Interstitial Cystitis: A Pathophysiology and Treatment Update

Interstitial Cystitis: APathophysiology andTreatment UpdateROBERT M. MOLDWIN, MD* andGRANNUM R. SANT, MD†*Department of Urology, Long Island Jewish Medical Center, NewHyde Park, New York and †Department of Urology, Tufts UniversitySchool of Medicine, New England Medical Center,Boston, Massachusetts

It has been said that the difficulty in treatingan illness is directly proportional to the num-ber of therapies espoused. This dictum cer-tainly holds true for the management of in-terstitial cystitis, a syndrome of bladder hy-persensitivity where treatment remainsessentially palliative. A recent study con-ducted through the Interstitial Cystitis (IC)Database, recorded 183 different types oftreatments predominantly used through aca-demic centers!1 This is not to mention thevast number of alternative approaches thatpatients may apply themselves. Fortunately,many forms of care, applied individually orin combination, do appear to reduce thesymptoms of IC. In retrospect, many ofthese treatments address newly identifiedpathologies documented in this patientpopulation. This article reviews the com-mon therapies used for IC with specific ref-erence to their probable mechanism(s) of ac-tion.

Theories of PathogenesisThe cause of IC is unknown, however, in-vestigations over the past 15 years havedemonstrated specific pathologies that maycontribute to symptoms. The common theo-ries of pathogenesis are listed below.

LEAKY EPITHELIUMThe urothelial surface is lined by bladdersurface mucin (BSM), a heterogeneous, gel-like substance composed of numerous sulfo-nated glycosaminoglycans and glycopro-teins. BSM is thought to function as a “blad-der protectant,” decreasing the ability oforganisms to bind to the underlying urothe-lial cells. Although morphologic studies ofthe bladder surface have not demonstratedstriking differences between IC patients andcontrol populations,2–4 qualitative changeshave been described in some patients and inanimal models of IC.5–8 It has been specu-lated that these qualitative changes in BSMmay cause permeability alterations; the per-meability changes ultimately resulting inbladder inflammation and/or hyperalgesia.Robert M. Moldwin, M.D., E-mail: [email protected]

CLINICAL OBSTETRICS AND GYNECOLOGYVolume 45, Number 1, 259–272© 2002, Lippincott Williams & Wilkins, Inc.

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Permeability changes of the bladder wallwere first noted by Parsons et al, who in-stilled a urea solution into the bladders of ICand control patients. The solutions wereheld in place for 45 minutes and thendrained. The urea concentration of thedrained IC urine was markedly lower thanthe control group, suggesting enhanced ureaabsorption.7 In another study, blood fluores-cein levels were higher in IC patients thancontrols after an oral dose was administered,presumably due to increased absorption ofthe agent from the bladder surface upon ex-cretion.9 Worsening symptoms noted afterthe instillation of KCl into the bladders of ICpatients without significant responses incontrol population also speaks to some alter-ation in urothelial absorption in IC.10 Con-tradictory findings were noted with the in-travesical instillation of 99mtechnetium-diethylenetriaminepentaacetic, where nostatistical differences in serum concentra-tions were found between IC and control pa-tients.11 The specific role of BSM is unclear.Parsons et al7 performed the only study todate that specifically addresses this issue.They instilled protamine, a highly chargedcation that disrupts BSM, into the bladdersof volunteers. This resulted in enhanced ureaabsorption and new irritative voiding symp-toms. The irritative effect of the protaminewas tempered by the subsequent instillationof heparin sulfate, a glycosaminoglycancomponent of BSM. Critics of this studysuggest that protamine, apart from its abilityto eliminate BSM, may also directly injurethe bladder wall,12 thus enhancing urea ab-sorption by other mechanisms. Other indi-rect evidence of the role of BSM in thepathogenesis of IC is the symptomatic ben-efit often derived from epithelial coatingtechniques like as oral pentosanpolysulfate,intravesical heparin, or intravesical hyal-uronic acid, forms of therapy described laterin this review.

