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Part IV
Conservative Therapy
of Incontinence
IV
Chapter 12
Chapter 12 Pharmacological Treatment of Urinary Inconti-
Pharmacological Treatment
of Urinary Incontinence
Gert Naumann, Heinz Koelbl
169
12
Contents
12.1 Medical Treatment of Bladder Overactivity . . . . . . . . 171
12.2 Anticholinergic Drugs . . . . . . . . . . . . . . . . . . . . 171
12.3 Drugs with Mixed Anticholinergic Action . . . . . . . . . 171
12.3.1 Oxybutynin . . . . . . . . . . . . . . . . . . . . . . . . . . 171
12.3.2 Propiverine . . . . . . . . . . . . . . . . . . . . . . . . . . 173
12.4 Drugs with Antimuscarinic Action . . . . . . . . . . . . . 174
12.4.1 Propantheline . . . . . . . . . . . . . . . . . . . . . . . . . 174
12.4.2 Tolterodine . . . . . . . . . . . . . . . . . . . . . . . . . . 174
12.4.3 Trospium . . . . . . . . . . . . . . . . . . . . . . . . . . . 174
12.4.4 Darifenacin . . . . . . . . . . . . . . . . . . . . . . . . . . 175
12.4.5 Solifenacin . . . . . . . . . . . . . . . . . . . . . . . . . . . 175
12.5 Drugs Acting on Membrane Channels . . . . . . . . . . . 175
12.5.1 Calcium Antagonists . . . . . . . . . . . . . . . . . . . . . 175
12.5.2 Potassium Channel Openers . . . . . . . . . . . . . . . . . 176
12.6 α-Adrenoceptor Antagonists
and β-Adrenoceptor Agonists . . . . . . . . . . . . . . . . 176
12.7 Antidepressants . . . . . . . . . . . . . . . . . . . . . . . . 176
12.8 Afferent Nerve Inhibitors . . . . . . . . . . . . . . . . . . 176
12.8.1 Capsaicin and Resiniferatoxin . . . . . . . . . . . . . . . . 176
12.8.2 Botulinum toxin A . . . . . . . . . . . . . . . . . . . . . . 176
12.9 Drugs Used for Treatment of Stress Incontinence . . . . . 177
12.9.1 α-Adrenoceptor Antagonists . . . . . . . . . . . . . . . . . 177
12.9.2 β-Adrenoceptor Antagonists . . . . . . . . . . . . . . . . . 177
12.9.3 Imipramine . . . . . . . . . . . . . . . . . . . . . . . . . . 178
12.9.4 Duloxetine . . . . . . . . . . . . . . . . . . . . . . . . . . . 178
12.10 Hormonal Treatment of Urinary Incontinence . . . . . . . 178
12.10.1 Estrogens for Stress Incontinence . . . . . . . . . . . . . . 178
12.10.2 Estrogens for Urge Incontinence . . . . . . . . . . . . . . 179
12.11 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . 179
References . . . . . . . . . . . . . . . . . . . . . . . . . . . 179
11
170
Gert Naumann, Heinz Koelbl
Urinary incontinence is a major clinical problem and a significant cause of disability
and dependency in older adults. Prevalence of urinary incontinence is approaching
55%; in healthy nonelderly women residing in the community, it ranges from 11.3% to
62.7%.Stress incontinence is reported to be a predominant type of incontinence, with
prevalence rates of 14.7%–52%. Mixed incontinence is also quite common with rates of
3.1%–47.9%. Urge incontinence occurs less often with rates of 2.4%–13.3%.
Overactive bladder is characterized by various symptoms of urgency and frequen-
cy with or without urinary urge through involuntary loss of urine. Overactive bladder
has a profound affect on decreasing the quality of life with isolation in social activities
and depression.
In contrast to the high prevalence and the costs for private help, only 37% of pa-
tients report their symptoms to a doctor. The reasons for this are unclear but include
suboptimal therapeutic effects, many side effects and ignorance regarding treatment
options.Sometimes it is an acceptance of the disorder as a natural part of aging or being unaware that treatment exists. On the other hand,patients are sometimes told by
healthcare professionals that urinary incontinence is a normal consequence of aging
and that nothing can be done.
