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

2. 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

3. 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:
Stewart WF, Van Rooyen JB, Cundiff GW, et al. Prevalence and burden of overactive bladder in the United States. World J Urol. 2003;20:
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.

4. Conservative therapy Behavioral modification Physical therapy
Stress reduction
Dietary manipulation

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

6. 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

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

8. 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

9. 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

10. 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

11. 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

12. 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

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

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

15. 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

16. 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

17. 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

18. Clinical trials in amitriptyline
A prospective, randomized, placebo controlled,
double-blind study
Characteristic Amitriptyline Placebo p Value
Score-sum ± ±
Pain intensity ± ± <0.001
Urgency intensity ± ± <0.001
24-hr frequency ± ±
Functional bladder vol ± ±
Changes in symptoms from baseline to 4 months
Van Ophoven et al, J Urol 2004;172:533

19. Long-term results of amitriptyline treatment
GRA Category Overall NIDDK NonNIDDK
Markedly worse
Mod. worse
Slightly worse
No change
Slightly improved
Mod. Improved
Markedly improved
No. responder (%) /94 (63.8) /59 (64.4) /35 (62.8)
Self-administered GRA response to amitriptyline
Van Ophoven and Hertle, J Urol 2004;172:533

20. 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

21. 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

22. 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

23. 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

24. Treatment outcome of DMSO & BCG
Max. Functional Capacity Voids/24hrs Pain Score (VAS)
Av. classic
Baseline ( ) (12-28) (2-10)
After BCG (60-300) (11-22) (1-10)
After DMSO ( ) (8-16) (1-4)
Av. Nonulcer
Baseline ( ) (8-39) (1-8)
After BCG ( ) (8-17) (1-9)
After DMSO ( ) (8-17) (1-7)
Treatment outcome of DMSO and BCG
Peeker, et al, J Urol 2000;164:1912

25. Treatment algorithm
First-line
treatment
Inadequate
2nd line treatment

26. 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

27. 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