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Guidelines on Urinary Incontinence A. Schröder, P. Abrams (co-chairman), K-E. Andersson, W. Artibani, C.R. Chapple, M.J. Drake, C. Hampel, A. Neisius, A. Tubaro, J.W. Thüroff (chairman) © European Association of Urology 2010 TABLE OF CONTENTS 1. page Introduction 1.1 References 4 5 2. Epidemiology 2.1 Introduction 2.2 Risk factors in women 2.2.1 Risk factors in pelvic organ prolapse (POP) 2.3 Risk factors in men 2.4 Overactive bladder (OAB) 2.5 Disease progression 2.5.1 Longitudinal studies 2.5.2 Genetic epidemiology 2.5.3 Twin studies 2.5.4 Worldwide estimates of current and future lower urinary tract symptoms (LUTS) including urinary incontinence (UI) and OAB in individuals > 20 yrs 2.5.5 Conclusions 2.6 References 5 5 5 5 5 6 6 6 6 6 6 6 6 3. Pharmacotherapy 3.1 Introduction 3.2 Drugs used in the treatment of OAB/detrusor overactivity (DO) 3.3 Drugs used in the treatment of stress urinary incontinence (SIU) 3.4 Drugs used for the treatment of ‘overflow incontinence’ 3.5 Hormonal treatment of UI 3.5.1 Oestrogen 3.5.2 Other steroid hormones/receptor ligands 3.5.3 Desmopressin 3.6 References 7 7 7 8 9 9 9 10 10 10 4. 11 11 12 12 12 12 13 13 13 13 14 14 14 14 Incontinence in men 4.1 Initial assessment 4.2 Initial treatment 4.2.1 General management 4.2.2 Post-radical prostatectomy (RP) incontinence 4.2.3 Conclusions 4.3 Specialised management 4.3.1 Assessment 4.3.2 Interventions 4.3.3 Sphincter incompetence 4.3.3.1 Detrusor overactivity (DO) 4.3.3.2 Poor bladder emptying 4.3.3.3 Bladder outlet obstruction (BOO) 4.4 Surgical treatment 4.4.1 Incontinence after surgery for benign prostatic obstruction (BPO) or prostate cancer (CaP) 4.4.1.1 Incontinence after surgery for BPO 4.4.1.2 Incontinence after surgery for CaP 4.4.1.3 Definitions of post-RP continence 4.4.1.4 Incontinence risk factors 4.4.1.5 Interventional treatment for post-RP incontinence 4.4.1.6 Age 4.4.1.7 Post-RP incontinence with bladder neck stricture 4.4.2 Incontinence after external beam radiotherapy for CaP 4.4.2.1 Artificial urinary sphincter (AUS) after radiotherapy 4.4.2.2 Conclusion 4.4.2.3 Other treatments for SIU after radiotherapy 4.4.3 Incontinence after other treatment for CaP 4.4.3.1 Brachytherapy 2 15 15 15 15 15 15 16 16 16 16 16 16 16 16 Update march 2009  4.4.3.2 Cryotherapy 4.4.3.3 High-intensity focused ultrasound (HIFU) 4.4.3.4 Recommendation 4.4.4 Treatment of incontinence after neobladder 4.4.5 Urethral and pelvic floor injuries 4.4.5.1 Recommendation 4.4.6 Incontinence in adult epispadias-exstrophy complex 4.4.7 Refractory urge urinary incontinence (UUI) and idiopathic DO 4.4.8 Incontinence and reduced capacity bladder 4.4.9 Urethro-cuteneous fistula and recto-urethral fistula 4.4.10 Management of AUS complications 4.5 References 16 16 16 16 16 17 17 17 17 17 17 17 5. INCONTINENCE IN WOMEN 5.1 Initial Assessment 5.2 Initial treatment of UI in women 5.2.1 Pelvic floor muscle training (PFMT) under special circumstances 5.3 Specialised management of UI in women 5.3.1 Assessment 5.3.2 Treatment 5.4 Surgery for UI in women 5.4.1 Outcome measures 5.5 References 28 28 28 29 31 31 31 32 33 34 6. URINARY INCONTINENCE IN FRAIL / OLDER MEN AND WOMEN 6.1 History and symptom assessment 6.1.1 General principles 6.1.2 Nocturia 6.1.3 Post-void residual (PVR) volume 6.2 Clinical diagnosis 6.3 Initial management 6.3.1 Drug therapy 6.4 Ongoing management and reassessment 6.5 Specialised management 6.5.1 Surgical approaches to UI in the frail / older men and women 6.6 References 42 43 43 43 43 44 44 44 44 44 45 46 7. APPENDIX: 2010 ADDENDUM TO 2009 URINARY INCONTINENCE GUIDELINES 50 8. Abbreviations used in the text 54 Update march 2009 3 1. INTRODUCTION In the first International Consultation on Incontinence in 1998, a structure of ‘Clinical Guidelines for Management of Incontinence’ was developed (1). This included a summary and overview, which were presented in flow sheets (‘algorithms’), with recommendations for ‘Initial Management’ and ‘Specialised Management’ of urinary incontinence (UI) in children, men, women, patients with