In regulation of urine storage and bladder emptying, a complex pattern of efferent
and afferent signaling in parasympathetic, sympathetic and somatic nerves is involved.
Overactive bladder can occur as a result of sensitization of afferent nerve terminals
in the bladder or outlet region.Disorders of any of these neural structures or changes
in the bladder’s smooth muscle with denervation, damage to the CNS inhibitory pathways,as can be seen in various neurological disorders such as multiple sclerosis,cerebrovascular disease,Parkinson’s disease, brain tumors and spinal cord injury are examples. Overactive bladder may also occur in elderly patients because of changes in the
brain or bladder during aging. Normal bladder contraction in humans is mediated
mainly through stimulation of muscarinic receptors in the detrusor muscle.
Accurate assessment of the patient is essential in order to optimize treatment. Uri-
nary incontinence is a symptom and not a diagnosis. For starting any kind of treatment it is necessary to have an adequate evaluation of the pelvic floor. The clinical
evaluation of the urethrovesical, vulvovaginal and anorectal compartment is the stepping stone for all diagnostic and therapeutic decisions. Investigation of the incontinent patient should start with simple and noninvasive tests.The first step in the diagnosis of incontinence is a detailed history, including any medical conditions and patterns of urination. The history of urinary symptoms should be listed. The physical examination with the pelvic examination helps to evaluate both the structural and functional integrity of the pelvic structures and organs and gives a great deal of information on the external and internal genital region, shows abnormalities or enlargement
in the area, pelvic organ prolapse or genital atrophy. One of the important measurements for urinary incontinence is the postvoid residual urine volume. Urinalysis and
culture is an essential screening test for the patient with urinary tract symptoms. In
order to provide information on urination to the physician, the patient might find it
helpful to keep a diary for 3 or 4 days before the office visit.
Recent advantages in diagnosis of urinary tract disorders have resulted in the de-
velopment of highly complex testing procedures. First the clinician should perform
the simplest, least invasive and most informative test.Approximately 20% of patients
will require more sophisticated urodynamic testing. Urodynamic studies have become
an integral part of the evaluation of female patients with lower urinary tract dysfunction.
Chapter 12 Pharmacological Treatment of Urinary Incontinence
Major improvements and technological advances in ultrasonic instrumentation
have facilitated the establishment of ultrasound as a diagnostic tool in the management of female patients with urinary incontinence. Ultrasound has also been suggested as an alternative source for imaging the urethrovesical anatomy.As an alternative to
the commonly used radiological procedure, the ultrasonographic evaluation of the
upper and the distal tract belongs to routine assessment in the pre- and post-therapeutic concept of urogynecology. To exclude pathology in the bladder or urethra,
endoscopic techniques such as urethrocystoscopy are very helpful in the diagnostic
approach.
For many patients with urinary incontinence,surgical intervention may not repre-
sent the optimal approach for management of their incontinence.Just as other medical disorders are controlled pharmacologically, many causes of urinary incontinence
respond positively to medical intervention.
12.1 Medical Treatment of Bladder Overactivity
A number of different pharmacological therapies have been studied in the treatment
of the hyperactive detrusor (Table 12.1). Most results are based on nonrandomized,
controlled clinical trials.Most studies show a high level of placebo effect without great
benefit for pharmacological therapies. On the other hand, typical side effects are reported and are responsible for short treatment times (Huggins et al. 2003).
171
12.2 Anticholinergic Drugs
Anticholinergic drugs are the most active drugs in inhibiting detrusor overactivity
through inhibiting the binding of acetylcholine to muscarinic receptors. Of the five
types of muscarinic receptors identified (M1–M5), the smooth muscle of the human
bladder contains 80% M2 receptors. The remaining receptors are of the M3 type
and coordinate contractions of the detrusor muscles. The M3 receptors are also
concentrated on the salivary glands. Therefore the systemic anticholinergic drugs specific to the M3 receptor typically induce impaired salivation as well as bladder relaxation.
12.3 Drugs with Mixed Anticholinergic Action
Some drugs used to block bladder overactivity have been shown to have more than
one mechanism of action. They all have a more or less pronounced antimuscarinic effect and, in addition,an often poorly defined direct action on bladder muscle.
