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9144001143000PHARMACOLOGICAL TREATMENTS OF INTERSTITIAL CYSTITIS: A REVIEW OF THE LITERATUREbyAnna Leigh ZilinskasBS, Indiana University of Pennsylvania, 2013Submitted to the Graduate Faculty ofthe Department of EpidemiologyGraduate School of Public Health in partial fulfillment of the requirements for the degree ofMaster of Public Health University of Pittsburgh201700PHARMACOLOGICAL TREATMENTS OF INTERSTITIAL CYSTITIS: A REVIEW OF THE LITERATUREbyAnna Leigh ZilinskasBS, Indiana University of Pennsylvania, 2013Submitted to the Graduate Faculty ofthe Department of EpidemiologyGraduate School of Public Health in partial fulfillment of the requirements for the degree ofMaster of Public Health University of Pittsburgh20171011555186055UNIVERSITY OF PITTSBURGHGRADUATE SCHOOL OF PUBLIC HEALTHThis essay is submittedbyAnna Leigh ZilinskasonDecember 15, 2017and approved byEssay Advisor:Nancy W. Glynn, PhD ______________________________________Assistant ProfessorDepartment of EpidemiologyGraduate School of Public HealthUniversity of PittsburghEssay Reader:Martha Ann Terry, PhD______________________________________Associate ProfessorDepartment of Behavioral and Community Health SciencesGraduate School of Public HealthUniversity of PittsburghEssay Reader:Pradeep Tyagi, PhD______________________________________Associate ProfessorDepartment of UrologySchool of MedicineUniversity of Pittsburgh00UNIVERSITY OF PITTSBURGHGRADUATE SCHOOL OF PUBLIC HEALTHThis essay is submittedbyAnna Leigh ZilinskasonDecember 15, 2017and approved byEssay Advisor:Nancy W. Glynn, PhD ______________________________________Assistant ProfessorDepartment of EpidemiologyGraduate School of Public HealthUniversity of PittsburghEssay Reader:Martha Ann Terry, PhD______________________________________Associate ProfessorDepartment of Behavioral and Community Health SciencesGraduate School of Public HealthUniversity of PittsburghEssay Reader:Pradeep Tyagi, PhD______________________________________Associate ProfessorDepartment of UrologySchool of MedicineUniversity of Pittsburgh11239504305300Copyright ? by Anna Leigh Zilinskas201700Copyright ? by Anna Leigh Zilinskas2017ABSTRACTcenter-222250Nancy W. Glynn, PhDPHARMACOLOGICAL TREATMENTS OF INTERSTITIAL CYSTITIS: A REVIEW OF THE LITERATUREAnna Leigh Zilinskas, MPHUniversity of Pittsburgh, 201700Nancy W. Glynn, PhDPHARMACOLOGICAL TREATMENTS OF INTERSTITIAL CYSTITIS: A REVIEW OF THE LITERATUREAnna Leigh Zilinskas, MPHUniversity of Pittsburgh, 2017It is reported that three to eight million women suffer from interstitial cystitis/bladder pain syndrome in the United States. Two front-line pharmacological methods of treatment include: Pentosan Polysulfate and Dimethyl Sulfoxide. Secondary to these treatments, patients can receive injections of Onabotulinum Toxin A, although not FDA approved. The primary objective of this literature review was to examine the existing work and identify the gaps in knowledge surrounding the current treatment protocols. A literature review was conducted through the PubMed database on November 1, 2017 yielding 21 articles that met inclusion criteria. Each article was reviewed for adherence to topic, method, results, and limitations. Overall, the nature of all the papers evaluated was generally lacking relevant details to directly compare across studies. This included missing relevant information on age and racial breakdown of patients, making it difficult to decipher if there is an age or race effect on treatment improvement by modality, and lack of information on the magnitude of the change in the key symptomatology outcome measures. However, these studies still provided valuable information to preliminarily compare their effectiveness and is a first step towards designing better trials to evaluate this problem. In conclusion, there is limited research on DMSO, with most recent findings unsupportive of the treatment. Orally administered PPS has the best-designed studies, with multiple placebo controlled, randomized clinical trials supporting the efficacy of symptom treatment, but findings indicated limited success in symptom reduction. While Onabotulinum Toxin A is considered to be a treatment that is administered at a later point of disease treatment, there is a substantial amount of published research that uses updated methods of pain and symptom evaluation which leads to a belief of efficacy. Given the stronger findings for Onabotulinum Toxin A, future research should be directed to determine if this modality should be considered as the primary intravesical treatment method of IC/BPS treatment despite its possible side effect of increasing UTIs. The public health implications of the existing and future work could allow for quicker and more effective relief of symptoms of IC/BPS for the millions of adults suffering from this painful condition.TABLE OF CONTENTS TOC \o "2-4" \h \z \t "Heading 1,1,Appendix,1,Heading,1" preface PAGEREF _Toc506563077 \h x1.0Introduction