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]

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 Repair endothelial dysfunction the interstitial space.11 The recom- Antidepressants 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 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- Pentosan polysulfate malities, and neurogenic inflamma- agement of mast cell dysfunction.13 tion (see Table 1). The side effects of Because of its sedative properties, it Antihistamines the medications selected need to be is generally administered at night in Antidepressants considered so that if two medications doses ranging from 25 to 75 mg. In have similar side effects, such as patients who are highly sensitive, Anticholinergics sedation, dose modifications may be doses as low as 10 mg can be used. Urinary analgesics made. Table 2 lists the components In the spring and fall, when many IC of oral therapy discussed below. patients suffer from seasonal aller- Narcotics/pain relievers gies, an additional 10–25 mg every 6 Gabapentin Pentosan Polysulfate hours can be beneficial. In patients Pentosan polysulfate (PPS) remains who cannot tolerate a sedating anti- Other the cornerstone of drug therapy for histamine, cetirizine hydrochloride

S18 VOL. 4 SUPPL. 1 2002 REVIEWS IN UROLOGY Multimodality Therapy for IC

bladder discomfort by lowering uri- Pentosan nary acidity. Bladder insult polysulfate Pelvic floor dysfunction is often sodium present concomitantly with IC. Benzodiazopines or other skeletal More injury Epithelial layer damage muscle relaxants are appropriate therapy. Moldwin has demonstrated that doses as low as 2 mg t.i.d. of diazapam can relax the pelvic floor Mast cell activation and Potassium leak into and ease dysfunctional voiding (per- histamine release interstitium sonal communication, RM Moldwin). Anecdotal use of alpha blockers, Antihistamine Activation of C-fibers and including tamsulosin hydrochloride, therapy release of substance P for male and female patients with dysfunctional voiding may be bene- Tricyclic therapy ficial, but no controlled studies have been completed.

Figure 2. The role of multimodality therapy as related to the proposed multifactorial etiology of interstitial cystitis. Intravesical Agents For patients who do not respond to thomimetic effect of this agent often with side effects such as sedation. If oral therapy or for those patients who exacerbates dysfunctional voiding. a urologist is uncomfortable using suffer from a flare and require addi- Patients who truly cannot tolerate agents of this nature, referral to a tional treatment, several intravesi- tricyclic antidepressants may benefit pain clinic is appropriate. Phenytoin, cal agents are available. Although from the administration of selective carbamazepine, and valproic acid are dimethyl sulfoxide (DMSO) is the prin- serotonin reuptake inhibitor (SSRI) alternatives to gabapentin. ciple intravesical agent approved by antidepressants. This is particularly the U.S. Food and Drug Administration true for patients who also suffer from Supplementary Oral Therapies (FDA), numerous other agents have fibromyalgia. Commonly used SSRIs Urinary analgesics and antiseptics been used.18 DMSO is generally include paroxetine hydrochloride, such as phenazopyridine hydrochlo- administered once weekly for at least fluoxetine hydrochloride, citalopram ride, Uromax, and Urised are not 6 weeks, and administration can be hydrobromide, venlafaxine hydrochlo- effective as primary therapy, but can done either in the clinic or at home ride, and sertraline hydrochloride. be helpful for the management of by patients capable of self-catheteri- There have been no placebo-controlled short-term symptom flares or after zation. Multidrug cocktails, including trials for SSRI as treatment for IC. urologic instrumentation. Other agents DMSO (50 cc), sodium bicarbonate that are occasionally helpful include (48 meq), heparin (20,000 units), and Gabapentin urinary alkalizers, which can decrease triamcinolone acetonide (1 amp) are Pain and dysfunctional voiding may continue even after appropriate ther- Figure 3. A summary of multimodality therapy for interstitial cystitis. apy with pentosan polysulfate and other agents. This may be due to • Diet and Self Help “up-regulation" and the development of neurogenic inflammation within the spinal cord. Gabapentin can Pathogenic Factor Therapy decrease neurogenic inflammation Epithelial dysfunction Pentosan polysulfate and is used in patients with severe Neuromodulation Antidepressants and unrelenting chronic pain.17 It is usually given in divided doses rang- Mast cell activation Antihistamines ing from 300 mg to 2400 mg daily. This drug requires very careful dose • Don’t withdraw therapy when adding new modalities titration, balancing symptom control

VOL. 4 SUPPL. 1 2002 REVIEWS IN UROLOGY S19 Multimodality Therapy for IC continued

