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

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

Foods high in arylalkylamines

Acidic foods

• Symptom exacerbation related to the intake of specific

foods and beverages

Dietary manipulation

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 activationImmunogenic

allergic responseC-fiber activation

More injuryUrology 2004;63(3 Suppl 1):85

Drug to correct a defect in the epithelial permeability barrier

Bladder insult

Epithelial layer damage

Potassium leak

Mast cell activationImmunogenicallergic response

C-fiber activation

More injury

Pentosan polysulfateHyaluronic acid

HeparinChondroitin sulfate

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

Hwang et al, Urology 1997;50:39

0

10

20

30

40

50

60

Pain Urgency Frequency Nocturia

% I

mpr

oved

Placebo

PPS

Result of meta-analysis of PPS

*

*

*

Efficacy of PPS compared to placebo (n=398)

PPS dose-ranging study

Nickel et al, Urology 2005;65:654

0

10

20

30

40

50

60

4 8 12 16 24 32

week

% o

f p

atie

nts

imp

rove

d

300 mg/d

600 mg/d

900 mg/d

Randomized, double-blind, dose-ranging study of PPS (n=380)

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

Bladder insult

Epithelial layer damage

Potassium leak

Mast cell activationImmunogenic

allergic responseC-fiber activation

More injury

Tricyclic antidepressantDMSO

AntihistamineCromolyn

Inhibition of mast cell activation

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

Self-administered GRA response to amitriptyline

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)

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

Bladder insult

Epithelial layer damage

Potassium leak

Mast cell activationImmunogenic

allergic responseC-fiber activation

More injury

DMSOAnalgesics

RTXCapsaicinL-arginine

Inhibition of C-fiber activaiton

Bladder insult

Epithelial layer damage

Potassium leak

Mast cell activationImmunogenic

allergic responseC-fiber activation

More injury

BCGCyclosporine

Immunologic drug

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/ICMayer 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

2nd line treatment

First-linetreatment

Inadequate

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