neuropathic bladder and elderly patients. These algorithms have already been presented in the previous EAU Guidelines on Incontinence and continue to be the skeleton of the guidelines. The algorithms are uniformly constructed to follow from top to bottom a chronological pathway from patient’s history and symptoms assessment, clinical assessment using appropriate studies, and tests so that the condition of the underlying pathophysiology can be defined as a basis for rational treatment decisions. To limit the number of diagnostic pathways in the algorithms, clinical presentations that require a similar complexity of diagnostic evaluation have been grouped together by history and symptoms. Again, for simplification, treatment options have been grouped under a few diagnoses (‘conditions’) and their underlying pathophysiology, for which the terminology as standardised by the International Continence Society (ICS) is used. As a rule, the least invasive treatment option is recommended first, proceeding in a stepwise escalation to a more invasive treatment option, when the former fails. Depth and intensity of diagnostic evaluation and therapeutic interventions are grouped into two levels, ‘Initial Management’ and ‘Specialised Management’. The level of ‘Initial Management’ comprises measures generally needed at the first patient contact with a health professional. Depending on the healthcare system and local or general service restrictions, this first contact maybe with an incontinence nurse, a primary care physician, or a specialist. The primary information about the patient’s condition is established by medical history, physical examination, and applying basic diagnostic tests, which are readily available. If treatment is at all installed at this level of care, it will be mostly of an empirical nature. The level of ‘Specialised Management’ appeals to patients in whom a diagnosis could not be established at the ‘Initial Management’, in whom primary treatment failed, or in whom history and symptoms suggest a more complex or serious condition requiring more elaborate diagnostic evaluation and/or specific treatment options. For instance, at this level urodynamic studies are usually required for establishing a diagnosis on the grounds of pathophysiology, and treatment options at this level include invasive interventions and surgery. The principles of ‘evidence-based medicine’ (EBM) apply for analysis and rating of the relevant papers published in the literature, for which a modified Oxford system has been developed (2,3). This approach applies ‘levels of evidence’ (LE) to the body of analysed literature and, from there, derives ‘grades of recommendation’ (GR) (Tables 1 and 2). This document presents a synthesis of the findings of the 4th International Consultation on Incontinence held in July 2008 (4). References have been included in the text, with a focus on new publications covering the time span 2005 to the present. An exhaustive reference list is available for consultation on line at the society website (http://www.uroweb.org/guidelines/online-guidelines/) and on the CD-rom version. Additionally, an ultra short document is available. Following the complete updating in 2009 of the EAU Guidelines on Urinary Incontinence, the Incontinence Guidelines Writing Panel considered it would be helpful to provide an addendum to the Guidelines on the use of drugs for the treatment of urinary incontinence and the role of weight loss (see Appendix). Table 1: Level of evidence* Level Type of evidence 1a Evidence obtained from meta-analysis of randomised trials 1b Evidence obtained from at least one randomised trial 2a Evidence obtained from one well-designed controlled study without randomisation 2b Evidence obtained from at least one other type of well-designed quasi-experimental study 3  vidence obtained from well-designed non-experimental studies, such as comparative studies, E correlation studies and case reports 4  vidence obtained from expert committee reports or opinions or clinical experience of respected E authorities Modified from Sackett et al. (2,3). 