Overactive bladder: Diagnosis and management

Maturitas 71 (2012) 188–193

Contents lists available at SciVerse ScienceDirect

Maturitas journal homepage: www.elsevier.com/locate/maturitas

Mini review

Overactive bladder: Diagnosis and management Dudley Robinson ∗ , Linda Cardozo Department of Urogynaecology, Kings College Hospital, London, UK

a r t i c l e

i n f o

Article history: Received 3 November 2011 Received in revised form 15 November 2011 Accepted 17 November 2011

Keywords: Overactive bladder Urinary incontinence Antimuscarinics

a b s t r a c t Overactive bladder (OAB) is a clinical syndrome describing the symptom complex of urgency, with or without urgency incontinence and is usually associated with frequency and nocturia. Whilst a number of women may be managed based on a clinical diagnosis alone urodynamic studies may be useful in those women with complex or refractory symptoms. In the first instance all women will benefit from a conservative approach using bladder retraining although a number will require antimuscarinic therapy. For those women with persistent symptoms following medical therapy alternative treatment modalities such as intravesical Botulinum Toxin, neuromodulation or reconstructive surgery may be considered. This review, whilst giving an overview of the syndrome, will focus on a practical clinical approach to managing women with symptoms of overactive bladder (OAB). © 2011 Published by Elsevier Ireland Ltd.

1. Introduction Overactive bladder (OAB) is the term used to describe the symptom complex of urinary urgency, usually accompanied by frequency and nocturia, with or without urgency urinary incontinence, in the absence of urinary tract infection or other obvious pathology [1]. The aim of this review is to provide practical clinical advice regarding the investigation and management of women complaining of lower urinary tract symptoms suggestive of OAB as well as providing an evidence based approach to treatment. 2. Prevalence Epidemiological studies from North America have reported a prevalence of OAB in women of 16.9% and the prevalence increases with age rising to 30.9% in those over the age of 65 years [2]. Further prevalence data from Europe [3] also has shown the overall prevalence in men and women over the age of 40 years to be 16.6%. Frequency was the most commonly reported symptom (85%) whilst 54% complained of urgency and 36% urgency incontinence. More recently a further population based survey of lower urinary tract symptoms in Canada, Germany, Italy, Sweden and the United Kingdom has reported on 19 165 men and women over the age of 18 years [4]. Overall 11.8% were found to complain of symptoms suggestive of OAB and 64.3% reported at least one

∗ Corresponding author. Tel.: +0203 299 9000. E-mail address: [email protected] (D. Robinson). 0378-5122/$ – see front matter © 2011 Published by Elsevier Ireland Ltd. doi:10.1016/j.maturitas.2011.11.016

urinary symptom. Nocturia was the most prevalent lower urinary tract symptom being reported by 48.6% of men and 54.5% of women. 3. Pathophysiology The symptoms of OAB are due to involuntary contractions of the detrusor muscle during the filling phase of the micturition cycle. These involuntary contractions are termed detrusor overactivity [1] and are mediated by acetylcholine-induced stimulation of bladder muscarinic receptors [5]. However OAB is not synonymous with detrusor overactivity as the former is a symptom based diagnosis whilst the latter is a urodynamic diagnosis. It has been estimated that 64% of patients with OAB have urodynamically proven detrusor overactivity and that 83% of patients with detrusor overactivity have symptoms suggestive of OAB [6]. Hence the terms are not synonymous. 4. Clinical presentation Overactive bladder usually presents with a multiplicity of symptoms. Those most commonly seen are urgency, daytime frequency, nocturia, urgency incontinence, stress incontinence, nocturnal enuresis and often coital incontinence. However it is important to remember that there are numerous other causes of urgency and frequency (Table 1). There are no specific clinical signs in women with overactive bladder but it is always important to look for vulval excoriation, urogenital atrophy, a urinary residual and stress incontinence. Occasionally an underlying neurological lesion such as multiple

