Pharmacological Treatment of Urinary Incontinence

Transcription

FELLOWS ARTICLE
Pharmacological Treatment of Urinary Incontinence
Lucio M.A. Cipullo, MD, Fulvio Zullo, MD, Cosimo Cosimato, MD, Attilio Di Spiezio Sardo, MD,
Jacopo Troisi, MD, and Maurizio Guida, MD
Abstract: We present an overview of the current pharmacological
treatment of urinary incontinence (UI) in women, according to the latest
evidence available. After a brief description of the lower urinary tract receptors and mediators (detrusor, bladder neck, and urethra), the potential
sites of pharmacological manipulation in the treatment of UI are discussed.
Each class of drug used to treat UI has been evaluated, taking into account
published rate of effectiveness, different doses, and way of administration.
The prevalence of the most common adverse effects and overall compliance had also been pointed out, with cost evaluation after 1 month of treatment for each class of drug. Moreover, we describe those newer agents
whose efficacy and safety need to be further investigated. We stress the
importance of a better understanding of the causes and pathophysiology of
UI to ensure newer and safer treatments for such a debilitating condition.
Key Words: urinary incontinence, pharmacological treatment,
anticholinergic, USA pharmacotherapy cost evaluation
(Female Pelvic Med Reconstr Surg 2014;20: 185Y202)
T
he term urinary incontinence (UI) refers to any type of involuntary urinary loss [International Continence Society (ICS)].
Urinary incontinence has an observed prevalence of 25%, and this
tends to increase with age.1 Normal functions of the female lower
urinary tract are the storage of urine within the bladder and the
timely release during micturition at appropriate intervals. Bladder
and urethra act together as a functional unit during filling and
voiding phases. Effective micturition and bladder control both
require a well-functioning nervous system altogether with local
regulatory factors.2 Functional impairment at various levels may
result in bladder control disorders, which can be roughly classified as disturbances of storage and disturbances of emptying. The
various types of UIs in women, according to the ICS, are reported
in Table 1.3 The annual incidence of UI in women ranges from 2%
to 11%, with the highest incidence occurring during pregnancy.
Rates of complete remission of UI range from 0% to 13%, with
the highest remission rates after pregnancy.4 The annual incidence
of overactive bladder (OAB) ranges from 4% to 6%, with annual
remission rates of OAB ranging from 2% to 3%.5 Although conservative and behavioral therapy are important in the UI management in women, many patients may benefit from pharmacological
therapy. The aim of this article was to provide an overview of the
current therapeutical options in the pharmacological management
of women with UI. New developments in the drug treatment of
this condition are also pointed out. Drug therapy recommendations are based on the Oxford Classification System for Levels of
Evidence.6 The prices of the single drugs reported in this article
and the weighted average cost for a monthly treatment are based
on the US rates.
From the Department of Gynecology and Obstetrics of San Giovanni di Dio
and Ruggi d’Aragona Hospital, University of Salerno, Salerno, SA, Italy.
Reprints: Lucio M.A. Cipullo, MD, University of Salerno, Largo Ippocrate
n- 1, 84131 Salerno, SA, Italy. E-mail: [email protected].
The authors have declared they have no conflicts of interest.
Copyright * 2014 by Lippincott Williams & Wilkins
DOI: 10.1097/SPV.0000000000000076
Female Pelvic Medicine & Reconstructive Surgery
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FUNCTIONAL ANATOMY AND
NEUROPHYSIOLOGY OF THE LOWER
URINARY TRACT
The female bladder and urethra have a somatic (pudendal)
and an autonomic (sympathetic and parasympathetic) innervation
(Fig. 1). The pudendal nerve arises from the sacral nerve roots S2YS4
and supplies the external urethral sphincter. The parasympathetic
nerves, which govern bladder contraction, are derived from the
second, third, and fourth sacral segments of the spinal cord to the
detrusor muscle. Sympathetic nerve supply of the bladder originates in the intermediolateral nuclei in the thoracolumbar region
(T10-L2) of the spinal cord. Bladder storage and voidance involve
a complex interplay of efferent and afferent signals in a way that
parasympathetic, sympathetic, somatic, and sensory nerves can
work synergically.7 Contraction of the detrusor smooth muscle and relaxation of the outflow region result from the activation
of parasympathetic neurons (S2YS4). The predominant effects of
the sympathetic nerves in the lower urinary tract are inhibition of
the parasympathetic pathways at spinal and ganglion levels and
mediation of contraction of the bladder base and the urethra.
During bladder filling, the outlet is closed, and the bladder smooth
muscle is quiescent. When bladder volume increases to the micturition threshold, the activation of a micturition center in the dorsolateral pons (the pontine micturition center) elicits bladder
contraction and the reciprocal relaxation of the urethra, leading to
bladder emptying. During voiding, sacral parasympathetic pelvic
nerves provide an excitatory input (cholinergic and purinergic) to
the bladder and an inhibitory input (nitrergic) to the urethra (Fig. 2).
These peripheral networks are integrated by means of a feedback
and feedforward regulation at spinal cord and brain levels.8 There is
increasing evidence showing that the urothelium has got specialized
sensory and signaling properties, including expression of nicotinic,
muscarinic, tachykinin, adrenergic, bradykinin, and transient receptor potential receptors, close physical association with the afferent nerves, and ability to release chemical molecules such as
adenosine triphosphate (ATP), acetylcholine (ACh), and nitric
oxide (NO).8Y10 At present, the functional role of the muscarinic
receptors in the urothelium has largely been indirectly investigated, that is, by studying the effects after urothelium removal or
administration of pharmacological inhibitors. Thus, it seems that
the muscarinic receptors in the urothelium also contribute to the
overall bladder function regulation, but their specific roles have
not been fully established.11 The parasympathetic pelvic nerves
stimulate the detrusor muscle via the muscarinic receptors M2 and
M3. These receptors are activated by ACh, whereas purinergic
receptors (P2X1) are activated by ATP, inducing relaxation of the
urethral smooth muscle, mediated by NO. Apparently, most muscarinic receptors in the bladder are found on the detrusor smooth
muscle cells. Although the detrusor expresses far more M2 (80%)
than M3 (20%) receptors, it seems that detrusor contraction under
physiological conditions is largely (if not exclusively) mediated
by the M3 receptor.12Y16 The >1-adrenoceptors (ARs) and the
3 A-AR subtypes (A1, A2, and A3) have been investigated in the
human detrusor. Human urothelium as well contains all 3 receptor
subtypes.17,18 Real-time PCR and immunostaining revealed high
concentrations of A3-AR throughout the urothelium, the detrusor
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Cipullo et al
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FIGURE 1. Innervation of the lower urinary tract (LUT) (A) with relative distribution of the different classes of afferent fibers in the bladder
wall and urethra (B) and efferent pathways and neurotransmitter mechanisms that regulate the LUT (C). Adapted from Kanai et al9
and Fowler et al.10
smooth muscle, and the peripheral nerves,19Y21 and the functional
evidence of their important role in both normal and neurogenic
bladders is convincing.22Y28 The human detrusor also contains
A2-ARs: most probably, both receptors are involved in the physiological effects (relaxation) of noradrenaline in this structure.21,29,30
Sympathetic postganglionic neurons release noradrenaline (NA),
which activates A3 adrenergic receptors to relax the bladder
smooth muscle and activates >1-adrenergic receptors to contract
the urethral smooth muscle. Somatic axons in the pudendal
nerve also release ACh, which produces a contraction of the external sphincter striated muscle by activating nicotinic cholinergic receptors. Parasympathetic postganglionic nerves also
release ATP, which excites the bladder smooth muscle, and NO,
which relaxes the urethral smooth muscle. Targets of the stress
urinary incontinence (SUI) pharmacological treatment are the >
and A-ARs, whereas in the OAB/urgency urinary incontinence
(UUI) treatment, the site of interaction is the muscarinic receptor
(Figs. 3 and 4).