4 Update march 2009 Table 2: Grade of recommendation* Grade Nature of recommendations A  ased on clinical studies of good quality and consistency addressing the specific recommendations B and including at least one randomised trial B Based on well-conducted clinical studies, but without randomised clinical trials C Made despite the absence of directly applicable clinical studies of good quality Modified from Sackett et al. (2,3). 1.1 References 1. Thüroff JW, Abrams P, Artibani W, et al. Clinical guidelines for the management of incontinence. In: Abrams P, Khoury S, Wein A, (eds). Incontinence. Plymouth: Health Publications Ltd, 1999, pp. 933-943. 2. Oxford Centre for Evidence-based Medicine Levels of Evidence (March 2009). Produced by Bob Phillips, Chris Ball, Dave Sackett, Doug Badenoch, Sharon Straus, Brian Haynes, Martin Dawes since November 1998. Updated by Jeremy Howick March 2009. http://www.cebm.net/index.aspx?o=1025 [accessed January 2011]. 3. Abrams P, Khoury S, Grant A. Evidence-based medicine overview of the main steps for developing and grading guideline recommendations. In: Abrams P, Cardozo L, Khoury S, Wein A, (eds). Incontinence. Paris: Health Publications Ltd, 2005, pp. 10-11. 4. Abrams P, Cardozo L, Wein A, et al. 4th International Consultation on Incontinence. Paris, July 5-8, 2008. Publication due in the course of 2009. 2. EPIDEMIOLOGY* 2.1 Introduction There is a large variation in the estimated prevalence of urinary incontinence (UI), even after taking into account differences in definitions, epidemiological methodology, and demographic characteristics. However, recent prospective studies have provided much data on the incidence of UI and the natural history (progression, regression, and resolution) of UI (1-4). Urinary incontinence, or urine loss occurring at least once during the last 12 months, has been estimated as occurring in 5-69% of women and 1-39% of men. In general, UI is twice as common in women as in men. Limited data from twin studies suggest there is a substantial genetic component to UI, especially stress urinary incontinence (SUI) (5,6). 2.2 Risk factors in women Pregnancy and vaginal delivery are significant risk factors, but become less important with age. Contrary to previous popular belief, menopause per se does not appear to be a risk factor for UI and there is conflicting evidence regarding hysterectomy. Diabetes mellitus is a risk factor in most studies. Research also suggests that oral oestrogen substitution and body mass index are important modifiable risk factors for UI. Although mild loss of cognitive function is not a risk factor for UI, it increases the impact of UI. Smoking, diet, depression, urinary tract infections (UTIs), and exercise are not risk factors. 2.2.1 Risk factors in pelvic organ prolapse (POP) Pelvic organ prolapse (POP) has a prevalence of 5-10% based on the finding of a mass bulging in the vagina. Childbirth carries an increased risk for POP later in life, with the risk increasing with the number of children. It is unclear whether Caesarean section (CS) prevents the development of POP though most studies indicate CS carries less risk than vaginal delivery for subsequent pelvic floor morbidity. Several studies suggest hysterectomy and other pelvic surgery increase the risk of POP. Further research is needed. 2.3 Risk factors in men Risk factors for UI in men include increasing age, lower urinary tract symptoms (LUTS), infections, functional and cognitive impairment, neurological disorders, and prostatectomy. *This section of the guidelines is based on the recommendations of the ICI committee chaired by Ian Milsom (Committee 1: Epidemiology). Update march 2009 5 2.4 Overactive bladder (OAB) The prevalence of OAB in adult males varies from 10% to 26% and in adult females from 8% to 42%. It increases with age and often occurs with other LUTS. Several common chronic conditions, such as depression, constipation, neurological conditions, and erectile dysfunction, have been significantly associated with OAB, even after adjusting for important covariates, such as age, gender and country (7). 