pharmacological treatment of urinary incontinence · oxide (no).8y10 at present, the functional...

Pharmacological Treatment of Urinary IncontinenceLucio 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 pharmacologicaltreatment of urinary incontinence (UI) in women, according to the latestevidence available. After a brief description of the lower urinary tract re-ceptors and mediators (detrusor, bladder neck, and urethra), the potentialsites of pharmacological manipulation in the treatment of UI are discussed.Each class of drug used to treat UI has been evaluated, taking into accountpublished rate of effectiveness, different doses, and way of administration.The prevalence of the most common adverse effects and overall compli-ance had also been pointed out, with cost evaluation after 1 month of treat-ment for each class of drug. Moreover, we describe those newer agentswhose efficacy and safety need to be further investigated. We stress theimportance of a better understanding of the causes and pathophysiology ofUI 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)

The term urinary incontinence (UI) refers to any type of in-voluntary urinary loss [International Continence Society (ICS)].

Urinary incontinence has an observed prevalence of 25%, and thistends to increase with age.1 Normal functions of the female lowerurinary tract are the storage of urine within the bladder and thetimely release during micturition at appropriate intervals. Bladderand urethra act together as a functional unit during filling andvoiding phases. Effective micturition and bladder control bothrequire a well-functioning nervous system altogether with localregulatory factors.2 Functional impairment at various levels mayresult in bladder control disorders, which can be roughly classi-fied as disturbances of storage and disturbances of emptying. Thevarious types of UIs in women, according to the ICS, are reportedin 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%, withthe highest remission rates after pregnancy.4 The annual incidenceof overactive bladder (OAB) ranges from 4% to 6%, with annualremission rates of OAB ranging from 2% to 3%.5 Although con-servative and behavioral therapy are important in the UI manage-ment in women, many patients may benefit from pharmacologicaltherapy. The aim of this article was to provide an overview of thecurrent therapeutical options in the pharmacological managementof women with UI. New developments in the drug treatment ofthis condition are also pointed out. Drug therapy recommenda-tions are based on the Oxford Classification System for Levels ofEvidence.6 The prices of the single drugs reported in this articleand the weighted average cost for a monthly treatment are basedon the US rates.

FUNCTIONAL ANATOMY ANDNEUROPHYSIOLOGY OF THE LOWER

URINARY TRACTThe 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 S2YS4and supplies the external urethral sphincter. The parasympatheticnerves, which govern bladder contraction, are derived from thesecond, third, and fourth sacral segments of the spinal cord to thedetrusor muscle. Sympathetic nerve supply of the bladder origi-nates in the intermediolateral nuclei in the thoracolumbar region(T10-L2) of the spinal cord. Bladder storage and voidance involvea complex interplay of efferent and afferent signals in a way thatparasympathetic, sympathetic, somatic, and sensory nerves canwork synergically.7 Contraction of the detrusor smooth mus-cle and relaxation of the outflow region result from the activationof parasympathetic neurons (S2YS4). The predominant effects ofthe sympathetic nerves in the lower urinary tract are inhibition ofthe parasympathetic pathways at spinal and ganglion levels andmediation of contraction of the bladder base and the urethra.During bladder filling, the outlet is closed, and the bladder smoothmuscle is quiescent. When bladder volume increases to the mictu-rition threshold, the activation of a micturition center in the dorso-lateral pons (the pontine micturition center) elicits bladdercontraction and the reciprocal relaxation of the urethra, leading tobladder emptying. During voiding, sacral parasympathetic pelvicnerves provide an excitatory input (cholinergic and purinergic) tothe bladder and an inhibitory input (nitrergic) to the urethra (Fig. 2).These peripheral networks are integrated by means of a feedbackand feedforward regulation at spinal cord and brain levels.8 There isincreasing evidence showing that the urothelium has got specializedsensory and signaling properties, including expression of nicotinic,muscarinic, tachykinin, adrenergic, bradykinin, and transient re-ceptor potential receptors, close physical association with the af-ferent nerves, and ability to release chemical molecules such asadenosine triphosphate (ATP), acetylcholine (ACh), and nitricoxide (NO).8Y10 At present, the functional role of the muscarinicreceptors in the urothelium has largely been indirectly investi-gated, that is, by studying the effects after urothelium removal oradministration of pharmacological inhibitors. Thus, it seems thatthe muscarinic receptors in the urothelium also contribute to theoverall bladder function regulation, but their specific roles havenot been fully established.11 The parasympathetic pelvic nervesstimulate the detrusor muscle via the muscarinic receptors M2 andM3. These receptors are activated by ACh, whereas purinergicreceptors (P2X1) are activated by ATP, inducing relaxation of theurethral smooth muscle, mediated by NO. Apparently, most musca-rinic receptors in the bladder are found on the detrusor smoothmuscle cells. Although the detrusor expresses far more M2 (80%)than M3 (20%) receptors, it seems that detrusor contraction underphysiological conditions is largely (if not exclusively) mediatedby the M3 receptor.12Y16 The >1-adrenoceptors (ARs) and the3 A-AR subtypes (A1, A2, and A3) have been investigated in thehuman detrusor. Human urothelium as well contains all 3 receptorsubtypes.17,18 Real-time PCR and immunostaining revealed highconcentrations of A3-AR throughout the urothelium, the detrusor

FELLOWS ARTICLE

Female Pelvic Medicine & Reconstructive Surgery & Volume 20, Number 4, July/August 2014 www.fpmrs.net 185

From the Department of Gynecology and Obstetrics of San Giovanni di Dioand 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] authors have declared they have no conflicts of interest.Copyright * 2014 by Lippincott Williams & WilkinsDOI: 10.1097/SPV.0000000000000076

Copyright © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

mailto:[email protected]

smooth muscle, and the peripheral nerves,19Y21 and the functionalevidence of their important role in both normal and neurogenicbladders is convincing.22Y28 The human detrusor also containsA2-ARs: most probably, both receptors are involved in the physi-ological effects (relaxation) of noradrenaline in this structure.21,29,30

Sympathetic postganglionic neurons release noradrenaline (NA),which activates A3 adrenergic receptors to relax the bladdersmooth muscle and activates >1-adrenergic receptors to contractthe urethral smooth muscle. Somatic axons in the pudendal

nerve also release ACh, which produces a contraction of the ex-ternal sphincter striated muscle by activating nicotinic cho-linergic receptors. Parasympathetic postganglionic nerves alsorelease ATP, which excites the bladder smooth muscle, and NO,which relaxes the urethral smooth muscle. Targets of the stressurinary 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 Definition/Symptoms

SUI Involuntary urine loss duringphysical exertion/exercise(coughing, sneezing, sports)without urgency

Urge incontinence(UI)

Involuntary urine loss combined withsudden sensation of urgency

Y With detrusor instability (formerlymotor urge incontinence)

Y Without detrusor instability (formerlysensory urge incontinence)

Mixed incontinence(MI)

Involuntary urine loss associated notonly with urinary urgency but alsowith physical exertion. It can be withpredominant SUI or UUI symptoms

Special forms Among others, neurogenic incontinence,extraurethral incontinence (eg, in thepresence of fistula), overflowincontinence, giggle incontinence

*From Bump et al.3 FIGURE 2. Micturition reflexes. [Representation from Yoshimuraet al.8