PAGEREF _Toc506563078 \h 11.1Definition of Interstitial Cystitis/Bladder Pain Syndrome PAGEREF _Toc506563079 \h 11.2Diagnosis of IC/BPS PAGEREF _Toc506563080 \h 11.3Epidemiology of Interstitial Cystitis/Bladder Pain Syndrome PAGEREF _Toc506563081 \h 31.4Treatments for Interstitial Cystitis/Bladder Pain Syndrome PAGEREF _Toc506563082 \h 31.5Measurements PAGEREF _Toc506563083 \h 41.6Public health significance and Objective PAGEREF _Toc506563084 \h 52.0methods PAGEREF _Toc506563085 \h 73.0results PAGEREF _Toc506563086 \h 103.1pentosan polysulfate PAGEREF _Toc506563087 \h 103.1.1Population and Definition of Interstitial Cystitis/Bladder Pain Syndrome PAGEREF _Toc506563088 \h 103.1.2Measurements PAGEREF _Toc506563089 \h 113.1.3Study Design and Outcomes PAGEREF _Toc506563090 \h 113.1Dimethyl Sulfoxide PAGEREF _Toc506563091 \h 143.1.3Population and Definition of Interstitial Cystitis/Bladder Pain Syndrome PAGEREF _Toc506563092 \h 143.1.4Measurements PAGEREF _Toc506563093 \h 153.1.5Study Design and Outcomes PAGEREF _Toc506563094 \h 153.3Onabotulinum toxin a PAGEREF _Toc506563095 \h 173.3.1Population and Definition of Interstitial Cystitis/Bladder Pain Syndrome PAGEREF _Toc506563096 \h 173.3.2Measurements PAGEREF _Toc506563097 \h 173.3.3Study Design and Outcomes PAGEREF _Toc506563098 \h 184.0Discussion PAGEREF _Toc506563099 \h 21bibliography PAGEREF _Toc506563100 \h 26List of tables(The following tables are attached as pdfs in the D-Scholarship record)Table 1. Comprehensive Summary Table on Literature Review of Pentosan PolysulfateTable 2. Comprehensive Summary Table on Literature Review of Dimethyl SulfoxideTable 3. Comprehensive Summary Table on Literature Review of Onabotulinum Toxin AList of figuresFigure 1. Literature review search strategy and selection criteria of Pubmed articles (1966-November 1, 2017) on the efficacy and management of symptoms of dimethyl sulfoxide (DMSO), Elmiron/Pentosan polysulfate (PPS), and OnabotulinumtoxinA for the treatment of Interstitial Cystitis/Bladder Pain Syndrome……………………………………………………….9prefaceI would like to thank my friends and family for their unending support. I would also like to thank Dr. Martha Ann Terry and Dr. Pradeep Tiyagi for being members of my essay committee and for their patience and efforts in the process. Most of all, I would like to thank Dr. Nancy Glynn, for always believing in me, supporting me, and for never giving up, I would not be here without her. IntroductionDefinition of Interstitial Cystitis/Bladder Pain SyndromeAs defined by the National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), Interstitial Cystitis/Bladder Pain Syndrome (IC/BPS) is a condition that causes discomfort or pain in the bladder and a need to urinate frequently and urgently ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "URL" : "", "accessed" : { "date-parts" : [ [ "2017", "11", "28" ] ] }, "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "0" ] ] }, "publisher" : "National Library of Medicine", "title" : "Interstitial Cystitis: Medline Plus", "type" : "webpage" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(\u201cInterstitial Cystitis: Medline Plus\u201d n.d.)", "plainTextFormattedCitation" : "(\u201cInterstitial Cystitis: Medline Plus\u201d n.d.)", "previouslyFormattedCitation" : "(\u201cInterstitial Cystitis: Medline Plus\u201d n.d.)" }, "properties" : { }, "schema" : "" }(“Interstitial Cystitis: Medline Plus” n.d.). Symptoms of IC/BPS can vary from person to person, or throughout the individual’s experience with the disease. For example, some people may feel discomfort, pressure and struggle with urinary urgency. Other patients may experience intense pain in the bladder with a sudden need to urinate more frequently than normal ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "URL" : "", "accessed" : { "date-parts" : [ [ "2017", "11", "28" ] ] }, "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "0" ] ] }, "title" : "General IC Symptoms - Interstitial Cystitis Association", "type" : "webpage" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(\u201cGeneral IC Symptoms - Interstitial Cystitis Association\u201d n.d.)", "plainTextFormattedCitation" : "(\u201cGeneral IC Symptoms - Interstitial Cystitis Association\u201d n.d.)", "previouslyFormattedCitation" : "(\u201cGeneral IC Symptoms - Interstitial Cystitis Association\u201d n.d.)" }, "properties" : { }, "schema" : "" }(“General IC Symptoms - Interstitial Cystitis Association” n.d.). Researchers do not know the exact cause of IC/BPS, though some believe that IC/BPS could result from conditions that cause inflammation in various parts of the body ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "URL" : "", "accessed" : { "date-parts" : [ [ "2017", "11", "28" ] ] }, "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "0" ] ] }, "title" : "Definition &amp; Facts of Interstitial Cystitis | NIDDK", "type" : "webpage" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(\u201cDefinition &amp; Facts of Interstitial