D. Robinson, L. Cardozo / Maturitas 71 (2012) 188–193 Table 1 Common causes of frequency and urgency of micturition. Urological Urinary tract infection Detrusor overactivity Small-capacity bladder Interstitial cystitis Chronic urinary retention/chronic urinary residual Bladder mucosal lesion, e.g. papilloma Bladder calculus Urethral syndrome Urethral diverticulum Urethral obstruction Gynaecological Pregnancy Stress incontinence Cystocoele Pelvic mass, e.g. fibroids Previous pelvic surgery Radiation cystitis/fibrosis Postmenopausal urogenital atrophy Sexual Coitus Sexually transmitted disease Contraceptive diaphragm Medical Diuretic therapy Upper motor neurone lesion Impaired renal function Congestive cardiac failure (nocturia) Hypokalaemia Endocrine Diabetes mellitus Diabetes insipidus Hypothyroidism Psychological Excessive drinking Habit Anxiety

sclerosis will be discovered by examining the cranial nerves and S2, 3 and 4 outflow. 5. Investigation Whilst overactive bladder (OAB) is a symptomatic diagnosis all patients require a basic assessment in order to confirm the diagnosis as well as excluding any other underlying cause for lower urinary tract dysfunction. 5.1. Urine culture A midstream specimen of urine should be sent for microscopy, culture and sensitivity in all cases of incontinence. 5.2. Frequency/volume chart All patients should complete a frequency/volume chart in order to evaluate their fluid intake and voiding pattern. As well as the number of voids and incontinence episodes, the mean volume voided over a 24-h period can also be calculated as well as the diurnal and nocturnal volumes. 5.3. Urgency severity scales Urgency is now generally regarded as being the driving symptom of OAB and is known to play an important role in the development of daytime frequency, nocturia and urgency incontinence. Several validated urgency scoring systems have been developed to attempt to measure urgency severity (Table 2) and

189

Table 2 Urgency severity scales. Patient Perception of Intensity of Urgency Score (PPIUS)a Urgency Perception Score (UPS)b Indevus Urgency Severity Scale (IUSS)c a Cartwright R, Panayi D, Cardozo L, Khullar V. Reliability and normal ranges for the Patient’s Perception of Intensity of Urgency Scale in asymptomatic women. BJU Int 2010;105:832–6. b Cardozo L, Coyne KS, Versi E. Validation of the Urgency Perception Scale. BJU Int 2005;95:591–6. c Nixon A, Colman S, Sabounjian L, et al. A validated patient reported measure of urinary urgency severity in overactive bladder for use in clinical trials. J Urol 2005;174:604–7.

Table 3 Disease-specific quality of life questionnaires (Grade A). Urogenital distress inventory (UDI)a Quality of life in persons with urinary incontinence (I-QoL)b King’s Health Questionnaire (KHQ)c Incontinence impact questionnaire (IIQ)d a Shumaker SA, Wyman JF, Uebersax JS, McClish D, Fantl JA. Health related quality of life measures for women with urinary incontinence: the Incontinence Impact Questionnaire and the urogenital distress inventory. Qual Life Res 1994;3:291–306. b Wagner TH, Patrick DL, Bavendam TG, Martin ML, Buesching DP. Quality of life of persons with urinary incontinence: development of a new measure. Urology 1996;47:67–72. c Ref. [8]. d Wyman JF, Harkins SW, Taylor JR, Fantl JA. Psychosocial impact of urinary incontinence in women. Obstet Gynaecol 1987;70:378–81.

