribed to elderly women,
especially in long-term care facilities.
 Pharmacologic Management of Urinary Incontinence 499

Table 2
Comparative efficacy of different antimuscarinic medications

Study Drugs Compared Efficacy Side Effects

Pooled data Oxybutinin and Similar in most Slightly less dry
(Cochrane, tolterodine outcome mouth and
2005)42 variables withdrawals
with
tolterodine
Pooled data Oxybutinin ER Similar in most Slightly less dry
(Cochrane, and outcome mouth with
2005)42 tolterodine ER variables tolterodine ER
OPERA (Diokno Oxybutinin ER Similar in most Slightly less dry
et al, 2003)22 and outcome mouth with
tolterodine ER variables tolterodine ER,
overall
tolerability
similar
Trospium and Oxybutinin and Similar in most Slightly less dry
oxybutinin trospium outcome mouth with
(Halaska et al, variables trospium
2003)82
STAR (Chapple Solifenacin and Solifenacin had Similar rates of
et al, 2005)31 tolterodine ER slightly better side effects
efficacy than
tolterodine ER
Tolterodine and Tolterodine and Fesoterodine Slightly less dry
fesoterodine fesoterodine had slightly mouth with
(Chapple et al, better efficacy tolterodine ER
2008)83 than
tolterodine ER

BOTULINUM-A TOXIN

Injection of botulinum toxin into the detrusor muscle for the treatment of neurogenic
detrusor overactivity was first described by Schurch and coworkers.48 Botulinum
toxin, a potent neurotoxic protein produced by the bacterium Clostridium botulinum,
binds to the presynaptic terminals of motor neurons and impedes the fusion of
synaptic vesicles with the neuronal membrane.49 This inhibits the release of neuro-
transmitters, including acetylcholine, causing an interruption in neuronal transmission
that affects both the efferent and the afferent branches of the micturition reflex and
inhibits detrusor contractions. It may also decrease sensory input to the bladder by
down-regulating the neurotransmitter receptors of afferent neurons in the detrusor
muscle.50 In clinical practice, the technique for botulinum injection has not been stan-
dardized. It usually involves multiple injections of the drug into the detrusor muscle of
the bladder under cystoscopic guidance using local anesthesia, with sparing of the
trigone.
Botulinum toxin injections have been shown to be beneficial in several conditions
associated with neurogenic detrusor overactivity, including neurogenic detrusor hy-
perreflexia and detrusor external sphincter dyssynergia. In a large review of patients
with neurogenic detrusor overactivity, there was marked reduction in the number of
incontinence episodes in between episodes of clean intermittent self-catheterization
with improved quality of life.50 The effects were noted within 1 to 2 weeks of treatment
500 Saks & Arya

and lasted for 8 to 9 months. Urodynamics showed reduced mean detrusor pressures
with increased postvoid residual volumes. There were minimal injection sites or
systemic adverse effects.
The role of botulinum toxin injection has also been investigated in the treatment of
refractory, idiopathic, urge incontinence in neurologically normal women.51 In a clinical
trial investigating botulinum injection in women with urge incontinence refractory to at
least two other first-line treatments, significant improvement in symptoms were noted
in 60% women with sustained clinical effects for almost 1 year. Unexpectedly high
rates of urinary retention and urinary tract infections led to early discontinuation of
the trial. The clinical significance of asymptomatic increased postvoid residual volume
remains unclear.
A Cochrane review52 evaluating botulinum toxin for both neurogenic and idiopathic
overactive bladder concluded that although the drug can improve symptoms of over-
active bladder, too little data exist on safety and efficacy compared with placebo and
other treatments. A clear consensus on use of the drug in clinical practice including
optimal dose, location, and number and timing of initial and repeat injections has
not yet emerged. Experts recommend use of the drug in treatment of refractory symp-
toms in neurogenic and idiopathic detrusor overactivity53 but recommend caution
because the risk of voiding difficulty and duration of effect have not yet been accu-
rately evaluated.54

