DECREASING SYMPTOMS IN INTERSTITIAL CYSTITIS PATIENTS: PENTOSAN POLYSULFATE VS. SACRAL NEUROMODULATION. A Research Project by. Katy D.

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1 DECREASING SYMPTOMS IN INTERSTITIAL CYSTITIS PATIENTS: PENTOSAN POLYSULFATE VS. SACRAL NEUROMODULATION. A Research Project by Katy D. Prce Bachelor of General Studes, Unversty of Kansas, 2005 Submtted to the Department of Physcan Assstant and the faculty of the Graduate School of Wchta State Unversty n partal fulfllment of Master of Physcan Assstant May 2007 Wchta State Unversty

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3 ACKNOWLEDGEMENTS I would lke to thank my famly and frends for ther contnued encouragement and belef n me. Wthout ther support and love I would not have been able to accomplsh what I have today. Lastly, I would lke to thank my research advsor, Audrey Grffn. It s through her contnual nsght and support that ths project developed nto what t s today. Thank you for gudance and support throughout ths research.

4 ABSTRACT Objectves: Oral pentosan polysulfate (PPS) s the only FDA-approved drug for ntersttal cystts (IC). Several studes have been conducted that show PPS wll reduce IC symptoms. Sacral neuromodulaton s a newer therapy for IC that has been FDAapproved n ncontnent patents. Studes conducted n IC patents have shown that sacral neuromodulaton reduces IC symptoms. Both therapes have documents reducton n IC symptoms, but no studes have compared these therapes to see whch s more effectve. Methods: An evdence-based systematc lterature revew was conducted usng Pubmed, Medlne, and Proquest nursng journals. Incluson crtera for the studes were a peerrevewed artcle, publsh date of 1990 or later, level 1 or 2 evdence, were dagnosed wth IC, and were only treated wth ether oral PPS or sacral neuromodulaton durng the study. Patents were excluded f they were on multple therapes for IC or a non-ic dagnoss. Results: Three PPS studes ft all ncluson crtera. Wth successful treatment beng defned as a 50% overall mprovement n symptoms, studes had a success rate of 26-32%. Four studes ft the crtera for sacral neuormodulaton. In these studes 40-94% of the patents had a 50% mprovement n one or more of the presentng symptoms of IC. Conclusons: PPS and sacral neuromodulaton have both been shown to reduce IC symptoms. Sacral neuromodualton has been shown to have a hgher rate of symptom relef n IC patents. Based on level 2 evdence, a Grade B recommendaton can be made for sacral neuromodulaton. Ths evdence as lmted by sacral neuromodulaton studes havng only a level 2 evdence, whle PPS has level 1 evdence studes. More studes are needed for each of these therapes. v

5 TABLE OF CONTENTS Chapter Page 1. INTRODUCTION Dagnoss of Intersttal Cystts Etology Treatment 2 2. METHODOLOGY Research Methods LITERATURE REVIEW Introducton Pentosan Polysulfate Sacral Neuromodulaton RESULTS Results DISCUSSION Pentosan Polysulfate Sacral Neuromodulaton CONCLUSION. 25 LIST OF REFERENCES.. 26 APPENDIX 29 A. Evdence-Based Medcne Evdence Ratng Gudelnes 30 B. Matrces.. 31 v

6 TABLE OF FIGURES Fgure Page 1. Evdence-based medcne evdence ratng gudelnes Overall IC treatment success Summaton of lterature revew Outcomes of success based on technque n sacral neuromodulaton.. 23 v

7 CHAPTER 1 INTRODUCTION 1.1 Dagnoss of Intersttal Cystts Intersttal Cystts (IC) s a clncal syndrome of unknown etology, whch has led to much debate over ts dagnoss crtera and treatment regmens. Patents wth IC present wth urnary frequency and urgency, burnng sensatons whle vodng, and pelvc pan. There are many condtons that present wth the same symptoms, whch have led to naccurate dagnoss, treatment, and symptom resoluton. The Natonal Insttute of Dabetes and Dgestve and Kdney Dseases (NIDDK) have developed dagnostc crtera to help ad n dagnoss. The NIDDK states that the patent must present wth the above symptoms and upon examnaton, patents wth IC have a negatve urnanalyss, have no sgns of gentournary nfectons, bladder cancer, or prostatts, and have no hstory of radaton or tuberculoss cystts. The defntve sgn of an IC dagnoss s the presence of glomerulatons or ulcers on the bladder wall found durng a cystoscopc examnaton. 1 There are two dfferent forms of IC. The non-ulceratve type s the most prevalent at 90% and patents have mld symptoms. The second type s characterzed by Hunner s ulcers and makes up the other 10% of IC dagnoses. Hunner s ulcers are found upon cystoscopc examnaton and nvolve all layers of the bladder. Patents wth Hunner s ulcers present wth the most severe and debltatng symptoms Etology The etology of IC s stll beng debated, but has generally been narrowed down to two theores. The epthelum of the bladder contans a glycosamnoglycan layer. Ths layer s hydrophlc so t forms a protectve barrer from urne and ts rrtatve 1

8 components. 2 It s beleved that n patents wth IC ths layer s degraded. Ths degradaton allows urne to rrtate the lnng of the bladder. Ths process s what leads to symptoms of IC. In some patents wth IC glycosamnoglycans are found n ther urne. 3 The second theory behnd the etology of IC nvolves the actvaton of mast cells n the bladder wall. It s beleved that these cells release certan hormones as they are exposed to rrtatve substances. These hormones then lead to changes n the smooth muscle and ncreased nflammaton. 2 It s also beleved that the cause of IC s possbly lnked to both of these theores. 4 Ths hypothess adds to the complexty of dagnoss and the severty of the dsease. 1.3 Treatment Due to the lack of a defntve cause of IC the treatment for ths condton s usually mult-modal. There s no defnte cure for IC and the goal of treatment s to decrease the severty and frequency of the symptoms. Oral treatments such as pentosan polysulfate, anthstamnes, and trcyclc antdepressants have been used to try and reverse the proposed causes of the dsease and reduce the panful symptoms. Intravescular treatments have been used to attempt to coat and protect the lnng of the bladder. 4 A more nvasve therapy, whch has been studed, s sacral neuromodulaton n whch a devce stmulates sacral nerve roots n an effort to reduce symptoms. Nonpharmacologcal treatments, lke behavoral therapy, have been used to try and reduce the control that the symptoms have over IC patents. Det changes have also been helpful n some patents as a reducton n acdc and arylalkylamnc foods, such as bananas, cheese, chocolate, nuts, rasns, and beer, have been found to reduce symptoms. 5 2