2.5 Disease progression 2.5.1 Longitudinal studies The literature on incidence and remission of UI is still scarce, particularly among men. However, the annual incidence rates 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 rate after pregnancy. The annual incidence rates of OAB range from 4% to 6%, while annual remission rates of OAB range from 2% to 3%. The annual incidence of prolapse surgery ranges from 0.16% to 0.2%. The estimated life-time cumulative risk for prolapse surgery is estimated to be 7-11%. 2.5.2 Genetic epidemiology The familial transmission of UI is well documented. However, it is often difficult to differentiate between heritability and non-inherited transmission (environmental factors) in the family environment. Ethnic and racial differences for UI and POP are also well documented. 2.5.3 Twin studies It is possible to estimate the relative proportions of phenotypic variance caused by genetic and environmental factors by comparing monozygotic female twins (who have an identical genotype) with dizygotic female twins (who share an average of 50% of their segregating genes). A genetic influence is suggested when monozygotic twins are more concordant for the disease than dizygotic twins. Suggested candidate genes include, for example, a polymorphism of the gene for collagen type I. In contrast, an environmental effect is suggested when monozygotic twins are discordant for the disease. Worldwide estimates of current and future LUTS including UI and OAB in individuals > 20 years old The EPIC study is a population-based study estimating the prevalence of UI, OAB and other LUTS among men and women from five countries using the 2002 ICS definitions. The age- and gender-specific prevalence rates from the EPIC study were used to estimate the current and future worldwide number of individuals with LUTS, OAB and UI (8). This was done by extrapolating prevalence rates to the worldwide population aged 20 years and older (4.2 billion). Males and females from the age of 20 to 80+ years were stratified into five-year age groups (e.g. 20-24 years) to estimate the current and future worldwide number of individuals with LUTS, OAB and UI, and the age- and gender-specific prevalence rates. Projected population estimates for all worldwide regions are based on information from the United States (US) Census Bureau International Database (IDB) (9). 2.5.4 2.5.5 Conclusions As the population ages, the prevalence of LUTS is also expected to increase. LUTS are burdensome to individuals. The projected increase in the number of individuals experiencing LUTS has implications for healthcare resources and overall health burden. The estimated number of individuals with LUTS has been based on a conservative prevalence rate. Thus, the future number of those with LUTS may be much higher. 2.6 References* 1. Offermans MP, Du Moulin MF, Hamers JP, et al. Prevalence of urinary incontinence and associated risk factors in nursing home residents: A systematic review. Neurourol Urodyn 2009;28(4):288-94. http://www.ncbi.nlm.nih.gov/pubmed/19191259 2. Botlero R, Davis SR, Urquhart DM, et al. Age-specific prevalence of, and factors associated with, different types of urinary incontinence in community-dwelling Australian women assessed with a validated questionnaire. Maturitas 2009 Feb 20;62(2):134-9. http://www.ncbi.nlm.nih.gov/pubmed/19181467 6 Update march 2009 3. Wennberg AL, Molander U, Fall M, et al. A Longitudinal Population-based Survey of Urinary Incontinence, Overactive Bladder, and Other Lower Urinary Tract Symptoms in Women. Eur Urol 2009 Apr;55(4):783-91. http://www.ncbi.nlm.nih.gov/pubmed/19157689 4. Long RM, Giri SK, Flood HD. Current concepts in female stress urinary incontinence. Surgeon 2008 Dec;6(6):366-72. http://www.ncbi.nlm.nih.gov/pubmed/19110826 5. Altman D, Forsman M, Falconer C, et al. Genetic influence on stress urinary incontinence and pelvic organ prolapse. Eur Urol 2008 Oct;54(4):918-22. Epub 2007 Dec 17. http://www.ncbi.nlm.nih.gov/pubmed/18155350 6. Rohr G, Kragstrup J, Gaist D, et al. Genetic and environmental influences on urinary incontinence: a Danish