these may be used in conjunction with frequency volume charts in clinical practice. 5.4. Quality of life Quality of life (QoL) is assessed by the use of questionnaires completed by the patient alone or as part of the consultation and allows the quantification of morbidity and the evaluation of treatment efficacy as well as being a measure of how lives are affected and coping strategies adopted. Generic questionnaires, such as the Short Form 36 [7], are general measures of QoL and are therefore applicable to a wide range of populations and clinical conditions whilst disease-specific questionnaires, such as the Kings Health Questionnaire (KHQ) [8] are designed to focus on lower urinary tract symptoms (Table 3). 6. Urodynamic investigations Whilst a number of women complaining of symptoms suggestive of OAB may be managed on the basis of simple investigations those women with refractory or complex symptoms may benefit from urodynamic investigations. Urodynamic investigations include uroflowmetry, filling cystometry and pressure/flow voiding studies. 6.1. Uroflowmetry Although voiding difficulties are uncommon in women, a large chronic urinary residual may present with symptoms of urgency and frequency of micturition, so it is important to assess the urine flow rate and to exclude a significant urinary residual. 6.2. Filling cystometry Cystometry is used to describe retrograde filling of the bladder at a constant rate. Pressure transducers in the bladder and rectum measure pressure changes during filling and this allows

190

D. Robinson, L. Cardozo / Maturitas 71 (2012) 188–193

Fig. 1. Cystometrogram trace showing detrusor contractions during filling.

the calculation of the subtracted detrusor pressure. Detrusor overactivity is defined as ‘a urodynamic observation characterised by involuntary detrusor contractions during filling which may be spontaneous or provoked’ and can only be made following urodynamic investigation (Fig. 1). 6.3. Pressure/flow studies Pressure flow voiding studies are useful to determine voiding function. A high voiding pressure with low flow may be associated with outflow obstruction whilst a low pressure void may be associated with detrusor hypocontractility. Voiding dysfunction may be associated with the development of symptoms suggestive of OAB and outflow obstruction is associated with detrusor overactivity [9]. 7. Cystourethroscopy Although endoscopy is not helpful in diagnosing detrusor overactivity it may be used to exclude other causes for the symptoms associated with OAB such as a bladder tumour or calculus. In addition cystourethroscopy should be considered in all women complaining of haematuria, painful bladder syndrome and recurrent incontinence.

also increasing evidence to suggest that weight loss may improve symptoms of urinary incontinence [11].

8.1. Bladder retraining Bladder retraining was first described by Jeffcoate and Francis [12] and both inpatient and outpatient therapy can be effective. Jarvis and Millar [13] have reported a controlled trial of bladder retraining in 60 consecutive incontinent women with idiopathic overactive bladder. Following inpatient treatment, 90% of the bladder drill group were continent and 83.3% remained symptom free after 6 months. In the control group 23.2% were continent and symptom free due to the placebo effect. However, despite the excellent early results up to 40% of patients relapse within 3 years [14]. A meta-analysis has concluded that bladder retraining is more effective than placebo and medical therapy although there is insufficient evidence to support the effectiveness of electrical stimulation and too few studies to evaluate the effect of pelvic floor exercises and biofeedback in women with urinary urge incontinence [15]. Nevertheless the National Institute of Clinical Excellence (NICE) [16] and International Consultation on Incontinence (ICI) [17] recommend that bladder retraining should be considered as first line treatment in all women with OAB.

9. Medical management 8. Conservative management All women with OAB benefit from advice regarding simple measures which they can take to help alleviate their symptoms. Many patients drink too much and they should be told to reduce their fluid intake to between 1 and 1.5 l/day [10] and to avoid tea, coffee and alcohol if these exacerbate their problem. In addition there is

Whilst a conservative approach is justified initially drug therapy remains integral in the management of women with OAB and there are a number of different agents available. Traditionally tolerability, compliance and persistence have limited the usefulness of many of the antimuscarinic agents although with the introduction of newer bladder selective drugs, once daily dosing and differing

D. Robinson, L. Cardozo / Maturitas 71 (2012) 188–193 Table 4 Drugs used in the treatment of overactive bladder. Antimuscarinic drugs

Level of evidence

Grade of recommendation

Darifenacin Fesoterodine Oxybutynin Propiverine Solifenacin Tolterodine Trospium

1 1 1 1 1 1 1

A A A A A A A

Ref. [18].