Cystitis | NIDDK\u201d n.d.)", "plainTextFormattedCitation" : "(\u201cDefinition &amp; Facts of Interstitial Cystitis | NIDDK\u201d n.d.)", "previouslyFormattedCitation" : "(\u201cDefinition &amp; Facts of Interstitial Cystitis | NIDDK\u201d n.d.)" }, "properties" : { }, "schema" : "" }(“Definition &amp; Facts of Interstitial Cystitis | NIDDK” n.d.). Diagnosis of IC/BPSPatients with IC/BPS may have a presence of Hunner’s ulcers, which are not ulcers in the typical sense, but rather a distinct area of inflammation on the bladder wall. Hunner’s ulcers can lead to a definite diagnosis of IC/BPS, but are prevalent in only about 10% of diagnosed cases, and are confirmed by cystoscopy (insert IC help). Often, symptoms are more severe in the ulcerative IC/BPS than in cases lacking ulcers. Glomerulations, pin-point areas of bleeding, may be present in the bladder wall but do not lead to a definite diagnosis of IC/BPS. Health care professionals diagnose IC/BPS based on pain in or near the bladder, usually associated with urinary frequency and urgency as well as the absence of other diseases and conditions that could cause similar symptoms ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "URL" : "", "accessed" : { "date-parts" : [ [ "2017", "11", "28" ] ] }, "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "0" ] ] }, "title" : "Definition &amp; Facts of Interstitial Cystitis | NIDDK", "type" : "webpage" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(\u201cDefinition &amp; Facts of Interstitial Cystitis | NIDDK\u201d n.d.)", "plainTextFormattedCitation" : "(\u201cDefinition &amp; Facts of Interstitial Cystitis | NIDDK\u201d n.d.)", "previouslyFormattedCitation" : "(\u201cDefinition &amp; Facts of Interstitial Cystitis | NIDDK\u201d n.d.)" }, "properties" : { }, "schema" : "" }(“Definition &amp; Facts of Interstitial Cystitis | NIDDK” n.d.). In 1987, the NIDDK put forth a definition for diagnosis that includes 18 exclusion requirements and three inclusion requirements, one of which is Hunner’s Ulcer or glomerulations on cystoscopic exam, although diagnosis can still occur – just in non-classic type IC/BPS ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "URL" : "", "accessed" : { "date-parts" : [ [ "2017", "11", "28" ] ] }, "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "0" ] ] }, "title" : "Definition &amp; Facts of Interstitial Cystitis | NIDDK", "type" : "webpage" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(\u201cDefinition &amp; Facts of Interstitial Cystitis | NIDDK\u201d n.d.)", "plainTextFormattedCitation" : "(\u201cDefinition &amp; Facts of Interstitial Cystitis | NIDDK\u201d n.d.)", "previouslyFormattedCitation" : "(\u201cDefinition &amp; Facts of Interstitial Cystitis | NIDDK\u201d n.d.)" }, "properties" : { }, "schema" : "" }(“Definition &amp; Facts of Interstitial Cystitis | NIDDK” n.d.). Diagnosing IC/BPS in women can be challenging because symptoms are consistent with other common conditions such as: overactive bladder, endometriosis, urinary tract infections, pelvic floor dysfunction pudendal neuralgia and other conditions. Women may also have one or more of these conditions in addition to IC/BPS ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "URL" : "", "accessed" : { "date-parts" : [ [ "2017", "11", "28" ] ] }, "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "0" ] ] }, "title" : "General IC Symptoms - Interstitial Cystitis Association", "type" : "webpage" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(\u201cGeneral IC Symptoms - Interstitial Cystitis Association\u201d n.d.)", "plainTextFormattedCitation" : "(\u201cGeneral IC Symptoms - Interstitial Cystitis Association\u201d n.d.)", "previouslyFormattedCitation" : "(\u201cGeneral IC Symptoms - Interstitial Cystitis Association\u201d n.d.)" }, "properties" : { }, "schema" : "" }(“General IC Symptoms - Interstitial Cystitis Association” n.d.). While the root cause of IC/BPS is still unknown, symptom flare ups can exacerbate IC/BPS and increase pain and discomfort. Women have reported symptom flares when they: are stressed/emotional with anger and sadness, have sex, have a menstrual cycle, urinate or hold urine for too long, skip meals or are dehydrated, feel changes in the seasons or weather, go through sudden or bumpy movements, inconsistent with prescribed medications, stand for long periods of time, have a pap smear, wear tight pants/undergarments, use laundry detergent with certain chemicals, complete different physical activities, such as pushing or lifting heavy objects ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1007/s00192-015-2652-6", "ISSN" : "1433-3023", "PMID" : "25792349", "abstract" : "INTRODUCTION AND HYPOTHESIS Although in-depth qualitative information is critical to understanding patients' symptom experiences and to developing patient-centered outcome measures, only one previous qualitative study has assessed urological chronic pelvic pain syndrome (UCPPS) symptom exacerbations (\"flares\"). METHODS