PROF. Rosita Aniuliene LITHUANIAN UNIVERSITY OF HEALTH SCIENCES President of Lithuanian Association of Urogynecology

Lithuanian Statistics, 2009 Population3,5 million GDP per capita in USD17,7 Total expenditures on health as % of GDP 5,9 Literacy99,6% Birth rate per 1,000 pop.9,11 Mortality per 1,000 pop.11,18 Natural increase per 1000 pop.- 2,6 Life expectancy (years)74,9 (male-70, female-80) Total fertility rate1,231,23

Perinatal mortality

Infant Mortality 4,9/1000 live births 2008

Maternal mortality in Lithuania in ( live births)

Maternal Mortality in Lithuania and the world "Maternal health around the world" poster. World Health Organization and World Bank, 1997.

Overactive bladder syndrome Symptom complex, not a urodynamic diagnosis (ICS) “Urgency with or without urge incontinence, ussually with frequency and nocturia” (Abrams et al )

Detrusor overactivity “A urodynamic observation characterised by involuntary detrusor contractions during the filling phase which may be spontaneous or provoked” (Abrams et al., 2002)

Diagnostic History-taking and physical examination Assessment of pelvic floor muscles Assessment of prolapse Urine testing A urine dipstick test should be undertaken in all women presenting with Ul to detect the presence of blood, glucose, protein, leucocytes and nitrites in the urine.

Diagnostic Assessment of residual urine Symptom scoring and quality-of-life assessment Bladder diaries Women should be encouraged to complete a minimum of 3 days of the diary covering variations in their usual activities, such as both working and leisure days.

Diagnostic Pad testing Pad tests are not recommended in the routine assessment of women with Ul. Urodynamic testing The use of multi-channel cystometry, ambulatory urodynamics or video urodynamics is not recommended before starting conservative treatment. Imaging Imaging (magnetic resonance imaging, computed tomography, X-ray) is not recommended for the routine assessment of women with Ul. Ultrasound is not recommended other than for the assessment of residual urine volume.

Non-invasive treatment for OAB Lifestyle modification Behavioural intervention Electrical stimulation Acupuncture Hypnotherapy Drugs

Life style intervention (fluid intake, caffeine, tea, coke, water reduction) Significant reduction in urination frequency and nocturia with 25% reduction in fluid intake, increasing fluid intake worsened frequency (Haskim et al., 2008) High caffeine intake is an independent risk factor for detrusor overactivity. The relationship may be dose dependent (Myers et al., 2008) Tea drinking (but not coffee) epidemiologically associated with all forms of incontinence (Hannested et al., 2003) Diet Coke and caffeine – free diet coke cause greater urination and frequency than carbonated water or classic coke (Cartwright, ICS 2007) Weigt loss decreases incontinence in moderately and morbidly obese women (4 th ICI 20008, Level 1)

Pelvic floor muscle training Bladder training 4 th ICI 2008 (ICI 0 imperial chemical industry) PFMT is better than no treatment, placebo drug or inactive control treatment for women with SUI, urge or mixed urinary incontinence (LEVEL 1) Supervise PFMT should be offered as a first line therapy in all patients with SUI, urge or mixed urinary incontinence (GRADE A) Not clear whether body training is more effective than drug therapy for women with detrusor overactivity or urge urinary incontinence (LEVEL 1) In a choice between body training and anticholinergic drug for women with detrusor overactivity or urge urinary incontinence, either may be effective (GRADE B)

Behavioral intervention Improves central control Underlying psychological abnormality Learn/re-learn both consious and unconscious physiological proccesses Avoids side effects of drugs

Pharmacological treatment of OAB Antimuscarinics Drugs with mixed action Antidepresants Alpha – adrenoreceptor antagonists Beta – adrenoreceptor agonists Drugs acting on membrane channels Toxins Future drugs

Pharmacological treatment of OAB Antimuscarinic agents After lifestyle changes antimuscarinic agents are the most common and currently the most widely used therapy for OAB syndrome (Anderson, 2004) Antimuscarinics Reduce intra-vesical pressure Increase compliance Raise volume thershold for micturition Reduce uninhibited contractions (Abrams et al., 2002)