routes of administration it is possible that persistence with therapy may increase. There are now a number of different licensed antimuscarinic drugs available on the market within the UK. These have all been recently reviewed by the International Consultation on Incontinence [18] (Table 4) and all have Level 1 evidence [19] and a Grade A recommendation [20]. The most recent systematic review and meta-analysis of 83 studies, including 30 699 patients and six different drugs (fesoterodine, oxybutynin, propiverine, solifenacin, tolterodine and trospium), supports the efficacy of antimuscarinic therapy in the management of OAB. Overall there was a significantly higher return to continence favouring active treatment over placebo; the pooled RR across different studies and different drugs being 1.3–3.5 (p < 0.01). Antimuscarinic therapy was also shown to be statistically significantly more effective in reduction of incontinence episodes per day, reduction in number of micturitions per day and reduction of urgency episodes per day [21]. Whilst these data confirm the efficacy of antimuscarinic drugs the evidence comparing drugs with one another is less robust. The available evidence would suggest that extended release oxybutynin and tolterodine have superior efficacy to the immediate release preparations [22]. In addition solifenacin has been shown to be noninferior to [23], and fesoterodine superior to [24,25] tolterodine extended release. Antimuscarinic therapy may be a useful addition to conservative therapy. In a Cochrane review of 13 trials including 1770 patients symptomatic improvement was more common amongst those on antimuscarinic therapy compared to bladder retraining (RR 0.73; 95% CI 0.59–0.90) and combination treatment was also associated with more improvement than bladder training alone (RR 0.55; 95% CI: 0.32–0.93). Similarly there was a trend towards greater improvement with a combination of antimuscarinic therapy with bladder retraining compared to antimuscarinic therapy alone (RR 0.81; 95% CI: 0.61–1.06) although this was not statistically significant [26]. 10. Oestrogens and overactive bladder The most recent meta-analysis of the effect of oestrogen therapy on the lower urinary tract has been performed by the Cochrane group [27] and is notable as the conclusions are considerably different to those drawn from the previous review [28]. Overall 33 trials were identified, including 19 313 incontinent women (1262 involved in trials of local administration) of which 9417 received oestrogen therapy. Systemic administration (of unopposed oral oestrogens – synthetic and conjugated equine oestrogens) resulted in worse incontinence than placebo (RR 1.32; 95% CI: 1.17–1.48). When considering combination therapy there was a similar worsening effect on incontinence when compared to placebo (RR 1.11; 95% CI: 1.04–1.18). There was some evidence suggesting that the use of local oestrogen therapy may improve incontinence (RR 0.74; 95%

191

CI: 0.64–0.86) and overall there were 1–2 fewer voids in 24 h and less frequency and urgency. The authors conclude that local oestrogen therapy for incontinence may be beneficial although there was little evidence of long term effects. The evidence would suggest that systemic hormone replacement using conjugated equine oestrogens may make incontinence worse. In addition they comment that there are too few data to comment reliably on the dose, type of oestrogen and route of administration. More recent evidence would appear to suggest that combination treatment with antimuscarinic agents and vaginal oestrogens may improve efficacy in women with OAB although at present the two studies investigating this have given conflicting results [29,30]. 11. Refractory OAB Whilst the majority of patients with OAB will respond to conservative therapy and drug treatment a minority will continue to complain of distressing lower urinary tract symptoms. Intravesical Botulinum Toxin offers an alternative in those women with intractable detrusor overactivity although the effect is only temporary and there is a significant risk of voiding difficulties [31] although these would appear to dose related [32]. Whilst there are little long term data regarding the efficacy and complications associated with repeat injections the current evidence would suggest that repeat procedures are safe and remain effective [33]. Neuromodulation may also be used in women with refractory symptoms. Peripheral neuromodulation using the posterior tibial nerve has been shown to be effective [34] and would appear to offer a similar improvement in QoL as antimuscarinic agents [35]. In addition sacral neuromodulation has been shown to be effective although is expensive, more invasive and may be associated with high revision rates [36]. More recently a cutaneous sacral neuromodulation system has been developed which may offer a less invasive approach [37]. Ultimately a small number of women who have failed to respond to medical therapy may benefit from reconstructive surgery and may be considered for a ileal diversion, clam cystoplasty or detrusor myectomy. However, reconstructive surgery is associated with high morbidity and long term complications and really should only be considered when all other treatment modalities have failed. 12. Conclusions Overactive bladder is a common and distressing condition which is known to have a significant effect on QoL. The clinical diagnosis of OAB is often one of exclusion although urodynamic investigations are helpful in those women with refractory or unusual symptoms. The majority of women will benefit from conservative measures in the first instance although many will eventually require drug therapy. For those with refractory symptoms Botulinum Toxin and neuromodulation now offer effective alternatives to reconstructive surgery. 13. Research agenda Antimuscarinic drugs are currently the most commonly used agents although may be associated with poor compliance and persistence. The emergence of more bladder specific drugs and alternative routes of delivery may help to improve patient acceptance. New drugs are currently under development. Whilst the use of calcium blocking agents [38] and potassium channel opening drugs [39] showed initial promise neither have proved to be useful in the clinical setting [40,41] and at present there are no further trials