TABLE 1. Types of UI in Women (Modified)*
Type of Incontinence
SUI
Urge incontinence
(UI)
Mixed incontinence
(MI)
Special forms
*From Bump et al.3
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Definition/Symptoms
Involuntary urine loss during
physical exertion/exercise
(coughing, sneezing, sports)
without urgency
Involuntary urine loss combined with
sudden sensation of urgency
Y With detrusor instability (formerly
motor urge incontinence)
Y Without detrusor instability (formerly
sensory urge incontinence)
Involuntary urine loss associated not
only with urinary urgency but also
with physical exertion. It can be with
predominant SUI or UUI symptoms
Among others, neurogenic incontinence,
extraurethral incontinence (eg, in the
presence of fistula), overflow
incontinence, giggle incontinence
FIGURE 2. Micturition reflexes. [Representation from Yoshimura
et al.8
* 2014 Lippincott Williams & Wilkins
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Pharmacological Treatment of UI
FIGURE 3. Continence with drugs for UUI (pooled with random effects from RCTs). [Representation from Shamliyan et al.31
A thorough knowledge of the body distribution of muscarinic
receptors is mandatory to start an appropriate pharmacological
treatment (Table 2). It is important to keep in mind that drugs acting
on the muscarinic receptors are not specific for those present in the
lower urinary tract.2,12,13 This suggests that these drugs may cause
systemic adverse effects (AEs) (Tables 2b and 2c). Theoretically,
drugs with selectivity for the bladder could be obtained if the
receptor subtype(s) mediating bladder contraction and those
producing the main AEs of antimuscarinic drugs were different.
Unfortunately, this does not seem to be the case.
PHARMACOTHERAPY TREATMENT
OF OAB AND UUI
Overactive bladder is the term used to describe the symptom
complex of urgency, with or without urge incontinence, usually
with frequency and nocturia. Overactive bladder symptoms are
FIGURE 4. Treatment discontinuation due to AEs from drugs for UUI (pooled results from RCTs by using rate arcsine transformation).
[Representation from Shamliyan et al.31
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Cipullo et al
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TABLE 2A. Distribution of Muscarinic Receptors
Type
M1
G Protein and
Transduction Mechanism
Gq/11
Location
(Decreasing Concentration)
Brain (cortex, hippocampus);
spinal cord; salivary glands
jIP3, DAG
,K+ conductance
jCa2+ conductance
Agonists
Ach
Antagonists
Atropine
Oxotremorine
Muscarine
Carbachol
Scopolamine
Diphenhydramine
Dimenhydrinate
Dicycloverine
Thorazine
Tolterodine
Oxybutynin
Ipratropium
Pirenzepine
Telenzepine
Chlorpromazine
Haloperidol
Gi/o
ACh
Atropine
,cAMP
Conductance:
Methacholine
Carbachol
Dicycloverine
Thorazine
,Ca2+ jK+
Oxotremorine
Muscarine
Diphenhydramine
Dimenhydrinate
Tolterodine
Oxybutynin
Ipratropium
Methoctramine
Tripitramine
Gallamine
Chlorpromazine
ACh
Atropine
Bethanechol
Carbachol
Oxotremorine
Pilocarpine
Diphenhydramine
Dimenhydrinate
Dicycloverine
Tolterodine
Oxybutynin
Ipratropium
Darifenacin
Tiotropium
ACh
Carbachol
Oxotremorine
Atropine
Diphenhydramine
Dimenhydrinate
M2
Gq/11
M3
Heart; brainstem, cerebellum;
gastrointestinal (GI), bladder
Exocrine glands, bladder; GI wall
smooth muscle and sphincters
jIP3, DAG
jCa2+ conductance
Gi/o
,cAMP
Conductance:
M4
CNS
,Ca2+ jK+
Gq/11
M5
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Dicycloverine
Tolterodine
Oxybutynin
Ipratropium
CNS; ciliary muscle of eye
ACh
Carbachol
Oxotremorine
Same to M4
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TABLE 2B. Muscarinic Agonist Effect and Related AEs in Different Districts
Organ System
Muscarinic Receptors
Agonist Effect
M2
Negative dromotropic, chronotropic,
and inotropic
Vasodilatation
Bronchial smooth musculature
stimulation; jbronchial secretion
jTone and muscle contraction; jsecretion
Heart
Vascular system
Respiratory system
Gastrointestinal tract
Exocrine glands
Urinary tract
Eyes
M3 (endothelial)
M1-M3
M1-M3
M3
M3 (more than) M2
M3-M5
jSecretion
Contraction of bladder detrusor muscle;
jureters peristalsis; sphincter relaxation
Miosis (for contraction of pupillary
sphincter muscle); accommodation lock
(for contraction of ciliary muscle);
,intraocular pressure
due to involuntary contractions of the detrusor muscle during the
filling phase of the micturition cycle. These involuntary contractions are termed detrusor overactivity (DO) and are mediated by
ACh-induced stimulation of the bladder muscarinic receptors.
Urgency urinary incontinence is an involuntary loss of urine associated with urgency. Urodynamic testing shows an involuntary
leakage from the urethra synchronous with the sensation of a
sudden, compelling desire to void that is difficult to defer; during
filling cystometry, involuntary detrusor muscle contractions can
be detected.31 Drug therapy continues to have an integral role in
the management of women with OAB, and there are now a
number of different agents available (Table 3). Despite the clinical
advantages of many of the pharmacological agents available, the
occurrence of significant AEs and impaired compliance has limited their use. The availability of bladder selective drugs in the
near future, once daily dosing and differing the routes of administration, may increase the compliance. However, in many cases,
drugs may be considered as an adjunct to conservative therapy.
An optimal treatment should be individualized, taking into consideration a number of factors, such as the patient’s comorbidities
AE
Excessive reduction of
cardiac contractility
Hypotension
Bronchospasm
Diarrhea, drooling, nausea,
sickness, abdominal cramps
Sweating
Urinary retention
Accommodation
problems, lachrymation
and concomitant medications, together with the pharmacological
profiles of different drugs.
DRUGS WITH MIXED ACTION
Oxybutynin
Oxybutynin (Table 4a) is a tertiary amine that undergoes an
extensive first-pass metabolism to its active metabolite, N-desmethyl
oxybutynin, which occurs in high concentrations and is thought to
be responsible for a significant part of the action of the parent
drug. T1/2 = 2 hours. It has a mixed action consisting of 32,33:
- Nonselective antimuscarinic = M1 and M3 99 M2 is its primary
mechanism of action;
- Direct smooth muscle relaxation (antispasmodic) = may involve
blockage of Ca2+ channels;
- Local anesthetic properties = important only for intravescical
infusion;
- Antihistamine properties.
TABLE 2C. Muscarinic Antagonist Effect and Related AE in Different Districts
Organ System
Heart
Vascular system
Respiratory system
Gastrointestinal tract
Exocrine glands
Urinary tract
Eyes
CNS
Muscarinic Receptors
M2
M3 (endothelial)
M1-M3
M1-M3
M3
M3 (more than) M2
M1-M3-M5
M1-M2-M4-M5
Ganglia and autonomic
nerves
M1
Antagonist Effect
jHeart rate
Slightly vasodilation
Bronchodilation; jbronchial
secretion; prevention of
laryngospasm in anesthesia
,Motility; ,secretion
,Secretion
,Tone and contraction of bladder
and ureters; ,urination rate
Mydriasis; accommodation lock
,Cognition = sedation, amnesia
AE
Tachycardia (for vagal block);
arrhythmias
Dry mouth; constipation;
Urinary retention; difficulty voiding
Cycloplegia; blurry vision
Delirium (rare); hallucination (?);
drowsiness
Inhibition of slow postsynaptic
potentials; jrelease ACh
(for lock of presynaptic receptors)
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Cipullo et al
TABLE 3. Drugs Used in the Treatment of OAB/UUI*
(Modified)
Drug
LoE GoR
Antimuscarinic drugs
Darifenacin
Fesoterodine
Solifenacin
Tolterodine
Trospium
Propantheline
Atropine
Drugs acting on membrane channels
Calcium antagonist
K+-channel openers
Drugs with mixed actions
Oxybutynin
Propiverine
Antidepressants
Duloxetine
Imipramine
>-Adrenoreceptor antagonists
Alfuzosin
Doxazosin
Prazosin
Terazosin
Tamsulosin
A-Adrenoreceptor agonists
Mirabegron (A3)
Albuterol (A2)
Terbutaline (A2)
COX inhibitors
Indomethacin
Flurbiprofen
Toxins
Botulinum toxin (neurogenic), injected into bladder
wall
Botulinum toxin (idiopathic), injected into bladder
wall
Capsaicin (neurogenic), intravescical
RTX (neurogenic), intravescical
Other drugs
Baclofen, intrathecal
Hormones
Estrogen
Desmopressin, for nocturia.
