Urinary Incontinence

1. Urinary Incontinence Mixed Urge Stress Jan Busby-Whitehead, MD Chief, Division of Geriatric Medicine University of North Carolina

2. Definition of Urinary Incontinence “The involuntary loss of urine which is objectively demonstrable and a social or hygienic problem.” * The International Continence Society

3. URINARY INCONTINENCE University of North Carolina School of Medicine Center for Aging and Health

4. Prevalence • Community: 17% older men, up to 30% older women • Hospital: up to 50% older men and women • LTCF: 50-70% older men and women

5. Prevalence of Incontinence in Women Hunskaar, et.al., IntUrogynecol J, 2000

6. Prevalence of Incontinencein Community-Dwelling Women Hunskaar, et.al., Int Urogynecol J, 2000

7. Reversible causes of UI D - Delirium or Drugs - Restricted mobility - Infection, impaction - Polyuria R I P

8. Drugs Contributing to UI

9. Bladder Anatomy • Hollow, distensible, muscula organ • Reservoir of urine • Capacity ~600 mL • Desire ~200 mL • Normal void ~300 mL • Organ of excretion • Behind symphysis pubis • Female – against anterior wall of uterus • Trigone • Sphincter

10. Physiology

11. Aging Changes • Decreased bladder capacity • Reduced voiding volume • Reduced flow rates • Increased urine production at night • * Nordling, J Experimental Gerontology, 2002, 37:991

12. University of North Carolina School of Medicine Center for Aging and Health

13. Stress UI Abrams P et al. Urology. 2003;61:37-49. The complaint of involuntary leakage with effort or exertion or on sneezing or coughing Sudden increase in abdominal pressure Urethral pressure

14. Involuntary detrusor contractions Urethral pressure Urge UI Abrams P et al. Urology. 2003;61:37-49. Ouslander J. N Engl J Med. 2004;350(8):786-799. • The complaint of involuntary leakage accompanied by or immediately preceded by urgency

15. Overactive bladder • Includes urinary urgency with or without urge incontinence, urinary frequency, and nocturia • Associated with involuntary contractions of the detrusor muscle

16. Sudden increase in abdominal pressure Involuntary detrusor contractions Urethral pressure Mixed UI Abrams P et al. Urology. 2003;61:37-49. Chaliha C et al. Urology. 2004;63:51-57. The complaint of involuntary leakage associated with urgency and also with exertion, effort, sneezing, or coughing

17. Overflow • Urethral blockage • The Bladder is not able • to empty properly Neurogenic/Atonic Obstruction

18. Functional Incontinence • Immobility • Diminished vision • Aphasia • Environment • Psychological

19. Clinical Questions • How do you evaluate for incontinence? • Are behavioral techniques effective? For which patients? • What drug treatments are useful and how do you use them?

20. Office Evaluation of UI • Identify presence of UI • Assess for reversible causes and treat • If UI persistent, determine type and initiate treatment • Identify patient who needs further evaluation and referral

21. Basic Evaluation of UI • History: Bladder diary • Physical examination, especially Genitourinary and Neurological • Bladder stress test • Postvoid residual • Urinalysis, urine culture if indicated • BUN, creatinine, fasting glucose

22. Referral Criteria • Recurrent urinary tract infections • Hematuria • Elevated postvoid residual or other evidence of possible obstruction • Recent gynecological or urological surgery or pelvic radiation • Failed treatment of stress or urge UI

23. Cystometry • Gold standard for diagnosis • New definition for detrusor overactivity: Any rise in detrusor pressure during filling cystometry associated with symptoms and not related to abnormal bladder compliance • Provocative stimuli • Ambulatory monitoring

24. Treatment Options • Behavioral • Pharmacological • Functional Electrical Stimulation • Surgery

25. Are behavioral techniques effective? For whom? • Behavioral techniques are effective for treatment of stress and urge UI, and overactive bladder, but generally do not cure • Behavioral techniques are effective in community dwelling men and women • Behavioral techniques are most appropriate for cognitively intact, motivated persons

26. Behavioral Treatments for UI University of North Carolina School of Medicine Center for Aging and Health

27. Self Management • Fluid Intake • Don’t reduce amount • Do not drink fluids 2 hr before bedtime • Avoid: caffeine, alcohol, nicotine

28. Scheduled Voiding • Scheduled voiding with systematic delay of voiding • Schedule based on time interval pt can manage in daytime • Void at scheduled time even if urge not present; suppress urge if not time with “Quick Kegels” • Increase voiding interval by 30 min each week until continent for up to 4 hr

29. Pelvic Muscle Exercises • Isolation of the pelvic muscles • Avoidance of abdominal, buttock or thigh muscle contractions • Moderate repetitions of strongest contraction possible • Ability to hold contraction 10 seconds, repeat in groups of 10-30 TID

30. Efficacy of Behavioral Treatment PMFE Without Biofeedback PMFE With Biofeedback 100 90 80 70 60 50 40 30 20 10 0 98% 91% 50% 38% Range of Improvement Range of Improvement

31. Randomized Trials of Behavioral Treatment for Stress UI • 24 RCTs, but only 11 of high quality • Pelvic floor exercises were effective (up to 75%)in reducing symptoms of stress UI • Limited evidence for high vs low intensity • Benefits of adding biofeedback unclear * Berghmans et al. Br J Urol 1998:82:181-191

32. Behavioral Treatment for Urge/OAB • Bladder training • Initial approach • 3 RCT: 47-90% cure rate with 6 mo f/u • Recurrence in 43-58% after 2-3 yr • 35% fewer UI episodes vs controls: Cochrane Review 2004