We conducted eight focus groups of female UCPPS (interstitial cystitis/bladder pain syndrome) patients at four sites from the MAPP Research Network (n\u2009=\u200957, mean\u2009=\u20097/group) to explore the full spectrum of flares and their impact on patients' lives. RESULTS Flare experiences were common and varied widely in terms of UCPPS symptoms involved, concurrent nonpelvic symptoms (e.g., diarrhea), symptom intensity (mild to severe), duration (minutes to years), and frequency (daily to\u2009<\u2009once/year), although the most commonly described flares were painful flares lasting days. These latter flares were also most disruptive to participants' lives, causing some to cancel social events, miss work or school, and in the worst cases, go to the emergency room or on disability leave. Participants also reported a longer-term impact of flares, including negative effects on their sexual functioning and marital, family, and social relationships; and the loss of employment or limited career or educational advancement. Emerging themes included the need for a sense of control over unpredictable symptoms and reduced social engagement. CONCLUSIONS Given their negative impact, future research should focus on approaches to prevent flares, and to reduce their frequency, severity, and/or duration. Patients' quality of life may also be improved by providing them with a sense of control over their symptoms through ready access to flare medications/therapy, and by engaging them socially.", "author" : [ { "dropping-particle" : "", "family" : "Sutcliffe", "given" : "Siobhan", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bradley", "given" : "Catherine S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Clemens", "given" : "James Quentin", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "James", "given" : "Aimee S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Konkle", "given" : "Katy S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kreder", "given" : "Karl J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lai", "given" : "Hing Hung Henry", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mackey", "given" : "Sean C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ashe-McNalley", "given" : "Cody P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "V", "family" : "Rodriguez", "given" : "Larissa", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Barrell", "given" : "Edward", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hou", "given" : "Xiaoling", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Robinson", "given" : "Nancy A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mullins", "given" : "Chris", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Berry", "given" : "Sandra H", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "International urogynecology journal", "id" : "ITEM-1", "issue" : "7", "issued" : { "date-parts" : [ [ "2015", "7" ] ] }, "page" : "1047-60", "publisher" : "NIH Public Access", "title" : "Urological chronic pelvic pain syndrome flares and their impact: qualitative analysis in the MAPP network.", "type" : "article-journal", "volume" : "26" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Sutcliffe et al. 2015)", "plainTextFormattedCitation" : "(Sutcliffe et al. 2015)", "previouslyFormattedCitation" : "(Sutcliffe et al. 2015)" }, "properties" : { }, "schema" : "" }(Sutcliffe et al. 2015). Epidemiology of Interstitial Cystitis/Bladder Pain Syndrome IC/BPS is common in the United States (US). The Interstitial Cystitis Association (ICA) estimates that three to eight million women may have IC/BPS, about 3 to 6% of all women in the United States. These numbers were derived from the findings of the RAND IC Epidemiology Study (RICE), which surveyed more than 100,000 US households and was the largest IC/BPS epidemiology study ever completed ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "URL" : "", "accessed" : { "date-parts" : [ [ "2017", "11", "28" ] ] }, "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "0" ] ] }, "title" : "4 to 12 Million May Have IC - ICA - McLean, VA", "type" : "webpage" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(\u201c4 to 12 Million May Have IC - ICA - McLean, VA\u201d n.d.)", "plainTextFormattedCitation" : "(\u201c4 to 12 Million May Have IC - ICA - McLean, VA\u201d n.d.)", "previouslyFormattedCitation" : "(\u201c4 to 12 Million May Have IC - ICA - McLean, VA\u201d n.d.)" }, "properties" : { }, "schema" : "" }(“4 to 12 Million May Have IC - ICA - McLean, VA” n.d.). The onset of IC can occur at any age, but is most commonly found in adult women. Some research suggests that women who have a history of sexual abuse or physical traumatization are more likely to develop IC/BPS ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1007/s11934-009-0070-3", "ISBN" : "1534-6285 (Electronic)\\r1527-2737 (Linking)", "ISSN" : "15272737", "PMID" : "19863855", "abstract" : "Interstitial cystitis/painful bladder syndrome (IC/PBS) is a chronic