1
1
1
1
1
2
3
A
A
A
A
A
B
C
2
2
1
1
A
A
2
3
C
C
3
3
3
3
3
C
C
C
C
C
2
3
3
B
C
C
2
2
C
C
2
A
3
B
2
2
C
C
3
C
2
1
C
A
Oxybutynin has showed improvement in quality of life
(QoL) and leakage episodes or voids in the 24 hours, when compared to placebo, in several trials. When compared to tolterodine,
there are no differences in terms of clinical efficacy, but fewer
withdrawals due to adverse events with tolterodine [relative risk
(RR), 0.52; 95% confidence interval (CI), 0.40Y0.66] and less risk
of dry mouth (RR, 0.65; 95% CI, 0.60Y0.71).34Y36 Oxybutyninbased drugs include immediate release (IR) formulation, extended
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release formulation (ER or XL), syrup, and a transdermal release.
The OROS-based oxybutynin is an ER formulation (Ditropan
XL). Oxybutynin ER ensures a smoother plasma concentrationtime profile and a lower maximum plasma concentration than
those seen with oxybutynin IR. The ER formulation improves drug
tolerability, facilitating one-daily intake. Long-term and short-term
studies have reported significant improvements in health-related
QoL with oxybutynin ER therapy. In addition, pharmacoeconomic
studies have suggested that oxybutynin ER is more cost effective
than oxybutynin IR, and at least as cost effective as tolterodine
IR.37 The use of oxybutynin gel elicits more local AEs compared
to placebo (6.8% vs 2.8%).38 However, the gel formulation may
offer a better combination of reduced local and systemic AEs and
is an alternative to oral preparations in those women who experienced intolerable antimuscarinic AEs (Tables 4b, 4c, and 4d).
Propiverine
*Assessments have been done according to the Oxford modified
system and ICS.7
COX inhibitor indicates cyclooxygenase inhibitor; GoR, grade of
recommendation; K+, potassium; LoE, level of evidence.
190
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Propiverine hydrochloride is a benzilic acid derivative compound. It is rapidly absorbed and has a high first-pass metabolism.
Its mixed action involves antimuscarinic and Ca2+ channel antagonism.33 Propiverine has more recently been introduced as a
long-acting once-daily preparation and may be useful in those
women unable to tolerate other antimuscarinic drugs. Adverse
effects are dry mouth (14%) and other AEs not well documented.
ANTIMUSCARINIC DRUGS
Recent large meta-analyses of the most widely used antimuscarinic drugs have clearly shown that these drugs provide a
significant clinical benefit (Table 5).31,39,40 However, none of the
commonly used antimuscarinic drugs are an ideal first-line treatment for OAB/DO patients. There is no consistent evidence that 1
antimuscarinic drug is superior to an alternative antimuscarinic drug
for the cure or the improvement of UUI. An optimal treatment
should be individualized, taking into consideration any associate
conditions and concomitant medications and the pharmacological
profiles of different drugs. Recommendations on the use of these
drugs41 are shown in Table 6.
Contraindications are uncontrolled narrow-angle glaucoma,
significant cardiac arrhythmias, urinary retention, gastric retention,
myasthenia gravis, severe renal and hepatic diseases, acquired cognitive impairment and dementia (Alzheimer disease), and concomitant treatment with acetylcholinesterase (AChE) inhibitors.
The treatment of OAB/DO in the elderly deserves specific
considerations. Overactive bladder is more common in the elderly,
where it causes a detrimental effect on the QoL. It has been established that 30.9% of women older than 65 years have this condition. Studies have shown that 40% of patients with Alzheimer
dementia experience OAB.42 Many of these patients are taking
AChE inhibitors like donepezil, galantamine, and rivastigmine.
AChE inhibitors fall under the parasympathomimetic group of
medications, whose effects are antagonized by antimuscarinic
drugs.43 Overactive bladder treatment in patients taking AChE
inhibitors remains difficult. A pilot study44 found improvement
in OAB symptoms with the use of propiverine hydrochloride in
patients taking Donepezil for cognitive impairment, without
changes in cognition. More research is required in this field.
Solifenacin
This compound is a bladder-selective antimuscarinic33 agent
that has greater specificity for the M3 receptors over the M2 receptors and has much higher potency against M3 receptors in
smooth muscle than it does against M3 receptors in salivary
glands (Table 7a). It shows a long half-life. Its long-term efficacy
has been assessed in a 12-month follow-up study of 1637 patients.45
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TABLE 4A. Oxybutynin Costs Overview
Drug Name
Oxytrol patch (3.9 mg)
Active Ingredient
Dose
Prices for 30 d of Treatment
Oxybutynin
$42.71
Gelnique (gel)
Oxybutynin chloride
Anturol (Gel)
Oxybutynin chloride
Ditropan XL (ER)
(5 mg) (10 mg)
Oxybutynin chloride
Oxybutynin Cl ER
(5 mg) (10 mg)
Oxybutynin chloride
36-mg patch applied twice weekly
(every 3Y4 d); delivers 3.9 mg/24 h;
rotate administration sites
(abdomen, hip, buttock)
10% , 1 g applied daily to dry,
intact skin; rotate application
(abdomen, thigh, shoulder, upper arm)
3%, 3 pumps (84 mg); applied as above;
may rotate site if necessary
5Y10 mg q.d.; may be increased to a
maximum of 30 mg/d; swallowed
whole; should not be chewed,
divided, or crushed
2.5Y5 mg b.i.d; max 5 mg q.i.d.
Oxybutynin Cl
(IR) (5 mg)
Oxybutynin UD syrup
(200 mL) (480 mL)
Oxybutynin chloride
2.5Y5 mg b.i.d. or t.i.d.; max 5 mg q.i.d.
$24.3 (5 mg)
$20.52 (10 mg)
$4.03
Oxybutynin chloride
Usual dose is 1 teaspoonful (5 mg/5 mL)
b.i.d or t.i.d. Max q.i.d.
$37.04 (200 mL)
$6.45 (480 mL)
$39.09
,$150
$88.76 (5 mg)
$94.46 (10 mg)
b.i.d. indicates twice daily; q.d., once daily; q.i.d., 4 times daily; t.i.d., 3 times daily.
TABLE 4B. Efficacy and Safety of Oxybutynin*
Conclusion
SoE
& Increased continence rates and improved UI
& Increased treatment discontinuation due to AEs; dry mouth was the most common AE
& IR oxybutynin resulted in greater rates of AEs and dry mouth compared with controlled-release oral or transdermal oxybutynin
& Higher vs lower doses resulted in greater improvement in UI, the same rates of dry mouth, and greater rates of treatment withdrawal
High
High
Low
Low
*Adapted from Shamliyan et al.31
SoE indicates strength of evidence.