FIGURE 1. Innervation of the lower urinary tract (LUT) (A) with relative distribution of the different classes of afferent fibers in the bladderwall and urethra (B) and efferent pathways and neurotransmitter mechanisms that regulate the LUT (C). Adapted from Kanai et al9

and Fowler et al.10

Cipullo et al Female Pelvic Medicine & Reconstructive Surgery & Volume 20, Number 4, July/August 2014

186 www.fpmrs.net * 2014 Lippincott Williams & Wilkins


A thorough knowledge of the body distribution of muscarinicreceptors is mandatory to start an appropriate pharmacologicaltreatment (Table 2). It is important to keep in mind that drugs actingon the muscarinic receptors are not specific for those present in thelower urinary tract.2,12,13 This suggests that these drugs may causesystemic adverse effects (AEs) (Tables 2b and 2c). Theoretically,drugs with selectivity for the bladder could be obtained if thereceptor 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 TREATMENTOF OAB AND UUI

Overactive bladder is the term used to describe the symptomcomplex of urgency, with or without urge incontinence, usuallywith frequency and nocturia. Overactive bladder symptoms are

FIGURE 3. Continence with drugs for UUI (pooled with random effects from RCTs). [Representation from Shamliyan et al.31

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

Female Pelvic Medicine & Reconstructive Surgery & Volume 20, Number 4, July/August 2014 Pharmacological Treatment of UI

* 2014 Lippincott Williams & Wilkins www.fpmrs.net 187


TABLE 2A. Distribution of Muscarinic Receptors

TypeG Protein and

Transduction MechanismLocation

(Decreasing Concentration) Agonists Antagonists

M1 Gq/11 Brain (cortex, hippocampus);spinal cord; salivary glands

Ach Atropine

jIP3, DAG Oxotremorine Scopolamine,K+ conductance Muscarine DiphenhydraminejCa2+ conductance Carbachol Dimenhydrinate

DicycloverineThorazineTolterodineOxybutyninIpratropiumPirenzepineTelenzepine

ChlorpromazineHaloperidol

M2 Gi/o Heart; brainstem, cerebellum;gastrointestinal (GI), bladder

ACh Atropine

,cAMP Methacholine DicycloverineConductance: Carbachol Thorazine

,Ca2+ jK+ Oxotremorine DiphenhydramineMuscarine Dimenhydrinate

TolterodineOxybutyninIpratropium

MethoctramineTripitramineGallamine

Chlorpromazine

M3 Gq/11 Exocrine glands, bladder; GI wallsmooth muscle and sphincters

ACh Atropine

jIP3, DAG Bethanechol DiphenhydraminejCa2+ conductance Carbachol Dimenhydrinate

Oxotremorine DicycloverinePilocarpine Tolterodine

OxybutyninIpratropiumDarifenacinTiotropium

M4 Gi/o CNS ACh Atropine,cAMP Carbachol Diphenhydramine

Conductance: Oxotremorine Dimenhydrinate

,Ca2+ jK+ DicycloverineTolterodineOxybutyninIpratropium

M5 Gq/11 CNS; ciliary muscle of eye ACh Same to M4

CarbacholOxotremorine




due to involuntary contractions of the detrusor muscle during thefilling phase of the micturition cycle. These involuntary contrac-tions are termed detrusor overactivity (DO) and are mediated byACh-induced stimulation of the bladder muscarinic receptors.Urgency urinary incontinence is an involuntary loss of urine as-sociated with urgency. Urodynamic testing shows an involuntaryleakage from the urethra synchronous with the sensation of asudden, compelling desire to void that is difficult to defer; duringfilling cystometry, involuntary detrusor muscle contractions canbe detected.31 Drug therapy continues to have an integral role inthe management of women with OAB, and there are now anumber of different agents available (Table 3). Despite the clinicaladvantages of many of the pharmacological agents available, theoccurrence of significant AEs and impaired compliance has lim-ited their use. The availability of bladder selective drugs in thenear future, once daily dosing and differing the routes of admin-istration, 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 con-sideration a number of factors, such as the patient’s comorbidities

and concomitant medications, together with the pharmacologicalprofiles of different drugs.

DRUGS WITH MIXED ACTION

OxybutyninOxybutynin (Table 4a) is a tertiary amine that undergoes an

extensive first-pass metabolism to its active metabolite, N-desmethyloxybutynin, which occurs in high concentrations and is thought tobe responsible for a significant part of the action of the parentdrug. T1/2 = 2 hours. It has a mixed action consisting of32,33:

- Nonselective antimuscarinic =M1 andM3 99M2 is its primarymechanism of action;

- Direct smooth muscle relaxation (antispasmodic) = may involveblockage of Ca2+ channels;

- Local anesthetic properties = important only for intravescicalinfusion;

- Antihistamine properties.

TABLE 2B. Muscarinic Agonist Effect and Related AEs in Different Districts

Organ System Muscarinic Receptors Agonist Effect AE

Heart M2 Negative dromotropic, chronotropic,and inotropic

Excessive reduction ofcardiac contractility

Vascular system M3 (endothelial) Vasodilatation HypotensionRespiratory system M1-M3 Bronchial smooth musculature

stimulation; jbronchial secretionBronchospasm

Gastrointestinal tract M1-M3 jTone and muscle contraction; jsecretion Diarrhea, drooling, nausea,sickness, abdominal cramps

Exocrine glands M3 jSecretion SweatingUrinary tract M3 (more than) M2 Contraction of bladder detrusor muscle;

jureters peristalsis; sphincter relaxationUrinary retention

Eyes M3-M5 Miosis (for contraction of pupillarysphincter muscle); accommodation lock(for contraction of ciliary muscle);,intraocular pressure

Accommodationproblems, lachrymation

TABLE 2C. Muscarinic Antagonist Effect and Related AE in Different Districts

Organ System Muscarinic Receptors Antagonist Effect AE

Heart M2 jHeart rate Tachycardia (for vagal block);arrhythmias

Vascular system M3 (endothelial) Slightly vasodilationRespiratory system M1-M3 Bronchodilation; jbronchial

secretion; prevention oflaryngospasm in anesthesia

Gastrointestinal tract M1-M3 ,Motility; ,secretion Dry mouth; constipation;Exocrine glands M3 ,SecretionUrinary tract M3 (more than) M2 ,Tone and contraction of bladder

and ureters; ,urination rateUrinary retention; difficulty voiding

Eyes M1-M3-M5 Mydriasis; accommodation lock Cycloplegia; blurry visionCNS M1-M2-M4-M5 ,Cognition = sedation, amnesia Delirium (rare); hallucination (?);

drowsinessGanglia and autonomicnerves

M1 Inhibition of slow postsynapticpotentials; jrelease ACh(for lock of presynaptic receptors)




Oxybutynin has showed improvement in quality of life(QoL) and leakage episodes or voids in the 24 hours, when com-pared to placebo, in several trials. When compared to tolterodine,there are no differences in terms of clinical efficacy, but fewerwithdrawals due to adverse events with tolterodine [relative risk(RR), 0.52; 95% confidence interval (CI), 0.40Y0.66] and less riskof dry mouth (RR, 0.65; 95% CI, 0.60Y0.71).34Y36 Oxybutynin-based drugs include immediate release (IR) formulation, extended

release formulation (ER or XL), syrup, and a transdermal release.The OROS-based oxybutynin is an ER formulation (DitropanXL). Oxybutynin ER ensures a smoother plasma concentration-time profile and a lower maximum plasma concentration thanthose seen with oxybutynin IR. The ER formulation improves drugtolerability, facilitating one-daily intake. Long-term and short-termstudies have reported significant improvements in health-relatedQoL with oxybutynin ER therapy. In addition, pharmacoeconomicstudies have suggested that oxybutynin ER is more cost effectivethan oxybutynin IR, and at least as cost effective as tolterodineIR.37 The use of oxybutynin gel elicits more local AEs comparedto placebo (6.8% vs 2.8%).38 However, the gel formulation mayoffer a better combination of reduced local and systemic AEs andis an alternative to oral preparations in those women who expe-rienced intolerable antimuscarinic AEs (Tables 4b, 4c, and 4d).

