Treatment Approaches for Interstitial Cystitis: Multimodality Therapy Robert J

CLINICAL MANAGEMENT OF INTERSTITIAL CYSTITIS Treatment Approaches for Interstitial Cystitis: Multimodality Therapy Robert J. Evans, MD Moses Cone Health System, Greensboro, NC Interstitial cystitis is an increasingly common disease characterized by urgency, frequency, and pelvic pain. Its etiology is poorly understood but is likely to be multifactorial. A proposed pathophysiology describing a cascade of events, including epithelial dysfunction, mast cell activation, and neurogenic inflammation, is presented. Using this model, multimodality therapy regimens have been developed that treat all components of this cascade. Multimodality therapy appears more effective than single agents in the treatment of interstitial cystitis. [Rev Urol. 2002;4(suppl 1):S16–S20] © 2002 MedReviews, LLC Key words: Interstitial cystitis • Multimodality therapy • Pentosan polysulfate • Hydroxyzine hydrochloride • Amitriptyline hydrochloride nterstitial cystitis (IC) is a bladder condition that presents with a range of symptoms, including bladder pain, urinary urgency and frequency, and noc- turia. Current estimates of disease prevalence suggest that at least 1 million I 1 people in the United States are affected. The etiology remains uncertain, although a number of potential causal factors have been proposed.2–7 The variation seen in both the range of symptoms and in patients’ responses to therapy suggest that multiple factors are involved in this disease process. There remains the possibility that subgroups of patients may exist with differing etiologies. S16 VOL. 4 SUPPL. 1 2002 REVIEWS IN UROLOGY Multimodality Therapy for IC demonstrated that IC patients suffer Bladder insult from a defective GAG layer that allows urinary metabolites such as potassium to pass through the bladder wall and into the submucosal space.10 More injury Epithelial layer damage Potassium leaking through the uroepithelium causes depolarization of smooth muscles of the bladder and the pelvis, with activation of Mast cell activation and Potassium leak into sensory nerves. The constant irritation histamine release interstitium of the submucosal space by leakage of urinary metabolites through the defective bladder lining causes an Activation of C-fibers and inflammatory reaction marked by the release of substance P proliferation and activation of submucosal mast cells. When activated, Figure 1. A proposed model for the pathogenesis of interstitial cystitis. mast cells release histamine and other mediators, stimulating sensory nerve fibers and eliciting local tissue A large number of therapies are concerning the possible mechanisms damage and vascular constriction. available to treat patients with IC. for the development of IC, but also Mast cell degranulation activates Because of variation in response to the clinical histories commonly seen in capsacin-sensitive nerve fibers, lead- therapy, the clinical approach to this patient population (see Figure 1).8 ing to the release of substance P as treatment has been largely empirical. In this proposed model, the cascade well as other neuropeptides, causing Increased understanding of the etiol- of events that lead to the develop- additional cell damage and further ogy of IC and identification of factors ment of clinical IC begins with the activation of mast cells. Over time, involved in the pathophysiology of development of an injury to the the ongoing effects of both the mast the disease will allow treatment reg- bladder or epithelium. In many cases cell activation and the stimulation of imens to be better targeted toward this may have occurred following an the capsacin fibers are more local tis- each individual patient’s conditions. episode of bacterial cystitis, but in sue damage, ongoing injury to the other patients, pelvic surgery, child- GAG layer, further injury to the blad- A Proposed Model for IC birth, or urologic instrumentation may der smooth muscle, and development Pathogenesis be the initiating event. In normal of fibrotic changes within the bladder. Many theories have been proposed to patients, uroepithelium is expected Over time, if this cascade of events is explain the pathogenesis of IC, but to heal following appropriate therapy, left untreated, the bladder will none have been conclusively proven but in this group of patients healing decrease in size and the functional to be true. Proposed causative factors of the uroepithelium does not occur. bladder capacity will plummet. include epithelial dysfunction,3 mast Recent reports have suggested that The inflammation and activation cell abnormalities,5 subclinical infec- patients with IC have urine that con- of the capsacin fibers can lead to tion,4 neurogenic inflammation,6 vas- tains an anti-proliferative factor that neural up-regulation and the