9 Ths study wll compare treatment of IC wth oral pentosan polysulfate (PPS) versus sacral neuromodulaton to see whch treatment s more effectve n reducng symptoms. Pentosan polysulfate s one of two drugs that have been FDA-approved for the treatment of IC and the only oral treatment approved. One caveat of ths treatment s that t may take 3 months before an mprovement n symptoms s seen. 5 Hwang et al conducted a meta-analyss and found that pentosan polysulfate was more effectve than placebo at reducng pan, urgency and frequency. Sacral neuromodulaton s a more nvasve treatment whch requres a surgcal procedure to place a stmulus generator. 6 One study found that sacral neuromodulaton caused statstcally sgnfcant mprovements n frequency, pan, average voded volume, and maxmum voded volume. 7 IC patents experence a varety of symptoms rangng from mld to severe. Many of these symptoms cause alteratons n daly actvtes and a decrease n qualty of lfe. The objectve of ths study s to compare pentosan polysulfate versus sacral neuromodulaton n reducng symptoms n patents wth IC. The outcome of ths study wll help to determne whch treatment s the most effectve n reducng symptoms of IC. 3

10 CHAPTER 2 METHODOLOGY 2.1 Research Methods The method of research s an evdence-based systematc lterature revew. The databases used n the revew were PubMed, Medlne, Proquest nursng journals and Frst Search from 1990 to present. The year 1990 was chosen to nclude only the most recent data. The search terms used n ths revew were ntersttal cystts, polyura, dysura, treatments, pentosan polysulfate, and sacral neuromodulaton. Selected artcles for revew were based on level of evdence, journal type, and relevance to the topc. Incluson crtera for the artcles were a peer-revewed artcle, a publsh date of 1990 or later, level 1 or 2 evdence, subjects wth a dagnoss of ntersttal cystts, and were only treated wth ether oral pentosan polysulfate or sacral neuromodulaton therapy durng the study. Studes were excluded f subjects were treated wth multple therapes durng the study or were not dagnosed wth ntersttal cystts. Studes also had to meet the crtera of level 1 or level 2 evdence, whch were defned usng the Oxford Centre for EBM levels of evdence. 8 These are defned n Fgure 1, Appendx A. 4

11 CHAPTER 3 LITERATURE REVIEW 3.1 Introducton IC affects the lves of approxmately 700,000 women n the U.S. 9 Men and chldren can also be affected by ths dsease, but the ncdence s lower. The onset of ths dsease can occur at any age, but s more common n the mddle ages. 2 The symptoms of IC can range from mld to severe, where qualty of lfe can be mpared. Wth these numbers and symptoms fndng an approprate treatment could sgnfcantly mprove the lves of IC patents. The cause of IC has not yet been confrmed. Ths makes treatment of the dsease tself almost mpossble and treatment of the symptoms the goal. In ths systematc revew two treatment optons were examned to determne whch method s the most effectve n reducng the symptom complex assocated wth IC. 3.2 Pentosan Polysulfate Pentosan polysulfate s the FDA-approved oral drug therapy for IC. Ths drug prmarly targets the theory of degradaton of the glycosamnoglycan layer. PPS s a pharmacologcal agent whch acts lke glycosamnoglycans to help rebuld ths layer. 10 Intally, ths treatment has no effects on symptoms. PPS must be used for at least 3 months before a reducton n symptoms can be seen. 5 Because of the delayed onset of relef treatment complance s an ssue. In a study by Mulholland et al. t was found that there was a sgnfcant overall mprovement n IC symptoms after the use of PPS for three months. Ths doubleblnded, placebo-controlled study, examned the effects of 300mg/day oral PPS on 110 5

12 subjects. All subjects had symptoms of urnary urgency, frequency, noctura and pelvc pan for at least a year. They also had negatve urnary cultures and ether petechal hemorrhages or ulcers were found on cystoscopc exam. Subjects had no hstory or sgns of pelvc rradaton, urnary tuberculoss, or bladder cancer. The subjects were then randomly assgned to placebo and expermental groups usng a computer generated code. Subjects had a baselne evaluaton that conssted of symptom evaluaton and lab testng. They then followed-up n 3 months usng a questonnare that asked about overall mprovement, urgency, and pan. In ths study, the measure of the overall mprovement of each patent s condton was emphaszed as ndvdual symptoms of IC very wdely from patent to patent. The results focused on both the nvestgator s and patents reports. It was found that at 3 months 28 percent of the PPS patents found that ther overall condton had more that slghtly mproved as compared to the 13 percent of the placebo patents. The nvestgator s evaluaton confrmed ths sgnfcant fndng as they found that 26 percent of the PPS patents had sgnfcant overall mprovement as compared to 11 percent n the placebo patents. 10 Parsons et al. conducted a double-blnded, placebo-controlled study whch examned overall symptom reducton, pan, urgency, and vodng volumes n patents wth IC. The study enrolled 148 patents who had a dagnoss of IC for one year and a mnmum number of daly vods, bladder capactes, and epsodes of noctura. One hundred and thrty patents completed the 3 month study. Control and expermental groups were randomly assgned through a computer generated code. Labs and symptoms were assessed at baselne and after 3 months. A follow-up questonnare, vodng 6