There was a significantly greater reduction in urgency episodes in
the solifenacin arm compared to the placebo arm (P G 0.001) and
the difference in the median length of warning time was 31.5 seconds
TABLE 4C. Prevalence of AEs of Oxybutynin Compared With
Placebo (Modified)*
AE
&
&
&
&
&
&
&
&
&
&
Treatment failure
Dry mouth
Dry skin
Blurred vision
Constipation
Discontinuation: AEs
Headache
Serious AEs
Urine retention
Dysuria
RA, %
RC, %
12.2
34
10
10.4
7.3
10
4.1
3.7
3.2
0.8
22.9
15
10.4
9.1
5.5
5
4.5
2.0
0.5
0.2
RA indicates rate in active treatment group; RC, rate in control group.
in the solifenacin group compared to the 12.0 seconds of the
placebo group (P = 0.032).38 When compared with oxybutynin,
solifenacin showed a better efficacy with lower AEs.42 There were
statistically significant differences in QoL, patient reported cure,
all favoring solifenacin. The recommended starting dose of 5 mg
once daily has been compared to 10 mg, showing lower rate of
frequency and urgency. The dry mouth was significantly lower
with solifenacin when compared to tolterodine. Solifenacin 5 mg
once daily is the usual starting dose, which could be increased to
TABLE 4D. Comparative Effectiveness*
Head to Head
SoE
Oxybutynin vs tolterodine:
& Greater rate of treatment discontinuation due to AEs
& No difference in improvement in UI rates
& Low adherence to drug treatment; 950% of women
stopped treatments within 1 y
High
Moderate
Moderate
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TABLE 5. Patient-Centered Clinically Important Outcomes With Pharmacologic Interventions for UUI Compared With Placebo
(Modified)*
Outcome and Drug
Continence
& Fesoterodine
& Oxybutynin
& Solifenacin
& Tolterodine
& Trospium
Clinically important
improvement in
incontinence
& Darifenacin
& Fesoterodine
& Oxybutynin
& Solifenacin
& Tolterodine
& Trospium
RCTs
RA, %
RC, %
RR (95% CI)
2
4
5
4
4
61
27
39.2
53.2
28.3
48.5
16
28.1
43.7
16.6
1.3 (1.1
1.7 (1.3
1.5 (1.4
1.2 (1.1
1.7 (1.5
3
2
9
2
7
2
48.4
42
53
60.2
45
32.4
33
32
32
43
37
25.4
1.3 (1 to 1.5)
1.3 (1.2 to 1.5)
1.5 (1.2 to 1.9)
1.5 (1.0 to 2.1)
1.3 (1.1 to 1.4)
1.1 (0.6 to 2.0)
to
to
to
to
to
1.5)
2.1)
1.6)
1.4)
2.0)
Absolute Risk Difference (95% CI)
0.13 (0.06 to
0.11 (0.06 to
0.11 (0.06 to
0.09 (0.04 to
0.11 (0.08 to
0.20)
0.16)
0.16)
0.13)
0.14)
0.12 (0.06 to 0.17)
0.10 (0.06 to 0.15)
0.17 (0.10 to 0.24)
0.18 (0.10 to 0.26)
0.10 (0.04 to 0.15)
0.08 (j0.10 to 0.25)
SoE
Low
High
High
High
High
High
High
Moderate
Low
High
Low
RCT indicates randomized controlled trial.
10 mg once daily for better efficacy but with increased risk of dry
mouth (Tables 7b and 7c).
Tolterodine
Tolterodine (Table 8a) is a tertiary amine which is rapidly
absorbed. Its low lipid solubility implies a poor capacity to cross
the blood-brain barrier.33 T1/2 = 2Y3 hours. This drug is metabolized into the liver to its 5-hydroxymethyl derivative, which is an
active metabolite having a similar pharmacokinetic profile and is
thought to significantly contribute to the therapeutic effect.46 It is
a competitive muscarinic receptor antagonist with relative functional selectivity for bladder receptors,47 and, although it shows no
specificity for receptor subtypes, it does seem to target the bladder
over the salivary glands.48 No differences in QoL and improvement
of leakage episodes are reported when comparing tolterodine with
oxybutynin in 8 trials. Where the prescribing choice is between
oral IR oxybutynin and tolterodine, tolterodine might be preferred
for reduced risk of dry mouth. The starting dose is 2 mg twice
daily. The effects of 1-, 2-, and 4-mg doses were similar for
leakage episodes and micturitions in the 24 hours, with a greater
risk of dry mouth with the 2- and 4-mg doses at 2 to 12 weeks
(Tables 8b and 8c).36
Trospium
Trospium chloride is a quaternary ammonium compound
(this means that it crosses the blood-brain barrier to a limited
extent and hence would seem to have few cognitive effects) that
shows low biological availability (Table 9a).40 T1/2 = 20 hours. Its
mechanism of action is nonselective for muscarinic receptor
subtypes: it blocks detrusor smooth muscle receptors as well as
receptors in the ganglia.33 The efficacy and tolerability of once
daily trospium chloride has also been confirmed in a further large
study of 564 patients with OAB49; this drug seems to have a
meaningful impact on QoL.50 However, in 4 comparative studies,
TABLE 6. Recommendations for Antimuscarinic Drugs*
Offer IR or ER formulations of antimuscarinic drugs as initial drug therapy for adults with UUI.
If IR formulations of antimuscarinic drugs are unsuccessful for adults with urge urinary incontinence, offer ER formulations
or longer-acting antimuscarinic agents.
Consider using transdermal oxybutynin if oral antimuscarinic agents cannot be tolerated due to dry mouth.
Offer and encourage early review (of efficacy and AEs) of patients on antimuscarinic medication for urge urinary incontinence (G30 d)
When prescribing antimuscarinic drugs to elderly patients, be aware of the risk of cognitive AEs, especially in those receiving
cholinesterase inhibitors.
Avoid using oxybutynin IR in patients who are at risk of cognitive dysfunction.
Consider use of trospium chloride in patients known to have cognitive dysfunction.
Use antimuscarinic drugs with caution in patients with cognitive dysfunction.
Do an objective assessment of mental function before treating patients whose cognitive function may be at risk.
Check mental function in patients on antimuscarinic medication if they are at risk of cognitive dysfunction.
GR
A
A
B
A
C
A
B
B
C
C
*From EAU Guidelines on Urinary Incontinence, edition presented at the 27th EAU Annual Congress, Milan 2013. ISBN 978-90-79754-71-7.
192
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&
TABLE 7A. Solifenacin Costs Overview
Drug
Name
Active
Ingredient
VESIcare
Solifenacin
succinate
TABLE 8A. Tolterodine Costs Overview
Prices for 30 d
of Treatment
Dose
5Y10 mg q.d.;
$70.23 (5 mg)
swallowed whole $70.62 (10 mg)
with water
TABLE 7B. Efficacy and Safety of Solifenacin*
Conclusion
SoE
& Increased continence rates and greater
benefits with the higher dose in women
with urgency and mixed UI
& Increased risk for dry mouth, constipation,
and blurred vision; 10 mg increased
the risk for severe dry mouth and constipation
& Resulted in treatment discontinuation due
to AEs more often than did placebo
High
High
Drug
Name
Active
Ingredient
Detrol LA
2 mg (IR)
Tolterodine
tartrate
2Y4 mg q.d.;
swallowed whole
with liquid
Detrol LA
Tolterodine 4 mg q.d.;
4 mg (IR)
tartrate
swallowed whole
with liquid
Detrusitol
XL 4 mg
tartrate
swallowed whole
with liquid
Tolterodine
Tolterodine 2Y4 mg q.d.;
tartrate 2 mg
tartrate
swallowed whole
with liquid
Tolterodine
tartrate 4 mg
tartrate
swallowed whole
with liquid
Darifenacin
Darifenacin is a tertiary amine with a long half-life. It has
moderate lipophilicity and is a highly selective M3 receptor
antagonist which has been found to have a 5-fold higher affinity for the human M3 receptor, compared to the M1 receptor
(Table 10a).56 Its efficacy has been investigated in a multicenter,
double-blind, placebo-controlled, parallel-group study which enrolled 561 patients with symptoms of OAB.57 It is available for
TABLE 7C. Prevalence of AEs of Solifenacin Compared With
Placebo (Modified)*
,$87
,$29
(for 2 mg)
,$32.33
Conclusion
SoE
& Increased continence rates and improved UI
& Improved QoL
& AEs, including autonomic nervous system
disorders, abdominal pain, dry mouth, dyspepsia,
and fatigue, were significantly more common in
women taking tolterodine
& Discontinuation of the treatment and stopping
the treatment because of AEs did not differ
compared with placebo
High
Low
High
RA, %
RC, %
27.7
21
3
4
11
5
3
2.4
1.5
30.1
5
2
4
3
4
4
0.8
1.3
High
oral intake. Significant decreases in frequency and severity of
urgency, micturition frequency, and number of incontinence episodes were also observed, along with an increase in bladder
capacity. Darifenacin was well tolerated. The incidence of CNS
TABLE 8C. Prevalence of AEs of Tolterodine Compared With
Placebo (Modified)*
AE
Treatment failure
Dry mouth
Dizziness
Blurred vision
Constipation
Headache
Urine retention
Discontinuation: treatment failure
,$80.89
TABLE 8B. Efficacy and Safety of Tolterodine*
trospium seems not to be better than oxybutynin in terms of
efficacy.51Y55 It is available in oral IR and XR formulations. A
comparison that might benefit from further research is the evaluation of trospium versus oxybutynin or tolterodine in terms of
safety. Because trospium is a quaternary amine and oxybutynin
and tolterodine are tertiary amines, we could expect less neurological AEs in patients with cognitive impairment. Patients already on multiple medications could benefit from this compound
because of its low metabolism by liver enzymes (Tables 9b and 9c).