population-based twin study of middle-aged and elderly women. Acta Obstet Gynecol Scand 2004 Oct;83(10):978-82. http://www.ncbi.nlm.nih.gov/pubmed/15453898 7. Irwin DE, Milsom I, Reilly K, et al. Overactive bladder is associated with erectile dysfunction and reduced sexual quality of life in men. J Sex Med 2008 Dec;5(12):2904-10. http://www.ncbi.nlm.nih.gov/pubmed/19090944 8. Irwin DE, Milsom I, Hunskaar S, et al. Population-based survey of urinary incontinence, overactive bladder, and other lower urinary tract symptoms in five countries: results of the EPIC study. Eur Urol 2006;50(6):1306-14; discussion 1314-5. Epub 2006 Oct 2. http://www.ncbi.nlm.nih.gov/pubmed/17049716 9. US Census Bureau, International Data Base. http://www.census.gov/ipc/prod/wp02/wp02-1.pdf *An exhaustive reference list is available for consultation on line at the society website (http://www.uroweb.org/ guidelines/online-guidelines/) and on the guidelines CD-rom version. 3. PHARMACOTHERAPY* 3.1 Introduction More than 50 million people in the developed world are affected by UI and many drugs have been used for treatment (Table 3). Although drugs may be efficacious in some patients, side-effects mean they are often discontinued after short periods of time and they are best used as an adjuvant to conservative and surgical therapy (1). 3.2 Drugs used in the treatment of OAB/detrusor overactivity (DO) The clinical relevance of efficacy of antimuscarinic drugs relative to placebo has been widely discussed (2). However, recent large meta-analyses of the most widely used antimuscarinic drugs have clearly shown these drugs provide a significant clinical benefit (3,4). More research is needed to decide the best drugs for first-, second-, or third-line treatment (4). None of the commonly used antimuscarinic drugs (darifenacin, fesoterodine, oxybutynin, propiverine, solifenacin, tolterodine, and trospium) is an ideal first-line treatment for all OAB/DO patients. Optimal treatment should be individualised, considering the patient’s co-morbidities, concomitant medications, and the pharmacological profiles of the different drugs (5). *This section of the guidelines is based on the recommendations of the ICI committee chaired by Karl-Erik Andersson (Committee 8: Drug Treatment). Update march 2009 7 Table 3: Drugs used in the treatment of OAB/DO* Drugs Antimuscarinic drugs • Tolterodine • Trospium • Solifenacin • Darifenacin • Propantheline • Atropine, hyoscyamine Drugs acting on membrane channels • Calcium antagonists • K+-channel openers Drugs with mixed actions • Oxybutynin • Propiverine • Dicyclomine • Flavoxate Antidepressants • Imipramine • Duloxetine Alpha-adrenoreceptor antagonists • Alfuzosin • Doxazosin • Prazosin • Terazosin • Tamsulosin Beta-adrenoreceptor antagonists • Terbutaline (beta-2) • Salbutamol (beta-2) • YM-178 (beta-3) PDE-5 inhibitors (for male LUTS/OAB) • Sildenafil, taladafil, vardenafil COX inhibitors • Indomethacin • Flurbiprofen Toxins • Botulinum toxin (neurogenic), injected into bladder wall • Botulinum toxin (idiopathic), injected into bladder wall • Capsaicin (neurogenic), intravesical • Resiniferatoxin (neurogenic), intravesical Other drugs • Baclofen, intrathecal Hormones • Oestrogen • Desmopressin, for nocturia (nocturnal polyuria), but care should be taken because of the risk of hyponatraemia, especially in the elderly LE GR 1 1 1 1 2 3 A A A A B C 2 2 NR NR 1 1 3 2 A A C NR 3 2 C B 3 3 3 3 3 C C C C C 3 3 2 C C B 2 B 2 2 C C 2 3 2 2 A B C C 3 C 2 1 C A *Assessments have been done according to the Oxford modified system, see Tables 1 and 2. LE = level of evidence; GR = grade or recommendation; NR = no recommendation possible; PDE-5 inhibitor = phosphodiesterase-type 5 inhibitor; COX inhibitor = cyclo-oxygenase inhibitor. 3.3 Drugs used in the treatment of stress urinary incontinence (SUI) Factors that may contribute to urethral closure include: • the tone of urethral smooth and striated muscle; • the passive properties of the urethral lamina propria, particularly its vasculature. 