13 volumes and pan ratngs were also recorded at the end of the study. It was found that 32% of the PPS group and 16% of the control group reported an overall mprovement of 50% or greater. Pan was mproved by 50% or more n 38% of the PPS group and 18% of the control group. Vodng volumes ncreased by at least 20 cc s n 40% of the PPS group and 24% of the control. Sexual frequency was ncrease n 31% of the PPS patents and 18% of the control. The nvestgators evaluaton found that 36% of the PPS group and 15% of the control had experenced an overall mprovement. 11 In a study by Jepsen et al. PPS was shown to be less effectve than prevously thought n studes. Ths prospectve cohort study looked at 97 patents who presented wth rrtatve vodng symptoms, consstent wth IC, who had negatve urne cultures and a negatve cystoscopc exam to rule other causes. Patents were gven 300 mg/day oral PPS. They were gven a baselne symptom questonnare at the ntaton of therapy and then at 3 month follow-up ntervals. Ths study also examned the long-term effects of PPS therapy. After 18 months there were only 11 patents stll takng PPS. No sgnfcant correlatons were found between PPS therapy and IC symptoms. The only statstcally sgnfcant correlaton was a weak negatve correlaton between baselne constant pan and duraton of PPS therapy. It was also found that on a long-term bass only 6.2%-18.75% beneft from the use of PPS. 12 In a randomzed, double-blnded study by Nckel et al. dose-rangng of PPS was examned. They compared the recommended dose of 300mg daly to 600mg and 900mg doses. There were 380 patents wth IC enrolled ntally, wth 230 completng the 32 week study. Patents had to be dagnosed wth IC and have had symptoms for at least sx 7

14 months. Patents were gven the Patent s Overall Ratng of Symptom Index and the O Leary-Sant Intersttal Cystts Symptom Index at baselne and at 32 weeks. 13 The mean scores for symptom ndexes sgnfcantly mproved durng the 32 weeks for all dosages. These mprovements were not found to be dose dependent. 14 A meta-analyss by Hwang et al. examned four prospectve, randomly controlled tral studes, on the effectveness of PPS n IC patent populatons. Three of the studes were publshed pror to 1990 as a result the meta-analyss was excluded. The fourth study was publshed n 1990 by Mulholland and has been ncluded. 15 A retrospectve study by Waters et al. examned the effects of PPS by a chart revew and follow-up patent survey. Ths study focused on the PPS n the clncal settng. Patents n both expermental and control groups contnued other oral medcatons for IC and were requred to partcpate n the study. Ths study was excluded from the analyzed data due to patents beng on multple treatments, but ncluded mportant nformaton on how PPS works wth other IC treatments. 16 A thrd study examnng PPS therapy was excluded due to the publsh date of Parsons et al conducted a randomzed, controlled crossover that found that patents on PPS had a greater mprovement n symptoms than placebo n all symptom categores. The average voded volumes were sgnfcantly mproves on drug therapy Sacral Neuromodulaton Sacral neuromodulaton s a procedure that has been used for years to treat many bladder symptoms. Many studes have been done to test ths procedure n patents wth IC who have complex bladder symptoms. Sacral neuromodulaton s done by frst dong a test procedure, or percutaneous nerve evaluaton (PNE), where a cable s nserted n the 8

15 sacral foramna at the level of S3. A test shock s delvered to ensure adequate placement. Then the patent s sent home wth an external mpulse generator to use for the next 7-14 days. Patents are asked to keep a vodng dary and other records to see f the treatment s effectve. If sacral neuromodulaton s found to be effectve, they are defned as a postve responder, and the patent then receves a permanent mplant. 7 In a small cohort study by Maher et al favorable results were found wth the use of sacral neuromodulaton n women wth ntersttal cystts. The study looked at 15 patents who had met NIDDK crtera for ntersttal cystts and had faled to respond to other tradtonal treatments. Before recevng the procedure patents recorded pan scores, volumes voded, daytme frequency, noctura, and urgency. These varables were then recorded durng stmulaton. Qualty of lfe questonnares were also gven before and after the stmulaton. Patents only receved a PNE and no permanent placements were studed. It was found that 73% responded favorably to PNE wth sgnfcant mprovements n pelvc pan, daytme frequency, noctura, and urgency. These patents requested to have permanent sacral nerve root mplantaton. Qualty of lfe varables, whch were sgnfcantly mproved, were general health, socal health, and bodly pan. There was also a 50% decrease n bladder pan n 87% of the patents. A 50% decrease n 24 hour vodng was seen n 47% of patents. 18 In a slghtly larger study, Whtmore et al examned 33 patents who had IC symptoms, had NIDDK fndngs on cystoscopc exam, and had faled prevous therapes. They used a tradtonal testng method for the placement of a unpolar electrode. A baselne vodng dary that ncluded urnary frequency, urgency, and bladder pan was 9

16 kept and recordngs were contnued for three days after placement. Average and maxmum vodng volumes were also recorded for the same perod. The study found that there were statstcally sgnfcant dfferences between bladder pan, urnary frequency, and average and maxmum vodng volumes. No sgnfcant dfference was found for noctura. As a result, 51.5% of the patents requested a permanent placement. 7 Two studes examned the dfferences n symptom reducton when two dfferent technques were used to place the lead. Tradtonally, when sacral neuromodulaton s frst tested patents receve a unpolar lead placed n the S3 foramen. Ths lead s secured to the skn wth dressngs. If stmulaton s effectve, then the lead s replaced wth a permanent lead and an nternal mpulse generator s placed. 19 More recently, a new technque has been usng a more permanent method called stage testng. In ths procedure a permanent quadpolar lead s placed nto the patent as n the same locaton as the tradtonal testng. Ths lead s anchored to the fasca to prevent slppage. If the stmulaton s effectve ths lead stays and a permanent mpulse generator s placed. 19 Peters et al compared tradtonal testng to staged testng n 37 patents. All patents had IC symptoms, met the NIDDK crtera, and faled an average of 6 other treatments for IC. Vodng dares and pan scores were kept at baselne and durng stmulaton. Patents were gven the opton of havng a permanent placement after the testng perod. Patents qualfed for ths f they experenced a 50% decrease n urnary frequency or a 50% mprovement n IC symptoms. 10