OCCULT INFECTIONInterstitial Cystitis has many of the hallmarksymptoms of bacterial cystitis; however,

urinalyses and urine cultures routinely dem-onstrate no evidence of infection. A ques-tion remains whether an occult infectionsimilar to that found with the association ofchronic gastritis and Helicobacter pylori ispresent. To date, no consistent organism hasbeen isolated in the urine or bladder biopsyspecimens of the IC patient. Interestingly,many IC patients have had a documentedurinary tract infection after which chronicbladder-based symptoms began. This haslead many investigators to speculate that theepisode of cystitis might have caused per-manent “bladder injury” and the subsequentdevelopment of irritative voiding symp-toms.13,14

NEUROGENIC INFLAMMATIONNeurogenic inflammation describes a pro-cess by which sensory nerves may secreteinflammatory mediators, resulting in localinflammation and hyperalgesia. SubstanceP, a short chain peptide, is one central com-ponent of this process. Substance P func-tions as a nociceptive neurotransmitter in thecentral and peripheral nervous system. Inaddition, substance P functions as an inflam-matory mediator. When released by periph-eral nerves (C-fibers, fibers associated withpain transmission) an inflammatory cascadeoccurs that results in processes such as mastcell degranulation and the activation ofnearby nerve terminals. In support of thispathogenic mechanism is the finding of in-creased numbers of substance P containingnerves in the bladders of IC patients.15,16 Inaddition, increased concentrations of sub-stance P have been found in the urine of ICpatients, the concentration of substance Pbeing affected by the patient’s degree ofpain.17

MAST CELL ACTIVATIONMast cells contain numerous vasoactive andinflammation provoking substances such ashistamine, leukotrienes, prostaglandins, andtryptases. Many of these substances are con-tained within cytoplasmic granules. Releaseof the granules into the interstitium (de-granulation) may occur as part of an IgE-

260 MOLDWIN AND SANT

mediated hypersensitivity reaction or in re-sponse to multiple other stimuli includingneurotransmitters like substance P, cyto-kines, anaphylatoxins (complement: C3a,4a, 5a), bacterial toxins, hypoxia, physicalfactors, lectins, various allergens, toxins,stress, etc.18–21 Histochemical identificationof mastocytosis has been noted in the blad-ders of approximately 30–65% of IC pa-tients.22,23 This is probably an underestima-tion due to technical difficulties in identify-ing degranulated, activated mast cells.24

Indirect evidence of the mast cell involve-ment in the pathogenesis of IC comes fromincreased levels of histamine found in thebladder walls of IC patients25 and increasedurinary excretion of 1,4-methyl-imidazole-acetic-acid (1,4-MIAA), a histamine me-tabolite, in IC patients.10,26

TOXIC SUBSTANCES IN THE URINEBased on findings of enhanced bladder wallpermeability in many IC patients, the nor-mal constituents of urine (ie, K+27 Tamm-Horsfall protein)28 may act as neurotoxinsor inflammatory mediators when exposed tothe bladder’s interstitium.29,30 Recent stud-ies suggest other toxic compounds found ex-clusively in the urine of IC patients may re-sult in bladder hyperalgesia and/or inflam-mation.31–33

AUTOIMMUNITYClinically, IC has many of the features of anautoimmune disease: symptom chronicitywith exacerbations and remissions; frequentorgan-specific mononuclear cell infiltrates,the lack of a clearly defined pathogen, occa-sional clinical response to steroids or otherimmunosuppressants,34 the high prevalenceof antinuclear antibodies, and associationswith well-described autoimmune syn-dromes. Further studies investigating therole of autoimmunity in IC are far from con-clusive and are often conflicting. Althoughheightened levels of bladder specific auto-antigens have been identified in some pa-tients,35 this has not been a universal find-ing.36,37 Most literature suggests that this

phenomenon is simply an indirect responseto local cellular damage.38

THE POSSIBLE ROLE OF MULTIPLECOEXISTING PATHOLOGIESNo one pathologic process has been identi-fied in every IC patient. Indeed, the syn-drome of IC may have multiple etiologies,all of which result in a similar clinical pic-ture. This may explain the varied clinical re-sponse to various forms of treatment. An-other widely held belief is that many of thepathologic processes described above mayact in concert to produce the features of IC(Fig. 1).

Treatment for the InterstitialCystitis PatientMultiple forms of therapy are available tothe IC patient. Although few randomized,placebo-controlled data have amassed forany given IC treatment, many forms of carehave shown efficacy in other painful or in-flammatory conditions and their usefulnessin the care of the IC patient is largely undis-puted. Interestingly, many of these therapiesaddress previously discussed pathologicfeatures found in the IC patient.