devel- cular abnormalities,7 and autoimmune retards or prevents normal epithelial opment of neural changes within the phenomena.2 With so many possible healing.9 In addition, epithelial growth spinal cord. Once this occurs, patients factors influencing the development factor is decreased in urine of IC will suffer from chronic pelvic pain, of IC, it is likely that there is not a patients. This combination of elevated urgency, and frequency. The “up-reg- single etiology for the disease. It is anti-proliferative factor and dimin- ulation" that occurs in patients with far more likely that the etiology is ished epithelial growth factor seems long-standing IC explains why many multifactorial. A model has been pro- to prevent normal uroepithelial repair. patients continue to have vaginal and posed for the development of IC that Over time, these patients develop pelvic pain even after cystectomy. takes into account not only the abnormalities of the glycosamino- Although it is not clear why this experimental data currently available glycan (GAG) layer. Parsons has cascade of events occurs in this VOL. 4 SUPPL. 1 2002 REVIEWS IN UROLOGY S17 Multimodality Therapy for IC continued most patients. Although the exact may be a reasonable alternative. The Table 1 nature of PPS on the bladder is not addition of H2 blockers to more Principles of Multimodality completely clear, it is felt to function standard antihistamine therapy has Therapy for Intersitial Cystitis by coating the bladder lining, re-estab- been reported, but the results are lishing normal GAG layer function somewhat inconclusive.14 and decreasing potassium leak into I Repair endothelial dysfunction the interstitial space.11 The recom- Antidepressants I Modulate neural activity mended dose is 100 mg t.i.d., but IC patients often benefit from an higher doses such as 200 mg t.i.d. or antidepressant therapy, particularly I Stabilize mast cells 300 mg t.i.d. have been used. tricyclic antidepressants such as Alternative dosing schedules to amitriptyline hydrochloride.15 These improve patient compliance have antidepressants are particularly patient population, this theory of a been used at many IC centers, with effective, because in addition to the multifactorial etiology for IC is 200 mg b.i.d. a common starting dose. antidepressant effect they modify extremely helpful in planning effective Patients starting therapy with PPS pain, have a mild antihistamine effect, therapy. To prevent the development need to be told that the full effect can decrease urgency and frequency of end-stage IC, aggressive and early may not be seen for 6–9 months, but through a modest anticholinergic detection, combined with a multi- they can be reassured that many effect, and are also effective as sleep modality therapy approach to address patients see improvement in as little aids.16 Amitriptyline is generally not only the deficiency of the GAG as 4 weeks. Patients taking PPS need to administered at night in doses ranging layer but also mast cell abnormalities be encouraged to stick with therapy, from 25 to 100 mg q.h.s. with dose and neurogenic inflammation, may because the most important factor in titration over time until adequate help stop the progression of the dis- determining the benefit of therapy symptom control is achieved. If ease and over time allow for the with PPS is the length of time under patients are also taking an antihista- redevelopment of a more normally treatment. Patients on PPS need to mine the dose may need to be functioning bladder epithelium. be reassured that the side effects decreased, with some patients respond- sometimes seen with this medication ing to doses as low as 10 mg q.h.s. Implementing a Multimodality (including headache, gastrointestinal If patients cannot tolerate Treatment Strategy upset, and hair loss) are generally amitriptyline they may respond to Given the multifactorial nature of IC, mild and usually will not necessitate alternative tricyclics, including tra- it is unusual for patients, particularly withdrawal of the medication. zodone, doxepin, and nortriptyline. those with more severe disease, to One antidepressant that should be respond to a single agent. It is crucial Antihistamines avoided is imipramine, as the sympa- to utilize a multimodality treatment The central role of the mast cell in IC 12 strategy in selecting appropriate is clear. Any form of multimodality Table 2 therapy for IC. In patients who are therapy should include therapy that Components of Oral Therapy candidates for long-term oral therapy, blocks the effect of histamine. for Interstitial Cystitis select agents that will treat GAG Hydroxyzine hydrochloride remains layer dysfunction, mast cell abnor- the most effective agent for the man- I Pentosan polysulfate malities, and neurogenic

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