192

D. Robinson, L. Cardozo / Maturitas 71 (2012) 188–193

being performed. More recently evidence from phase III studies would suggest that ␤3 agonists may offer an alternative to antimuscarinic therapy [42] and Mirabegron has recently been launched in Japan. In addition there is now considerable evidence to suggest that the sensory pathways also play a role in the development of OAB and neurokinin antagonists remain under investigation [43]. Ultimately perhaps a better understanding of the pathophysiology of OAB syndrome may facilitate the development of new treatment modalities allowing effective treatment of such a common and troublesome condition. 14. Practice points • Overactive bladder is a common condition and the prevalence increases with age. • OAB is known to have a significant impact on QoL. • OAB is a symptomatic diagnosis whilst detrusor overactivity is a urodynamic diagnosis. The terms, although often used interchangeably are not synonymous. • All women require basic assessment to exclude urinary tract infection and voiding dysfunction. Urodynamic investigations may be useful in women with persistent symptoms. • Conservative measures should be used as first line therapy prior to starting antimuscarinic therapy. • Women with refractory OAB may benefit from intravesical Botulinum Toxin or neuromodulation. • Reconstructive surgery should be reserved for those women who have not responded to all other treatment modalities. Contributors DR wrote the paper and LC proofread the paper. Competing interests DR is a consultant for Astellas, Pfizer, Ferring and Gynaecare; lectured for Astellas, Pfizer and Gynaecare; researcher for Astellas, Pfizer and Allergan. LC is a consultant for Astellas, Pfizer, Taevo and Lilly; lectured for Astellas and Pfizer; researcher for Astellas, Pfizer. Provenance and peer review Commissioned and externally peer reviewed. References [1] Haylen BT, de Ridder D, Freeman RM, et al. An International Urogynaecological Association (IUGA)/International Continence Society (ICS) joint report on the terminology for female pelvic floor dysfunction. Int Urogynecol J 2010;21:5–26. [2] Stewart WF, Corey R, Herzog AR, et al. Prevalence of overactive bladder in women: results from the NOBLE program. Int Urogynecol J 2001;12(3):S66. [3] Milsom I, Abrams P, Cardozo L, Roberts RG, Thuroff J, Wein AJ. How widespread are the symptoms of overactive bladder and how are they managed? A population-based prevalence study. BJU Int 2001;87(9):760–6. [4] 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;50:1306–15. [5] Anderson KE. The overactive bladder: pharmacologic basis of drug treatment. Urology 1997;50:74–89. [6] Hashim H, Abrams P. Is the bladder a reliable witness for predicting detrusor overactivity? J Urol 2006;175:191–5. [7] Jenkinson C, Coulter A, Wright L. Short Form 36 (SF-36) health survey questionnaire. Normative data for adults of working age. Br Med J 1993;306:1437–40. [8] Kelleher CJ, Cardozo LD, Khullar V, Salvatore S. A new questionnaire to assess the quality of life of urinary incontinent women. Br J Obstet Gynaecol 1997;104:1374–9. [9] Van Koeveringe GA. Effect of partial urethral obstruction on force development of the guinea pig bladder. Neurourol Urodyn 1993;12:555–6. [10] Swithinbank L, Hashim H, Abrams P. The effect of fluid intake on urinary symptoms in women. J Urol 2005;174(July (1)):187–9.