GENERAL MANAGEMENT PRINCIPLESThe clinician should convey to the patientthat the primary goal of therapy is symptomreduction and an associated improvement in

FIG. 1. The possible interaction of multiplepathologies in the interstitial cystitis patient.

Interstitial Cystitis: A Pathophysiology and Treatment Update 261

the quality of life. Complete remission, al-though often attained, should not be ex-pected. The patient should also understandthat not every therapy will work for everypatient. Often, several different approachesof care are used before finding one that re-sults in significant symptom reduction. Un-derstanding these basic issues “up front”will defuse a great deal of patient frustration.

SPECIFIC TREATMENTS FOR THEINTERSTITIAL CYSTITIS PATIENT

Self-Care and Dietary ChangesSelf-care, as the name implies, involvestechniques that the patient may use to lessensymptom severity. Dietary changes have be-come a fundamental and first line approachof self-care in many practices. Unknown uri-nary metabolites of certain foods are postu-lated to traverse the bladder surface, therebyfurther stimulating hypersensitive nervesand/or elicit an inflammatory response. Al-though clinical data substantiating the effectof diet on symptoms are lacking, a large per-centage of patients do report this phenom-enon. Avoidance of certain foods or bever-ages (caffeinated or alcoholic beverages, cit-rus fruits, etc., Table 1)39 appears to improvesymptoms in many patients. From a practi-cal perspective, there is great variabilityamong IC patients in terms of food sensitivi-ties. That is to say that not every patient issensitive to every food mentioned in Table 1and, indeed, many patients have no obviousfood sensitivities. In fact, leaving every po-tential offending food from the diet of all ICpatients will likely lead to malnutrition. Asimple strategy to deal with this problem isthe “elimination diet.” Patients are encour-aged to begin with a bland diet and to addpossible “problem” foods one-by-one backinto their diets. In general, if a patient is sen-sitive to a particular food or beverage, symp-toms will worsen within 30 minutes to 6hours. Another tendency in the IC patient,much like the patient with an overactivebladder, is to fluid restrict. This may de-crease urinary frequency somewhat, but

pain often worsens, likely owing to a higherconcentration of offending agents in theurine. Furthermore, the practice of fluid re-striction may lead to clinical dehydration.Urinary alkalinizing agents, like potassiumcitrate or sodium bicarbonate (baking soda),have anecdotally been useful. Prelief(AkPharma, Inc., Pleasantville, NJ. USA), anonprescription food additive and buffer,appears to decrease symptoms in some pa-tients with food sensitivities.

TABLE 1. Foods That May Cause aWorsening of Interstitial CystitisSymptoms

Citrus fruits (apples, apricots, avocados, bananas,cantaloupes (can eat other melons), citrus fruits,cranberries, grapes, nectarines, peaches, plums,rhubarb, strawberries)

Caffeinated beverages (Watch out. Manynoncaffeinated brands still have plenty ofcaffeine)

ChocolateAlcoholic beverages (particularly red wines)Tomatoes and tomato saucesSpicy foodsCarbonated beverages

Other foods, food additives, or beverages that mightworsen symptoms include:

Aspartame (Nutrasweet), saccharine, foods withartificial colors, monosodium glutamate (MSG),citric acid

Cheeses (except American, cottage, cream, ricotta)Sour creamYogurtChicken liversCorned Beef and other smoked meatsPickled herringVinegarSalad dressingMayonnaiseLentils, Lima beans, fava beans, soy beansNuts (except almonds, pine nuts, and peanuts)OnionsRaisins, cranberries, prunesRye and sourdough breadSoy sauceTea (except some herbal teas; others can be a

problem; hard to tell who will have a negativeeffect)

Adapted with permission from Gillespie L, Blakesue B. YouDon’t Have to Live with Cystitis. New York, Avon Books, andthe Interstitial Cystitis Association www.ichel.org.


Bladder Retraining ProtocolsThe dominant symptom of IC is often void-ing frequency. Constant low volume voidsmay result in a further loss of bladder capac-ity and worsening symptoms. A protocol ofprogressive, small increases in voiding in-tervals has been helpful for the managementof this problem. Parsons and Koprowski40

reported that this technique resulted in a50% improvement in urinary urgency, fre-quency, and nocturia. The technique wasbest suited to those patients in whom painwas not a dominant symptom.