syndrome characterized by irritative voiding symptoms and pelvic pain or discomfort. IC/PBS represents localized bladder pathophysiologic changes and central nervous system upregulation. Patients exhibit bladder hyperalgesia and allodynia. Childhood sexual abuse occurs in up to 27% of females in the United States. Adults with a prior history of abuse or traumatization demonstrate hypothalamic-pituitary-adrenal (HPA) axis abnormalities, similar to IC/PBS patients. Childhood sexual abuse and physical traumatization are associated with subsequent lifelong risks of chronic pain syndromes. IC/PBS patients have increased rates of sexual abuse or physical traumatization histories compared with controls. IC/PBS patients with abuse histories tend to have greater pain intensity and lesser irritative voiding symptoms compared with nonabused IC/PBS patients. This article reviews the relationship between sexual abuse, HPA axis abnormalities, IC/PBS pathophysiology, and the role of sexual abuse on subsequent IC/PBS.", "author" : [ { "dropping-particle" : "", "family" : "Teichman", "given" : "Joel M. H.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mayson", "given" : "Brian E.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Current Urology Reports", "id" : "ITEM-1", "issue" : "6", "issued" : { "date-parts" : [ [ "2009", "11", "6" ] ] }, "page" : "441-447", "publisher" : "Current Science Inc.", "title" : "The relationship between sexual abuse and interstitial cystitis/painful bladder syndrome", "type" : "article", "volume" : "10" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Teichman and Mayson 2009)", "plainTextFormattedCitation" : "(Teichman and Mayson 2009)", "previouslyFormattedCitation" : "(Teichman and Mayson 2009)" }, "properties" : { }, "schema" : "" }(Teichman and Mayson 2009). IC/BPS can affect quality of life (QOL) significantly as patients are more likely to struggle with sleep loss, anxiety, depression and relationship struggles due to painful sex ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1007/s11255-014-0908-6", "ISSN" : "0301-1623", "PMID" : "25577231", "abstract" : "PURPOSE To explore the association between bladder pain syndrome/interstitial cystitis (BPS/IC) and the risk of subsequent healthcare-seeking behavior for common mental disorders in Taiwan using a population-based administrative database. MATERIALS AND METHODS Both BPS/IC subjects and their age- and sex-matched non-BPS/IC control subjects who had no previous insomnia and mental diseases, including anxiety, depression, were subsequent serviced for these mental disorders by psychiatrists from the recruited date between 2002 and 2010. The risk of outcomes was assessed with Kaplan-Meier curves; and the impact of BPS/IC was estimated with Poisson regression analysis and Cox proportional hazards models. RESULTS We included 16,185 BPS/IC subjects and 32,370 non-BPS/IC subjects, with a mean age of 46 years and 73.5 % of women. Difference of the prevalence of hypertension, diabetes, chronic kidney disease, and hyperlipidemia between groups was not significant difference. Subjects with BPS/IC had a significant higher incidence rate of anxiety, depression, and insomnia than the matched controls (92.9 vs 38.4, 101.0 vs 42.2, 47.5 vs 23.0; per 10,000 person-year). After adjusting for age, sex, and common comorbidities in multivariable analysis, BPS/IC remained a significant predictor with hazard ratio and 95 % confidence incidence, 2.4 (2.2-2.7), 2.4 (2.2-2.6), and 2.1 (1.8-2.4) for anxiety, depression, and insomnia, respectively. CONCLUSION Patients with BPS/IC are at risk of development of anxiety, depression, and insomnia. These findings can help guide urologists, urogynecologists, and psychiatrists toward early identification and treatment of psychological complications that may develop in BPS/IC patients.", "author" : [ { "dropping-particle" : "", "family" : "Chuang", "given" : "Yao-Chi", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Weng", "given" : "Shih-Feng", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hsu", "given" : "Ya-Wen", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Huang", "given" : "Charles Lung-Cheng", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Wu", "given" : "Ming-Ping", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "International Urology and Nephrology", "id" : "ITEM-1", "issue" : "2", "issued" : { "date-parts" : [ [ "2015", "2", "11" ] ] }, "page" : "275-281", "title" : "Increased risks of healthcare-seeking behaviors of anxiety, depression and insomnia among patients with bladder pain syndrome/interstitial cystitis: a nationwide population-based study", "type" : "article-journal", "volume" : "47" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "URL" : "", "accessed" : { "date-parts" : [ [ "2017", "11", "28" ] ] }, "id" : "ITEM-2", "issued" : { "date-parts" : [ [ "0" ] ] }, "title" : "Definition &amp; Facts of Interstitial Cystitis | NIDDK", "type" : "webpage" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Chuang