DRUGS TO DECREASE AFFERENTS

The afferent nerve input for the voiding reflex from bladder to brain requires stimulation
of the A delta fibers that detect bladder fullness and increased wall tension and C
fibers that detect noxious stimuli and initiate painful sensations. Abnormal detrusor
contractions may be triggered by hypersensitive C fiber afferent neurons.55 Intraves-
ical instillation of vanilloid neurotoxins, resiniferatoxin and capsaicin, have been inves-
tigated for the treatment of refractory neurogenic and nonneurogenic idiopathic
detrusor overactivity. Intravesically administered neurotoxin, such as capsaicin and
its analog resiniferatoxin, bind to vanilloid receptors in the bladder epithelium and
desensitize the C fiber sensory neurons while sparing the A delta unmyelinated fibers
involved in the normal micturition reflex.15 Both drugs have similar rates of reduced
urinary frequency and incontinence episodes; however, resiniferatoxin causes less
side effects, such as acute pain and irritation, than capsaicin.55 Because of the lack
of well-designed randomized controlled trials, neither is approved for use in the United
States. A small study showed that botulinum toxin may be better than resiniferatoxin in
the treatment of refractory detrusor overacitivity.56 The use of either resinferatoxin or
botulinum toxin for overactive bladder is off-label, should be considered experimental,
and probably restricted to patients who have failed conventional therapies.57
Desmopressin nasal spray,58 an oxytocin analog, is currently the only medication
approved for nocturia. Nocturia is common in older women and often coexists with
sleep disorders, such as insomnia and sleep apnea.59 Because of the risk of hypona-
tremia, the drug should be prescribed with extreme caution in older women.

VOIDING DYSFUNCTION

Anatomic bladder outlet obstruction is rare in women and is usually iatrogenic (post-
surgical). Functional causes of bladder outlet obstruction including detrusor sphincter
dysynnergia, and primary bladder neck obstruction along with other causes of urinary
retention, such as impaired detrusor contractility and detrusor hyperactivity with
 Pharmacologic Management of Urinary Incontinence 501

impaired contractility, are treated primarily with clean intermittent self-catheterization.

Drug therapy has a small secondary role in their management.
Detrusor sphincter dyssynergia, characterized by a lack of coordination of detrusor
muscle contraction with external sphincter relaxation, usually occurs as a result of
a neurologic lesion caudal to the pontine micturition center. It is usually treated with
clean intermittent self-catheterization to prevent increased intravesical pressures
and overflow incontinence. Intraurethral injections of botulinum toxin may be benefi-
cial in improving voiding function as suggested in several small studies of patients
with spinal cord injury and detrusor sphincter dysynnergia.60–62 Attempts have also
been made to decrease outlet resistance with baclofen or diazepam.15
Primary bladder neck obstruction has an unclear etiology in women. Suggested
underlying causes include hypertrophy of the bladder neck or increased tone of
urethral smooth muscle from an increased number of a-adrenergic receptors.63
Most treatment options for primary bladder neck obstruction in women, including
pharmacologic and surgical therapies, are based on anecdotal evidence. Although
some studies suggest that a-adrenergic antagonists, such as terazosin or doxazosin,
may be effective, there are little available scientific data.64,65 Postural hypotension is
a significant side effect.
Impaired detrusor contractility may be a side effect of various drugs and the first-line
treatment should be to stop these medications if possible. If the condition persists, the
mainstay of treatment is clean intermittent self-catheterization while attempting to
improve detrusor contractions with muscarinic agonists or b-adrenergic antago-
nists.66 Bethanechol, a muscarinic agonist, has been used anecdotally, but does
not have proved efficacy.67
Detrusor hyperactivity with impaired contractility is a condition characterized by
urge incontinence and retention of urine with prominent detrusor trabeculations on
cystoscopy and is common in older women with overactive bladder.68 Patients with
detrusor hyperactivity with impaired contractility may benefit from antimuscarinic
medications or botulinum toxin,69 recognizing that women may require intermittent
catheterization even after injection.