ORAL THERAPY

Pentosan Polysulfate Sodium (Elmiron)Pentosan polysulfate sodium is a synthetic,highly sulfated polysaccharide similar instructure to heparin sulfate, one of the gly-cosaminoglycan constituents of BSM, butwith approximately 1/15th of heparin’s anti-coagulant effect.41 When taken orally, ap-proximately 2–6% is excreted unchanged inthe urine.42 Although its specific mecha-nism of action has not been clearly substan-tiated, pentosan polysulfate sodium isthought most likely to “augment” the normallining of the bladder, thus decreasing alteredbladder surface permeability. Pentosanpolysulfate sodium is one of the only oralmedications used in the treatment of IC toundergo randomized, placebo-controlledevaluation and is the only oral therapy ap-proved by the Food and Drug Administra-tion used for the treatment of IC. Successrates vary considerably in the literature. OneEuropean study found no differences insymptoms, urodynamic findings, mast cellcounts, or cystoscopic appearance within 4months of therapy.43 Opposite conclusionscame from two American studies showingresponse rates varying from 28–32% withplacebo response rates ranging from 13–16%.44,45 The discrepancies between theEuropean and American studies may haveresulted from differences in patient popula-tion and the authors’ definition of “re-sponse.”46 The dosage of pentosan polysul-fate sodium is 100 mg three times a day. The

medication is generally well tolerated withadverse reaction rates ranging from 1–4%.The most common adverse reaction encoun-tered is dyspepsia. Other uncommon reac-tions include reversible alopecia and in-creased bruising. Recent dose ranging stud-ies demonstrate no significant worsening ofthe side effect profile, apart from an increasein diarrhea, with doses up to 900 mg perday.47

Amitriptyline (Elavil)Amitriptyline is a tricyclic antidepressantcommonly used for pain management. Thismedication has unique qualities that are use-ful for the IC patient. Pain modulation ap-pears to be due to its ability to decrease se-rotonin and norepinephrine reuptake in thecentral nervous system. Amitriptyline alsoappears to stabilize mast cells and has amoderate anticholinergic effect. One espe-cially helpful feature of amitriptyline is itsability to promote sleep. To date there havebeen no randomized, placebo-controlled tri-als of amitriptyline for the treatment of IC.However, uncontrolled studies have shownsignificant improvement in 64–90% of pa-tients.48–51 Amitriptyline appears to workbest for patients with a substantial pain com-ponent to their symptoms and anestheticbladder capacities greater than 600 cc.46 Thestarting dose of amitriptyline is 10 to 25 mgat suppertime. The dose may be increased ona weekly basis to 75 to 100 mg, but held atthe lowest dosage that satisfactory clinicalimprovement is seen. Side effects may in-clude weight gain, fatigue, decrease inlibido/ability to achieve orgasm, palpita-tions, urinary retention, dry mouth, consti-pation, and it may affect thyroid function.Hepatotoxicity and bone marrow suppres-sion are rare. Although other tricyclic anti-depressants have been used in the manage-ment of chronic pain, none have been stud-ied with reference to IC.

Hydroxyzine (Atarax, Vistaril)Hydroxyzine, an H-1 antagonist, has beenfound in open-labeled studies to reduce ICsymptoms in 40% of patients. Efficacy im-


proved to 55% in patients with a history ofallergy.52 Its mechanism of action is pre-sumably related to its inhibition of mast celldegranulation. Other qualities of hydroxy-zine that may be beneficial to the IC patientinclude its soporific effect and action as askeletal muscle relaxant (approximately70% of IC patients have pelvic floor spastic-ity53). The dose of hydroxyzine is usually 10to 75 mg each evening. Clinical responsemay take up to 3 months to be achieved.

CimetidineThis H-2 antagonist has demonstrated use-fulness in small, uncontrolled series at anoral dosage of 600 mg per day in divideddoses.54,55 Its mechanism of action is un-clear since there is no significant evidence tosuggest H-2 blockers effective in the treat-ment or prophylaxis of urticaria (ie, mastcell degranulation).

Antiseizure MedicationsThe GABA-agonist, gabapentin (Neurontin,Parke-Davis) and the sodium channelblocker, carbamazepine (Tegretol, NovartisPharmaceuticals), both antiseizure medica-tions, have been found useful in the treat-ment of neuropathic pain.56 Both can be use-ful in the management of IC patients, how-ever, are usually reserved as second lineagents. Of the two medications, gabapentinis usually preferred due to its excellentsafety profile. Its most common side effect isfatigue. The dose of gabapentin is usuallyslowly increased from 100 mg every day to3,600 mg per day in three divided doses, de-pending on patient tolerance and the degreeof pain control achieved.

