Painful Bladder Syndrome/Interstitial Cystitis: First Line Treatment Joon Chul Kim The Catholic University of Korea

Natural history of PBS/IC is very poorly described Whether to - institute to therapy - consider a course of “watchful waiting” : If the patients’ symptom are tolerable, and do not significantly impact QoL, a policy of withhoding treatment is reasonable

Patient education is an important initial step First line treatment of PBS/IC - Conservative therapy - Drug therapy Oral therapy Intravesical therapy Milsom I, Abrams P, Cardozo L, Roberts RG, Thüroff J, Wein AJ. How widespread are the symptoms of an overactive bladder and how are they managed? A population-based prevalence study. BJU Int. 2001;87:760-766. Stewart WF, Van Rooyen JB, Cundiff GW, et al. Prevalence and burden of overactive bladder in the United States. World J Urol. 2003;20:327-336. Homma Y, Yamaguchi O, Hayashi K, et al. Nation-wide epidemiologic survey on lower urinary tract symptoms in Japan. Presented at: Annual Meeting of the International Continence Society; October 5-9, 2003; Florence, Italy.

Conservative therapy Behavioral modification Physical therapy Stress reduction Dietary manipulation

Behavioral modification Voiding diary, bladder training, controlled fluid intake, pelvic floor muscle training May have modest benefit for some IC patients

Stress reduction Stress reduction, exercise, warm tub baths, and maintain a normal lifestyle contribute to overall QoL Higher levels of stress were related to greater pain and urgency Stress may impact adversely on symptoms There is no conclusive literature to show it

Dietary manipulation Symptom exacerbation related to the intake of specific foods and beverages Foods high in arylalkylamines Acidic foods

Oral therapy of PBS/IC Sodium pentosanpolysulfate (PPS) Amitriptyline and the tricyclic antidepressants Hydroxyzine Cimetidine L-arginine Miscellaneous - IPD-1151T, quercetin, antibiotics, methotrexate, montelukast, nifedipine, misoprostol, cyclosporine, analgesics

Intravesical therapy of PBS/IC Dimethyl sulfoxide (DMSO) Hyaluronic acid/sodium hyaluronate Resiniferatoxin (RTX) Botulinum toxin type A (BTX-A) Miscellaneous - Chlorpactin, heparin, PPS, BCG, etc

Proposed pathogenesis Bladder insult Epithelial layer damage Potassium leak Mast cell activation Immunogenic allergic response C-fiber activation More injury Urology 2004;63(3 Suppl 1):85

Drug to correct a defect in the epithelial permeability barrier Bladder insult Epithelial layer damage Pentosan polysulfate Hyaluronic acid Heparin Chondroitin sulfate Potassium leak Immunogenic allergic response Mast cell activation C-fiber activation More injury

Sodium pentosanpolysulfate Only medication approved by FDA 100mg tid Mechanism of PPS - correct GAG layer defect - inhibit histamine release from connective tissue and mucosal mast cells, and possible effect mediated by nonspecific binding of the inflammatory molecule Oral and intravesical

Result of meta-analysis of PPS Efficacy of PPS compared to placebo (n=398) * * * Hwang et al, Urology 1997;50:39

PPS dose-ranging study Randomized, double-blind, dose-ranging study of PPS (n=380) Nickel et al, Urology 2005;65:654

Hyaluronic acid Intravesical instillation of 40mg weekly for 4-6 weeks Approved in Europe and Canada Double blind, placebo-controlled, multicenter clinical studies - no significant efficacy compared to placebo Bioniche Life Science Inc, 2003 Seikagaku Corporation, 2004

Inhibition of mast cell activation Bladder insult Tricyclic antidepressant DMSO Antihistamine Cromolyn Epithelial layer damage Potassium leak Immunogenic allergic response Mast cell activation C-fiber activation More injury

Amitriptyline and the tricyclic antidepressants Has become a staple of oral treatment for IC - One of the most potent TCA in terms of blocking H1- histaminergic receptors - Some central and peripheral anticholinergic actions - Inhibition of reuptake of the released amine neruotransmitters serotonin and noradrenaline Side effects: fatigue, weight-gain, dry mouth  J Urol 1989;141:846

Clinical trials in amitriptyline A prospective, randomized, placebo controlled, double-blind study Characteristic Amitriptyline Placebo p Value Score-sum -8.4±7.2 -3.5±5.4 0.005 Pain intensity -22.8±26.1 1.0±14.8 <0.001 Urgency intensity -43.8±23.5 -0.1±3.2 <0.001 24-hr frequency -4.0±5.1 -0.6±5.8 0.063 Functional bladder vol. 19.0±54.62 -7.7±47.5 0.083 Changes in symptoms from baseline to 4 months Van Ophoven et al, J Urol 2004;172:533

Long-term results of amitriptyline treatment GRA Category Overall NIDDK NonNIDDK Markedly worse 2 1 1 Mod. worse 3 2 1 Slightly worse 11 8 3 No change 18 10 8 Slightly improved 16 9 7 Mod. Improved 17 12 5 Markedly improved 27 17 10 No. responder (%) 60/94 (63.8) 38/59 (64.4) 22/35 (62.8) Self-administered GRA response to amitriptyline Van Ophoven and Hertle, J Urol 2004;172:533

Hydroxyzine H-1 receptor antagonist Response rate - 23% vs. 13% on placebo - None of the results reached statistical significance May have a beneficial effect in a small proportion of IC patients, but larger trials would be necessary Sant et al, J Urol 2003;170:810

Inhibition of C-fiber activaiton Bladder insult DMSO Analgesics RTX Capsaicin L-arginine Epithelial layer damage Potassium leak Immunogenic allergic response Mast cell activation C-fiber activation More injury

Immunologic drug BCG Cyclosporine Immunogenic allergic response Bladder insult BCG Cyclosporine Epithelial layer damage Potassium leak Immunogenic allergic response Mast cell activation C-fiber activation More injury

DMSO and BCG DMSO - basis of intravesical therapy - desensitize nociceptive pathways in the LUT BCG - immunologic and/or anti-inflammatory mechanisms - a large, multicenter, randomized controlled trial by NIDDK: 21% response rate vs. 12% on placebo - no place in the treatment of PBS/IC Mayer et al, J Urol 2005;173:1186

Treatment outcome of DMSO & BCG Max. Functional Capacity Voids/24hrs. Pain Score (VAS) Av. classic Baseline 200 (100-350) 18 (12-28) 6 (2-10) After BCG 174 (60-300) 17 (11-22) 6 (1-10) After DMSO 250 (190-400) 13 (8-16) 2 (1-4) Av. Nonulcer Baseline 298 (200-500) 15 (8-39) 6 (1-8) After BCG 343 (240-550) 11 (8-17) 5 (1-9) After DMSO 344 (200-650) 11 (8-17) 4 (1-7) Treatment outcome of DMSO and BCG Peeker, et al, J Urol 2000;164:1912

Treatment algorithm First-line treatment Inadequate 2nd line treatment

Conclusion Many forms of therapy are available to PBS/IC patients, although not all therapies will be effective in every individual Currently, few randomized, placebo-controlled trials have been performed Often, combining several different approaches is necessary

Conclusion Little is understood about the pathophysiology of PBS/IC Nearly every potential target in PBS/IC is getting research attention, so urologists can look forward to more, and likely more effective, therapies in the not- too-distant future