[11] Subak LL, Wing R, West DS, et al. PRIDE InvestigatorsWeight loss to treat urinary incontinence in overweight and obese women. N Engl J Med 2009;360(5):481–90. [12] Jeffcoate TNA, Francis WJA. Urgency incontinence in the female. Am J Obstet Gynecol 1966;94:604–18. [13] Jarvis GT, Millar DR. Controlled trial of bladder drill for overactive bladder. Br Med J 1980;281:1322–3. [14] Holmes DM, Stone AR, Barry PR, Richards CJ, Stephenson TP. Bladder training – years on. Br J Urol 1983;55:660–4. [15] Berghmans LC, Hendricks HJ, de Bie RA, van Waalwijk van Doorn ES, Bo K, van Kerrebroeck PE. Conservative treatment of urge urinary incontinence in women: a systematic review of randomised clinical trials. Br J Urol Int 2000;85:254–63. [16] NICE Guideline 40. The Management of Urinary Incontinence in Women. Department of Health. www.nice.org.uk; 2006. [17] Hay-Smith J, Berghmans B, Burgio K, et al. Adult conservative management. In: Abrams P, Cardozo L, Khoury S, Wein A, editors. Incontinence. 4th edition Paris, France: Health Publication Ltd.; 2009. p. 1025–120 [Editions 21]. [18] Andersson KE, Chapple CR, Cardozo L, et al. Pharmacological treatment of urinary incontinence. In: Abrams P, Cardozo L, Khoury S, Wein A, editors. Incontinence. 4th edition Paris, France: Health Publication Ltd.; 2009. p. 631–700 [Editions 21]. [19] Hadorn DC, Baker D, Hodges JS, Hicks N. Rating the quality of evidence for clinical practice guidelines. J Clin Epidemiol 1996;49(7):749–54. [20] Harbour R, Miller J. A new system for grading recommendations in evidence based guidelines. BMJ 2001;323:334–6. [21] Chapple CR, Khullar V, Gabriel Z, Muston D, Bitoun CE, Weinstein D. The effects of antimuscarinic treatments in overactive bladder: an update of a systematic review and meta-analysis. Eur Urol 2008;54(3):543–62. [22] Diokno AC, Appell RA, Sand PK, et al. OPERA Stuy Group. Prospective, randomised, double blind study of the efficacy and tolerability of the extendedrelease formulations of oxybutynin and tolterodine for overactive bladder: results of the OPERA trial. Mayo Clin Proc 2003;78(6):687–95. [23] Chapple CR, Martinez-Garcia R, Selvaggi L, et al. 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;48:464–70. [24] Herschorn S, Swift S, Guan Z, et al. Comparison of fesoterodine and tolterodine extended release for the treatment of overactive bladder: a head to head placebo controlled trial. BJU Int 2009;105:58–66. [25] Kaplan SA, Schneider T, Foote JE, Guan Z, Carlsson M, Gong J. Superior efficacy of fesoterodine over tolterodine extended release with rapid onset: a prospective, head-to-head, placebo-controlled trial. BJU Int 2011;107(9):1432–40. [26] Alhasso AA, McKinlay J, Patrick K, Stewart L. Anticholinergic drugs versus non drug active therapies for overactive bladder syndrome in adults. Cochrane Database Syst Rev 2006;(4), doi:10.1002/14651858.CD003193.pub3. Art No: CD003193. [27] Cody JD, Richardson K, Moehrer B, Hextall A, Glazener CMA. Oestrogen therapy for urinary incontinence in post-menopausal women. Cochrane Database Syst Rev 2009;(4), doi:10.1002/14651858.CD001405.pub2. Art. No: CD001405. [28] Moehrer B, Hextall A, Jackson S. Oestrogens for urinary incontinence. Cochrane Database Syst Rev 2003;(2). [29] Tseng LH, Wang