Selective Serotonin Reuptake InhibitorsApart from their antidepressant activity, theselective serotonin reuptake inhibitors arehelpful in the management of pain. Thisgroup of medications does not appear to beas useful in pain management as the tricyclicantidepressants, but may be helpful to dealwith associated depression in conjunctionwith tricyclic therapy. Commonly used se-lective serotonin reuptake inhibitors include

Venlafaxine (Effexor, Wyeth Ayerst), 37.5to 150 mg every day and Paroxetine (Paxil,GlaxcoSmithKline), 10 to 20 mg every day.

NarcoticsThe use of narcotics for acute exacerbationsof pain is part of all medical practices and iscertainly commonly carried out for symp-tom flares in the IC patient. However,chronic narcotic therapy for patients withnonmalignant pain was not acceptablewithin most medical circles until the 1980s.The fear of patient addiction was of greatconcern to many physicians until the prob-lem was found to be quite uncommon.57,58

Although most clinicians would agree thatthis is not first line therapy for the IC patient,chronic narcotic therapy clearly has an im-portant role in the management of those pa-tients who have had a suboptimal responseto other more conventional therapies. Theuse of long-acting narcotics and narcoticpatches has now become a “standard ofcare.” Probably the most problematic aspectof narcotic therapy for the IC patient is itsadverse effect on bowel function. Constipa-tion produced from opioids is often associ-ated with worsening symptoms of pelvicpressure. Other potential adverse effects in-cluding sedation, respiratory depression,nausea, and physical dependency warrantconsideration to use the talents of pain man-agement specialists in the care of the IC pa-tient.59

INTRAVESICAL THERAPYIntravesical therapy is usually used as a sec-ond line management alone or in conjunc-tion with oral therapy and other forms ofconservative management.

DimethysulfoxideDimethysulfoxide (DMSO) was first syn-thesized in 1867 as a by-product of the woodpulp industry. The agent was soon found tohave excellent solvent characteristics, beingfreely miscible with water, lipids, and or-ganic agents. The medicinal qualities ofDMSO were first described by Jacob etal60,61 who noted its antiinflammatory, anal-


gesic, and bacteriostatic properties. Dime-thysulfoxide rapidly traverses cell mem-branes. This quality, along with its excep-tional solvent activity, allow it to act as avehicle for coadministered agents. Since the1960s DMSO has been used clinically in thetreatment of IC and remains one of the cri-terion standards of IC therapy.62 The benefi-cial effects of DMSO appear to derive fromits ability to initially release and ultimatelydeplete substance P from the bladder wall.63

Dimethysulfoxide may stimulate mast celldegranulation.64 It has also been shown tostimulate bladder afferent pathways and tocause nitric oxide release from afferentnerves, both effects eventually causing de-sensitization of nociceptive pathways in thelower urinary tract.65 These effects may bethe cause for the worsening of symptoms of-ten experienced by patients during the firstfew intravesical instillations. Dimethysulf-oxide is partially excreted through the al-veoli and is always associated with a garlic-like odor to the breath that may last 6 to 24hours.

Although DMSO is traditionally admin-istered as a 50% solution, most clinical siteshave adopted the use of the “DMSO cock-tail.”66 The components of the administeredsolution usually consist of 50 cc of 50%DMSO (Rimso-50), 10 mL of sodium bicar-bonate, 75 mg/cc vial, a steroid (like 40 mgtriamcinolone), and heparin sulfate (10,000to 20,000 IU). A prophylactic antibiotic maybe added to the solution or it may be givenorally after the instillation. Then, 30 to 50mL of the cocktail are administered and thepatient is asked to hold the solution for 30 to60 minutes. Initially, patients may not beable to hold the solution for more than 2 to 3minutes. This problem may be avoided onsubsequent office visits by decreasing thevolume of instilled solution and/or by theadministration of a Belladonna and Opium(B&O Supprettes, Polymedica) suppositoryprevious to instillation. As intravesicaltherapy continues, patients can often holdthe solution for progressively longer peri-ods. Instillations are usually performed on a

weekly basis for 6 to 8 weeks. Patients arethen placed on maintenance therapy (everyother week, every third week, every month).Therapy is ultimately discontinued whensymptoms have been reduced and stabilized.