OAB: antimuscarinics Oxybutinin (oral, transdermal, intra-vesical, gel) Ditropan 2,5–5 mg x3/day per os Kentera-wk 3,9 mg x 2/wk transdermal patch Lyrinel XL 5-20 mg per day intra-vesical Oxybutinin in water 10 mg transdermal gel Tolterodine (oral) Detrusitol 2 mg x 2/day per os Detrusitol XL 4 mg x 1/day per os Propiverine (oral) Detrunorm 15 mg

OAB: antimuscarinics Solifenacin (oral) Vesicare 5-10 mg per os Trospium (oral) Regurin mg per os Darifenacin (oral) Emselex, Enablex 7,5-15 mg per os Fesoterodine (oral) Toviaz 4-8 mg per os

Antimuscarinic side effects Dry mouth Constipation Blurred vision Somnolence Can drug treatment be improved?

What is desirable in a drug? Specificity of action Maximisation of efficacy-dose relationship Reduction of adverse side effects Enhancement of patient compliance Controlled administration of a therapeutic dose at a desirable rate of delivery Maintenance of drug concentration within optimal therapeutic range

How do we improve compliance and persistence? Extended release formulations OxybutyninLyrinel XL TolterodineDetrusitol XL PropiverineDetrunorm XL Trospium Regurin XL Selective M3 antagonists Solifenacin Vesicare Darifenacin Emselex Bladder selective agents Fesoterodine Toviaz Alternative delivery mechanisms Oxybutynin patch Kentera Oxybutinin gelGelnique

Extended release formulations OPERA TRIAL OAB: Performance of extended release agents Oxybutynin ER (10 mg/day) vs. Tolterodine ER (4 mg/day) Improvement in urge incontinence similar in both groups Oxybutynin more effective in reducing frequency No episodes of urinary incontinence (dry): Oxybutynin ER:23% vs. Tolterodine ER:16,8% Dry mouth was more common with Oxybutynin ER, but tolerability was otherwise comparable Diokno et al., 2003

STAR study – efficacy summary Solifenacin equivalent to Tolterodine ER Micturition frequency (p=0,0681) Nocturia (p=0,7298) Solifenacin superior to Tolterodine ER Urgery episodes (p=0,0353) Incontinence (p=0,0059) % dry (p=0,0059) Pad use (p=0,0023) Volume voided (p=0,00103) Patient perception of bladder condition (p=0,0061)

Darifenacin Quality of life assessed using KHQ in 2 year open label study 7,5mg/15mg: 303 patients/85 elderly, 41 men 2/3 of Darifenacin continuation groups either satisfied or extremely satisfied with treatment Dwyer et al., 2008 Darifenacin did not impair cognition Kay and Ebinger, 2008

Trospium ER 12 weeks randomised trial 989 women (Trospium = 484, placebo = 505) 60 mg oral per day End point: No of toilet voids, urge urinary incontinence episodes/day Significantly greater mean reductions (p=0,0001) Adverse events: dry mouth (11,4%), constipation (8,9%) Sand et al., 2009

Fesoterodine 12 week post hoc analysis from 2 clinical trials 4/8 mg fesoterodine or tolterodine ER 4 mg or placebo: 1548 women 3 day bladder diary at baseline, 2 weeks and 12 weeks Fesoterodine 8 mg more efficacious than 4 mg and tolterodine ER in improving Urgency urinary incontinence episodes Continent days/week Sand et al., 2009

Oxybutinin Gel: Gelnique 12 week parallel group, double-blind placebo controlled study 789 patients in 76 centers (89,2% women) Randomised to: oxybutynin gel, placebo Significant reduction in: Urge incontinence episodes (-3.0, p<0,0001) Frequency (-2,7, p=0,0017) Significant increase in voided volume (21 ml; p=0,0018) Dry mouth higher with oxybutynin (6,9% vs. 2,8%) No difference in skin site reaction (5,4% vs. 10%) Staskin et al., 2009