ESTROGEN

The increased prevalence of urgency, frequency, and incontinence in postmeno-

pausal women may at least partially be caused by the urogenital effects of estrogen
loss including thinning of mucosa, loss of sphincter muscle tone, and alteration of
the urethrovesical angle.70 Although oral estrogen replacement seems to improve
some urogenital symptoms, such as urgency, frequency, and recurrent urinary tract
infections in menopausal women, estrogen does not improve incontinence symp-
toms.71,72 In two large clinical trials, women taking oral hormone-replacement therapy
reported significantly more incontinence symptoms when compared with
controls.73,74 Vaginal estrogen may be the most useful form of administration for
reducing irritative voiding symptoms and recurrent infections.71

ROLE OF BEHAVIORAL THERAPIES WITH PHARMACOLOGIC MANAGEMENT

A recent Cochrane review reported that in women with overactive bladder, symptom
improvement is greater when antimuscarinics are combined with bladder training as
compared with each therapy alone.75 Studies have also suggested additive effects
of behavioral therapy when combined with pharmacologic agents in the treatment
of stress urinary incontinence. A recent trial comparing antimuscarinic medication
alone with combined medication and behavioral therapies in the treatment of
502 Saks & Arya

overactive bladder found no difference in the number of women who remained off anti-
muscarinics or reported a reduction in incontinence episodes among the two groups,
but women who received both behavioral treatment and antimuscarinic medications
reported greater satisfaction as compared with the women who received antimuscar-
inics alone.76

NEW HORIZONS

Several neurotransmitters are being recognized as having a role in urinary storage and
voiding through their effect on central and peripheral pathways. These include gluta-
mate and serotonin for central pathways and norepinephrine, nitric oxide, tachykinins,
and dopamine for peripheral pathways. Several new drugs, targeted toward these
neurotransmitters, are currently under investigation for the treatment of overactive
bladder. Preclinical studies suggest that b3-adrenergic receptors predominate in the
detrusor muscle77 and preliminary data evaluating solabegron, a b3-adrenergic
agonist, seem promising.57 Two additional clinical trials assessing mirabegron78 and
solabegron79 were completed earlier this year and results should be available shortly.
Gabapentin, which binds to calcium channels, is being investigated in patients with
neurogenic and idiopathic detrusor overactivity.57 Tramadol is a weak m-receptor
agonist that also inhibits serotonin and norepinephrine reuptake. Both actions may
inhibit bladder contractions and improve the symptoms of overactive bladder.80 Ta-
chykinins including substance P and neurokinins A and B play a role in the mincturition
reflex. Neurokinin receptors are found on neurons of the dorsal horn and it is thought
that upregulation of tachykinin-mediated bladder-spinal reflex signaling may lead to
urge urinary incontinence. Initial clinical trials with aprepitant, a neurokinin-1 receptor
antagonist, have shown promising preliminary results in the treatment of urge urinary
incontinence.81

SUMMARY

Most pharmacologic agents used for the treatment urinary incontinence and voiding
dysfunction exert their effect on the neuromuscular transmission of the central or
peripheral nervous system. Surgery remains the mainstay of treatment for stress
urinary incontinence. Several different antimuscarinic medications are available for
the treatment of overactive bladder. Despite multiple routes of administration, most
of these drugs have similar efficacy and tolerability. Overall adherence to the medica-
tions is low. Despite the high prevalence of overactive bladder in the elderly, studies
regarding safety and efficacy of these drugs in this population are lacking. Several
medications with different mechanisms of action are being investigated for urge
urinary incontinence and overactive bladder and are still in the preclinical phase. Clean
intermittent self-catheterization is the mainstay of treatment for voiding dysfunction
with medications playing a small secondary role.

REFERENCES

1. de Groat WC. A neurologic basis for the overactive bladder. Urology 1997;
50(Suppl 6A):36–52.
2. DeLancey JO. Structural support of the urethra as it relates to stress urinary
incontinence: the hammock hypothesis. Am J Obstet Gynecol 1994;170(6):
1713–20.
3. Fraser MO, Chancellor MB. Neural control of the urethra and development of
pharmacotherapy for stress urinary incontinence. BJU Int 2003;91(8):743–8.
 Pharmacologic Management of Urinary Incontinence 503