&
&
&
&
&
&
&
&
&
,$77
(for 2 mg)
High
AE
Price for 30 d
of Treatment
Dose
&
&
&
&
&
&
&
&
&
&
&
&
&
General body disorders
Treatment failure
Dry mouth
Autonomic nervous system disorder
Blurred vision
Constipation
Headache
Urine tract infection
Nasopharyngitis
Diarrhea
Serious AEs
RA, %
RC ,%
22.3
9
18.4
27.2
1.3
4
4
4
2
0.7
3
2
1.8
18
16
6.7
15.5
3
3
3
4
3
1.6
3
2
3.1
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TABLE 9A. Trospium Costs Overview
Drug Name
Active Ingredient
Dose
Sanctura (IR) (20 mg)
Trospium chloride
Sanctura XR (60 mg)
Trospium chloride
Trospium chloride (20 mg)
Trospium chloride
Trospium chloride (60 mg)
Trospium chloride
20 mg b.i.d., at least 1 h before meals
or on empty stomach
60 mg q.d. in morning, at least 1 h before
breakfast, with water or on empty stomach
20 mg b.i.d., at least 1 h before meals or on
empty stomach
60 mg q.d. in the morning, at least 1 h before
breakfast, with water or on empty stomach
TABLE 9B. Efficacy and Safety of Trospium*
Conclusion
SoE
& Increased continence rates
& Dry mouth, dry eye, dry skin, and constipation
occurred more often than with placebo
& AEs resulted in treatment discontinuation more
often than did placebo
High
Moderate
High
and cardiovascular adverse events were comparable to placebo
(Tables 10b and 10c).58
Fesoterodine
Price for 30 d of Treatment
,$88
,$96.42
,$69.45
,$39
leakage episodes. Patients taking fesoterodine had higher risk
of withdrawal due to adverse events. Fesoterodine, 8 mg daily, is
more effective than tolterodine ER, 4 mg daily, for the cure and
the improvement of UUI (Tables 11b, 11c, and 11d).41
Atropine Sulfate
Drug Name: Levsin
Derived from the plant Atropa belladonna, this is the prototype of all antimuscarinic agents.33 It is rarely used for the treatment of OAB/DO because of its systemic AEs, which preclude its
use as an oral treatment. However, in patients with neurogenic DO
(NDO), intravesical atropine may be effective for increasing bladder capacity without causing any systemic AEs, as shown in open
pilot trials.60Y64 Sublingual form may have fewer AEs, whereas
intravescical form may be effective without AEs.33
Propantheline Bromide
Drug Name: Pro-Banthine
Fesoterodine is a new and novel derivative of 3,3diphenylpropyl-amine. Fesoterodine is a competitive muscarinic
receptor antagonist (Table 11a).59 After oral administration,
the compound is rapidly hydrolyzed in its active metabolite,
5-hydroxymethyl tolterodine (5-HMT), which is responsible for
the antimuscarinic activity of the drug and has the same activity as
tolterodine. T1/2 = 7Y8 hours [approved by the Food and Drug
Administration (FDA) for the treatment of OAB]. The lipophilicity
and permeability across biological membranes has been shown to
be considerably lower for 5-HMT as compared to tolterodine, and
5-HMT formation from fesoterodine by the ubiquitous nonspecific
esterases is more consistent.60 The efficacy of fesoterodine versus
ER tolterodine has been evaluated in 3 trials, later included in a
recent Cochrane review36: fesoterodine was superior to tolterodine in terms of reduction of urgency episodes, frequency, and
It is a quaternary ammonium compound with a nonselective
antimuscarinic action. It has a low (5%Y10%) and individually
varying biological availability. After metabolization has occurred,
TABLE 9C. Prevalence of AEs of Trospium Compared With
Placebo (Modified)*
TABLE 10B. Efficacy and Safety of Darifenacin*
AE
&
&
&
&
&
&
&
Dry mouth
Diarrhea
Central nervous system disorders
Constipation
Headache
Urinary tract infections
194
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RA, %
RC, %
15.1
2.5
3.9
9.3
5.8
3.3
2.6
4.5
4
3.8
2.6
3.9
3.5
1.3
TABLE 10A. Darifenacin Costs Overview
Drug
Name
Active
Ingredient
Dose
Price for 30 d
of Treatment
Enablex ER Darifenacin
7.5Y15 mg q.d.;
(7.5 mg)
hydrobromide
swallowed whole
(15 mg)
with liquid; should
not be chewed,
divided, or crushed
$84.62
(7.5 mg)
$84.64
(15 mg)
Conclusion
SoE
& At 7.5 and 15 mg, improved urgency UI and several
domains of QoL when compared with placebo
& Caused AEs more often than did placebo; among
examined AEs, darifenacin increased rates of
constipation, dry mouth, dyspepsia, and headache
& Higher dosage (30 mg/d) did not result in better
benefits but caused greater rates of AEs
& Treatment discontinuation rates due to AEs were
the same with darifenacin and placebo
High
Moderate
High
High
&
TABLE 10C. Prevalence of AEs of Darifenacin Compared With
Placebo (Modified)*
TABLE 11C. Prevalence of AEs of Fesoterodine Compared
With Placebo (Modified)*
AE
AE
RA, %
&
&
&
&
&
&
&
&
&
&
&
&
&
4
27
5.7
7
11
6
2
2.1
2
2.5
2
3.7
2
&
&
&
&
&
&
&
Dry mouth
Constipation
Dyspepsia
Urinary tract infection
Serious AEs
RA, %
Pl, %
22
14.6
4.6
4.4
2.9
1.2
1
5.6
5.7
3.3
1.3
2.3
2.1
1.7
Pl indicates placebo.
TABLE 11A. Fesoterodine Costs Overview
Drug
Name
Active
Ingredient
Dose
Treatment failure
Dry mouth
Influenza-like symptoms
Headache
Constipation
Back pain
Upper respiratory tract infection
Nasopharyngitis
Nausea
Abdominal pain
RC, %
8
7
8
6
3
3
3
3
3.5
3.3
3.1
2.7
2
Price for 30 d
of Treatment
$90.57
(4 and 8 mg)
treatment option for women affected by nonneurogenic voiding
dysfunction.70
its metabolites remain inactive.65 The effect of propantheline on
OAB/DO has not been well documented in controlled trials satisfying current standards; it can be considered effective, and may,
in individually titrated doses, be clinically useful.7
A-Adrenoceptors have been previously treated. The exact
mechanism of signaling pathway involving this class of drugs at
the urothelium level has to be clarified. Several studies conducted
in vitro and in vivo have shown a myorelaxant effect of A-AR
agonists; however, role of the A3-AR agonists remains to be elucidated.7 A number of A3-AR selective agonists, including
solabegron (phase II), are currently being evaluated as potential
treatments for OAB in humans.