PropiverinePropiverine hydrochloride is a benzilic acid derivative com-

pound. It is rapidly absorbed and has a high first-pass metabolism.Its mixed action involves antimuscarinic and Ca2+ channel an-tagonism.33 Propiverine has more recently been introduced as along-acting once-daily preparation and may be useful in thosewomen unable to tolerate other antimuscarinic drugs. Adverseeffects are dry mouth (14%) and other AEs not well documented.

ANTIMUSCARINIC DRUGSRecent large meta-analyses of the most widely used anti-

muscarinic drugs have clearly shown that these drugs provide asignificant clinical benefit (Table 5).31,39,40 However, none of thecommonly used antimuscarinic drugs are an ideal first-line treat-ment for OAB/DO patients. There is no consistent evidence that 1antimuscarinic drug is superior to an alternative antimuscarinic drugfor the cure or the improvement of UUI. An optimal treatmentshould be individualized, taking into consideration any associateconditions and concomitant medications and the pharmacologicalprofiles of different drugs. Recommendations on the use of thesedrugs41 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 cog-nitive impairment and dementia (Alzheimer disease), and con-comitant treatment with acetylcholinesterase (AChE) inhibitors.

The treatment of OAB/DO in the elderly deserves specificconsiderations. Overactive bladder is more common in the elderly,where it causes a detrimental effect on the QoL. It has been estab-lished that 30.9% of women older than 65 years have this condi-tion. Studies have shown that 40% of patients with Alzheimerdementia experience OAB.42 Many of these patients are takingAChE inhibitors like donepezil, galantamine, and rivastigmine.AChE inhibitors fall under the parasympathomimetic group ofmedications, whose effects are antagonized by antimuscarinicdrugs.43 Overactive bladder treatment in patients taking AChEinhibitors remains difficult. A pilot study44 found improvementin OAB symptoms with the use of propiverine hydrochloride inpatients taking Donepezil for cognitive impairment, withoutchanges in cognition. More research is required in this field.

SolifenacinThis compound is a bladder-selective antimuscarinic33 agent

that has greater specificity for the M3 receptors over the M2 re-ceptors and has much higher potency against M3 receptors insmooth muscle than it does against M3 receptors in salivaryglands (Table 7a). It shows a long half-life. Its long-term efficacyhas been assessed in a 12-month follow-up study of 1637 patients.45

TABLE 3. Drugs Used in the Treatment of OAB/UUI*(Modified)

Drug LoE GoR

Antimuscarinic drugsDarifenacin 1 AFesoterodine 1 ASolifenacin 1 ATolterodine 1 ATrospium 1 APropantheline 2 BAtropine 3 C

Drugs acting on membrane channelsCalcium antagonist 2K+-channel openers 2

Drugs with mixed actionsOxybutynin 1 APropiverine 1 A

AntidepressantsDuloxetine 2 CImipramine 3 C

>-Adrenoreceptor antagonistsAlfuzosin 3 CDoxazosin 3 CPrazosin 3 CTerazosin 3 CTamsulosin 3 C

A-Adrenoreceptor agonistsMirabegron (A3) 2 BAlbuterol (A2) 3 CTerbutaline (A2) 3 C

COX inhibitorsIndomethacin 2 CFlurbiprofen 2 C

ToxinsBotulinum toxin (neurogenic), injected into bladderwall

2 A

Botulinum toxin (idiopathic), injected into bladderwall

3 B

Capsaicin (neurogenic), intravescical 2 CRTX (neurogenic), intravescical 2 C

Other drugsBaclofen, intrathecal 3 CHormonesEstrogen 2 CDesmopressin, for nocturia. 1 A

*Assessments have been done according to the Oxford modifiedsystem and ICS.7

COX inhibitor indicates cyclooxygenase inhibitor; GoR, grade ofrecommendation; K+, potassium; LoE, level of evidence.




There was a significantly greater reduction in urgency episodes inthe solifenacin arm compared to the placebo arm (P G 0.001) andthe difference in themedian length of warning timewas 31.5 seconds

in the solifenacin group compared to the 12.0 seconds of theplacebo group (P = 0.032).38 When compared with oxybutynin,solifenacin showed a better efficacy with lower AEs.42 Therewerestatistically significant differences in QoL, patient reported cure,all favoring solifenacin. The recommended starting dose of 5 mgonce daily has been compared to 10 mg, showing lower rate offrequency and urgency. The dry mouth was significantly lowerwith solifenacin when compared to tolterodine. Solifenacin 5 mgonce daily is the usual starting dose, which could be increased to

TABLE 4A. Oxybutynin Costs Overview

Drug Name Active Ingredient Dose Prices for 30 d of Treatment

Oxytrol patch (3.9 mg) Oxybutynin 36-mg patch applied twice weekly(every 3Y4 d); delivers 3.9 mg/24 h;rotate administration sites(abdomen, hip, buttock)

$42.71

Gelnique (gel) Oxybutynin chloride 10% , 1 g applied daily to dry,intact skin; rotate application(abdomen, thigh, shoulder, upper arm)

$39.09

Anturol (Gel) Oxybutynin chloride 3%, 3 pumps (84 mg); applied as above;may rotate site if necessary

,$150

Ditropan XL (ER)(5 mg) (10 mg)

Oxybutynin chloride 5Y10 mg q.d.; may be increased to amaximum of 30 mg/d; swallowedwhole; should not be chewed,divided, or crushed

$88.76 (5 mg)$94.46 (10 mg)

Oxybutynin Cl ER(5 mg) (10 mg)

Oxybutynin chloride 2.5Y5 mg b.i.d; max 5 mg q.i.d. $24.3 (5 mg)$20.52 (10 mg)

Oxybutynin Cl(IR) (5 mg)

Oxybutynin chloride 2.5Y5 mg b.i.d. or t.i.d.; max 5 mg q.i.d. $4.03

Oxybutynin UD syrup(200 mL) (480 mL)

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)

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 High& Increased treatment discontinuation due to AEs; dry mouth was the most common AE High& IR oxybutynin resulted in greater rates of AEs and dry mouth compared with controlled-release oral or transdermal oxybutynin Low& Higher vs lower doses resulted in greater improvement in UI, the same rates of dry mouth, and greater rates of treatment withdrawal Low

*Adapted from Shamliyan et al.31

SoE indicates strength of evidence.