12.3.1 Oxybutynin
Oxybutynin is one of the more commonly used medications for urinary urgency and
urge incontinence and has been the agent of choice in the treatment of overactive
bladder (OAB) for three decades. This tertiary amine shows antimuscarinic activity
at the M2 and M3 receptors and also local anesthetic and smooth muscle relaxant effects.
172
Gert Naumann, Heinz Koelbl
Table 12.1. Drugs used in the treatment of detrusor overactivity.Assessment according to the Oxford system (Andersson et al. 2002)
11
Drug Level Grade
of evidence of recommendation
Antimuscarinic drugs
Tolterodine 1 A
Trospium 1 A
Propantheline 2 B
Atropine,hyoscyamine 2 D
(Darifenacin, solifenacin) Under investigation
Drugs acting on membrane channels
Calcium antagonists Under investigation
Potassium channel openers Under investigation
Drugs with mixed actions
Oxybutynin 1 A
Propiverine 1 A
Flavoxate 4 D
Alpha-adrenoceptor agonists
Alfuzosin, doxazosin 4 D
Prazosin, terazosin,tamsulosin 4 D
Beta-adrenoceptor agonists
Terbutaline, clenbuterol, salbutamol 4 D
Antidepressants
Imipramine 2 C
Prostaglandin synthesis inhibitors
Indomethacin, flurbiprofen 4 C
Vasopressin analogues
Desmopressin 1 A
Other drugs
Baclofen (intrathecal use) 2 C
Capsaicin 3 C
Resiniferatoxin Under investigation
Many studies of noncomparative design have shown that 55%–70% of patients who
received the recommended oral dose of the immediate-release form – 2.5–5 mg t.i.d.or
q.i.d, for up to 2 years – reported improvement in symptoms of urge incontinence.
Comparing 15 randomized controlled studies of 476 patients treated with oxybuty-
nin, Thuroff et al. (1998) showed a mean decrease in incontinence of 52% and a mean
reduction in frequency for 24 h of 33%. Despite the overall subjective improvement
rate of 74% (range,61%–100%),the mean percentage of patients reporting side effects
was 70% (range, 17%–93%).
The major problem associated with the clinical use of oxybutynin is its adverse ef-
fect profile with side effects in up to 80% of patients due to poor uroselectivity.Mainly these are dry mouth, constipation, blurred vision and tachycardia.
Because oxybutynin passes the blood–brain barrier, in the elderly patient cognitive
impairment can occur.
Chapter 12 Pharmacological Treatment of Urinary Incontinence
The development of once daily formulations of oxybutynin (oxybutynin ER; Ditro-
pan XL) showed substantial advantages with better compliance, a lower incidence of
dry mouth and same efficacy. Clinical trials on oxybutynin ER have compared this
drug with immediate-release oxybutynin.
In a multicenter, randomized, double-blind study on 105 patients with urge incon-
tinence, or mixed incontinence with a clinically significant urge component,Anderson
et al. (2002) showed a decrease in weekly urge incontinence episodes from 27.4 to 4.8
in the extended-release (ER) group and from 23.4 to 3.1 in the immediate-release (IR)
group after therapy, and total incontinence episodes decreased from 29.3 to 6 and from
26.3 to 3.8, respectively. There were decreased dry mouth symptoms (68% in the ER
group vs 87% in the IR group),moderate or severe dry mouth symptoms were recorded in 25% and 4%, respectively.
Versi et al. (2000) compared efficacy and safety of oxybutynin ER and IR in 226 pa-
tients with urge incontinence and showed a significant reduction in urge urinary incontinence in both groups without significance.In the oxybutynin ER group,there was
a significantly lower proportion of moderate to severe dry mouth symptoms.
To minimize side effects through oral intake, other pass forms of oxybutynin have
been developed.Rectal administration is one possible way and shows fewer adverse effects than the conventional tablets.
Using an oxybutynin transdermal system in treatment of overactive bladder with
eliminating the first-pass effect, there are no significant differences in the incidence of
typical side effects compared with placebo. Common side effects of oxybutynin-TDS
were pruritus and erythema at the cutaneous application site.
Oxybutynin given intravesically showed clinical improvement in various types of
bladder overactivity with only a few side effects. Clinical studies are underway to establish this application form.
In summary,oxybutynin shows good efficacy in the treatment of detrusor overac-
tivity,and is, together with tolterodine, the drug of first choice in patients with this disorder.