17 The study found that staged testng s superor to tradtonal testng. Of the 16 patents who had receved staged testng 94% were postve responders as compared to 67% of the 21 patents who had receved tradtonal testng. Permanent placement was done n 94 percent of the postve responders n the staged testng group. Only 52% of the postve responders n the tradtonal testng group chose permanent placement. 19 After permanent placement, nvestgators found that there was a 51% decrease n 24 hour vodng. Sgnfcant mprovements were found n both daytme vods (47%) and noctura (60%). At least sxty percent of all patents saw a moderate mprovement n urnary frequency and urgency, pelvc pan and pressure, qualty of lfe, ncontnence, and vagnal pan. Of the patents who had receved permanent placement, 96% sad they would receve the mplant agan. 19 In a second study examnng outcomes based on technque, Comter found smlar results. Ths study ncluded 25 patents who had met the IC crtera for NIDDK and had faled other treatments. Patents n group 1 receved temporary placement through tradtonal testng, whle group 2 receved placement through staged testng. Patents n both groups kept a vodng log and recorded pan for 7 days pror and 9 days after placement. If a patent experence a 50% decrease n symptoms they were elgble for a permanent placement. In the ndvduals who chose permanent placement, they followed-up wth a vodng log, pan dary, and an ntersttal cystts problem and symptom ndex at 2 months and then every 3-6 months. The study found that after temporary placement, 40% of patents n group 1 had a satsfactory response as compared to 87% of the patents n group 2 who had a satsfactory response. After permanent placement a statstcally sgnfcant mprovement 11

18 was found n pelvc pan, vodng symptoms, valdated symptom scores, and qualty of lfe. 20 A study by Peters et al. examned the effects of sacral neuromodualton on narcotc requrements. Twenty-one IC patents were selected for ths prospectve cohort study based on the crtera that they had been experencng urgency, frequency, and pelvc pan, and had faled sx prevous IC treatments. A baselne chart revew was done to examne the use of narcotcs before operaton. Post-operaton pan scores and a narcotc use questonnare were then gven to the patents. Ths study found a 36% decrease n narcotc use from 81.6 mg/day to 52.0 mg/day. 21 A study by Elhala et al. examned the long-term effcacy of sacral neuromodulaton. Ths study demonstrated mxed results between patent groups. It was excluded due to only 2 of the 41 patents havng an actual dagnoss of IC. 6 12

19 CHAPTER 4 RESULTS 4.1 Results The systematc lterature revew found 3 studes examnng PPS therapy that ft all ncluson crtera. Two of these studes were a 1b level of evdence and the thrd study was a 2b level of evdence. Table 1 descrbes the evdence ratng gudelnes used n ths lterature revew. Two studes found that the use of PPS n IC patents resulted n a reducton n IC symptoms. The thrd study only found a very weak relatonshp n the use of PPS and reducton of IC symptoms n patents. In ths study only one IC symptom was reduced wth PPS use. The studes ncluded a combned total of 355 subjects. Successful treatment was defned as a 50% overall mprovement n symptoms. Two PPS studes wth a postve correlaton, had a success rate of 26-32% n the subjects. Four studes ft the ncluson crtera for sacral neuromodualton. These studes partcpants were all dagnosed wth IC, had used prevous IC therapes wthout mprovement, and patents were not takng other medcatons for IC durng sacral neuromodulaton. All studes were 2b level of evdence. All studes found that sacral neuromodulaton caused a reducton IC symptoms. The studes ncluded a combned total of 110 patents. Successful treatment was defned as 50% mprovement n one of more presentng IC symptoms, whch s the crtera for permanent mplantaton, rates were found to be between 40-94% of the subjects. Comparson of the successful treatment percentages can be seen n Fgure 2. Maxmum relef s defned as the hghest percent of patents experencng treatment success n a sngle study. Mnmum relef s 13

20 the lowest percent of patents experencng treatment success n a sngle study. Fgure 3 shows summaton of the artcles examned durng the lterature revew Pentosan Polysulfate Sacral Neuromodulaton Max % Relef Mn % Relef Fgure 2. Overall IC treatment success. Fgure 3. Summaton of lterature revew. 14

21 CHAPTER 5 DISCUSSION 5.1 Pentosan Polysulfate Intersttal cystts s a debltatng llness for many of ts sufferers. The IC symptom-complex has been dffcult to treat and control due to the lack of a defnte etology. In ths systematc lterature revew two treatments for IC were examned to fnd whch has a greater effect on decreasng symptoms n IC patents. Pentosan polysulfate has been the only oral treatment FDA approved for the treatment of IC. In ths systematc lterature revew t was found that PPS does play a role n IC symptom reducton. Studes n ths revew found overall success rates from 26 to 32 percent. One lmtaton of PPS therapy s the amount of tme t takes for symptom relef. PPS takes up to 8 weeks to start experencng symptom reducton. Many patents experence complance ssues, as many have relapses durng the frst weeks of treatment. Ths prolonged onset of acton lmts the fndngs n PPS studes. If a patent relapses durng a study they wll be more lkely to wthdraw, whch wll ncrease falure rates. The use of 300 mg of PPS daly was an ncluson crteron for PPS studes n ths systematc lterature revew. Nckel et al. studed dose-rangng n IC patents. The study examned 300 mg, 600mg, and 900mg daly doses of PPS. Ths study showed that ncreasng the daly dose of PPS dd not sgnfcantly reduce IC symptoms. Patents n all groups found symptom relef, but t was not dose-dependent. In a retrospectve study by Waters et al. subjects were ncluded n the study f they had been on other oral medcatons whle on PPS. By ncludng these patents nstead of 15