TABLE 4C. Prevalence of AEs of Oxybutynin Compared WithPlacebo (Modified)*

AE RA, % RC, %

& Treatment failure 12.2 22.9& Dry mouth 34 15& Dry skin 10 10.4& Blurred vision 10.4 9.1& Constipation 7.3 5.5& Discontinuation: AEs 10 5& Headache 4.1 4.5& Serious AEs 3.7 2.0& Urine retention 3.2 0.5& Dysuria 0.8 0.2


RA indicates rate in active treatment group; RC, rate in control group.

TABLE 4D. Comparative Effectiveness*

Head to Head SoE

Oxybutynin vs tolterodine:& Greater rate of treatment discontinuation due to AEs High& No difference in improvement in UI rates Moderate&Low adherence to drug treatment; 950% of womenstopped treatments within 1 y

Moderate





10 mg once daily for better efficacy but with increased risk of drymouth (Tables 7b and 7c).

TolterodineTolterodine (Table 8a) is a tertiary amine which is rapidly

absorbed. Its low lipid solubility implies a poor capacity to crossthe blood-brain barrier.33 T1/2 = 2Y3 hours. This drug is metabo-lized into the liver to its 5-hydroxymethyl derivative, which is anactive metabolite having a similar pharmacokinetic profile and isthought to significantly contribute to the therapeutic effect.46 It isa competitive muscarinic receptor antagonist with relative func-tional selectivity for bladder receptors,47 and, although it shows nospecificity for receptor subtypes, it does seem to target the bladderover the salivary glands.48 No differences in QoL and improvementof leakage episodes are reported when comparing tolterodine withoxybutynin in 8 trials. Where the prescribing choice is betweenoral IR oxybutynin and tolterodine, tolterodine might be preferred

for reduced risk of dry mouth. The starting dose is 2 mg twicedaily. The effects of 1-, 2-, and 4-mg doses were similar forleakage episodes and micturitions in the 24 hours, with a greaterrisk of dry mouth with the 2- and 4-mg doses at 2 to 12 weeks(Tables 8b and 8c).36

TrospiumTrospium chloride is a quaternary ammonium compound

(this means that it crosses the blood-brain barrier to a limitedextent and hence would seem to have few cognitive effects) thatshows low biological availability (Table 9a).40 T1/2 = 20 hours. Itsmechanism of action is nonselective for muscarinic receptorsubtypes: it blocks detrusor smooth muscle receptors as well asreceptors in the ganglia.33 The efficacy and tolerability of oncedaily trospium chloride has also been confirmed in a further largestudy of 564 patients with OAB49; this drug seems to have ameaningful impact on QoL.50 However, in 4 comparative studies,

TABLE 5. Patient-Centered Clinically Important Outcomes With Pharmacologic Interventions for UUI Compared With Placebo(Modified)*

Outcome and Drug RCTs RA, % RC, % RR (95% CI) Absolute Risk Difference (95% CI) SoE

Continence& Fesoterodine 2 61 48.5 1.3 (1.1 to 1.5) 0.13 (0.06 to 0.20) Low& Oxybutynin 4 27 16 1.7 (1.3 to 2.1) 0.11 (0.06 to 0.16) High& Solifenacin 5 39.2 28.1 1.5 (1.4 to 1.6) 0.11 (0.06 to 0.16) High& Tolterodine 4 53.2 43.7 1.2 (1.1 to 1.4) 0.09 (0.04 to 0.13) High& Trospium 4 28.3 16.6 1.7 (1.5 to 2.0) 0.11 (0.08 to 0.14) HighClinically importantimprovement inincontinence

& Darifenacin 3 48.4 33 1.3 (1 to 1.5) 0.12 (0.06 to 0.17) High& Fesoterodine 2 42 32 1.3 (1.2 to 1.5) 0.10 (0.06 to 0.15) High& Oxybutynin 9 53 32 1.5 (1.2 to 1.9) 0.17 (0.10 to 0.24) Moderate& Solifenacin 2 60.2 43 1.5 (1.0 to 2.1) 0.18 (0.10 to 0.26) Low& Tolterodine 7 45 37 1.3 (1.1 to 1.4) 0.10 (0.04 to 0.15) High& Trospium 2 32.4 25.4 1.1 (0.6 to 2.0) 0.08 (j0.10 to 0.25) Low


RCT indicates randomized controlled trial.

TABLE 6. Recommendations for Antimuscarinic Drugs*

GROffer IR or ER formulations of antimuscarinic drugs as initial drug therapy for adults with UUI. AIf IR formulations of antimuscarinic drugs are unsuccessful for adults with urge urinary incontinence, offer ER formulationsor longer-acting antimuscarinic agents.

A

Consider using transdermal oxybutynin if oral antimuscarinic agents cannot be tolerated due to dry mouth. BOffer and encourage early review (of efficacy and AEs) of patients on antimuscarinic medication for urge urinary incontinence (G30 d) AWhen prescribing antimuscarinic drugs to elderly patients, be aware of the risk of cognitive AEs, especially in those receivingcholinesterase inhibitors.

C

Avoid using oxybutynin IR in patients who are at risk of cognitive dysfunction. AConsider use of trospium chloride in patients known to have cognitive dysfunction. BUse antimuscarinic drugs with caution in patients with cognitive dysfunction. BDo an objective assessment of mental function before treating patients whose cognitive function may be at risk. CCheck mental function in patients on antimuscarinic medication if they are at risk of cognitive dysfunction. C

*From EAU Guidelines on Urinary Incontinence, edition presented at the 27th EAU Annual Congress, Milan 2013. ISBN 978-90-79754-71-7.




trospium seems not to be better than oxybutynin in terms ofefficacy.51Y55 It is available in oral IR and XR formulations. Acomparison that might benefit from further research is the eval-uation of trospium versus oxybutynin or tolterodine in terms ofsafety. Because trospium is a quaternary amine and oxybutyninand tolterodine are tertiary amines, we could expect less neuro-logical AEs in patients with cognitive impairment. Patients al-ready on multiple medications could benefit from this compoundbecause of its lowmetabolism by liver enzymes (Tables 9b and 9c).

DarifenacinDarifenacin is a tertiary amine with a long half-life. It has

moderate lipophilicity and is a highly selective M3 receptorantagonist which has been found to have a 5-fold higher affin-ity 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 en-rolled 561 patients with symptoms of OAB.57 It is available for

oral intake. Significant decreases in frequency and severity ofurgency, micturition frequency, and number of incontinence epi-sodes were also observed, along with an increase in bladdercapacity. Darifenacin was well tolerated. The incidence of CNS

TABLE 7A. Solifenacin Costs Overview

DrugName

ActiveIngredient Dose

Prices for 30 dof Treatment

VESIcare Solifenacinsuccinate

5Y10 mg q.d.;swallowed whole

with water

$70.23 (5 mg)$70.62 (10 mg)

TABLE 7B. Efficacy and Safety of Solifenacin*

Conclusion SoE

& Increased continence rates and greaterbenefits with the higher dose in womenwith urgency and mixed UI

High

& Increased risk for dry mouth, constipation,and blurred vision; 10 mg increasedthe risk for severe dry mouth and constipation