8 Update march 2009 The relative contribution of these factors to intraurethral pressure is still debated. However, evidence shows that a substantial part of urethral tone is mediated through stimulation of alpha-adrenoreceptors in the urethral smooth muscle by released noradrenaline (6,7). A contributory factor to SUI, mainly in elderly women with a lack of oestrogen, may be a deterioration in the mucosal co-adaptation function. Pharmacological treatment of SUI aims to increase the force of intraurethral closure by increasing tone in the urethral smooth and striated muscles. Several drugs may contribute to such an increase (8,9). Their clinical use is limited by low efficacy and/or side-effects (Table 4). Table 4: Drugs used in the treatment of stress urinary incontinence Drug Duloxetine Imipramine Clenbuterol Methoxamine Midodrine Ephedrine Norephedrine (phenylpropanolamine) Oestrogen 3.4 LE GR 1 B 3 NR 3 C 2 NR 2 C 3 NR 3 NR 2 NR Drugs used for the treatment of ‘overflow incontinence’ Incontinence may occur when there are large quantities of residual urine with a markedly distended bladder (chronic urinary retention). The ICS no longer approves of the term, ‘overflow incontinence’ (10). Various medical approaches to overflow incontinence have been suggested (11,12) based upon theoretical reasoning, animal studies (13,14) and reports of drugs associated with poor bladder emptying (15). These include direct or indirect muscarinic receptor agonists and alpha-1-adrenoreceptor antagonists. However, a recent review of controlled clinical studies on direct and indirect parasympathetic agonists in patients with an underactive detrusor found these drugs were not consistently beneficial and may even be harmful (16). In contrast, alpha-1-adrenoreceptor antagonists have been consistently beneficial in patients with acute urinary retention (17). A recent Medline search using the keyword ‘overflow incontinence’ did not find any randomised controlled trials (RCT) for treatment using parasympathomimetic drugs or alpha-1-adrenoreceptor antagonists nor even a case series with a meaningful number of patients. This indicates that medical treatments currently used to treat overflow incontinence are being used on the basis of empirical evidence. Any previous recommendations for the medical treatment of overflow incontinence can be considered as ‘expert opinion’ at best. In addition, it is important to make sure any medical treatment for overflow incontinence is likely to reduce or eliminate residual urine better than the alternatives of catheterisation or surgery. 3.5 Hormonal treatment of UI 3.5.1 Oestrogen Oestrogen deficiency is an aetiological factor in the pathogenesis of several conditions. However, oestrogen treatment, either alone or combined with progestogen, has achieved only poor results in UI. The current evidence (LE: 1) against the treatment of UI with oestrogen is based on studies originally designed to assess oestrogen for preventing cardiovascular events. In fact, the evidence is derived from secondary analyses of these studies using subjective, self-reported symptoms of urinary leakage. Nevertheless, these large RCTs showed a worsening of pre-existing UI (stress and urgency) and an increased new incidence of UI, with either oestrogen monotherapy or oestrogen combined with progestogen. It should be noted, however, that most patients were taking combined equine oestrogen, which may not be representative of all oestrogens taken by all routes of administration. A systematic review of the effects of oestrogen on symptoms suggestive of OAB concluded that oestrogen therapy may be effective in alleviating OAB symptoms and local administration may be the most beneficial route of administration (18). It is possible that urinary urgency, frequency, and urgency incontinence are symptoms of urogenital atrophy in older post-menopausal women (19). There is good evidence that lowdose (local) vaginal oestrogen therapy may reverse the symptoms and cytological changes of urogenital atrophy. However, oestrogens (with or without progestogens) should not be used to treat UI, as there is no evidence to show they have a direct effect on the lower urinary tract. Update march 2009 9 3.5.2 Other steroid hormones/receptor ligands There are no reported clinical trials evaluating the effect of androgens, particularly testosterone, on UI in women. 