Toviaz ER Fesoterodine 4Y8 mg q.d.; swallowed
(4 mg)
fumarate
whole with liquid;
(8 mg)
should not be chewed,
divided, or crushed
A-AR AGONISTS
>-ADRENERGIC ANTAGONISTS
Mirabegron
Their mechanism of action is urethral sphincter tone increase. So far, there are no controlled clinical trials showing that
>-adrenergic antagonist is an effective alternative in the treatment
of OAB/DO.7 A randomized controlled trial (RCT), comprising
364 women with OAB, revealed no effect of tamsulosin versus
placebo.66 On the other hand, voiding symptoms in women with
functional outflow obstruction, or lower urinary tract symptoms,
were successfully treated with an >1-AR antagonist.67,68 In women,
these drugs may produce stress incontinence due to their >-lytic
mechanism.69 Tamsulosin demonstrated effectiveness in female
patients with voiding dysfunction, independently of the obstruction grade. A recent study on >1-AR antagonists offers an initial
In June 28, 2012, the FDA approved Myrbetriq (mirabegron,
hitherto known as YM-178) to treat adults with OAB/UUI.
Myrbetriq relaxes the detrusor smooth muscle during filling by
activation of A3-ARs, increasing bladder capacity (Table 12a).71,72
Its safety and efficacy were demonstrated in 3 double-blind,
placebo-controlled, multicenter clinical trials (Table 12b).70
Recommended starting dose is 25 mg once daily; 25 mg is
effective within 8 weeks.72 In a study by Nitti et al,73 1329
patients were randomized to receive placebo, mirabegron 50 mg,
or 100 mg once daily for 12 weeks. At the final visit, mirabegron 50 and 100 mg showed statistically significant improvements in efficacy and mean volume voided/micturition compared
with placebo.
Chapple et al74 compared the long-term administration
safety and efficacy of mirabegron 50 and 100 mg and tolterodine
TABLE 11B. Efficacy and Safety of Fesoterodine*
Conclusion
SoE
TABLE 11D. Comparative Effectiveness and Safety*
&
&
&
&
Low
High
Low
High
Head to Head
Increased continence rate when compared with placebo
Improved urgency UI and better response with 8 vs 4 mg
Improved QoL
Resulted in higher rates of AEs and discontinuation of the
treatments due to AEs; AEs were more common with
8 than 4 mg
SoE
Fesoterodine vs tolterodine
Greater rates of continence
Greater rates of reduced UI
Greater rate of treatment discontinuation due to AEs
Low
High
Moderate
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TABLE 12A. Mirabegron Costs Overview
Drug
Name
Active
Ingredient
Dose
Myrbetriq Mirabegron 25 mg q.d.; swallow
25 mg
whole with water, with
or without food
Myrbetriq Mirabegron 50 mg q.d.; swallow
50 mg
whole with water,
with or without food
&
TABLE 12C. Prevalence of AEs of Mirabegron 50 mg, 100 mg
Compared With Placebo (Modified)*
Price for 30 d
of Treatment
,$240.99
,$240.99
in a 12-month, 3-arm, parallel-group study (with no placebo arm).
Both mirabegron and tolterodine improved key OAB symptoms
from the first measurement after 4 weeks, and effectiveness
was maintained throughout the 12-month treatment period. Van
Kerrebroeck et al75 have demonstrated a significant reduction of
incontinence episodes and micturition frequency.
In patients with severe renal impairment or with moderate
hepatic dysfunction, maximum dose is 25 mg once daily. In
patients with end-stage renal disease or with severe hepatic
impairment, the use of this drug is not recommended. In pregnancy, it can be used only if the benefit to the mother outweighs
the potential risk of the fetus. Myrbetriq is not recommended in
breast-feeding mothers because it is excreted in human milk.
In a proof-of-concept study of mirabegron 100 and 150 mg
twice daily,76 AEs were reported by 45.2% of patients, and the
incidence was similar among those treated with placebo
(43.2%) and mirabegron (43.8%Y47.9%). The most commonly
reported AEs were treatment-related gastrointestinal disorders,
including constipation, dry mouth, dyspepsia, and nausea. There
was no patient-reported acute retention.
In a study reported by Khullar et al,77 the incidence of AEs
was similar across the placebo, mirabegron 50 and 100 mg
groups (50.1%, 51.6%, and 46.9%, respectively; Table 12c).
Comparative studies with tolterodine,78,79 shown in Table 12d,
were also carried out.
NEUROTOXINS
Botulinum
Botulinum toxin (BONT onabotulinumtoxinA) is a neurotoxin produced by Clostridium botulinum (Table 13). Uninhibited urinary bladder contractions in people with some
neurological conditions can lead to the inability to store urine.
The treatment consists of Botox injection into the bladder that
induces detrusor relaxation, an increase in its storage capacity,
and a decrease in UI.80 In 2011 the FDA approved Botox injections to treat UI in people with neurologic conditions, such as
spinal cord injury and multiple sclerosis, experiencing OAB.
Observational studies are currently in progress with the aim to
assess Botox efficacy and safety in neurogenic treatment in
patients affected by Parkinson disease, and to assess risks and
AE
RA 50 mg, % RA 100 mg, % RC, %
Hypertension
Headache
Nasopharyngitis
Dry mouth
Constipation
6.1
2.7
3.2
3.4
2.8
1.6
TABLE 12D. Comparative Effectiveness
Head to Head
Mirabegron vs tolterodine:
The incidence and severity of treatment-emergent serious AEs (primary outcome parameters) were similar across the mirabegron
50 mg (59.7%), mirabegron 100 mg (61.3%), and tolterodine
sustained-release 4 mg (62.6%) groups.76
During 12 mo of treatment, 2.8% of mirabegron 50 mg once daily
recipients reported dry mouth compared with 8.6% with tolterodine ER 4 mg once daily recipients.77
On the basis of descriptive analyses from a 12-mo trial, once-daily
mirabegron 50 mg and tolterodine ER 4 mg were both efficacious
in reducing urinary symptoms and improving health-related QoL.77
benefits of its long-term use for OAB/UUI treatment.81Y83 The
recommended dose is 200 U of BOTOX per treatment, and
should not be exceeded.
Adverse effects are urinary tract infections and retention.
Vanilloid Receptors Agonist
These receptors are present on the afferent sensory neurons
innervating detrusor and urethra. The rationale for intravesical
vanilloid agonist application in patients with DO was offered by
the demonstration that capsaicin, after bladder C-fiber desensitization, suppresses involuntary detrusor contractions dependent upon a sacral micturition reflex.84 The C-fiber micturition
reflex is usually inactive but it was shown that it is enhanced in
patients with chronic spinal-cord lesions above sacral segments
and in those with chronic bladder outlet obstruction.85
Capsaicin
Capsaicin has been used for intravescical instillation in
patients affected by NDO.7,33 Capsaicin suppresses involuntary
detrusor contractions after chronic spinal cord lesions above
TABLE 13. Botulinum Costs Overview
Conclusion
Drug
Name
196
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6.6
1.8
2
2.9
2.6
1.4
*Adapted from Khullar et al.77
TABLE 12B. Efficacy and Safety of Mirabegron
Mirabegron caused a statistically significant improvement from
baseline compared with placebo in the numbers of urgency incontinence episodes and micturitions per 24 h.73
Mirabegron 25 and 50 mg, both doses were associated with significant improvements in efficacy measures of incontinence episodes and micturition frequency.75
4.9
3.7
3
2.5
2.8
1.6
Active
Ingredient
Dose
OnabotulinumtoxinA Total dose 200 U,
Botox
200UNT
as 1 mL (~6.7 U)
injections across
30 sites into
the detrusor
Price for a
Single Dose
$939.20
&
TABLE 14. Drugs Used for SUI Treatment (Modified)*
Drug
Duloxetine
Midodrine
Clenbuterol
Estrogen
Methoxantine
Imipramine
Ephedrine
Norephedrine (phenylpropanolamine)
TABLE 15B. Efficacy and Safety of Duloxetine*
LoE
GoR
1
2
3
2
2
3
3
3
B
C
C
D
D
D
D
D
*From Thüroff et al5 and Andersson et al.7
GoR indicates grade of recommendation; LoE, level of evidence.
sacral segments. Intravesical capsaicin for NDO was studied in
6 noncontrolled and 1 controlled clinical trials. After capsaicin
has been dissolved in 30% alcohol and 100 to 125 mL of sterile
water, 1 to 2 mM are instilled into the bladder and left in contact
with the mucosa for 30 minutes. The pungency of alcoholic
capsaicin solutions has prevented the widespread use of this
compound.7 In the single randomized study comparing the
capsaicin solution against the use of 30% ethanol, a significant
reduction of urge incontinence was found. The pungency of
alcoholic capsaicin solutions has prevented the widespread use
of this compound.