High

& Resulted in treatment discontinuation dueto AEs more often than did placebo

High


TABLE 7C. Prevalence of AEs of Solifenacin Compared WithPlacebo (Modified)*

AE RA, % RC, %

& Treatment failure 27.7 30.1& Dry mouth 21 5& Dizziness 3 2& Blurred vision 4 4& Constipation 11 3& Discontinuation: AEs 5 4& Headache 3 4& Urine retention 2.4 0.8& Discontinuation: treatment failure 1.5 1.3


TABLE 8A. Tolterodine Costs Overview

DrugName


Price for 30 dof Treatment

Detrol LA2 mg (IR)

Tolterodinetartrate

2Y4 mg q.d.;swallowed wholewith liquid

,$77(for 2 mg)

Detrol LA4 mg (IR)

Tolterodinetartrate

4 mg q.d.;swallowed wholewith liquid

,$80.89

DetrusitolXL 4 mg

Tolterodinetartrate


,$87

Tolterodinetartrate 2 mg

Tolterodinetartrate

2Y4 mg q.d.;swallowed wholewith liquid

,$29(for 2 mg)

Tolterodinetartrate 4 mg

Tolterodinetartrate


,$32.33

TABLE 8B. Efficacy and Safety of Tolterodine*

Conclusion SoE

& Increased continence rates and improved UI High& Improved QoL Low& AEs, including autonomic nervous systemdisorders, abdominal pain, dry mouth, dyspepsia,and fatigue, were significantly more common inwomen taking tolterodine

High

& Discontinuation of the treatment and stoppingthe treatment because of AEs did not differcompared with placebo

High


TABLE 8C. Prevalence of AEs of Tolterodine Compared WithPlacebo (Modified)*

AE RA, % RC ,%

& General body disorders 22.3 18& Treatment failure 9 16& Dry mouth 18.4 6.7& Autonomic nervous system disorder 27.2 15.5& Blurred vision 1.3 3& Constipation 4 3& Discontinuation: AEs 4 3& Headache 4 4& Urine tract infection 2 3& Discontinuation: treatment failure 0.7 1.6& Nasopharyngitis 3 3& Diarrhea 2 2& Serious AEs 1.8 3.1





and cardiovascular adverse events were comparable to placebo(Tables 10b and 10c).58

FesoterodineFesoterodine is a new and novel derivative of 3,3-

diphenylpropyl-amine. Fesoterodine is a competitive muscarinicreceptor antagonist (Table 11a).59 After oral administration,the compound is rapidly hydrolyzed in its active metabolite,5-hydroxymethyl tolterodine (5-HMT), which is responsible forthe antimuscarinic activity of the drug and has the same activity astolterodine. T1/2 = 7Y8 hours [approved by the Food and DrugAdministration (FDA) for the treatment of OAB]. The lipophilicityand permeability across biological membranes has been shown tobe considerably lower for 5-HMT as compared to tolterodine, and5-HMT formation from fesoterodine by the ubiquitous nonspecificesterases is more consistent.60 The efficacy of fesoterodine versusER tolterodine has been evaluated in 3 trials, later included in arecent Cochrane review36: fesoterodine was superior to tolter-odine in terms of reduction of urgency episodes, frequency, and

leakage episodes. Patients taking fesoterodine had higher riskof withdrawal due to adverse events. Fesoterodine, 8 mg daily, ismore effective than tolterodine ER, 4 mg daily, for the cure andthe improvement of UUI (Tables 11b, 11c, and 11d).41

Atropine Sulfate

Drug Name: LevsinDerived from the plant Atropa belladonna, this is the proto-

type of all antimuscarinic agents.33 It is rarely used for the treat-ment of OAB/DO because of its systemic AEs, which preclude itsuse as an oral treatment. However, in patients with neurogenic DO(NDO), intravesical atropine may be effective for increasing blad-der capacity without causing any systemic AEs, as shown in openpilot trials.60Y64 Sublingual form may have fewer AEs, whereasintravescical form may be effective without AEs.33

Propantheline Bromide

Drug Name: Pro-BanthineIt is a quaternary ammonium compound with a nonselective

antimuscarinic action. It has a low (5%Y10%) and individuallyvarying biological availability. After metabolization has occurred,

TABLE 9A. Trospium Costs Overview

Drug Name Active Ingredient Dose Price for 30 d of Treatment

Sanctura (IR) (20 mg) Trospium chloride 20 mg b.i.d., at least 1 h before mealsor on empty stomach

,$88

Sanctura XR (60 mg) Trospium chloride 60 mg q.d. in morning, at least 1 h beforebreakfast, with water or on empty stomach

,$96.42

Trospium chloride (20 mg) Trospium chloride 20 mg b.i.d., at least 1 h before meals or onempty stomach

,$69.45

Trospium chloride (60 mg) Trospium chloride 60 mg q.d. in the morning, at least 1 h beforebreakfast, with water or on empty stomach

,$39

TABLE 9B. Efficacy and Safety of Trospium*

Conclusion SoE

& Increased continence rates High& Dry mouth, dry eye, dry skin, and constipationoccurred more often than with placebo

Moderate

& AEs resulted in treatment discontinuation moreoften than did placebo

High


TABLE 9C. Prevalence of AEs of Trospium Compared WithPlacebo (Modified)*

AE RA, % RC, %

& Dry mouth 15.1 4.5& Diarrhea 2.5 4& Central nervous system disorders 3.9 3.8& Constipation 9.3 2.6& Discontinuation: AEs 5.8 3.9& Headache 3.3 3.5& Urinary tract infections 2.6 1.3


TABLE 10A. Darifenacin Costs Overview

DrugName



Enablex ER(7.5 mg)(15 mg)

Darifenacinhydrobromide

7.5Y15 mg q.d.;swallowed wholewith liquid; shouldnot be chewed,divided, or crushed

$84.62(7.5 mg)$84.64(15 mg)

TABLE 10B. Efficacy and Safety of Darifenacin*

Conclusion SoE

& At 7.5 and 15 mg, improved urgency UI and severaldomains of QoL when compared with placebo

High

& Caused AEs more often than did placebo; amongexamined AEs, darifenacin increased rates ofconstipation, dry mouth, dyspepsia, and headache

Moderate

& Higher dosage (30 mg/d) did not result in betterbenefits but caused greater rates of AEs

High

& Treatment discontinuation rates due to AEs werethe same with darifenacin and placebo

High





its metabolites remain inactive.65 The effect of propantheline onOAB/DO has not been well documented in controlled trials sat-isfying current standards; it can be considered effective, and may,in individually titrated doses, be clinically useful.7

>-ADRENERGIC ANTAGONISTSTheir mechanism of action is urethral sphincter tone in-

crease. So far, there are no controlled clinical trials showing that>-adrenergic antagonist is an effective alternative in the treatmentof OAB/DO.7 A randomized controlled trial (RCT), comprising364 women with OAB, revealed no effect of tamsulosin versusplacebo.66 On the other hand, voiding symptoms in women withfunctional 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 >-lyticmechanism.69 Tamsulosin demonstrated effectiveness in femalepatients with voiding dysfunction, independently of the obstruc-tion grade. A recent study on >1-AR antagonists offers an initial

treatment option for women affected by nonneurogenic voidingdysfunction.70

A-AR AGONISTSA-Adrenoceptors have been previously treated. The exact

mechanism of signaling pathway involving this class of drugs atthe urothelium level has to be clarified. Several studies conductedin vitro and in vivo have shown a myorelaxant effect of A-ARagonists; however, role of the A3-AR agonists remains to be elu-cidated.7 A number of A3-AR selective agonists, includingsolabegron (phase II), are currently being evaluated as potentialtreatments for OAB in humans.