AC, Chang YL, Soong YK, Lloyd LK, Ko YJ. Randomized comparison of tolterodine with vaginal estrogen cream versus tolterodine alone for the treatment of postmenopausal women with overactive bladder syndrome. Neurourol Urodyn 2009;28(1):47–51. [30] Serati M, Salvatore S, Uccella S, Cardozo L, Bolis P. Is there a synergistic effect of topical oestrogens when administered with antimuscarinics in the treatment of symptomatic detrusor overactivity? Eur Urol 2009;55(March (3)):713–9 [Epub 2008 June 20]. [31] Popat R, Apostolidis A, Kalsi V, Gonzales G, Fowler CJ, Dasgupta P. A comparison between the response of patients with idiopathic detrusor overactivity and neurogenic detrusor overactivity to the first intradetrusor injection of Botulinum-A toxin. J Urol 2005;174:984–9. [32] Dmochowski R, Chapple C, Nitti V, et al. Efficacy and safety of onabotulinum toxin A for idiopathic overactive bladder: a double-blind, placebo controlled randomised dose ranging trial. J Urol 2010;184:2416–22. [33] Sahai A, Dowson C, Kahn MS, Dasgupta P. Repeated injections of botulinum toxin-A for idiopathic detrusor overactivity. Urology 2010;75:552–8. [34] Vandoninick V, van Balken MR, Finazzi Agro E, et al. Posterior tibial nerve stimulation in the treatment of urge incontinence. Neurourol Urodyn 2003;22:17– 23. [35] Peters KM, Macdiarmid SA, Wooldridge LS, et al. Randomised trial of percutaneous tibial nerve stimulation versus extended release tolterodine: results from the overactive bladder innovative therapy trial. J Urol 2009;182:1055–61. [36] van Kerrebroeck PE, van Voskuilen AC, Heesakkers JP, et al. Results of sacral neuromodulation therapy for urinary voiding dysfunction: outcomes of a prospective, worldwide clinical study. J Urol 2007;178(November (5)):2029–34. [37] Monga A, Dmochowski R, Miller D. Evaluation of a novel, non invasive, patientmanaged neuromodulation system (PMNS) on urgency urinary incontinence and patient reported outcomes in subjects with overactive bladder syndrome who had previously failed therapy: a four week, multicentre, prospective randomised trial. Neurourol Urodyn 2011;30:936–8. [38] Levin RM, Kitada S, Hayes L, et al. Experimental hyperreflexia: effect of intravesical administration of various agents. Pharmacology 1991;42:54.

D. Robinson, L. Cardozo / Maturitas 71 (2012) 188–193 [39] Andersson KE. The overactive bladder: pharmacologic basis of drug treatment. Urology 1997;50:74. [40] Laval KU, Lutzeyer W. Spontaneous phasic activity of the detrusor: a cause of uninhibited contractions in unstable bladder. Urol Int 1980;35:182–7. [41] Chapple C, Patroneva A, Raines S. Effect of an ATP-sensitive potassium channel opener in subjects with overactive bladder: a randomized double-blind placebo controlled study (ZD0947IL/0004). Eur Urol 2006:879–86.

193

[42] Chapple CR, Yamaguchi O, Ridder A. Clinical proof of concept study (Blossom) shows novel ␤3 adrenoceptor agonist YM178 is effective and well tolerated in the treatment of symptoms of overactive bladder. Eur Urol Suppl 2008;7: 239. [43] Green SA, Alon A, Ianus J, Mc Naughton, Tozzi CA, Reiss TF. Efficacy and safety of a neurokinin-1 receptor antagonist in postmenopausal women with overactive bladder with urge urinary incontinence. J Urol 2006;176:2535–40.