2. Painful bladder (in women) Professor Douglas Tincello University of Leicester

3. Declaration of Interest Industry related 2012 – Honorarium for Allergan advisory board – Honorarium, registration, accomodation for Ethicon symposium at UKCS – PI on RELAX study (onaBoNT-A) Independent funding All funding managed via University business office Tincello DG Kuwait Feb 16 th -18 th 2013

4. Hypotheses for aetiology? Four major theories – Autoimmune disease – Chronic infection – Neurogenic inflammation – Epithelial permeability None sufficient or totally convincing Tincello DG Kuwait Feb 16 th -18 th 2013

5. ? Mast cell Cytokines Substance P Histamine Complement “Toxins” K+ Bacteria Viruses Antiproliferative factor Tincello DG Kuwait Feb 16 th -18 th 2013

6. Antiproliferative factor APF similar to frizzled 8 protein-related sialoglycopeptide (Keay J Urol 2005;173:909) – G protein coupled receptor protein family – ? Inhibition of proliferation signals Specific receptor identified (CKAP4/p63) – Cytoskeleton associated receptor – (Conrads et al J Biol Chem 2006;281:37836) Tincello DG Kuwait Feb 16 th -18 th 2013

7. Antiproliferative factor Urine of IC patients inhibits urothelial growth – 86% of IC patient vs 12% cystitis vs 8% controls – (Keay et al Urol 1998;52:974) APF produced by urothelium – 19/20 bladder urine vs 1/20 renal pelvis urine – (Keay et al J Urol 1999;162:1487) 95% sensitivity; 94% specificity – (Keay et al Urology 2001;57(6A):9) Irrespective of ethnic origin – (Zhang et al Urology 2003;61:897) Tincello DG Kuwait Feb 16 th -18 th 2013

8. Antiproliferative factor APF inhibits HB-EGF release from urothelium Exogenous HB-EGF blocks inhibition – (Keay et al J Urol 2000;164:2112) Hyrdodistention causes APF ↓ & HB-EGF ↑ – (Keay et al J Urol 2000;163:1440) APF increases permeability of urothelium – (Zhang et al J Urol 2005;174:2382) Urothelial cells from IC patients grow slowly – (Keay et al Urol 2003;61:1278) Gene expression is “non proliferative” – (Keay et al Physiol Genomics 2003;14:107) Tincello DG Kuwait Feb 16 th -18 th 2013

9. Antiproliferative factor HB-EGF APF - “Toxins” K+ Bacteria Viruses ? Tincello DG Kuwait Feb 16 th -18 th 2013

10. Diagnostic criteria… Interstitial cystitis (NIDDK criteria) – Originally for research, but were adopted – Tight, specific limits on functional volumes, cystoscopic findings, symptom severity – Comprehensive exclusion criteria IC/CPPS (Diokno A et al. Int J Urol, 10: S3, 2003) – “Pain” includes: burning, pressure, discomfort – At least 3 months’ duration – May be exacerbated by intercourse – Patient must have frequency and urgency Tincello DG Kuwait Feb 16 th -18 th 2013

11. …continued… European Society for the Study of IC/PBS Consensus statement June 2006 Stop using “interstitial cystitis” “Bladder pain syndrome” – Chronic pain related to bladder – Plus one other symptom – Exclusion of “confusable diseases” – Cystoscopy with hydrodistension and biopsy Tincello DG Kuwait Feb 16 th -18 th 2013

12. Confusable diseases “The diagnosis of a confusable disease does not necessarily exclude a diagnosis of bladder pain syndrome”

13. A word about cystoscopy Cystoscopy is for excluding discrete pathology – IC & sensory urgency have same leucocytes (Al Hadithi, 2002) – Mast cells present in up to 40% of SU patients (Frazer, 1993) – Glomerulations occur in normal bladders (Waxman, 1998) – Symptoms not related to cystoscopic or urodynamic data (Messing, Nigro; ICDB study, 1997) No longer a requirement for making a diagnosis Tincello DG Kuwait Feb 16 th -18 th 2013

14. Patients… Present with bladder pain ± other symptoms Pelvic pain can arise from several sources – common autonomic/visceral pain pathways – may be a common pathway for diverse initial insult Various “pseudonyms” – urethral syndrome, sensory urgency, vulvodynia, myofascial syndrome, endometriosis, “chronic pelvic pain” Management algorithm to screen for causes Tincello DG Kuwait Feb 16 th -18 th 2013

15. How I assess patients... Based upon: – literature Nordling J Eur Urol 2004;45:662 O’Leary MP Urol 1997;49:58 Daha LK J Urol 2003;170:807 – Learning from conferences – clinical experience Tincello DG Kuwait Feb 16 th -18 th 2013

16. Assessment-history Site, radiation and associations of pain Duration, and exacerbations in relation to urinary symptoms (esp bladder filling) Presence, site and duration of dyspareunia post coital ache Frequency and nocturia Haematuria? ? Proven urinary tract infection – including fastidious organisms Tincello DG Kuwait Feb 16 th -18 th 2013