Intravesical HeparinHeparin sulfate is a glycosaminoglycan con-stituent of BSM. Weaver et al67 were thefirst to report its usefulness in the treatmentof IC. Like pentosanpolysulfate, intravesicaladministration of heparin is thought to en-hance the protective features of BSM.68,69

Heparin also has antiinflammatory effects,inhibits angiogenesis, and fibroblast andsmooth muscle proliferation, all of these at-tributes potentially correcting pathologiesidentified in many IC patients. Parsons etal68,69 performed the largest open-labeledtrial to date using this agent. In that study, 48IC patients self-administered 10,000 IU ofheparin sulfate into the bladder three timesper week. Of these patients, 56% described“good clinical remissions” within 3 months.No changes in coagulation studies wereseen. That group currently advocates theuse of daily heparin (20,000 IU) self-instillations. The solution is held in the blad-der for 30 to 45 minutes, if possible, and thenvoided. They noted that 4 to 12 months oftherapy is often needed to attain a beneficialclinical response. Once that occurs, the doseis tapered down to three times per week

Anesthetic CocktailAssuming that the bladder is the source ofpain in the IC patient, direct treatment of itssurface with an anesthetic may produce im-mediate and profound symptom improve-ment. In addition, symptom improvementderived from administration of this type mayhelp the clinician differentiate bladder-based pain from other forms of pelvic dis-comfort. As with the application of DMSO,the trend in clinical practice has been to cre-ate a cocktail that may benefit the patient byaddressing several pathogenic processescommonly seen in the IC population. Thecocktail used at the author’s (RM) institu-tion typically consists of 30 cc of a 1:1 0.5%


bupivacaine and 2% lidocaine jelly. To thissolution is added 20,000 IU heparin sulfate,40 mg triamcinolone, and 80 mg gentamy-cin. Patients are instructed to hold the solu-tion for 30 minutes (if possible), and thenvoid. Instillations are usually given on aweekly basis for 8 to 12 weeks, then the in-tervals are increased as the patient toleratesthe procedure. Although the instilled solu-tion should theoretically improve symptomsfor 3 to 5 hours, patients usually describepain relief that lasts for days. This effect ap-pears to improve as the instillations prog-ress. Patients may self-administer the cock-tail, a technique that can be particularlyhelpful when symptom flares arise. Rare ad-verse effects may include worsening ofsymptoms when the effects of the anesthetichave ceased and urinary retention.

Silver Nitrate/Clorpactin WCS-90Topical therapy of the bladder wall for thetreatment of IC began in the 1940s with theintravesical instillation of relatively causticagents including silver nitrate,70,71 and oxy-chlorosene (Clorpactin WCS-90, Guard-ian)72 in varying concentrations. Successrates have ranged for both agents between50% and 80%. Of those patients who re-spond favorably to therapy, mean responseis approximately 6 to 8 months. The down-side of these treatments is their caustic na-ture. When used in the conventional manner,instillation of these agents causes significantpelvic pain, which requires the use of anes-thesia. Instillation of these agents in the faceof vesicoureteral reflux may result in ure-teral fibrosis.73 A cystogram, to excludevesicoureteral reflux, is required previous toinstillation. Bladder biopsy is contraindi-cated along with instillation for fear of peri-vesical extravasation.

Bacillus Calmette-GuérinBacillus Calmette-Guérin (BCG) is an at-tenuated strain of Mycobacterium bovis. Itsmost common usage as an intravesical agentis in the treatment of recurrent or multifocalbladder cancer. Peters et al.74 conducted aprospective double-blinded, placebo-

controlled study to evaluate the efficacy of 6weekly BCG treatments in IC patients. Thegroup initially reported a 60% favorable re-sponse rate with a 27% placebo response.Long-term follow-up demonstrated that89% of patients continued to have symptomimprovement 24 to 33 months after their ini-tial treatment. No adverse events occurredduring the study.