4. Diokno AC, Taub M. Ephedrine in treatment of urinary incontinence. Urology

1975;5(5):624–5.
5. Mariappan P, Ballantyne Z, N’Dow JM, et al. Serotonin and noradrenaline reup-
take inhibitors (SNRI) for stress urinary incontinence in adults. Cochrane Data-
base Syst Rev 2005;(3):CD004742.
6. Hunsballe JM, Djurhuus JC. Clinical options for imipramine in the management of
urinary incontinence. Urol Res 2001;29(2):118–25.
7. Castleden CM, Duffin HM, Gulati RS. Double-blind study of imipramine and placebo
for incontinence due to bladder instability. Age Ageing 1986;15(5):299–303.
8. Woodman PJ, Misko CA, Fischer JR. The use of short-form quality of life question-
naires to measure the impact of imipramine on women with urge incontinence. Int
Urogynecol J Pelvic Floor Dysfunct 2001;12(5):312–5.
9. Thor KB, Katofiasc MA. Effects of duloxetine, a combined serotonin and norepi-
nephrine reuptake inhibitor, on central neural control of lower urinary tract function
in the chloralose-anesthetized female cat. J Pharmacol Exp Ther 1995;274(2):
1014–24.
10. Bump RC, Norton PA, Zinner NR, et al. Mixed urinary incontinence symptoms:
urodynamic findings, incontinence severity, and treatment response. Obstet
Gynecol 2003;102(1):76–83.
11. Steers WD, Herschorn S, Kreder KJ, et al. Duloxetine compared with placebo for
treating women with symptoms of overactive bladder. BJU Int 2007;100(2):
337–45.
12. Norton PA, Zinner NR, Yalcin I, et al. Duloxetine versus placebo in the treatment of
stress urinary incontinence. Am J Obstet Gynecol 2002;187(1):40–8.
13. Bump RC, Voss S, Beardsworth A, et al. Long-term efficacy of duloxetine in
women with stress urinary incontinence. BJU Int 2008;102(2):214–8.
14. Nabi G, Cody JD, Ellis G, et al. Anticholinergic drugs versus placebo for overac-
tive bladder syndrome in adults. Cochrane Database Syst Rev
2006;(4):CD003781.
15. Wein AJ, Rovner ES. Pharmacologic management of urinary incontinence in
women. Urol Clin North Am 2002;29(3):537–50, viii.
16. Abrams P, Andersson KE, Buccafusco JJ, et al. Muscarinic receptors: their distri-
bution and function in body systems, and the implications for treating overactive
bladder. Br J Pharmacol 2006;148(5):565–78.
17. Roxburgh C, Cook J, Dublin N. Anticholinergic drugs versus other medications
for overactive bladder syndrome in adults. Cochrane Database Syst Rev
2007;(4):CD003190.
18. Anderson RU, Mobley D, Blank B, et al. Once daily controlled versus immediate
release oxybutynin chloride for urge urinary incontinence. OROS Oxybutynin
Study Group. J Urol 1999;161(6):1809–12.
19. Andersson KE, Chapple CR. Oxybutynin and the overactive bladder. World J Urol
2001;19(5):319–23.
20. Hegde SS. Muscarinic receptors in the bladder: from basic research to therapeu-
tics. Br J Pharmacol 2006;147(Suppl 2):S80–7.
21. Zobrist RH, Quan D, Thomas HM, et al. Pharmacokinetics and metabolism of
transdermal oxybutynin: in vitro and in vivo performance of a novel delivery
system. Pharm Res 2003;20(1):103–9.
22. Diokno AC, Appell RA, Sand PK, et al. Prospective, randomized, double-blind
study of the efficacy and tolerability of the extended-release formulations of oxy-
butynin and tolterodine for overactive bladder: results of the OPERA trial. Mayo
Clin Proc 2003;78(6):687–95.
504 Saks & Arya