et al. 2015; \u201cDefinition &amp; Facts of Interstitial Cystitis | NIDDK\u201d n.d.)", "plainTextFormattedCitation" : "(Chuang et al. 2015; \u201cDefinition &amp; Facts of Interstitial Cystitis | NIDDK\u201d n.d.)", "previouslyFormattedCitation" : "(Chuang et al. 2015; \u201cDefinition &amp; Facts of Interstitial Cystitis | NIDDK\u201d n.d.)" }, "properties" : { }, "schema" : "" }(Chuang et al. 2015; “Definition &amp; Facts of Interstitial Cystitis | NIDDK” n.d.). Other conditions that women with IC/BPS are likely to have include irritable bowel syndrome, fibromyalgia, chronic fatigue syndrome, allergies, and some autoimmune diseases ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/j.juro.2010.06.005", "ISSN" : "00225347", "PMID" : "20719340", "abstract" : "PURPOSE We characterized and compared the impact of clinical phenotypic associations between interstitial cystitis/painful bladder syndrome and controls in relation to potentially related conditions, particularly irritable bowel syndrome, fibromyalgia and chronic fatigue syndrome. MATERIALS AND METHODS Female patients with interstitial cystitis/painful bladder syndrome and controls with no interstitial cystitis/painful bladder syndrome completed a biopsychosocial phenotyping questionnaire battery which included demographics/history form, self-reported history of associated conditions, and 10 validated questionnaires focused on symptoms, suffering/coping and behavioral/social factors. RESULTS Questionnaires were completed by 205 patients with interstitial cystitis/painful bladder syndrome and 117 controls matched for age. Prevalence of self-reported associated condition diagnosis in interstitial cystitis/painful bladder syndrome vs controls was irritable bowel syndrome 38.6% vs 5.2%, fibromyalgia 17.7% vs 2.6% and chronic fatigue syndrome 9.5% vs 1.7% (all p <0.001). In the interstitial cystitis/painful bladder syndrome cohort 50.3% reported no other associated condition, 24.4% had interstitial cystitis/painful bladder syndrome + irritable bowel syndrome only, 2.5% had interstitial cystitis/painful bladder syndrome + fibromyalgia only, 1.5% had interstitial cystitis/painful bladder syndrome + chronic fatigue syndrome only, while 20.2% had multiple associated conditions. As the number of associated conditions increased (ie localized, regional, systemic), pain, stress, depression and sleep disturbance increased while social support, sexual functioning and quality of life deteriorated. Anxiety and catastrophizing remained increased in all groups. Symptom duration was associated with this apparent phenotypic progression. CONCLUSIONS Irritable bowel syndrome, fibromyalgia and chronic fatigue syndrome are more prevalent in patients with interstitial cystitis/painful bladder syndrome than in asymptomatic control subjects, and result in significant impact. There are at least 3 distinct clinical phenotypes based on identification of overlapping syndrome patterns. A suggestion that remains to be proven with longitudinal studies is that there may be progression over time from an organ centric to a regional and finally to a systemic pain syndrome with progression of symptom severity, and deterioration of cognitive and psychosocial parameters.", "author" : [ { "dropping-particle" : "", "family" : "Nickel", "given" : "J. Curtis", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Tripp", "given" : "Dean A.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Pontari", "given" : "Michel", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Moldwin", "given" : "Robert", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mayer", "given" : "Robert", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Carr", "given" : "Lesley K.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Doggweiler", "given" : "Ragi", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Yang", "given" : "Claire C.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mishra", "given" : "Nagendra", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Nordling", "given" : "Jorgen", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "The Journal of Urology", "id" : "ITEM-1", "issue" : "4", "issued" : { "date-parts" : [ [ "2010", "10" ] ] }, "page" : "1358-1363", "title" : "Interstitial Cystitis/Painful Bladder Syndrome and Associated Medical Conditions With an Emphasis on Irritable Bowel Syndrome, Fibromyalgia and Chronic Fatigue Syndrome", "type" : "article-journal", "volume" : "184" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "URL" : "", "accessed" : { "date-parts" : [ [ "2017", "11", "28" ] ] }, "id" : "ITEM-2", "issued" : { "date-parts" : [ [ "0" ] ] }, "title" : "Definition &amp; Facts of Interstitial Cystitis | NIDDK", "type" : "webpage" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Nickel et al. 2010; \u201cDefinition &amp; Facts of Interstitial Cystitis | NIDDK\u201d n.d.)", "plainTextFormattedCitation" : "(Nickel et al. 2010; \u201cDefinition &amp; Facts of Interstitial