173
12.3.2 Propiverine
Propiverine is a benzylic acid derivate, has a combined antimuscarinic and calcium
antagonistic action and leads to improved efficacy and tolerability. Recommended
dosage is 15 mg, two to three times a day,not to exceed 60 mg per day.
Clinical advantages were seen in treatment of detrusor overactivity with increasing
bladder capacity and decreasing maximum detrusor contractions.
In a review of nine randomized studies on a total of 230 patients, Thuroff et al.
(1998) found reduction in frequency (30%) and micturitions per 24 h (17%), a 64 ml
increase in bladder capacity, and a 77% (range, 33%–80%) subjective improvement.
Side effects were found in 14% (range, 8%–42%). A controlled trial comparing propiverine, oxybutynin and placebo (Madersbacher et al. 1999), has confirmed the efficacy
of propiverine and suggested that the drug may have equal efficacy and fewer side effects than oxybutynin.
11
174
Gert Naumann, Heinz Koelbl
12.4 Drugs with Antimuscarinic Action
12.4.1 Propantheline
Propantheline bromide is a quaternary ammine that does not have affinity for muscarinic receptor subtypes. The daily dose is 15–30 mg four times; for an optimal effect an
individual titration of the dose and often higher dosages is necessary. In comparison
of oxybutynin 5 mg × 3,propantheline 15 mg × 3 and placebo in a randomized, double-
sor hyperreflexia Thuroff et al. (1991) found no differences between the placebo and
propantheline groups.
Newer more specific agents with better dosing schedules and fewer side effects
make this older oral antimuscarinic drug less desirable.
12.4.2 Tolterodine
Tolterodine is selective for the bladder rather than the salivary glands and fewer side
effects have been reported. Several studies show a significant reduction in incontinence episodes and micturition frequency in case of idiopathic detrusor instability
and detrusor hyperreflexia. In a dose of 1–4 mg per day tolterodine is well tolerated.
In a double-blind, randomized study on 1,022 patients with tolterodine 2 mg b.i.d.,
Chancellor et al. (2000) showed a significant reduction in urge incontinence episodes
by 46% v base-line in a comparison with placebo.
The next step to improve patient compliance was the development of a once daily
formulation of tolterodine ER. In a study of 1,529 patients, tolterodine extended-release 4 mg once daily and tolterodine immediate-release 2 mg twice daily both significantly reduced the mean number of urge incontinence episodes per week compared
with placebo, 71% for tolterodine ER, 60% for tolterodine IR, and 33% for placebo (van
Kerrebroeck et al.2001). The dry mouth side effect (of any severity) was 23% for tolterodine ER, 30% for tolterodine IR, and 8% for placebo.
Tolterodine has become a safe and effective drug with good efficacy and fewer side
effects.
12.4.3 Trospium
Trospium chloride is a quaternary ammonium derivate with a high affinity for selective muscarinic receptors but has negligible affinity for nicotinic receptors. Is does not
cross the blood–brain barrier and is well tolerated in elderly patients without cognitive impairment. It has no known drug–drug interactions, an advantage for patients
taking many medications.
The drug is excreted unchanged in the bladder because of no hepatic metabolism;
consequently a large percentage of the drug has direct action on the bladder. Several
open studies have indicated that the drug may be useful in the treatment of detrusor
overactivity.
In a double-blind,randomized study over 12 months investigating 358 patients with
urge symptoms or urge incontinence, Hofner et al. (2000) reported the effects of oxybutynin 5 mg b.i.d. with those of trospium 20 mg b.i.d.When there were identical re-
Chapter 12 Pharmacological Treatment of Urinary Incontinence
sults in improving urge symptoms, oxybutynin produced a significantly higher rate of
side effects, and the drop-out rate was higher in the oxybutynin group. At the 2003
American Urological Association conference, data from a randomized, double-blind,
placebo-controlled phase III trial of 523 patients with urge incontinence was presented. Trospium 20 mg daily was shown to significantly improve frequency, incontinent
episodes and bladder capacity. The most common side effects were dry mouth and
constipation,occurring in 21.9% and 9.5%, respectively. Trospium was approved by US
Food and Drug Administration (FDA) for the indication of overactive bladder in May
2004.