MirabegronIn June 28, 2012, the FDA approvedMyrbetriq (mirabegron,

hitherto known as YM-178) to treat adults with OAB/UUI.Myrbetriq relaxes the detrusor smooth muscle during filling byactivation ofA3-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 iseffective within 8 weeks.72 In a study by Nitti et al,73 1329patients were randomized to receive placebo, mirabegron 50 mg,or 100 mg once daily for 12 weeks. At the final visit, mira-begron 50 and 100 mg showed statistically significant improve-ments in efficacy and mean volume voided/micturition comparedwith placebo.

Chapple et al74 compared the long-term administrationsafety and efficacy of mirabegron 50 and 100 mg and tolterodine

TABLE 10C. Prevalence of AEs of Darifenacin Compared WithPlacebo (Modified)*

AE RA, % Pl, %

& Dry mouth 22 5.6& Constipation 14.6 5.7& Discontinuation: AEs 4.6 3.3& Dyspepsia 4.4 1.3& Urinary tract infection 2.9 2.3& Serious AEs 1.2 2.1& Discontinuation: treatment failure 1 1.7


Pl indicates placebo.

TABLE 11A. Fesoterodine Costs Overview

DrugName



Toviaz ER(4 mg)(8 mg)

Fesoterodinefumarate

4Y8 mg q.d.; swallowedwhole with liquid;should not be chewed,divided, or crushed

$90.57(4 and 8 mg)

TABLE 11B. Efficacy and Safety of Fesoterodine*

Conclusion SoE

& Increased continence rate when compared with placebo Low& Improved urgency UI and better response with 8 vs 4 mg High& Improved QoL Low& Resulted in higher rates of AEs and discontinuation of thetreatments due to AEs; AEs were more common with8 than 4 mg

High


TABLE 11C. Prevalence of AEs of Fesoterodine ComparedWith Placebo (Modified)*

AE RA, % RC, %

& Treatment failure 4 8& Dry mouth 27 7& Influenza-like symptoms 5.7 8& Headache 7 6& Constipation 11 3& Discontinuation: AEs 6 3& Discontinuation: treatment failure 2 3& Back pain 2.1 3& Upper respiratory tract infection 2 3.5& Nasopharyngitis 2.5 3.3& Nausea 2 3.1& Abdominal pain 3.7 2.7& Urinary tract infection 2 2


TABLE 11D. Comparative Effectiveness and Safety*

Head to Head SoE

Fesoterodine vs tolterodineGreater rates of continence LowGreater rates of reduced UI HighGreater rate of treatment discontinuation due to AEs Moderate





in a 12-month, 3-arm, parallel-group study (with no placebo arm).Both mirabegron and tolterodine improved key OAB symptomsfrom the first measurement after 4 weeks, and effectivenesswas maintained throughout the 12-month treatment period. VanKerrebroeck et al75 have demonstrated a significant reduction ofincontinence episodes and micturition frequency.

In patients with severe renal impairment or with moderatehepatic dysfunction, maximum dose is 25 mg once daily. Inpatients with end-stage renal disease or with severe hepaticimpairment, the use of this drug is not recommended. In preg-nancy, it can be used only if the benefit to the mother outweighsthe potential risk of the fetus. Myrbetriq is not recommended inbreast-feeding mothers because it is excreted in human milk.

In a proof-of-concept study of mirabegron 100 and 150 mgtwice daily,76 AEs were reported by 45.2% of patients, and theincidence was similar among those treated with placebo(43.2%) and mirabegron (43.8%Y47.9%). The most commonlyreported AEs were treatment-related gastrointestinal disorders,including constipation, dry mouth, dyspepsia, and nausea. Therewas no patient-reported acute retention.

In a study reported by Khullar et al,77 the incidence of AEswas similar across the placebo, mirabegron 50 and 100 mggroups (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

BotulinumBotulinum toxin (BONT onabotulinumtoxinA) is a neu-

rotoxin produced by Clostridium botulinum (Table 13). Unin-hibited urinary bladder contractions in people with someneurological conditions can lead to the inability to store urine.The treatment consists of Botox injection into the bladder thatinduces detrusor relaxation, an increase in its storage capacity,and a decrease in UI.80 In 2011 the FDA approved Botox in-jections to treat UI in people with neurologic conditions, such asspinal cord injury and multiple sclerosis, experiencing OAB.Observational studies are currently in progress with the aim toassess Botox efficacy and safety in neurogenic treatment inpatients affected by Parkinson disease, and to assess risks and

benefits of its long-term use for OAB/UUI treatment.81Y83 Therecommended dose is 200 U of BOTOX per treatment, andshould not be exceeded.

Adverse effects are urinary tract infections and retention.

Vanilloid Receptors AgonistThese receptors are present on the afferent sensory neurons

innervating detrusor and urethra. The rationale for intravesicalvanilloid agonist application in patients with DO was offered bythe demonstration that capsaicin, after bladder C-fiber desen-sitization, suppresses involuntary detrusor contractions depen-dent upon a sacral micturition reflex.84 The C-fiber micturitionreflex is usually inactive but it was shown that it is enhanced inpatients with chronic spinal-cord lesions above sacral segmentsand in those with chronic bladder outlet obstruction.85

CapsaicinCapsaicin has been used for intravescical instillation in

patients affected by NDO.7,33 Capsaicin suppresses involuntarydetrusor contractions after chronic spinal cord lesions above

TABLE 12B. Efficacy and Safety of Mirabegron

Conclusion

Mirabegron caused a statistically significant improvement frombaseline compared with placebo in the numbers of urgency in-continence episodes and micturitions per 24 h.73

Mirabegron 25 and 50 mg, both doses were associated with sig-nificant improvements in efficacy measures of incontinence ep-isodes and micturition frequency.75

TABLE 12C. Prevalence of AEs of Mirabegron 50 mg, 100 mgCompared With Placebo (Modified)*

AE RA 50 mg, % RA 100 mg, % RC, %

Hypertension 6.1 4.9 6.6Urinary tract infection 2.7 3.7 1.8Headache 3.2 3 2Nasopharyngitis 3.4 2.5 2.9Dry mouth 2.8 2.8 2.6Constipation 1.6 1.6 1.4

*Adapted from Khullar et al.77

TABLE 12A. Mirabegron Costs Overview

DrugName



Myrbetriq25 mg

Mirabegron 25 mg q.d.; swallowwhole with water, withor without food

,$240.99

Myrbetriq50 mg

Mirabegron 50 mg q.d.; swallowwhole with water,with or without food

,$240.99

TABLE 12D. Comparative Effectiveness

Head to Head

Mirabegron vs tolterodine:The incidence and severity of treatment-emergent serious AEs (pri-mary outcome parameters) were similar across the mirabegron50 mg (59.7%), mirabegron 100 mg (61.3%), and tolterodinesustained-release 4 mg (62.6%) groups.76

During 12 mo of treatment, 2.8% of mirabegron 50 mg once dailyrecipients reported dry mouth compared with 8.6% with tolter-odine ER 4 mg once daily recipients.77

On the basis of descriptive analyses from a 12-mo trial, once-dailymirabegron 50 mg and tolterodine ER 4 mg were both efficaciousin reducing urinary symptoms and improving health-related QoL.77

TABLE 13. Botulinum Costs Overview

DrugName


Price for aSingle Dose

Botox200UNT

OnabotulinumtoxinA Total dose 200 U,as 1 mL (~6.7 U)injections across30 sites intothe detrusor

$939.20




sacral segments. Intravesical capsaicin for NDO was studied in6 noncontrolled and 1 controlled clinical trials. After capsaicinhas been dissolved in 30% alcohol and 100 to 125 mL of sterilewater, 1 to 2 mM are instilled into the bladder and left in contactwith the mucosa for 30 minutes. The pungency of alcoholiccapsaicin solutions has prevented the widespread use of thiscompound.7 In the single randomized study comparing thecapsaicin solution against the use of 30% ethanol, a significantreduction of urge incontinence was found. The pungency ofalcoholic capsaicin solutions has prevented the widespread useof this compound.