Cystitis | NIDDK\u201d n.d.)", "previouslyFormattedCitation" : "(Nickel et al. 2010; \u201cDefinition &amp; Facts of Interstitial Cystitis | NIDDK\u201d n.d.)" }, "properties" : { }, "schema" : "" }(Nickel et al. 2010; “Definition &amp; Facts of Interstitial Cystitis | NIDDK” n.d.).Treatments for Interstitial Cystitis/Bladder Pain SyndromeIn March of 2011, the American Urological Association released clinical guidelines including a paper describing the recommended diagnosis and treatment approaches for IC/BPS recommended clinical guidelines for the diagnosis and treatment approaches of IC/BPS (Hanno et al. 2014). First-line treatments involve a relaxed approach and include education, behavioral modifications, over-the-counter medications, and stress management. Suggested second-line treatments include: physical therapy of the pelvic floor, pain management with drugs, oral medications including Elmiron/Pentosan polysulfate (PPS), and intravesical medications including dimethyl sulfoxide (DMSO). Cytoscopy and hydrodistension along with removal of Hunner’s lesions are considered to be third-line treatments. A recent study did not find any additional clinical benefit from combination of hydrodistension followed by DMSO instillation ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.3978/j.issn.2223-4683.2015.09.01", "ISSN" : "2223-4691", "PMID" : "26816859", "abstract" : "BACKGROUND Dimethylsulfoxide (DMSO) is the most-used agent for intravesical instillation. We conducted this retrospective clinical study to determine in what type of the interstitial cystitis (IC)/bladder pain syndrome (BPS) DMSO was effective. METHODS We combined DMSO with hydrodistension in 2003 and from 2004 we performed hydrodistension alone. Hydrodistension had been performed in 7 cases of IC/BPS with Hunner's lesions (H group) and 7 cases of IC/BPS without Hunner's lesions (non-H group), and they served as the control group (C group; n=14). There was also a DMSO group (D group; n=14) that consisted of an H group of 7 cases and an non-H group of 7 cases in which the hydrodistension had been immediately followed by intravesical instillation of 50% DMSO 50 mL. Before, and 2, 6, 12, 18, and 24 months (M) after the intervention, the patients were asked to complete a 4-day frequency-volume chart (FVC) and the O'Leary-Sant IC symptom index (ICSI) questionnaire and IC problem index (ICPI) questionnaire, and to rate their pain on a visual analogue scale (VAS). RESULTS All parameters were improved after hydrodistension in both the C group and the D group. However, comparison of the C group and D group according to whether Hunner lesions were present showed that there were no significant differences in any of the postoperative parameters between the non-H groups in the C group and D group, but in the H groups, average and maximum voided volume were significantly higher and the ICSI, ICPI, and VAS scores were lower in the D group. Moreover, the significant differences increased with the duration of the postoperative period. CONCLUSIONS DMSO intravesical instillation therapy was useful in both maintaining and improving the effectiveness of hydrodistension in IC/BPS with Hunner lesions. However, DMSO did not have any particular efficacy in the treatment of IC/BPS in the absence of Hunner lesions.", "author" : [ { "dropping-particle" : "", "family" : "Tomoe", "given" : "Hikaru", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Translational andrology and urology", "id" : "ITEM-1", "issue" : "6", "issued" : { "date-parts" : [ [ "2015", "12" ] ] }, "page" : "600-4", "publisher" : "AME Publications", "title" : "In what type of interstitial cystitis/bladder pain syndrome is DMSO intravesical instillation therapy effective?", "type" : "article-journal", "volume" : "4" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Tomoe 2015)", "plainTextFormattedCitation" : "(Tomoe 2015)", "previouslyFormattedCitation" : "(Tomoe 2015)" }, "properties" : { }, "schema" : "" }(Tomoe 2015) Fourth-line treatments include Botulinum toxin A (Onabotulinum toxin A) injections into the bladder muscle and neuromodulation ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "abstract" : "Purpose: The purpose of this Guideline is to provide a clinical framework for the diagnosis and treatment of interstitial cystitis/bladder pain syndrome (IC/BPS). Methods: A systematic review of the literature using the MEDLINE\u00ae database (search dates 1/1/83-7/22/09) was conducted to identify peer-reviewed publications relevant to the diagnosis and treatment of IC/BPS. Insufficient evidence was retrieved regarding diagnosis; this portion of the guideline, therefore, is based on Clinical Principles and Expert Opinion. The review yielded an evidence base of 86 treatment articles after application of inclusion/exclusion criteria. The AUA update literature review process, in which an additional systematic review is conducted periodically to maintain guideline currency with newly-published relevant literature, was