23. Dmochowski RR, Sand PK, Zinner NR, et al. Comparative efficacy and safety
of transdermal oxybutynin and oral tolterodine versus placebo in previously
treated patients with urge and mixed urinary incontinence. Urology 2003;
62(2):237–42.
24. Staskin DR, Dmochowski RR, Sand PK, et al. Efficacy and safety of oxybutynin
chloride topical gel for overactive bladder: a randomized, double-blind, placebo
controlled, multicenter study. J Urol 2009;181(4):1764–72.
25. Diokno A, Ingber M. Oxybutynin in detrusor overactivity. Urol Clin North Am 2006;
33(4):439–45, vii.
26. Van Kerrebroeck P, Kreder K, Jonas U, et al. Tolterodine once-daily: superior effi-
cacy and tolerability in the treatment of the overactive bladder. Urology 2001;
57(3):414–21.
27. Cardozo L, Chapple CR, Toozs-Hobson P, et al. Efficacy of trospium chloride in
patients with detrusor instability: a placebo-controlled, randomized, double-blind,
multicentre clinical trial. BJU Int 2000;85(6):659–64.
28. Staskin DR. Trospium chloride: distinct among other anticholinergic agents avail-
able for the treatment of overactive bladder. Urol Clin North Am 2006;33(4):
465–73, viii.
29. Rovner ES. Trospium chloride in the management of overactive bladder. Drugs
2004;64(21):2433–46.
30. Cardozo L, Lisec M, Millard R, et al. Randomized, double-blind placebo
controlled trial of the once daily antimuscarinic agent solifenacin succinate in
patients with overactive bladder. J Urol 2004;172(5 Pt 1):1919–24.
31. Simpson D, Wagstaff AJ. Solifenacin in overactive bladder syndrome. Drugs
Aging 2005;22(12):1061–9.
32. Chapple CR, Martinez-Garcia R, Selvaggi L, et al. A comparison of the efficacy
and tolerability of solifenacin succinate and extended release tolterodine at treat-
ing overactive bladder syndrome: results of the STAR trial. Eur Urol 2005;48(3):
464–70.
33. Haab F, Stewart L, Dwyer P. Darifenacin, an M3 selective receptor antagonist, is
an effective and well-tolerated once-daily treatment for overactive bladder. Eur
Urol 2004;45(4):420–9.
34. Zinner N. Darifenacin: a muscarinic M3-selective receptor antagonist for the treat-
ment of overactive bladder. Expert Opin Pharmacother 2007;8(4):511–23.
35. Chapple C, Van KP, Tubaro A, et al. Clinical efficacy, safety, and tolerability of
once-daily fesoterodine in subjects with overactive bladder. Eur Urol 2007;
52(4):1204–12.
36. Nitti VW, Dmochowski R, Sand PK, et al. Efficacy, safety and tolerability of feso-
terodine for overactive bladder syndrome. J Urol 2007;178(6):2488–94.
37. Khullar V, Chapple C, Gabriel Z, et al. The effects of antimuscarinics on health-
related quality of life in overactive bladder: a systematic review and meta-anal-
ysis. Urology 2006;68(Suppl 2):38–48.
38. Gopal M, Haynes K, Bellamy SL, et al. Discontinuation rates of anticholinergic
medications used for the treatment of lower urinary tract symptoms. Obstet
Gynecol 2008;112(6):1311–8.
39. Shaya FT, Blume S, Gu A, et al. Persistence with overactive bladder pharma-
cotherapy in a Medicaid population. Am J Manag Care 2005;11(Suppl 4):
S121–9.
40. Yu YF, Nichol MB, Yu AP, et al. Persistence and adherence of medications for
chronic overactive bladder/urinary incontinence in the California Medicaid
program. Value Health 2005;8(4):495–505.
 Pharmacologic Management of Urinary Incontinence 505