The mechanism of action for these dra-matic improvements is unclear. The investi-gators speculate that BCG may be respon-sible for stimulating the type 1 T-helper cellresponse, thus leading to the destruction ofstressed inflammatory cells and a decreasein type 2 T-helper cell mediated allergic re-sponses. Uncontrolled trials suggest that uri-nary nitric oxide levels are decreased in ICpatients and increases are often associatedwith symptom improvement. BCG appearsto increase urinary nitric oxide levels inbladder cancer patients and is another hy-pothesized mode of action for this agent.70

Peeker et al.75 failed to see any significantfavorable response to BCG therapy whencompared with DMSO instillation. Al-though no BGC-related complications havebeen reported in IC patients to date, compli-cations are well described in oncology lit-erature and include: irritative voiding symp-toms, gross hematuria, the development ofinflammatory bladder lesions (“BCG granu-lomas”), and in rare instances, frank sepsis.Multicenter trials are now underway to de-termine the ultimate role of BCG in the careof the IC patient.

Hyaluronic Acid (Cystistat)Hyaluronic acid is a glycosaminoglycancomponent of BSM. Like intravesical hepa-rin sulfate and pentosanpolysulfate therapy,intravesical administration of Cystistat (Bi-oniche, Montreal, Quebec, Canada) isthought to further protect the bladder surfacefrom the irritating effects of urine. Moraleset al.76 evaluated 25 IC patients who wererefractory to other standard forms oftherapy. Patients received 40 mg hyaluronicacid intravesically on a weekly basis for 4


weeks, then monthly. Complete and partialresponse was 71% by week 12. A moderatedecrease in efficacy was noted at week 24.Nordling et al.77 conducted a 3-year follow-up to a 3-month prospective, open, nonran-domized study evaluating the effects of Cys-tistat. Nineteen patients elected to continueintravesical instillations. Of those 19 pa-tients, 11 continued therapy. Four of those11 patients ultimately stopped the medica-tion; 2 due to full recovery and 2 due to achange in therapy. Seven patients continuedto receive therapy for a mean of 37 months.Although this study was not placebo-controlled, the relatively high therapy con-tinuance rate suggests drug efficacy. Cysti-stat is produced in Canada and is not avail-able in the United States. Multisiterandomized, double-blinded, placebo-controlled trials are planned.

Capsaicin and ResiniferatoxinCapsaicin is the pungent component of thehot pepper. Initial contact with this agenttypically causes significant burning.Chronic application is known to be associ-ated with C-fiber (unmyelinated nerve fibersknown for transmitting painful stimuli) de-sensitization. Topical application of capsa-icin is used in the clinical management ofdermatologic pain syndromes and has mostrecently been used as an intravesical instil-lation for the treatment of detrusor hyperre-flexia and bladder hypersensitivity.78,79 Re-ports on success have varied probably due todiffering capsaicin concentrations and in-stillation regimens among investiga-tors.80,81 The main drawback of capsaicin isthe severe burning that patients initially de-scribe despite preinstillation of an intravesi-cal anesthetic. This problem seems to havebeen solved with the introduction of the cap-saicin analogue, resiniferatoxin. Resinifera-toxin is 100 to 10,000 times more potentthan capsaicin but is not associated with se-vere burning. In initial placebo-controlledstudies by Lazzari et al82 IC patients demon-strated a significant reduction of symptoms(pain, urgency, nocturia) after one instilla-

tion of this agent (10 nM). Symptoms startedto return by 90 days, but these results cer-tainly suggest that resiniferatoxin holdsgreat promise as an addition to the arma-mentarium for the future.

SURGICAL INTERVENTIONMultiple forms of surgery are available tothe IC patient and are usually used whenmore conservative approaches have failed.A spectrum of approaches is described be-low.

HydrodistentionOften used to help establish a diagnosis ofIC, hydrodistention may afford symptom re-lief in 30–50% of patients. Most patientshave a worsening of symptoms 2 to 3 weeksand achieve symptom relief after that periodof time. Patients with small bladder capaci-ties under anesthesia tend to have better re-lief than those with large capacities.51 Whensymptom improvement occurs, the meanduration of improvement is only approxi-mately 3 months. The procedure is per-formed sparingly for this reason. Further-more, personal observations suggest that hy-drodistention provides progressively lesssymptom relief when repeated multipletimes. Why hydrodistention provides symp-tom relief is unknown, however, is specu-lated to be secondary to a bladder wall neu-ropraxia or stimulation of BSM produc-tion.83

Bladder Wall Resection and LaserTherapyThese procedures are usually reserved onlyfor those patients suffering from gross in-flammatory lesions of the bladder wall(Hunner’s patches). Consequently these ab-lative procedures apply to only a small per-centage of IC patients. These endoscopicprocedures were developed due to encour-aging results attained with partial cystec-tomy. Like partial cystectomy, excellentsymptom improvement is usually achievedpostoperatively, however, recurrences arecommon within 1 year. Most recently, theneodymium (Nd): YAG laser has been used


for Hunner’s patch ablation.84 This proce-dure has the advantage of deep bladder wallpenetration and less scatter to “normal” ad-jacent tissue. The disadvantage of Nd:YAGtherapy is the potential for bladder perfora-tion and subsequent bowel injury.85 Unfor-tunately, these injuries are rarely noted at thetime of surgery since no discrete region ofbladder perforation is seen.