22 excludng them Waters demonstrated the effcacy of PPS n a true clncal settng where IC patents are on multple therapes. All patents were takng at least one or more oral medcatons for IC. The control group had not been treated wth PPS, whle the expermental group had been. The study found statstcally sgnfcant dfferences n the PPS group for urnary frequency, urgency, pan, and overall change. Symptoms dd mprove n both groups, but were only statstcally sgnfcant n the PPS group. 5.2 Sacral Neuromodulaton Sacral neuromodulaton also demonstrated effectve IC symptom reducton n ths revew. Studes have shown that ths treatment, even though more nvasve, has a very hgh response rate n IC patents. Whle ths treatment requres a surgcal procedure, t s mportant to note the amount of tme t takes for relef afterwards. Sacral neuromodulaton provdes almost nstant relef n patents who are postve responders. PPS takes at least 8 weeks before patents wll possbly experence relef. In patents who prefer not to wat for relef or have complance ssues, sacral neuromodulaton wll most lkely beneft them. Sacral neuromodulaton could decrease the use of concurrent therapes n IC patents. Peters et al. found that patents who had an mpulse generator placed decreased ther use of narcotcs by 36%. Snce most IC patents are on mult-modal therapy ths fndng could lead to decreased treatment costs and easer management of medcatons. More studes are needed see what effects sacral neuromodulaton has on other IC therapes. It has also been found that the technque used to ntally test nerve root stmulaton n patents s an mportant factor n ther outcome. Two studes ncluded n 16

23 ths revew both found that staged testng was superor to tradtonal testng. Peters et al. found that staged testng produced a 94% postve responder rate, whle only 67% of patents wth tradtonal testng were postve responders. Comter found smlar results wth 87% beng postve responders n the staged testng group and only 40% were postve responders wth tradtonal testng. Fgure 4 shows the postve responder percentages when comparng tradtonal versus staged test n sacral neuromodulaton. Maxmum success s defned as the hghest percent of postve responders n sngle study. Mnmum success s defned as the lowest percent of postve responders n a sngle study Tradtonal Staged Maxmum % Success Mnmum % Success Fgure 4. Outcomes of success based on technque n sacral neuromodulaton. Ths systematc lterature revew had several lmtatons. There s an overall lack of hgh level of evdence studes usng PPS and sacral neuromodulaton n IC patents. In ths lterature revew a total of seven studes ft the ncluson crtera. There s also a lmtaton n that a medcaton was compared wth a procedure. Ths lmted the level of evdence regardng sacroneuromodulaton because of the dffculty of conductng a 17

24 randomzed-controlled tral. Due to ths all studes are level 2 evdence. Many PPS studes are randomzed-controlled trals, gvng them a hgher level of evdence. 18

25 CHAPTER 6 CONCLUSION Pentosan polysulfate and sacral neuromodulaton have both been shown to reduce IC symptoms. PPS has a lower rate of symptom relef n IC patents. Due to slow onset of acton patents on PPS experence complance ssues and relapse of symptoms durng treatment ntaton. Sacral neuromodulaton has been shown to have a hgher rate of symptom relef n IC patents and demonstrates mmedate symptom relef n postve responders. Wthn sacral neuromodulaton, staged testng s superor to tradtonal testng durng PNE and produces a hgher rate of postve responders. Upon revew of the lterature, a level 2b recommendaton can be made for sacral neuromodulaton n the reducton of symptoms n IC patents. Grades of recommendaton were defned by the Oxford Centre for EBM levels of evdence found n Fgure 1, Appendx A. Sacral neuromodulaton studes are lmted by beng a lower level of evdence than PPS studes. More studes are needed to further examne the effectveness of these therapes n IC patents. 19

26 LIST OF REFERENCES 20

27 1. Gllenwater J, Wen A. Summary of the Natonal Insttute of Arthrts, Dabetes, Dgestve and Kdney Dseases workshop on ntersttal cystts, Natonal Insttute of Health, Bethesda, Maryland, August 28-29, Journal of Urology. July 1987;140: Metts JF. Intersttal Cystts: urgency and frequency syndrome. Amercan Famly Physcan. October ;64: Rugger M, Chelsky M, et al. Current fndngs and future research avenues n the study of ntersttal cystts. Urologc clncs of North Amerca. 1994;21: Chancellor M, Yoshmura N. Treatment of Intersttal Cystts. Journal of Urology. March ;63: Lukban J, Whtmore K, Sant G. Current management of ntersttal cystts. Urologc clncs of North Amerca. August ;29: Elhala M, Khaled S, et al. Sacral neuromodulaton: long-term experence of one center. Journal of Urology. June ;65: Whtmore K, Payne C, et al. Sacral neuromodulaton n patents wth ntersttal cystts: a multcenter clncal tral. Internatonal Urogynecology Journal and Pelvc Floor Dysfuncton. November, ;14: Scott A. Oxford Centre evdence-based medcne level of evdence gudelnes Ratner V, Taylor N, et al. Re: Epdemology of ntersttal: a populaton based study. Journal of Urology. 1999;162: Mulholland S, Hanno P, et al. Pentosan polysulfate sodum for therapy of ntersttal cystts. Journal of Urology. June, ;35: Parsons C, Benson G, et al. A quanttatvely controlled methods to study prospectvely ntersttal cystts and demonstrate the effcacy of pentosan polysulfate. Journal of Urology. September ;150: Jepsen J, Sall M. Long-term experence wth pentosan polysulfate n ntersttal cystts. Journal of Urology. March, ;51: O'Leary M, Sant G, Fowler F. The Intersttal Cystts Symptom Index and Problem Index. Urology. 1997;49(suppl 5A):