41. Kelleher CJ, Cardozo LD, Khullar V, et al. A medium-term analysis of the subjec-
tive efficacy of treatment for women with detrusor instability and low bladder
compliance. Br J Obstet Gynaecol 1997;104(9):988–93.
42. Hay-Smith J, Herbison P, Ellis G, et al. Which anticholinergic drug for overactive
bladder symptoms in adults. Cochrane Database Syst Rev 2005;(3):CD005429.
43. Chapple CR, Khullar V, Gabriel Z, et al. The effects of antimuscarinic treatments in
overactive bladder: an update of a systematic review and meta-analysis. Eur Urol
2008;54(3):543–62.
44. Sand P, Zinner N, Newman D, et al. Oxybutynin transdermal system improves the
quality of life in adults with overactive bladder: a multicentre, community-based,
randomized study. BJU Int 2007;99(4):836–44.
45. Malavaud B, Bagheri H, Senard JM, et al. Visual hallucinations at the onset of tol-
terodine treatment in a patient with a high-level spinal cord injury. BJU Int 1999;
84(9):1109.
46. Kay G, Crook T, Rekeda L, et al. Differential effects of the antimuscarinic agents
darifenacin and oxybutynin ER on memory in older subjects. Eur Urol 2006;50(2):
317–26.
47. Wagg A, Wyndaele JJ, Sieber P. Efficacy and tolerability of solifenacin in elderly
subjects with overactive bladder syndrome: a pooled analysis. Am J Geriatr Phar-
macother 2006;4(1):14–24.
48. Schurch B, Stohrer M, Kramer G, et al. Botulinum-A toxin for treating detrusor hy-
perreflexia in spinal cord injured patients: a new alternative to anticholinergic
drugs? Preliminary results. J Urol 2000;164(3 Pt 1):692–7.
49. Cruz F, Dinis P. Resiniferatoxin and botulinum toxin type A for treatment of lower
urinary tract symptoms. Neurourol Urodyn 2007;26(Suppl 6):920–7.
50. Karsenty G, Denys P, Amarenco G, et al. Botulinum toxin A (Botox) intradetrusor
injections in adults with neurogenic detrusor overactivity/neurogenic overactive
bladder: a systematic literature review. Eur Urol 2008;53(2):275–87.
51. Brubaker L, Richter HE, Visco A, et al. Refractory idiopathic urge urinary inconti-
nence and botulinum A injection. J Urol 2008;180(1):217–22.
52. Duthie J, Wilson DI, Herbison GP, et al. Botulinum toxin injections for adults with
overactive bladder syndrome. Cochrane Database Syst Rev 2007;(3):CD005493.
53. Apostolidis A, Dasgupta P, Denys P, et al. Recommendations on the use of botu-
linum toxin in the treatment of lower urinary tract disorders and pelvic floor
dysfunctions: a European consensus report. Eur Urol 2008. September 17,
2009. Epub ahead of print.
54. Giannantoni A, Mearini E, Del ZM, et al. Six-year follow-up of botulinum toxin a in-
tradetrusorial injections in patients with refractory neurogenic detrusor overac-
tivity: clinical and urodynamic results. Eur Urol 2009;55(3):705–11.
55. Chancellor MB, de Groat WC. Intravesical capsaicin and resiniferatoxin therapy:
spicing up the ways to treat the overactive bladder. J Urol 1999;162(1):3–11.
56. Giannantoni A, Mearini E, Di Stasi SM, et al. New therapeutic options for refrac-
tory neurogenic detrusor overactivity. Minerva Urol Nefrol 2004;56(1):79–87.
57. Andersson KE, Chapple CR, Cardozo L, et al. Pharmacological treatment of over-
active bladder: report from the International Consultation on Incontinence. Curr
Opin Urol 2009;19(4):380–94.
58. Hashim H, Abrams P. Novel uses for antidiuresis. Int J Clin Pract Suppl
2007;(155):32–6.
59. Gopal M, Sammel MD, Pien G, et al. Investigating the associations between
nocturia and sleep disorders in perimenopausal women. J Urol 2008;180(5):
2063–7.
506 Saks & Arya