ResiniferatoxinThis compound, derived from the cactus-like plant Euphorbia,

is 1000 timesmore potent, but much less pungent, than capsaicin.7,33

Different resiniferatoxin (RTX) concentrations, 10 nM, 50 nM, 100nM, and 10 KM, were tested. Resiniferatoxin brought a rapidimprovement or disappearance of UI in up to 80% of the selectedpatients and a 30% decrease in their daily urinary frequency.86

Furthermore, RTX also increased the volume to first detrusorcontraction and the maximal cystometric capacity. In general, inpatients receiving 50- to 100-nM RTX, the effect was long-lasting,with a duration of more than 6 months being reported. In patientstreated with 10-KM doses, transient urinary retention may occur.87

Currently, new experimental tests are in progress to test its safetyand efficacy.

PHARMACOLOGICAL TREATMENT OF SUIStress 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), inthe absence of a detrusor contraction.31 Although various agents

such as >1-AR agonists, estrogens, and tricyclic antidepressantshave all been used anecdotally in the past for the treatment of stressincontinence, duloxetine is the first drug to be specifically devel-oped and licensed for this indication.38 Drugs used for SUI areshown in Table 14.

ANTIDEPRESSANT

Selective Norepinephrine and SerotoninReuptake Inhibitors

DuloxetineDuloxetine (Cymbalta) is a potent and balanced serotonin

(5-hydroxytryptamine) and noradrenaline reuptake inhibitor(Table 15a).88 T1/2 = 12 hours. Its elimination is mainly throughhepatic metabolism. Its ability to stimulate the pudendal moto-neurons (target: Onuf’s nucleus, in the sacral spinal cord) and toincrease striated urethral sphincter contractility is thought to bethe basis for its efficacy in women with SUI. Dmochowskiet al89 randomized 683 women, 22 to 84 years old, to duloxetineor placebo. There was a significant decrease in incontinenceepisode frequency with duloxetine compared with placebo(50% vs 27%, P, 0.001), with comparably significant improve-ments in QoL (11.0 vs 6.8, P, 0.001). Duloxetine has been ap-proved for the treatment of SUI in Europe, although the FDA

TABLE 14. Drugs Used for SUI Treatment (Modified)*

Drug LoE GoR

Duloxetine 1 BMidodrine 2 CClenbuterol 3 CEstrogen 2 DMethoxantine 2 DImipramine 3 DEphedrine 3 DNorephedrine (phenylpropanolamine) 3 D

*From Thuroff et al5 and Andersson et al.7

GoR indicates grade of recommendation; LoE, level of evidence.

TABLE 15A. Duloxetine Costs Overview

Drug Name Active Ingredient DosePrice for 30 dof Treatment

Cymbalta CapOral 20 mg

Duloxetine 40 mg b.i.d. ,$218.55

Cymbalta CapOral 40 mg


Duloxetine20 mg


Duloxetine40 mg


TABLE 15B. Efficacy and Safety of Duloxetine*

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 withduloxetine, respectively. This shows that there was a statisticallysignificant 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 notresponding 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 withduloxetine.

There was a decrease of 30% in first month, around 40% to 45% at theend of second month and over 50% decrease in IEF in third month.

*Adapted from Deepak et al.92

TABLE 15C. Prevalence of AEs of Duloxetine Compared WithPlacebo (Modified)*

AE RA, % RC, %

& Nausea 25.1 3.9& Headache 14.5 8.7& Insomnia 13.7 2.6& Constipation 12.8 1.7& Dry mouth 12.3 1.7& Dizziness 11 2.6& Fatigue 10.1 3.5& Somnolence 8.4 0& Anorexia 6.6 0& Vomiting 6.2 1.7& Increased sweating 5.7 0.9& Discontinuation of AEs 91

*Adapted from Millard et al.93




has not approved it for this purpose. Liver toxicity and suicidalevents represent a great concern. However, an observation studyfrom Michel et al90 has shown that women with SUI treatedwith duloxetine doses lower than recommended reported a lowincidence of AEs and suicide attempts were not reported.Cymbalta was first used to treat major depressive disorder andgeneralized anxiety disorder. Subsequently, FDA approvedCymbalta to treat chronic musculoskeletal pain, including dis-comfort from osteoarthritis, chronic lower back pain, and fi-bromyalgia, but failed the US approval for SUI amid concernsover liver toxicity and suicidal events, whereas it was approvedfor this indication in Europe, where it is recommended as anadd-on medication instead of surgery. The efficacy and safetyof duloxetine (20, 40, and 80 mg; Table 15b) for treatment ofSUI has been evaluated in a study by Norton et al,91 that in-volved 48 centers in the United States, including 553 womenwith SUI, and Deepak et al.92 Duloxetine was associated with asignificant dose-dependent decrease in incontinence episodefrequency; 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 placeboand 9%, 12%, and 15% of 20, 40, and 80 mg, respectively.93

Nausea is the most frequently reported AE. There was a sig-nificant decrease in incontinence episode frequency and im-provement in QoL in those women taking duloxetine 40 mg o.d.when compared to placebo.38 Escalating the dose upon initia-tion of the treatment has been shown to reduce the frequency ofAEs.94 From the whole group, 20% of patients cancelled surgeryafter 2 months on duloxetine. The main adverse event was nau-sea, ranging from 23% to 25%. In these 6 trials, the percentage ofwithdrawals due to AEs resulted to be 17% in the druggroup compared to 4% in the placebo arm.7 The most frequentAEs are reported in Table 15c. Dysphoric mood, irritability,agitation, paresthesias, anxiety, confusion, emotional lability,hypomania, and tinnitus are generally self-limiting; some havebeen reported to be severe. In a systematic review performed toassess duloxetine safety and tolerability for SUI, no case ofsuicide has been reported.95 An observational study on the samesubject including 3233 women did not report any case of suicideduring the treatment.90

Tricyclic Antidepressants

Imipramine

Imipramine is a tertiary amine of the tricyclic antidepressantgroup; its mechanism of action is norepinephrine and serotoninreuptake inhibition and it is thought to improve contraction ofthe urethral smooth muscle (Table 16a).2 This drug is derivedfrom chlorpromazine, so it has the same blocking effects onmuscarinic (M1), adrenergic, and histaminergic receptors, that

cause the relative AEs. Several researchers have found a sig-nificant effect in the treatment of patients with DO96 althoughothers report little effect.97 It may be used to treat SUI ormixed incontinence. In the light of this evidence and the se-rious AEs associated with tricyclic antidepressants, their rolein DO remains of uncertain benefit, although they are oftenuseful in patients complaining of nocturia or bladder pain.38 Ithas been known for a long time that imipramine can havefavorable effects in the treatment of nocturnal enuresis inchildren, with a success rate of 10% to 70% in controlledtrials.98,99 Adverse effects are shown in Table 16b.