Cystectomy and Urinary DiversionCystectomy with urinary diversion is con-sidered a “last resort” procedure, being re-served for patients who have failed all othermodalities of care. These surgeries are oftenperformed for unremitting pelvic pain. Theclinician and the patient should bear in mindthat pain may persist in some instances evenafter undertaking such an aggressive thera-peutic approach, probably due to accompa-nying pelvic floor spasm or “centralization”of pain in the central nervous system. Amore clear-cut indication for surgery is blad-der wall fibrosis and severe urinary fre-quency. The use of urinary diversion with-out cystectomy is less invasive and mayafford good symptom improvement, par-ticularly for those patients plagued with in-capacitating urinary frequency. Disadvan-tages to this approach include the possibledevelopment of infection in the defunction-alized bladder and/or continuance of pelvicpain.46

NEUROMODULATIONA recent flurry of interest has developed inthe use of unilateral sacral nerve (S3) stimu-lation in the treatment of IC (InterStim de-vice, Medtronic, Inc., Minneapolis, MN).This form of care has been approved by theFood and Drug Administration for the treat-ment of urge incontinence, urinary reten-tion, and idiopathic urgency-frequency.86

Application of the InterStim device to the ICpatient has recently been shown to improvesymptoms including urinary frequency, ur-gency, and pain.87 In addition, abnormallyhigh urine antiproliferative activity and ab-normally low heparin-binding epidermalgrowth factor-like growth factor concentra-

tion appearing in the urine of most IC patientwas normalized after neuromodulation.88

The procedure is usually performed in twostages. The first stage involves the percuta-neous placement of a temporary electrode,usually within the S3 foramen. Appropriatestimulation is achieved through an externalstimulator. If satisfactory symptom im-provement occurs, the patient is a candidatefor permanent implantation of a small stimu-lator unit that rests in the upper buttocks.Most data compiled regarding this therapyrelates to temporary lead placement. Al-though successes rates of up to 73% havebeen achieved, further long-term permanentimplant evaluation is needed.89 Other formsof electrical nerve stimulation including thatassociated with acupuncture,90 transcutane-ous nerve stimulation, and transvaginalelectrical stimulation91 may be helpful forpatients.

MULTIMODAL AND MULTIFACETEDCAREAs previously described, one or multiple pa-thologies acting in concert may account forthe symptoms of IC. Given these circum-stances, several forms of therapy used incombination often result in a better clinicalresponse than one therapy alone. The use ofmultiple medications at low doses, as op-posed to few medications at high doses, isoften associated with a better clinical re-sponse and fewer adverse drug effects (Fig. 2).

A common dilemma that the cliniciantreating the IC patient often faces is the oc-currence of seemingly unrelated problemssuch as fibromyalgia, pelvic floor musclespasm, vulvar pain syndromes, migraineheadaches, and autoimmune phenom-enon.92,93 One should keep in mind thatthese problems may exist and often worsenbladder symptoms and/or the overall qualityof life for the patient.94 Referrals should bemade to appropriate medical practitionersfor definitive therapy.

ConclusionMultiple treatment strategies are availableand continue to evolve for the IC patient.


Many of these forms of care appear to affectone or more pathologic processes identifiedin this patient population. In general, treat-ment begins with the most conservativeforms of care including self-therapy, dietarychanges, and oral medications. Consultationfrom other medical practitioners may behelpful to assist with coexisting conditions.Intravesical therapy is usually used as a sec-ond line approach, but might be helpful touse earlier on in the treatment plan for thepatient who has multiple drug sensitivitiesor who has failed oral therapy when pre-scribed in other clinical settings. Surgeryshould be regarded as a last choice option forpatients in whom other forms of manage-ment have failed.

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Interstitial Cystitis: A Pathophysiology and Treatment Update

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