Conclusion
The mean IEF at baseline was 12.50 (2.2), and 9.02 (1.3), 7.50
(0.9), 6.02 (0.86) at the end of 1, 2, and 3 mo of treatment with
duloxetine, respectively. This shows that there was a statistically
significant reduction in the incontinence episode frequency (IEF)
at the end of each month when compared to the baseline.
Statistical reduction in the IEF at the end of 1 mo. In patients not
responding to treatment, the mean IEF at baseline was 13.10
(2.96) and 12.90 (2.88) at the end of 1 mo of treatment with
duloxetine.
There was a decrease of 30% in first month, around 40% to 45% at the
end of second month and over 50% decrease in IEF in third month.
*Adapted from Deepak et al.92
such as >1-AR agonists, estrogens, and tricyclic antidepressants
have all been used anecdotally in the past for the treatment of stress
incontinence, duloxetine is the first drug to be specifically developed and licensed for this indication.38 Drugs used for SUI are
shown in Table 14.
ANTIDEPRESSANT
Selective Norepinephrine and Serotonin
Reuptake Inhibitors
Duloxetine
Resiniferatoxin
This compound, derived from the cactus-like plant Euphorbia,
is 1000 times more potent, but much less pungent, than capsaicin.7,33
Different resiniferatoxin (RTX) concentrations, 10 nM, 50 nM, 100
nM, and 10 KM, were tested. Resiniferatoxin brought a rapid
improvement or disappearance of UI in up to 80% of the selected
patients and a 30% decrease in their daily urinary frequency.86
Furthermore, RTX also increased the volume to first detrusor
contraction and the maximal cystometric capacity. In general, in
patients receiving 50- to 100-nM RTX, the effect was long-lasting,
with a duration of more than 6 months being reported. In patients
treated with 10-KM doses, transient urinary retention may occur.87
Currently, new experimental tests are in progress to test its safety
and efficacy.
Duloxetine (Cymbalta) is a potent and balanced serotonin
(5-hydroxytryptamine) and noradrenaline reuptake inhibitor
(Table 15a).88 T1/2 = 12 hours. Its elimination is mainly through
hepatic metabolism. Its ability to stimulate the pudendal motoneurons (target: Onuf’s nucleus, in the sacral spinal cord) and to
increase striated urethral sphincter contractility is thought to be
the basis for its efficacy in women with SUI. Dmochowski
et al89 randomized 683 women, 22 to 84 years old, to duloxetine
or placebo. There was a significant decrease in incontinence
episode frequency with duloxetine compared with placebo
(50% vs 27%, P, 0.001), with comparably significant improvements in QoL (11.0 vs 6.8, P, 0.001). Duloxetine has been approved for the treatment of SUI in Europe, although the FDA
PHARMACOLOGICAL TREATMENT OF SUI
Stress urinary incontinence is defined as an involuntary loss of
urine on effort or physical exertion (or on sneezing or coughing)7
associated with increased intra-abdominal pressure (stress test), in
the absence of a detrusor contraction.31 Although various agents
TABLE 15A. Duloxetine Costs Overview
Drug Name
Cymbalta Cap
Oral 20 mg
Cymbalta Cap
Oral 40 mg
Duloxetine
20 mg
Duloxetine
40 mg
Active Ingredient
Dose
Price for 30 d
of Treatment
Duloxetine
40 mg b.i.d.
,$218.55
Duloxetine
40 mg b.i.d.
,$132.84
Duloxetine
40 mg b.i.d.
,$67.18
Duloxetine
40 mg b.i.d.
,$50.99
TABLE 15C. Prevalence of AEs of Duloxetine Compared With
Placebo (Modified)*
AE
&
&
&
&
&
&
&
&
&
&
&
&
Nausea
Headache
Insomnia
Constipation
Dry mouth
Dizziness
Fatigue
Somnolence
Anorexia
Vomiting
Increased sweating
Discontinuation of AEs
RA, %
RC, %
25.1
14.5
13.7
12.8
12.3
11
10.1
8.4
6.6
6.2
5.7
91
3.9
8.7
2.6
1.7
1.7
2.6
3.5
0
0
1.7
0.9
*Adapted from Millard et al.93
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TABLE 16A. Imipramine Costs Overview
Drug Name
Active
Ingredient
Tofranil CAP
25 mg
Tofranil CAP
50 mg
Tofranil CAP
75 mg
Imipramine
pamoate
Imipramine
pamoate
Imipramine
pamoate
Dose
Price for
Package
25Y75 mg q.h.s. ,$17 (for 25 mg
or b.i.d.
q.h.s.)
25Y75 mg q.h.s. $25.50 (for 50
or b.i.d.
mg q.h.s.)
25Y75 mg q.h.s. $36.50 (for 75
or b.i.d.
mg q.h.s.)
&
cause the relative AEs. Several researchers have found a significant effect in the treatment of patients with DO96 although
others report little effect.97 It may be used to treat SUI or
mixed incontinence. In the light of this evidence and the serious AEs associated with tricyclic antidepressants, their role
in DO remains of uncertain benefit, although they are often
useful in patients complaining of nocturia or bladder pain.38 It
has been known for a long time that imipramine can have
favorable effects in the treatment of nocturnal enuresis in
children, with a success rate of 10% to 70% in controlled
trials.98,99 Adverse effects are shown in Table 16b.
q.h.s. indicates every day at hours of sleep.
has not approved it for this purpose. Liver toxicity and suicidal
events represent a great concern. However, an observation study
from Michel et al90 has shown that women with SUI treated
with duloxetine doses lower than recommended reported a low
incidence of AEs and suicide attempts were not reported.
Cymbalta was first used to treat major depressive disorder and
generalized anxiety disorder. Subsequently, FDA approved
Cymbalta to treat chronic musculoskeletal pain, including discomfort from osteoarthritis, chronic lower back pain, and fibromyalgia, but failed the US approval for SUI amid concerns
over liver toxicity and suicidal events, whereas it was approved
for this indication in Europe, where it is recommended as an
add-on medication instead of surgery. The efficacy and safety
of duloxetine (20, 40, and 80 mg; Table 15b) for treatment of
SUI has been evaluated in a study by Norton et al,91 that involved 48 centers in the United States, including 553 women
with SUI, and Deepak et al.92 Duloxetine was associated with a
significant dose-dependent decrease in incontinence episode
frequency; reductions were 41% for placebo and 54%, 59%,
and 64% for the 20-, 40-, and 80-mg groups, respectively.