28 14. Nckel J, Barkn J, et al. Randomzed, double-blnd, dose-rangng study of pentosan polysulfate for ntersttal cystts. Urology. Aprl ;65(3): Hwang P, Auclar B, et al. Effcacy of pentosan polysulfate n ntersttal cystts. Journal of Urology. 1997;50: Waters M, Sulesky J, et al. Intersttal cystts: a retrospectve analyss of treatment wth pentosan polysulfate and follow-up patent survey. JAOA. March ;100(3):S13-S Parsons C, Mulholland S. Successful therapy of ntersttal cystts wth pentosan polysulfate. Journal of Urology. September, ;138: Maher C, Carey M, et al. Percutaneous sacral nerve root neuromodulaton for ntractable ntersttal cystts. Journal of Urology. March, ;195: Peters K, Carey J, Konstandt D. Sacral neuromodulaton for the treatment of refractory ntersttal cystts: outcomes based on technque. Internatonal Urogynecology Journal and Pelvc Floor Dysfuncton. October, ;14: Comter C. Sacral neuromodulaton for the symptomatc treatment of refractory ntersttal cystts: a prospectve study. Journal of Urology. Aprl, ;169: Peters K, Konstandt D. Sacral neuromodulaton decreases narcotc requrements n refractory ntersttal cystts. Brtsh Journal of Urology Internatonal. 2004;93:

29 APPENDIX 23

30 APPENDIX A OXFORD CENTRE EBM LEVELS OF EVIDENCE Levels of Evdence 1 Systematc Revews, RCTs 2 Systematc Revews of cohort 3 SR of case-control studes 4 Case seres 5 Expert opnon wthout explct crtcal apprasal Grades of Recommendaton A Consstent Level 1 studes B Consstent Level 2 or 3 studes or extrapolatons from Level 1 studes C D Level 4 studes of extrapolatons from Level 2 or 3 studes Level 5 evdence or nconsstent or nconclusve studes at any level 24

31 APPENDIX B PPS 1a Artcle: (Ttle, Journal, author, year) Effcacy of pentosan polysulfate n the treatment of Intersttal cystts: a meta-analyss. Hwang P, Auclar B, Beechnor D, Dment M, Emarson T Urology 50: 39-43, Study Queston Determne the effcacy of PPS to placebo n the treatment of IC. Independent Varable Oral Pentosan Polysulfate Dependent Varable Symptoms of IC (pan, urgency, frequency, noctura) Methodologcal Desgn (How was t done, samplng, etc.) -Meta-analyss of prospectve, randomzed clncal trals -Incluson: Prospectve RCT, >8 weeks duraton, Englsh language, PPS mnmum 300 mg daly, >1 symptom of IC, Normal UA, Neg. culture -Excluson: hemorrhagc cystts, drug-, mcrobal-, or radaton- nduces cystts, carcnoma n stu -Selecton: methods secton photocoped and selected by 2 nvestgators. -Study wthdrawals ncluded and consdered falures -Success defned as a decrease n symptoms by 50% or more. I n Fndngs -37% decrease n pan -28% decrease n urgency -54% decrease n frequency -48% decrease n noctura (not statstcally sgnfcant) What s Mssng? -severty of symptoms n IC patents Crtcal Analyss (Synthess) -had sgnfcant fndngs for PPS n decreasng symptoms -wll be excluded due to one study havng publsh date pror to

32 PPS 1b Artcle: (Ttle, Journal, author, year) Pentosan polysulfate sodum for the therapy of ntersttal cystts: a double-blnd placebo-controlled clncal study Mulholland S, Hanno P, Parsons C, Sant G, Staskn D Urology 35 (6) June 1990 Study Queston Effects of PPS on IC symptoms Independent Varable Oral PPS Dependent Varable Methodologcal Desgn (How was t done, samplng, etc.) Overall symptom reducton n IC patents -Double-blnd, placebo-controlled, 110 patents, 3 months, 300 mg oral PPS daly -Categorzed n terms of severty of dsease -Incluson: moderate urgency, frequency, noctura, and pan; symptoms.1 year, faled prevous therapy, neg. culture, pos. cystoscopc exam -Excluson: Chronc narcotcs, sgns of bacterura, pelvc rradtaton, cancer, tuberculoss, schstosomass -Groups were randomly assgned wth computer generated code -Evaluated at baselne and at 3 months wth questonnare I n Fndngs Investgator s overall evaluaton: 26% of PPS evaluated as sgnfcantly mproved compared to 11% What s Mssng? Crtcal Analyss (Synthess) -had sgnfcant fndngs for the use of PPS n IC patents 26

33 PPS 1b Artcle: (Ttle, Journal, author, year) A quanttatvely controlled method to study prospectvely ntersttal cystts and demonstrate the effcacy of pentsan polysulfate. Parsons C, Benson G, Chlds S, Hanno P, Sant G, Webster G Journal of Urology 150: 845-8, Sept Study Queston Evaluatng the effcacy of PPS n IC Independent Varable Oral PPS Dependent Varable Methodologcal Desgn (How was t done, samplng, etc.) Fndngs Overall symptom reducton, pan, urgency, and vodng volumes -Double-blnd, placebo-controlled- 148 patents (18 drop-outs), 3 months, 300 mg PPS daly -mult-center -Incluson: dagnoss of IC for 1 year, bladder capacty cc, >8 vods per day, average voded (50-200cc), and noctura Excluson: <18 years old, pregnancy or lactaton, actve bleed PUD, bleedng dathess, use of antcoagulant, chronc narcotc use, allergy to PPS, artfcal sweetener use, hstory of Elmron wthn 4 weeks of the study. -randomly assgned, computer generated code -Lab and symptoms checked at baselne and after 3 months -At 3 month follow-up questonnare and looked at recorded vodng volumes and pan ratngs -50% overall mproved -32% PPS, 16% placebo -Reduced pan (50% mproved)- 38%, 18% -Improved pressure to vod- 30%, 18% -Sex (ncrease n frequency)- 31%, 18% Investgator s evaluaton of overall mprovement- 36%, 15% -Vodng volumes ncreased by 20cc or more- 40%, 24% I n What s Mssng? Crtcal Analyss (Synthess) -had sgnfcant fndngs for the use of PPS n IC patents 27