3.5.3 Desmopressin Desmopressin (DDVAP) was found to be well tolerated and resulted in a significant improvement in UI compared to placebo in reducing nocturnal voids and increasing the hours of undisturbed sleep. Quality of life (QoL) also improved. However, hyponatraemia is one of the main, clinically important, side-effects of DDVAP administration. Hyponatraemia can lead to a range of adverse events from mild headache, anorexia, nausea, and vomiting to loss of consciousness, seizures, and death. The risk of hyponatraemia has been reported in a meta-analysis as about 7.6% (20) and seems to increase with age, cardiac disease, and a high 24-hour urine volume (21). 3.6 References* 1. Andersson K-E, Appell R, Cardozo L, et al. Pharmacological treatment of urinary incontinence, in Abrams P, Khoury S, Wein A (Eds), Incontinence, 3rd International Consultation on Incontinence. Plymouth, Plymbridge Distributors Ltd, UK, Plymouth, 2005, p 811. 2. Herbison P, Hay-Smith J, Ellis G, et al. Effectiveness of anticholinergic drugs compared with placebo in the treatment of overactive bladder: systematic review. Br Med J 2003 Apr 19;326(7394):841-4. http://www.ncbi.nlm.nih.gov/pubmed/12702614 3. Chapple CR, Martinez-Garcia R, Selvaggi L, et al; for the STAR study group. A comparison of the efficacy and tolerability of solifenacin succinate and extended release tolterodine at treating overactive bladder syndrome: results of the STAR trial. Eur Urol 2005 Sep;48(3):464-70. http://www.ncbi.nlm.nih.gov/pubmed/15990220 4. Novara G, Galfano A, Secco S, et al. A systematic review and meta-analysis of randomized controlled trials with antimuscarinic drugs for overactive bladder. Eur Urol 2008 Oct;54(4):740-63. http://www.ncbi.nlm.nih.gov/pubmed/18632201 5. Chapple CR, Van Kerrebroeck PE, Jünemann KP, et al. Comparison of fesoterodine and tolterodine in patients with overactive bladder. BJU Int 2008 Nov;102(9):1128-32. http://www.ncbi.nlm.nih.gov/pubmed/18647298 6. Andersson KE. Pharmacology of lower urinary tract smooth muscles and penile erectile tissues. Pharmacol Rev 1993 Sep;45(3):253-308. http://www.ncbi.nlm.nih.gov/pubmed/8248281 7. Andersson KE, Wein AJ. Pharmacology of the lower urinary tract: basis for current and future treatments of urinary incontinence. Pharmacol Rev 2004 Dec;56(4):581-631. http://www.ncbi.nlm.nih.gov/pubmed/15602011 8. Andersson KE. Current concepts in the treatment of disorders of micturition. Drugs 1988 Apr;35(4): 477-94. http://www.ncbi.nlm.nih.gov/pubmed/3292211 9. Zinner N, Gittelman M, Harris R, et al; Trospium Study Group.Trospium chloride improves overactive bladder symptoms: a multicenter phase III trial. J Urol 2004 Jun;171(6 Pt 1):2311-5, quiz 2435. http://www.ncbi.nlm.nih.gov/pubmed/15126811 10. Abrams P, Cardozo L, Fall M, et al; Standardisation Sub-committee of the International Continence Society. The standardisation of terminology of lower urinary tract function: report from the Standardisation Sub-committee of the International Continence Society. Neurourol Urodyn 2002;21(2):167-78. http://www.ncbi.nlm.nih.gov/pubmed/11857671 11. Chutka DS, Takahashi PY. Urinary incontinence in the elderly. Drug treatment options. Drugs 1998 Oct;56(4):587-95. http://www.ncbi.nlm.nih.gov/pubmed/9806105 12. Hampel C, Gillitzer R, Pahernik S, et al. [Drug therapy of female urinary incontinence] Urologe A 2005 Mar;44(3):244-55. [article in German] http://www.ncbi.nlm.nih.gov/pubmed/15711814 13. Kamo I, Chancellor MB, De Groat WC, et al. Differential effects of activation of peripheral and spinal tachykinin neurokinin(3) receptors on the micturition reflex in rats. J Urol 2005 Aug;174(2):776-81. http://www.ncbi.nlm.nih.gov/pubmed/16006975 14. Gu B, Fraser MO, Thor KB, et al. Induction of bladder sphincter dyssynergia by kappa-2 opioid receptor agonists in the female rat. J Urol 2004 Jan;171(1):472-7. http://www.ncbi.nlm.nih.gov/pubmed/14665958 10 Update march 2009