>-Adrenergic Agonists

Several drugs with agonistic effects on >-ARs have beenused in the treatment of SUI. However, ephedrine and nor-ephedrine (phenylpropanolamine) seem to have been the mostwidely used.100 There was weak evidence to suggest that useof an adrenergic agonist was better than placebo treatment.7

The limited evidence suggested that such drugs were betterthan placebo in reducing the number of pad changes and in-continence episodes, and in improving subjective symptoms.Phenylpropanolamine, clonidine (Catapres), ephedrine, andpseudoephedrine belong to this category. >-Adrenergic ago-nists are not selective for bladder receptors: they are notrecommended in people with glaucoma, diabetes, hyperthy-roidism, 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 agonistwhich is capable to bind A-adrenergic receptors and enhancesrelease of NE by presynaptic neurons.33 This drug can be ef-fective in patients with mid-SUI, but it is no longer dispensed inthe United States because of the AEs reported later. Phenyl-propanolamine is approved in Finland for the treatment ofSUI.101 Adverse effects are as follows: cardiac arrhythmias,hypertension, insomnia, headache, tremor, anxiety, and stroke(in women taking appetite suppressants).

A-AR AntagonistsA-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 16A. Imipramine Costs Overview

Drug NameActive

Ingredient DosePrice forPackage

Tofranil CAP25 mg

Imipraminepamoate

25Y75 mg q.h.s.or b.i.d.

,$17 (for 25 mgq.h.s.)

Tofranil CAP50 mg

Imipraminepamoate


$25.50 (for 50mg q.h.s.)

Tofranil CAP75 mg

Imipraminepamoate


$36.50 (for 75mg q.h.s.)

q.h.s. indicates every day at hours of sleep.

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 supportthis action is present in literature.

A-AR AgonistsA-Adrenoceptor stimulation is generally conceded to de-

crease urethral pressure,104 but A2-AR agonists have been re-ported to have a different action on fast- and slow-contractingskeletal muscle contractility.105 Clenbuterol, a selective A2-ARagonist, is approved for the treatment of SUI in Japan.106

PHARMACOTHERAPY OFMIXED INCONTINENCE

The optimum treatment of mixed urinary incontinence(MUI) may often require multiple treatment modalities. Oneshould treat most bothersome symptoms first.5 Behavioral ther-apy and lifestyle modification, such as moderate weight loss andcaffeine reduction, should be considered first-line options for allwomen with MUI. Pharmacological treatment of the urge com-ponent with antimuscarinics is effective. The addition of pelvicfloor muscle therapy may have an additional benefic effect. Oftena surgical procedure for the incontinence stress component sig-nificantly improves both symptoms. Anti-incontinence surgerymay have a positive impact on both the stress and the urge com-ponents of MUI; however, it seems that women with MUI mayhave lower cure rates compared to women with pure SUI.

If the initial pharmacological approach fails, consider theuse of botulinum toxin or neuromodulation.

HORMONAL TREATMENT OF UI

DesmopressinDesmopressin (Table 17) is a synthetic analog of vasopressin

(antidiuretic hormone). Desmopressin (DDVAP) was found to bewell tolerated and resulted in a significant improvement com-pared to placebo in reducing nocturnal voids/UI and increasingthe hours of undisturbed sleep.5 Studies are in progress to testif desmopressin improves nocturnal enuresis in patients afterradical cystectomy with bladder reconstruction, and the impacton sleep and daytime functioning. The drug is available in arange of formulations: intranasal solution (spray), injectablesolution, tablets and, most recently, an oral lyophilisate. Intra-nasal and oral formulations are generally well tolerated, andAEs 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 mostfeared AEs (although rare) is hyponatremia. However, precau-tions in prescribing desmopressin for this condition and com-pliance monitoring will help prevent this complication. Adverseeffects are as follows: dizziness, headache, mood change,

vomiting, weakness, loss of appetite, feeling restless or irri-table, confusion, and hallucinations.

EstrogensBladder, 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, aloneor combined with a progesterone, has poor results in terms ofcontinence. In the women health initiative study, HRT wasfound to increase the incidence of all types of UI at 1 year inthose women continent at baseline. The most recent meta-analysis on the effects of estrogen therapy on the lower uri-nary tract showed that overall systemic administration resultedin worse incontinence than that of placebo.107 The use of localestrogen therapy may improve incontinence (RR, 0.74; 95% CI,0.64Y0.86), reducing frequency and urgency.107 The subjectiveimprovement in symptoms may simply represent local estro-genic effects reversing urogenital atrophy rather than a directeffect on bladder function. Reliable data are too scant to suggestthe dose, type of estrogens, and route of administration.

PRACTICAL SUGGESTIONSConclusively, considering the similar pharmacological profile

of the different drugs used for the UUI treatment, we suggeststarting with instant release form of antimuscarinic drugs. Dari-fenacin, solifenacin and tolterodine seem to offer a good bioavail-ability and efficacy with acceptable AEs. Assessment of efficacyand AEs of the treatment within 30 days from the beginning of thetherapy is mandatory. Specific caution must be taken when usinginstant release oxybutynin in patient with cognitive dysfunction.Consider use of transdermal oxybutynin in those patients ex-periencing dry mouth. Regarding the use of duloxetine for SUI, theFDA has not given approval for this purpose. However, use ofduloxetine in the daily practicewith doses lower then recommendedhas shown a low incidence of AEs with a significant decrease inincontinence episode frequency and improvement in QoL.

SUGGESTIONS FOR FURTHER RESEARCHThe following classes of drugs need to be investigated to

find out if they could be helpful in the treatment of any form ofincontinence:

- 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

REFERENCES

1. Rortveit G, Hunskaar S. Urinary incontinence and age at the first andlast delivery: the Norwegian HUNT/EPINCONT study. Am J ObstetGynecol 2006;195(2):433Y438.

TABLE 17. Desmopressin Costs Overview

Drug NameActive

Ingredient DosePrice for 30 dof Treatment

DDAVP60 mcg melt

Desmopressinacetate

20Y60 mcgq.h.s.

,$72.98(for 60 mcg)

Minirin 0.2 mg Desmopressinacetate

0.2Y0.6 mgq.h.s.

,$149(for 0.2 mg)

Desmopressin0.2 mg

Desmopressinacetate

0.2Y0.6 mgq.h.s.

,$123.28(for 0.6 mcg)

Desmopressin60 mcg

Desmopressinacetate

20Y60 mcgq.h.s.

,$80(for 60 mcg)

TABLE 18. Vagifem Costs Overview

DrugName



Vagifem10 mcg

17A-estradiol 1 tablet q.d. for 2 wk,followed by 1 tablettwice weekly

,$70.49

Vagifem25 mcg

17A-estradiol 1 tablet q.d. for 2 wk,followed by 1 tablettwice weekly

,$40.79




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