commonly used. For patients who their antihistamine dose can be 1995;75:744–750. 7. Hohenfeller M, Nunes L, Schmidt RA, et al. are capable of self-catheterization, decreased and possibly eliminated. Interstitial cystitis: increased sympathetic innervation and related neuropeptide synthesis. an anesthetic cocktail consisting of The pentosan polysulfate dose can J Urol. 1992;147:587–589. bupivacaine (30 cc), heparin (20,000 also be titrated downward. Although 8. Keay S, Warren JW. A hypothesis for the etiology of interstitial cystitis based upon inhibition units), sodium bicarbonate (48 meq), some patients can eliminate all med- of bladder epithelial repair. Med Hypotheses. 1998;51:79–83. and triamcinolone acetonide (1 amp) ications and do well, most require a 9. Keay SK, Zhang C, Shoenfelt J, et al. Sensitivity can be self-administered on a daily maintenance dose of pentosan poly- and specificity of antiproliferative factor, heparin-binding epidermal growth factor-like basis. Patients who are unable to sulfate, often as little as one or two growth factor and epidermal growth factor as unique markers for interstitial cystitis. Urology. take pentosan polysulfate because of pills daily. Patients are encouraged to 57(6 suppl 1):9–14. side effects may respond to either follow their IC diet carefully and con- 10. Lilly JD, Parsons CL. Bladder surface gly- cosaminoglycans: a human epithelial perme- intravesical pentosan polysulfate or tinue with stress management tech- ability barrier. Surg Gynecol Obstet. intravesical heparin administered niques. If at any time symptoms flare, 1990;174:493–496. 11. Parsons CL, Benson G, Childs SJ, et al. A quan- daily.19 Intravesical oxybutynin (5–10 their medications can be temporarily titatively controlled method to prospectively study interstitial cystitis and demonstrate the mg crushed and suspended in 10 cc of increased and then once again efficacy of pentosan polysulfate. J Urol. water) has also been used to control decreased back to baseline once the 1993;150:845–848. 12. Theoharides TC, Sant GR, El-Monsoury M, et al. bladder spasms. symptom flare has been controlled. Activation of bladder mast cells in interstitial cystitis: a light and electron microscopic study. Other intravesical agents not FDA J Urol. 1995;153:629–636. approved include hyaluronidase20 and Conclusion 13. Theoharides TC, Sant GR. Hydroyzine therapy 21 for interstitial cystitis. Urol. 1997;49(suppl bacillus Calmette-Guérin (BCG). A The proposed multifactorial etiology 5A):108–109. 14. Seshadri P, Emerson L, Morales A. Cimetidine clinical trial of hyaluronidase is cur- of IC has led to the development of in the treatment of interstitial cystitis. Urol. rently underway, and it is anticipated an appropriate multimodality therapy 1994;44:614–616. 15. Hanno PM. Amitriptyline in the treatment of that a BCG trial will commence shortly. for the disease. Most patients will interstitial cystitis. Urol Clin North Am. 1994;21:89–92. respond to this multimodal approach 16. Watson CPN. Antidepressants as ajunctive Discussion with significant improvement and in analgesics. J Pain Symptom Manage. 1994;9:392–415. A majority of patients will respond general can tolerate this treatment 17. Brookoff D. The causes and treatment and pain to a multidisciplinary approach con- regimen in the long term. in interstitial cystitis. In: Sant GR, ed. Interstitial Cystitis. Philadelphia: Lippincott- sisting of dietary modification, Raven; 1997:177–192. 18. Parkin J, Shea C, Sant GR. Intravesical dimethyl behavioral modification, pentosan References sulfoxide (DMSO) for interstitial cystitis—a 1. Jones CA, Nyberg L. Epidemiology of intersti- practical approach. Urology. 1997;49(suppl polysulfate, and either hydroxyzine, tial cystitis. Urology. 1997;49(suppl 5A):2–9. 5A):105–107. 2. Oravisto KJ. Interstitial cystitis as an autoim- 19. Parsons CL, Housley T, Schmidt JD, Lebow D. a tricyclic antidepressant, or both mune disease: a review. Eur Urol. 1980;6:10–13. Treatment of interstitial cystitis with intravesi- 3. Parsons CL, Lilly JD, Stein P. Epithelial dys- (Figures 2 and 3). If patients respond cal heparin. Br J Urol. 1994;73:504–507. function in nonbacterial cystitis (interstitial 20. Peters KM, Diokno AC, Steinert BW, Gonzalez to multimodality therapy, they can be cystitis). J Urol. 1991;145:732–735. JA. The efficacy of intravesical bacillus 4. Warren JW. Interstitial cystitis as an infectious slowly weaned from their medications. Calmette-Guérin in the treatment of interstitial disease. Urol Clin North Am. 1994;21:31–39. cystitis: long-term follow up. J Urol. 5. Sant GR, Theoharides TC. The role of the mast Narcotics, neuroleptics, and antide- 1998;159:1483–1486. cell in interstitial cystitis. Urol Clin North Am. pressants are eliminated first. If 1994;21:41–53. 21. Morales A, Emerson L, Nickels JC. Intravesical patients tolerate this, continue to sleep 6. Pang X, Marchand J, Sant GR, Theoharides TC. hyaluronic acid in the treatment of refractory Increased number of substance P positive fibers interstitial cystitis. Urol. 1997;49(suppl well, and have good pain control, in interstitial cystitis. Br J Urol. 5A):111–113.

Main Points • A multifactorial model has been proposed for the development of interstitial cystitis (IC). • In this model, an injury to the bladder or epithelium of the IC patients does not heal normally; leakage of urinary metabolites through the defective bladder lining causes mast cell activation and neurogenic inflammation; over time, if this cascade of events is left untreated, the bladder will decrease in size and the functional bladder capacity will plummet. • When treating patients with IC, it is crucial to utilize a multimodality treatment strategy, including agents that will treat gly- cosaminoglycan (GAG) layer dysfunction, mast cell abnormalities, and neurogenic inflammation. • Pentosan polysulfate remains the cornerstone of drug therapy for most patients; it functions by coating the bladder lining, re- establishing normal GAG layer function and decreasing potassium leak into the interstitial space. Urinary analgesics and antiseptics, urinary alkalizers, and benzodiazopines can also be useful in some settings. • For patients who do not respond to oral therapy or for those patients who suffer from a flare and require additional treatment, several intravesical agents are available.

S20 VOL. 4 SUPPL. 1 2002 REVIEWS IN UROLOGY