Discontinuation rates were also dose dependent; 5% for placebo
and 9%, 12%, and 15% of 20, 40, and 80 mg, respectively.93
Nausea is the most frequently reported AE. There was a significant decrease in incontinence episode frequency and improvement in QoL in those women taking duloxetine 40 mg o.d.
when compared to placebo.38 Escalating the dose upon initiation of the treatment has been shown to reduce the frequency of
AEs.94 From the whole group, 20% of patients cancelled surgery
after 2 months on duloxetine. The main adverse event was nausea, ranging from 23% to 25%. In these 6 trials, the percentage of
withdrawals due to AEs resulted to be 17% in the drug
group compared to 4% in the placebo arm.7 The most frequent
AEs are reported in Table 15c. Dysphoric mood, irritability,
agitation, paresthesias, anxiety, confusion, emotional lability,
hypomania, and tinnitus are generally self-limiting; some have
been reported to be severe. In a systematic review performed to
assess duloxetine safety and tolerability for SUI, no case of
suicide has been reported.95 An observational study on the same
subject including 3233 women did not report any case of suicide
during the treatment.90
Tricyclic Antidepressants
Imipramine
Imipramine is a tertiary amine of the tricyclic antidepressant
group; its mechanism of action is norepinephrine and serotonin
reuptake inhibition and it is thought to improve contraction of
the urethral smooth muscle (Table 16a).2 This drug is derived
from chlorpromazine, so it has the same blocking effects on
muscarinic (M1), adrenergic, and histaminergic receptors, that
198
www.fpmrs.net
>-Adrenergic Agonists
Several drugs with agonistic effects on >-ARs have been
used in the treatment of SUI. However, ephedrine and norephedrine (phenylpropanolamine) seem to have been the most
widely used.100 There was weak evidence to suggest that use
of an adrenergic agonist was better than placebo treatment.7
The limited evidence suggested that such drugs were better
than placebo in reducing the number of pad changes and incontinence episodes, and in improving subjective symptoms.
Phenylpropanolamine, clonidine (Catapres), ephedrine, and
pseudoephedrine belong to this category. >-Adrenergic agonists are not selective for bladder receptors: they are not
recommended in people with glaucoma, diabetes, hyperthyroidism, heart disease, or high blood pressure. The selective
>1-AR agonist midodrine is approved for SUI in Portugal.101
Phenylpropanolamine
Phenylpropanolamine is a nonselective >-ARs agonist
which is capable to bind A-adrenergic receptors and enhances
release of NE by presynaptic neurons.33 This drug can be effective in patients with mid-SUI, but it is no longer dispensed in
the United States because of the AEs reported later. Phenylpropanolamine is approved in Finland for the treatment of
SUI.101 Adverse effects are as follows: cardiac arrhythmias,
hypertension, insomnia, headache, tremor, anxiety, and stroke
(in women taking appetite suppressants).
A-AR Antagonists
A-Adrenoceptor antagonists inhibit urethral A-ARs and
this may increase noradrenaline action on the urethral >-ARs.7
Propranolol has been reported to have beneficial effects in the
TABLE 16B. AEs of Imipramine*
&
&
&
&
&
&
&
&
&
&
&
&
&
Peripheral antimuscarinic effects
Orthostatic hypotension
Hypertension
Blurred vision
Tinnitus
Rush
Headache
Palpitation
Dry mouth
Dizziness
Drowsiness
Tachycardia
Urinary retention
*Adapted from Kanai et al.9
&
treatment of stress incontinence102,103 but no RCTs to support
this action is present in literature.
TABLE 18. Vagifem Costs Overview
A-AR Agonists
Drug
Name
A-Adrenoceptor stimulation is generally conceded to decrease urethral pressure,104 but A2-AR agonists have been reported to have a different action on fast- and slow-contracting
skeletal muscle contractility.105 Clenbuterol, a selective A2-AR
agonist, is approved for the treatment of SUI in Japan.106
PHARMACOTHERAPY OF
MIXED INCONTINENCE
The optimum treatment of mixed urinary incontinence
(MUI) may often require multiple treatment modalities. One
should treat most bothersome symptoms first.5 Behavioral therapy and lifestyle modification, such as moderate weight loss and
caffeine reduction, should be considered first-line options for all
women with MUI. Pharmacological treatment of the urge component with antimuscarinics is effective. The addition of pelvic
floor muscle therapy may have an additional benefic effect. Often
a surgical procedure for the incontinence stress component significantly improves both symptoms. Anti-incontinence surgery
may have a positive impact on both the stress and the urge components of MUI; however, it seems that women with MUI may
have lower cure rates compared to women with pure SUI.
If the initial pharmacological approach fails, consider the
use of botulinum toxin or neuromodulation.
HORMONAL TREATMENT OF UI
Desmopressin
Desmopressin (Table 17) is a synthetic analog of vasopressin
(antidiuretic hormone). Desmopressin (DDVAP) was found to be
well tolerated and resulted in a significant improvement compared to placebo in reducing nocturnal voids/UI and increasing
the hours of undisturbed sleep.5 Studies are in progress to test
if desmopressin improves nocturnal enuresis in patients after
radical cystectomy with bladder reconstruction, and the impact
on sleep and daytime functioning. The drug is available in a
range of formulations: intranasal solution (spray), injectable
solution, tablets and, most recently, an oral lyophilisate. Intranasal and oral formulations are generally well tolerated, and
AEs are usually minor. Usual adult dose, in oral formulations,
is 0.2 to 0.6 mg every day at hours of sleep. One of the most
feared AEs (although rare) is hyponatremia. However, precautions in prescribing desmopressin for this condition and compliance monitoring will help prevent this complication. Adverse
effects are as follows: dizziness, headache, mood change,
Active
Ingredient
Price for 30 d
of Treatment
Dose
Vagifem
17A-estradiol 1 tablet q.d. for 2 wk,
10 mcg
followed by 1 tablet
twice weekly
Vagifem
17A-estradiol 1 tablet q.d. for 2 wk,
25 mcg
followed by 1 tablet
twice weekly
,$70.49
,$40.79
vomiting, weakness, loss of appetite, feeling restless or irritable, confusion, and hallucinations.
Estrogens
Bladder, urethra, and pelvic floor estrogen sensibility plays
an important role in the continence mechanism (Table 18).7
Many studies have shown that oral estrogen replacement, alone
or combined with a progesterone, has poor results in terms of
continence. In the women health initiative study, HRT was
found to increase the incidence of all types of UI at 1 year in
those women continent at baseline. The most recent metaanalysis on the effects of estrogen therapy on the lower urinary tract showed that overall systemic administration resulted
in worse incontinence than that of placebo.107 The use of local
estrogen therapy may improve incontinence (RR, 0.74; 95% CI,
0.64Y0.86), reducing frequency and urgency.107 The subjective
improvement in symptoms may simply represent local estrogenic effects reversing urogenital atrophy rather than a direct
effect on bladder function. Reliable data are too scant to suggest
the dose, type of estrogens, and route of administration.
PRACTICAL SUGGESTIONS
Conclusively, considering the similar pharmacological profile
of the different drugs used for the UUI treatment, we suggest
starting with instant release form of antimuscarinic drugs. Darifenacin, solifenacin and tolterodine seem to offer a good bioavailability and efficacy with acceptable AEs. Assessment of efficacy
and AEs of the treatment within 30 days from the beginning of the
therapy is mandatory. Specific caution must be taken when using
instant release oxybutynin in patient with cognitive dysfunction.
Consider use of transdermal oxybutynin in those patients experiencing dry mouth. Regarding the use of duloxetine for SUI, the
FDA has not given approval for this purpose. However, use of
duloxetine in the daily practice with doses lower then recommended
has shown a low incidence of AEs with a significant decrease in
incontinence episode frequency and improvement in QoL.
SUGGESTIONS FOR FURTHER RESEARCH
The following classes of drugs need to be investigated to
find out if they could be helpful in the treatment of any form of
incontinence:
TABLE 17. Desmopressin Costs Overview
Drug Name
Active
Ingredient
DDAVP
Desmopressin
60 mcg melt
acetate
Minirin 0.2 mg Desmopressin
acetate
Desmopressin Desmopressin
0.2 mg
acetate
Desmopressin Desmopressin
60 mcg
acetate
Dose
20Y60 mcg
q.h.s.
0.2Y0.6 mg
q.h.s.
0.2Y0.6 mg
q.h.s.
20Y60 mcg
q.h.s.
Price for 30 d
of Treatment
,$72.98
(for 60 mcg)
,$149
(for 0.2 mg)
,$123.28
(for 0.6 mcg)
,$80
(for 60 mcg)
-
Solabegron (A3-adrenergic agonist): phase II;
Cizolirtine citrate (antimuscarinic agent): phase II;
Tramadol (K-receptor agonist): off-label;
Gabapentin: off-label;
Aprepitant (neurokinin-1 receptor antagonist): off-label
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Pharmacological Treatment of Urinary Incontinence

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