12.4.4 Darifenacin
Looking for antimuscarinic agents with more selectivity for M3 receptors,darifenacin
was found at the first selective muscarinic M3 receptor antagonist developed for treatment of bladder overactivity.
In a multicenter, double-blind, placebo-controlled, parallel-group study of 561 pa-
tients, Haab et al. (2004) showed a significant improvement of major symptoms of
OAB.Incontinence episodes per week were reduced from baseline by 67.7% with darifenacin 7.5 mg and 72.8% with darifenacin 15 mg compared with 55.9% with placebo.
The most common adverse events were dry mouth and constipation but very few subjects discontinued the trial because of these side effects.
Darifenacin is currently being evaluated in a phase III global clinical evaluation
program for the treatment of bladder overactivity, to identify the optimal dose regimen and to assess its potential clinical benefits. Doses of 7.5 mg and 15 mg once daily
seem effective and well tolerated.
175
12.4.5 Solifenacin
Solifenacin (YM905) is also a selective long-acting muscarinic M3 receptor antagonist.
The clinical relevance of these findings is currently being investigated in phase III clinical studies. In a randomized, double-blind placebo- and tolterodine-controlled trial of
the once daily agent, solifenacin in patients with symptomatic overactive bladder in
1,033 patients, Chapple et al. (2004) reported a significant improvement in urgency
episodes per day (solifenacin 5 mg, –52%; solifenacin 10 mg, –55%; tolterodine 2 mg
twice daily, –38%; and placebo, –33%). The same results were found in urge incontinence, a reduction in mean voids per day and an increase in voided volume.Treatment
with solifenacin was well tolerated; the rate of adverse events was low and comparable
with that of placebo.
12.5 Drugs Acting on Membrane Channels
12.5.1 Calcium Antagonists
Calcium channel blockers decrease bladder contractility and could be helpful as a
treatment option to increase bladder capacity and decrease the degree of leakage.
Combination of anticholinergics given intravesically and calcium antagonists in the
future can give good therapeutic results.
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Gert Naumann, Heinz Koelbl
12.5.2 Potassium Channel Openers
Hyperpolarization of the cell membrane through opening of K+ channels leads to relaxation and inhibition of detrusor contraction. Further studies are necessary to find
a drug with specific effects without side effects such as hypotension.
12.6 α-Adrenoceptor Antagonists and β-Adrenoceptor Agonists
Relaxation of the bladder neck and proximal urethra through α-adrenergic receptor
antagonists and bladder smooth muscle relaxation through β-adrenergic receptor agonists can be effective in selected cases of bladder overactivity.At the moment,no recent studies show safety and effective results in these drugs.
12.7 Antidepressants
Tricyclic antidepressants such as imipramine also work with anticholinergic and
α-adrenergic action. There is also an anxiolytic effect of the sympathetic nervous
system.
Imipramine is the only drug that has been widely used clinically to treat this disor-
der.Doses of 10–50 mg three times daily are well tolerated. In contrast to good clinical
experience, no randomized trials exist to show evidence in the treatment of detrusor
overactivity. Side effects on the cardiovascular system (orthostatic hypotension, ventricular arrhythmias) may be serious for the elderly patient.
11
12.8 Afferent Nerve Inhibitors
12.8.1 Capsaicin and Resiniferatoxin
The vanilloids capsaicin and resiniferatoxin target the unmyelinated fibers C in afferent nerves. The local anesthetic effect with intravesical administration is of interest.
Investigators are hopeful that treatment will consist of bladder instillation of medication, followed by 3–6 months without symptoms.
Typical side effects of intravesical capsaicin are burning sensation at the pubic/ure-
thral level during instillation and general discomfort.Therefore, before application of
the drug, an instillation of lidocaine is helpful without interfering with the beneficial
effects of capsaicin.
The intravesical application of resiniferatoxin shows a approximately 1,000 times
more potent activity than capsaicin. Resiniferatoxin can desensitize bladder sensory
fibers. Further studies have to show the advantage of resiniferatoxin as an interesting
alternative to capsaicin.
12.8.2 Botulinum toxin A
Botulinum toxin A, first isolated in 1897, acts by inhibiting ACH release at the presynaptic junction. This results in regionally decreased muscle contractility and muscle
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