34 PPS 1b Artcle: (Ttle, Journal, author, year) Successful therapy of ntersttal cystts wth pentosan polysulfate Parsons C, Mulholland S Journal of Urology v.138, September 1987 Study Queston Effcacy of PPS on IC Independent Varable Oral PPS Dependent Varable IC symptoms Methodologcal Desgn (How was t done, samplng, etc.) -Randomzed, controlled, crossover, 62 patents -Patents gven symptom questonnare before and durng treatment, vodng volumes recorded Incluson: Symptoms for 1 year, negatve culture, cystoscopc exam I n Fndngs -Drug dd better than placebo n all categores -Average vodng volumes were sgnfcantly mproved on drug therapy What s Mssng? Crtcal Analyss (Synthess) -had sgnfcant fndngs for the use of PPS n IC patents -excluded due to a publsh date pror to

35 PPS 1b Artcle: (Ttle, Journal, author, year) Randomzed, double-, dose-rangng study of pentosan polysulfate for ntersttal cystts. Nckel j, Barkn J, Forrest J, Mosbaugh P, Hernandez-Graulau J, Kaufman D, Lloyd K, Evans R, Parsons C, Atknson L Urology 65(4) : 654-8, Aprl 2005 Study Queston To compare current recommended dose of PPS wth doses 2-3 tmes hgher. Independent Varable PPS dosage Dependent Varable Methodologcal Desgn (How was t done, samplng, etc.) IC symptom reducton -randomzed, double-blnd, multcenter, 32 week study -380 patents enrolled, 230 patents completed study -Incluson: Dagnoss of IC and wth symptoms for at least 6 months, neg. UA, could speak understand and wrte Englsh -Excluson: f on other IC therapy, pregnant or lactatng, hepatc dsease or abnormal lver functon tests, were on antcoagulants, had aneurysms, thrombocytopena, hemophla, GI ulcers, polyps or dvertcula; pos. occult blood, hypersenstvty to PPS, hstory of bacteral cystts, neurogenc bladder, pelvc rradaton, chemcal cystts, carcnoma, tuberulous cystts, schstosomass, obstructve BPH, usng schedule II opods, actve gental herpes -Used the Patent s Overall Ratng of Symptom Index and the O Leary-Sant Intersttal Cystts Symptom Index to evaluate symptoms Doses: 300mg, 600mg, 900mg daly I n Fndngs Mean scores sgnfcantly mproved durng 32 weeks for all dosages, but response to treatment was not dose dependent What s Mssng? Lack of a placebo group. Crtcal Analyss (Synthess) -Symptom relef wth PPS s not dose-dependent 29

36 PPS 2b Artcle: (Ttle, Journal, author, year) Intersttal Cystts: a retrospectve analyss of treatment wth pentosan polysulfate and a follow-up patent survey. Waters M, Sulesky J, Fnkelsten L, Van Overbeke M, Zzza V, Stommel M JAOA 100(3): S13-S18, March 2000 Study Queston Evaluate the effcacy and safety of PPS n relevng symptoms of IC. Independent Varable Oral PPS Dependent Varable Methodologcal Desgn (How was t done, samplng, etc.) IC symptoms Retrospectve chart revew w/ follow-up questonnare, 260 charts revewed- 27 patents takng PPS, 27 control IC patents not takng PPS -Control and PPS treatment groups were elgble f had IC for at least one year and persstent symptoms of IC, had at least one cystoscopy/hydrodstenton procedure, and negatve urne cultures. -PPS treated group had to be on PPS therapy for at least 8 weeks. -Control patents had to be takng at least one oral med as treatment for IC -Excluson: <18 years old, PPS therapy for less than 8 weeks, IC dagnosed for less than 1 year, no prevous cystoscopy/hydrodstenton, nablty to complete the questonnare. I n Fndngs -Stastcally sgnfcant dfferences were seen n the PPS group for urnary frequency, urgency, pan, and overall change What s Mssng? Crtcal Analyss (Synthess) -had sgnfcant fndngs for use of PPS n IC patents -excluded due to use of multple drugs for IC durng study perod 30

37 PPS 2b Artcle: (Ttle, Journal, author, year) Long-term experence wth pentosan polysulfate n ntersttal cystts. Jepsen J, Sall M, Rhodes P, Schmdt D, Messng E, Bruskewtz R Urology 51: , Study Queston Long-term effects of PPS n IC Independent Varable Long-term oral PPS Dependent Varable Symptoms of IC (pan present, pan constant, vodng pan, bladder pan, pelvc pan, urgency, pan score) Methodologcal Desgn (How was t done, samplng, etc.) -Prospectve cohort study of 97 patents -Incluson: rrtable vodng symptoms, negatve culture, negatve endoscopy -Dosage 100mg TID -Questonnare at baselne and every 3 months -Routne UA and culture, CBC wth dfferental, lver and kdney functon tests I n Fndngs Very weak statstcally sgnfcant assocaton between less constant pan at baselne and long-term treatment wth PPS What s Mssng? Crtcal Analyss (Synthess) -found no sgnfcant correlaton between PPS and IC symptoms 31

38 SNM 2b Artcle: (Ttle, Journal, author, year) Sacral neuromodulaton: long-term experence of one center. Elhal M, Khaled S, Kashwabara T, Elzayat E, Corcos J Urology 65: , 2005 Study Queston To evaluate the long-term effcacy of sacral neuromodulaton. Independent Varable Sacral neuromodulaton (tradtonal testng) Dependent Varable Urnary symptoms Methodologcal Desgn (How was t done, samplng, etc.) Retrospectve cohort, 41 patents- 2 wth IC -Patents wth vodng dysfuncton who had PNE and 50% mprovement n symptoms n 3 days receved permanent mplants. -Patents kept 3-7 day vodng dary -Follow-up every 6 months I n Fndngs -of 17 patents, 45% reported mprovement n ther symptoms -2 patent wth IC showed no mprovement What s Mssng? -No menton of pan scales, dares, etc. used at follow-up to determne long-term effectveness. Crtcal Analyss (Synthess) -excluded due to only 2 patents havng dagnoss of IC 32