33. Limitations of Behavioral Treatment Studies • Studies varied in • types of UI • characteristics of subjects • intervention strategies • outcome measures used • duration of follow-up • Few studies compared the efficacy of PFME performed with and without biofeedback

34. NIH Treatment Trial Kincade, Dougherty, Busby-Whitehead Purpose: • Compare pelvic floor muscle exercises alone to PFME plus biofeedback in women with stress and mixed urge and stress UI • Design • 315 women randomized to 3 groups, including an attention control group • Followup up at 2 weeks, 6 months, 1 year

35. Drug Treatment for UI: What Works • Stress UI • Alpha adrenergic agents? • Estrogen? • Combination therapy?

36. Alpha Adrenergic Drugs • Phenylpropanoloamine • Once a first line drug • 8 randomized controlled trials • Study duration: 2-6 weeks • % cure: 0-14 • % side effects: 5-33% • WITHDRAWN FROM MARKET due to report of hemorrhagic stroke

37. Duloxetine(Cymbalta) • FDA application for stress UI withdrawn • Warning for liver dysfunction, alcohol

38. Estrogen • Combined study with Phenylpropanolamine suggested improvement in combination • Improves urogenital atrophy • Heart and Estrogen/Progestin Replacement Study 2001: 4 yr, randomized trial, 2763 postmenopausal women <80 given combined HRT or placebo for ischemic heart disease. • 55% had >1 episode UI/week • HRT group had worsening stress and urge UI sx

39. Drug Treatment of Overactive Bladder • Anticholinergic Drugs are mainstay • Oxybutynin IR 2.5-5 mg bid-qid • Ditropan XL 5-20 mg daily • Oxytrol patch TDS 3.9 mg 2x/wk • Tolterodinetartrate IR 1-2 mg bid • Detrol LA 2-4 mg daily New Drugs: • Trospium chloride (Sanctura) 20 mg bid • Darifenicin (Enablex) 7.5-15 mg daily • Solefenicin (Vesicare) 5-10 mg daily

40. Muscarinic Receptors • M1 – Brain (cortex, hippocampus), salivary • glands, sympathetic ganglia • M2 – Heart, hindbrain, smooth muscle (80% of detrusor) • M3 – Smooth muscle (20% of detrusor), salivary glands, brain, eye (lens, iris) • M4 – Brain (forebrain, striatum) • M5 – Brain (substantianigra), eye

41. Hepatic metabolism • Oxybutynin CYP 3A4 • Tolterodine CYP 3A4, CYP 2D6 • Darifenacin CYP 3A4, CYP 2D6 • Solifenacin CYP 3A4 • CYP 3A4: Interactions with macrolides, ketoconazole, nefazadone • CYP 2D6: interactions with TCAs, fluoxetine

42. Behavioral vs Drug Rx for Urge UI in Older Women • Randomized, controlled trial by Burgio et al JAMA 1998; 280; 1995-2000 • 197 women aged 55-92 • 8 weeks of BFB, 8 weeks of oxybutynin • 2.5 to 5 mg qd to tid, or placebo control • All 3 groups reduced UI frequency • Effectiveness: BFB>drug>placebo

43. Burgio et al JAMA 1998; 280:1995-2000 Oxybutyninvs Behavioral Treatment for Urge UI

44. Oxybutynin • Both anticholinergic and smooth muscle relaxant properties • 6/7 RCTs show benefit • 15-58% greater reduction in urge UI than placebo • Dose: 2.5 -5 mg qd-qid, 20 mg/d maximum

45. Oxybutynin Controlled Release • Once daily dosing • RCT showed rate of daytime continence similar to that for immediate release (53 vs 58%) • Lower rate of dry mouth than immediate release form

46. Tolterodinetartrate • Pure muscarinic receptor antagonist • Dry mouth most common side effect • 3 RCT compared tolterodine (2 mg bid) to oxybutynin (5 mg tid): Equally effective and superior to placebo • Decreased urge U(I in study of 293 pts:47% tolterodine, 71% oxybutynin, 19% placebo, dry mouth 86% oxybutynin, 50% tolerodine

47. OBJECT Study Appel et al Mayo Clin Proc 2001:76 • Compared efficacy and tolerability of extended release oxybutynin and tolterodine tartrate • 12 weeks • Prospective randomized,double-blind, parallel group study • 276 women and 56 men • Oxybutynin more effective for weekly urge UI, total incontinence, and urinary frequency

48. Trospium • Dose 20 mg bid • Renal metabolism • Nonselective for muscarinic receptors • Effective for detrusoroveractivity in placebo-controlled double-blind studies: • Trospium 20 mg bid vstolterodine 2 mg bid in 232 pts reduced voiding frequency and number of UI episodes • Dry mouth 7% and 9% respectively

49. Darifenicin • Dose 7.5 to 15 mg daily • Selective M3 receptor antagonist • Several RCTs • Mundy et al 2001 Randomized double-blind trial compared darifenacin 15 mg and 30 mg to oxybutynin 5 mg tid in 25 pts , similar efficacy • Side effects: Dry mouth, constipation(<2%)

50. Solefenacin • Dose 5 to 10 mg daily • Long acting muscarinic receptor antagonist, selective for M3 • Undergoes hepatic metabolism involving cytochrom P450 • Several multinational trials with over 800 pts, vs placebo, showed efficacy low side effects (2% dry mouth)