60. Dykstra DD, Sidi AA. Treatment of detrusor-sphincter dyssynergia with botulinum
A toxin: a double-blind study. Arch Phys Med Rehabil 1990;71(1):24–6.
61. de Seze M, Petit H, Gallien P, et al. Botulinum a toxin and detrusor sphincter dys-
synergia: a double-blind lidocaine-controlled study in 13 patients with spinal cord
disease. Eur Urol 2002;42(1):56–62.
62. Phelan MW, Franks M, Somogyi GT, et al. Botulinum toxin urethral sphincter injec-
tion to restore bladder emptying in men and women with voiding dysfunction.
J Urol 2001;165(4):1107–10.
63. Nitti VW, Tu LM, Gitlin J. Diagnosing bladder outlet obstruction in women. J Urol
1999;161(5):1535–40.
64. Kumar A, Mandhani A, Gogoi S, et al. Management of functional bladder neck
obstruction in women: use of alpha-blockers and pediatric resectoscope for
bladder neck incision. J Urol 1999;162(6):2061–5.
65. Low BY, Liong ML, Yuen KH, et al. Terazosin therapy for patients with female
lower urinary tract symptoms: a randomized, double-blind, placebo controlled
trial. J Urol 2008;179(4):1461–9.
66. Taylor JA III, Kuchel GA. Detrusor underactivity: clinical features and pathogen-
esis of an underdiagnosed geriatric condition. J Am Geriatr Soc 2006;54(12):
1920–32.
67. Finkbeiner AE. Is bethanechol chloride clinically effective in promoting bladder
emptying? A literature review. J Urol 1985;134(3):443–9.
68. Resnick NM, Yalla SV. Detrusor hyperactivity with impaired contractile function:
an unrecognized but common cause of incontinence in elderly patients. JAMA
1987;257(22):3076–81.
69. Kuo HC. Effect of botulinum a toxin in the treatment of voiding dysfunction due to
detrusor underactivity. Urology 2003;61(3):550–4.
70. Schaffer J, Fantl JA. Urogenital effects of the menopause. Baillieres Clin Obstet
Gynaecol 1996;10(3):401–17.
71. Cardozo L, Lose G, McClish D, et al. A systematic review of the effects of estro-
gens for symptoms suggestive of overactive bladder. Acta Obstet Gynecol
Scand 2004;83(10):892–7.
72. Cardozo L, Lose G, McClish D, et al. A systematic review of estrogens for
recurrent urinary tract infections: third report of the Hormones and Urogenital
Therapy (HUT) Committee. Int Urogynecol J Pelvic Floor Dysfunct 2001;
12(1):15–20.
73. Hendrix SL, Cochrane BB, Nygaard IE, et al. Effects of estrogen with and without
progestin on urinary incontinence. JAMA 2005;293(8):935–48.
74. Grady D, Brown JS, Vittinghoff E, et al. Postmenopausal hormones and inconti-
nence: the Heart and Estrogen/Progestin Replacement Study. Obstet Gynecol
2001;97(1):116–20.
75. Alhasso AA, McKinlay J, Patrick K, et al. Anticholinergic drugs versus non-drug
active therapies for overactive bladder syndrome in adults. Cochrane Database
Syst Rev 2006;(4):CD003193.
76. Burgio KL, Kraus SR, Menefee S, et al. Behavioral therapy to enable women with
urge incontinence to discontinue drug treatment: a randomized trial. Ann Intern
Med 2008;149(3):161–9.
77. Drake MJ. Emerging drugs for treatment of overactive bladder and detrusor over-
activity. Expert Opin Emerg Drugs 2008;13(3):431–46.
78. Available at: http://clinicaltrials.gov/ct2/show/NCT00343486?intr5%22GW427353%
22&rank51. Accessed June 6, 2009.
 Pharmacologic Management of Urinary Incontinence 507

79. Available at: http://clinicaltrials.gov/ct2/show/NCT00527033?cond5%22Urinary1

Bladder%2C1Overactive%22&rank51. Accessed June 6, 2009.
80. Safarinejad MR, Hosseini SY. Safety and efficacy of tramadol in the treatment of
idiopathic detrusor overactivity: a double-blind, placebo-controlled, randomized
study. Br J Clin Pharmacol 2006;61(4):456–63.
81. Green SA, Alon A, Ianus J, et al. Efficacy and safety of a neurokinin-1 receptor
antagonist in postmenopausal women with overactive bladder with urge urinary
incontinence. J Urol 2006;176(6 Pt 1):2535–40.
82. Halaska M, Ralph G, Wiedemann A, et al. Controlled, double-blind, multicentre
clinical trial to investigate long-term tolerability and efficacy of trospium chloride
in patients with detrusor instability. World J Urol 2003;20(6):392–9.
83. Chapple CR, Van Kerrebroeck PE, Junemann KP, et al. Comparison of fesotero-
dine and tolterodine in patients with overactive bladder. BJU Int 2008;102(9):
1128–32.
84. Wein AJ . Pharmacological agents for the treatment of urinary incontinence due to
overactive bladder. Expert Opin Investig Drugs 2001;10(1):65–83.
85. Benson JT, Walters MD. Neurophysiology and pharmacology of the lower urinary
tract. In: Walters MD, Karram MM, editors. Urogynecology and reconstructive
surgery. 3rd edition. Philadelphia: Mosby and Elsevier; 2007. p. 33.