17. Assessment-examination Symphyseal tenderness, sacroiliac tenderness – (pain on abduction of hips or limitation of ROM) Hyperaesthesia in lower abdomen/perineum – (nerve entrapment) Vulval erythema or hyperalgesia on cotton swab test in each quadrant of vestibule Palpate bladder base, pelvic muscles for tenderness (trigger points) reproduction of symptoms Cervical excitation, masses, endometriosis nodules Tincello DG Kuwait Feb 16 th -18 th 2013

18. Assessment-investigation Urine culture (including fastidious/anaerobes) 3 day urinary diary frequency, nocturia daytime voided volumes vs waking void volume Urodynamics – (sometimes) Double fill cystoscopy and hydrodistension – (sometimes) Tincello DG Kuwait Feb 16 th -18 th 2013

22. Treatment Specific treatment for specific conditions – endometriosis – vulvodynia – myofascial syndrome/pelvic muscle trigger points – Sacroiliac or symphyseal joint pain PBS symptoms & normal bladder capacity PBS and reduced bladder capacity Tincello DG Kuwait Feb 16 th -18 th 2013

23. Normal bladder capacity Bladder drill +/- diary to increase functional capacity Retrain sensations Anticholinergics may be of some benefit – modulate sensation of urgency & discomfort? If no improvement… – treat as if reduced capacity Tincello DG Kuwait Feb 16 th -18 th 2013

24. Reduced capacity “interstitial cystitis” or PBS – Quality of published work is poor – Most use NIDDK criteria (most severe patients) – Placebo effect is large – Few RCTs Pain control and patient support Intravesical therapy Oral therapy Recent systematic review (Giannantoni 2012 Eur Urol 61:29-53) Tincello DG Kuwait Feb 16 th -18 th 2013

25. Intravesical therapy Distension under GA for 10 minutes – 55% response rate but transient (Hanno 1991 Semin Urol 9:143; Pontari 1997 Urol 49 (5A):114) DMSO (Six to eight weeks of instillations 1-2/week) – Response rate up to 90%; 40% relapse rate – No RCT data (Parkin 1997 Urol 49 (5A):105; Pontari 1997 Urol 49 (5A):114; Peeker 2000 J Urol 164:1912) Hyaluronic acid – success rate of 30-70% – One randomised trial, no placebo (Kallestrup 2005 Scand J Urol Nephrol 39:143; Reidl 2008 IUGA J 19:717; Cervigni 2012 IUGA J 23: 1187; Yi-Song 2012 IUGA J in press; Lai M-C 2012 Int J Urol in press)

26. Intravesical therapy Botulinum toxin – Mixed data from non –RCTs – 75% improved at 3 months 80% fall in pain, 40% in frequency – 75% relapse by 6 months – RCT data (n=2) confirm efficacy Fall in pain and frequency @ 3/12 Trigone injection shows greater effect – 50% reduction in frequency & noturia (Liu 2007 Urol 10:463; Kuo 2005 Urol Int 75:170; Smith 2004 Urol 64:871; Giannantoni 2008 J Urol 179:1031; 2010 Curr Drug Del 7:1; Kuo 2009 BJU Int 104:657; Pinto 2010 Eur Urol 58; 360)

27. Oral treatments Cimetidine – RCT of 400 mg significant reductions in pain and nocturia (Seshadri 1994 Urol 44:614; Thilagarajah 2001 BJU Int 87:207) Pentosan polysulphate – 3 of 5 RCTs show a difference – 25%+ improvement in 25% vs 13% (Parsons 1987 J Urol 138:513; Mulholland 1990 Urol 35:552; Parsons 1993 J Urol 150:845) Amitriptyline – Success of 65-90% (Hanno 1994 Urol Clin N Amer 21:121; Pranikoff 2001 Urol 51 (5A); 179) – Titration from 25mg nocte to 100mg (van Ophoven 2004 J Urol 172:533)

28. Recent data Systematic review – Giannantoni Eur Urol 2012;61:29-53 – 29 RCTs and 57 non random studies – Standardised mean difference 0.8 = large effect 0.5 = moderate effect – Assessed four outcomes IC symptom index Pain Urgency Frequency

29. IC symptom index

30. Pain

31. Urgency

32. Frequency

33. Conclusions... Cyclosporin A – Effect on 3 of 4 outcomes (? Data) Amitriptyline – Effect on all four outcomes – 25mg – 100mg titrated at night PPS – Limited efficacy – Non-random studies suggest 50% long term effect Giannantoni Eur Urol 2012;61:29-53

34. ...cont’d... BCG – Limited effect – Concerns re use from cancer studies BoNTA – Effective at pain relief – ? Additional effect from trigone injection “The inability to propose definite conclusions from the results coming from most of the proposed treatments...” Giannantoni Eur Urol 2012;61:29-53

35. Pain clinic Oral Rx: cimetidine amitriptyline Oral Rx: cimetidine amitriptyline Intravesical Rx: DMSO BoNT-A Intravesical Rx: DMSO BoNT-A Reduced capacity Cystoscopy & distension Better? Disch’g Y Specific condition identified Treat Specific condition identified Treat Urodynamics ? Bladder drill, alkalinisation Normal capacity Day vols >350 mls Waking vol > 350ml All vols < 350mls N History, exam, MSSU, FV Chart