Desmopressin Double-blind, placebo controlled Oral Desmopressin 0,2 mg Adults with OAB Increase in the time to first urgency episode compared to placebo Subjective improvement in frequency, urgency, QOL Side effects All mild Headache being the commonest No hyponatraemia was recorded Haskin et al., 2009

LEVEL 1 drugs 4 th ICI, 2008 DrugLevel of evidenceGrade of recommendation Darifenacin1A Oxybutynin1A Propiverine1A Solifenacin1A Fesoterodine1A Tolterodine1A Trospium1A

Which drug – what evidence? DrugAdvantagesDisadvantages Oxybutynin IRFlexible dosing, rapid, onset of action, cheap Persistence limited by dry mouth Oxybutynin ERFlexible dosingCognitive impairment Oxybutynin TDSPlacebo rate of side effects 15-20% rate of pruritus Tolterodine ERWell toleratedSingle dose SolifenacinSuperior efficacy to Tolterodine ER High rate of dry mouth at 10 mg dose DarifenacinLow rate of cognitive impairment High rate of constipation TrospiumDoes not cross blood brain barrier Single dose PropiverineWell toleratedEfficacious only for frequency FesoterodineFlexible dosingLimited experience

OAB: new directions Calcium antagonists Potassium channel openers NK1/NK2 receptor antagonists B3 adrenergic receptor agonist Vitamin D3 receptor analogues Combination therapy Antimuscarinic and alfa antagonist

Detrusor Overactivity: Botulinum Toxin 59 patients with detrusor overactivity Botox (200/300µ) or placebo Single treatment, randomised, placebo controlled study Significant reduction in incontinence episodes Significant improvement in QOL Schurch et al., 2005 Systemic review of 18 papers in detrusor overactivity (normal and idiopathic) 40-80% of patients subjectively dry Karsentry et al., 2008 Multicenter double blind placebo controlled trial Dose dependent efficacy in OAB No benefit in efficacy of doses > 150µ Brubaker et al., 2008

Detrusor overactivity: surgery Augmentation cystoplasty Detrusor myectomy Urinary diversion (to sigma)

NICE guidelines : overactive bladder Caffeine reduction 6 weeks bladder retraining Oxybutynin IR first line Darifenacin, salifenacin, tolterodine, trospium or oxybutynin ER/transdermal second life Topical oestrogens Sacral neuromodulation NICE – National Institute for health and clinical excellence

NICE guidelines: detrusor overactivity Botulinum toxin A should be used in the treatment of idiopathic detrusor overactivity who have not responded to conservative therapy Use not currently licensed in UK for detrusor overactivity Botulinum toxin B is not recommended for idiopathic OAB Sacral nerve stimulation is recommended in women who have not responded to conservative therapy Sacral nerve stimulation should be offered based on the response to preliminary percutaneous nerve evaluation

NICE guidelines: detrusor overactivity Data is currently inadequate to support the use of PTNS (percuatneous tibial nerve stimulation) Augmentation cystoplasty should be restricted to those women who have failed conservative therapy Should be able to self catheterize and should be warned about long-term complications Role of detrusor myectomy not established Urinary diversion should only be considered if sacral nervous stimulation and cystoplasty are not appropriate

Conclusions Conservative therapy is indicated as primary treatment Antimuscarinic agents are most commonly used drugs Limited by tolerability and efficacy Significant effect on compliance and resistance Newer bladder specific agents may offer advantages Possible to individualise treatment for each patient New drugs currently remain under development Neuromodulation and botulinum toxin may be useful in patients with interactable detrusor overactivity Reconstructive surgery should be considered in those women who have failed other treatments Patients can be advised to reduce their fluid input by 25% to help control all OAB symptoms, providing they do not drink <1l/day, remembering that ml of fluids is provided by food

General conclusions Anticholinergics are the gold standard for the treatment of OAB Patient history, examination, urinanalysis, micturation diary is very important Bladder training programs Special treatment needs for transsexuals male-to- female pudendal nerve damage during operation, hormone disorders and aging (prostate problem)

Thank you for attention