39 SNM 2b Artcle: (Ttle, Journal, author, year) Sacral neuromodulaton for the treatment of refractory ntersttal cystts: outcomes based on technque. Peters K, Carey J, Konstandt D Internatonal Urogynecologcal Assocaton 14: 223-8, 2003 Study Queston Assess the effcacy of sacral nerve modulaton n treatng IC refractory to standard therapy. Independent Varable Sacral neuromodulaton (Tradatonal teat, Staged test) Dependent Varable Reducton n IC symptoms (day vods, Noctura, 24-h vods) Methodologcal Desgn (How was t done, samplng, etc.) Prospectve cohort (Tradtonal Vs. Staged testng) -Incluson: Symptom complex, met NIDDK crtera, faled avg. of 6 other therapes -Vodng dares and pan scores at baselne and durng stmulaton perod -Elgble for permanent mplant: 50% mprovement n urnary frequency or 50% mprovement n IC symptom complex I n Fndngs Staged testng s superor to tradtonal testng -94% were postve responders as compared to 67% Sacral neuromodulator permanently mplanted: 24 hours vods decreased by 51%, sgnfcant mprovements n daytme vods (47%) and noctura (60%) What s Mssng? -How long study lasted -Any concurrent use wth oral/ntravescular meds Crtcal Analyss (Synthess) -Found staged technque superor to tradtonal testng n sacral neuromodulaton 33

40 SNM 2b Artcle: (Ttle, Journal, author, year) Sacral neuromodulaton for the symptomatc treatment of refractory ntersttal cystts: a prospectve study. Comter, C Journal of Urology 169: , Aprl 2003 Study Queston Effcacy of sacral neuromodulaton for the treatment of symptoms n patents wth refractory IC. Independent Varable Sacral neuromodulaton (tradtonal and staged testng) Dependent Varable IC symptoms Methodologcal Desgn (How was t done, samplng, etc.) Prospectve cohort, 25 patents Incluson: Dagnoss of IC by NIDDK, faled other therapes -Group 1: tradtonal testng, Group 2: staged testng -measured by vodng dary and pan dary -Patents gven permanent SN followed up wth vodng log, pan dary, and IC problem and symptom ndex and 2 months and then every 3-6 months I n Fndngs -40% responded wth n unpolar group, 87% n quadpolar group -Statstcally sgnfcant mprovement n pelvc pan, vodng symptoms, valdated symptom scores, and qualty of lfe measures. What s Mssng? -group selecton Crtcal Analyss (Synthess) -Found staged testng was superor to tradtonal testng n sacral neuromodulaton 34

41 SNM 2b Artcle: (Ttle, Journal, author, year) Study Queston Sacral neuromodulaton n patents wth ntersttal cystts: a mult-center clncal tral. Whtmore K, Payne C, Dokno A, Lukban J Internatonal Urogynecologcal Journal 14: 305-9, 2003 Evaluate effcacy of sacral neuromodulaton n the allevaton of symptoms n patents wth severe IC who would have been canddates for major surgcal nterventon. Independent Varable Sacral Neuromodulaton (Tradtonal testng) Dependent Varable IC Symptoms Methodologcal Desgn (How was t done, samplng, etc.) Prospectve Cohort, 33 patents -All had tred prevous therapes -Incluson: Symptoms, cystoscopc NIADDK fndngs -Excluson: Pregnancy, UTI, stress ncontnence -Baselne and 3 days vodng dary (frequency, urgency, bladder pan), Average and max vodng volumes I n Fndngs -Statstcally sgnfcant dfferences between frequency, bladder pan, and average and max vodng volumes. -No sgnfcant dfference for noctura -51.5% permanent mplant rate What s Mssng? Crtcal Analyss (Synthess) -had sgnfcant fndngs for symptoms relef n IC patents for sacral neuromodulaton 35

42 SNM 2b Artcle: (Ttle, Journal, author, year) Sacral neuromodulaton decrease narcotc requrements n refractory ntersttal cystts. Peters k, Konstandt D Brtsh Journal of Urology Internatonal 93: 777-9, 2003 Study Queston Effcacy of sacral neuromodulaton n reducng IC symptoms. Independent Varable Permanent sacral neuromodulaton Dependent Varable IC symptoms Methodologcal Desgn (How was t done, samplng, etc.) Prospectve Cohort, 21 patents Incluson: urgency, frequency and pelvc pan; sx prevous treatments had faled -baselne narcotc by chart revew -Post-op pan scores and narcotc use by questonnares I n Fndngs -Found a decrease by 36% n narcotc use: from 81.6mg/day to 52.0 mg/day What s Mssng? -No nto on how temporary test was done Crtcal Analyss (Synthess) -Sacral neuromodulaton shown to decrease pan and narcotc usage n IC patents 36

43 SNM 2b Artcle: (Ttle, Journal, author, year) Percutaneous sacral nerve root neuromodualton for ntractable ntersttal cystts. Maher C, Carey M, Dwyer P, Schluter P Journal of Urology 165: 884-6, March 2001 Study Queston Effcacy of Percutaneous sacral nerve root neuromodualton n women wth refractory IC. Independent Varable Sacral neuromodulaton (Tradtonal testng)- PNE only Dependent Varable IC symptoms and qualty of lfe Methodologcal Desgn (How was t done, samplng, etc.) Prospectve cohort, 15 patents -women met NIDDK crtera, faled to respond to other therapes -1 week bedore and durng stmulaton pan scores, mean volume voded, day tme frequency, noctura, and urgency were recorded. -QOL questonnares were completes before and after PNE I n Fndngs -73% responded favorably to PNE-sgnfcant mprovement n pelvc pan, daytme frequency, noctura, urgency, and average volume voded -QOL varables sgnfcantly mproved -50% decrease n bladder pan n 87% of cases -50% decrease n 24 hour vodng n 47% What s Mssng? Crtcal Analyss (Synthess) -had sgnfcant fndngs for sacral neuromodulaton n patents wth IC 37

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