conducted in July 2013. This review identified an additional 31 articles relevant to treatment. These publications were used to create the majority of the treatment portion of the guideline. When sufficient evidence existed, the body of evidence for a particular treatment was assigned a strength rating of A (high), B (moderate), or C (low). Additional treatment information is provided as Clinical Principles and Expert Opinion when insufficient evidence existed. See text and algorithm for definitions and detailed diagnostic, management, and treatment frameworks. GUIDELINE STATEMENTS Diagnosis: 1. The basic assessment should include a careful history, physical examination, and laboratory examination to rule in symptoms that characterize IC/BPS and rule out other confusable disorders (see text for details). Clinical Principle 2. Baseline voiding symptoms and pain levels should be obtained in order to measure subsequent treatment effects. Clinical Principle 3. Cystoscopy and/or urodynamics should be considered as an aid to diagnosis only for complex presentations; these tests are not necessary for making the diagnosis in uncomplicated presentations. Expert Opinion Treatment: Overall Management: 4. Treatment strategies should proceed using more conservative therapies first, with less conservative therapies employed if symptom control is inadequate for acceptable quality of life; because of their irreversibility, surgical treatments (other than fulguration of Hunner's lesions) are appropriate only after other", "author" : [ { "dropping-particle" : "", "family" : "Hanno", "given" : "Philip M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Burks", "given" : "David Allen", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Clemens", "given" : "J Quentin", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Dmochowski", "given" : "Roger R", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Erickson", "given" : "Deborah", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Fitzgerald", "given" : "Mary Pat", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Forrest", "given" : "John B", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Gordon", "given" : "Barbara", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mayer", "given" : "Robert Dale", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Newman", "given" : "Diane K", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Jr", "given" : "Leroy Nyberg", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Christopher", "given" : "K", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Wesselmann", "given" : "Ursula", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Faraday", "given" : "Martha M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "id" : "ITEM-1", "issue" : "September", "issued" : { "date-parts" : [ [ "2014" ] ] }, "page" : "1-45", "title" : "American Urological Association (AUA) Guideline: Diagnosis and treatment of interstitial cystitis/bladder pain syndrome", "type" : "article-journal" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Philip M Hanno et al. 2014)", "plainTextFormattedCitation" : "(Philip M Hanno et al. 2014)", "previouslyFormattedCitation" : "(Philip M Hanno et al. 2014)" }, "properties" : { }, "schema" : "" }(Philip M Hanno et al. 2014).MeasurementsClinicians and researchers use a variety of questionnaires to evaluate the severity of patients’ symptoms and assess progress (i.e., outcomes) with treatment. Some are also used to help screen patients for possible IC, although none is considered to be appropriate for diagnosis. Many researchers and clinicians use the Global Response Assessment (GRA) to measure overall improvement with therapy. This assessment is used for a primary end-point in clinical trials of therapies for IC. This seven-point scale assesses symptoms with the question, “As compared to when you started the study/treatment, how would you rate your IC/BPS symptoms now?”, ranging from markedly worse, to markedly improved ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "URL" : "", "accessed" : { "date-parts" : [ [ "2017", "11", "28" ] ] }, "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "0" ] ] }, "title" : "General IC Symptoms - Interstitial Cystitis Association", "type" : "webpage" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(\u201cGeneral IC Symptoms - Interstitial Cystitis Association\u201d n.d.)", "plainTextFormattedCitation" : "(\u201cGeneral IC Symptoms - Interstitial Cystitis Association\u201d n.d.)", "previouslyFormattedCitation" : "(\u201cGeneral IC Symptoms - Interstitial Cystitis Association\u201d n.d.)" }, "properties" : { }, "schema" : "" }(“General IC Symptoms - Interstitial Cystitis Association” n.d.).The O’Leary-Sant questionnaire (OSS) assesses the severity of symptoms and how much of a problem the symptoms cause for the patient. The questionnaire is divided into two sections, the Interstitial Cystitis Symptom Index (ISCI), and the Interstitial Cystitis Problem Index (ICPI). Scores are evaluated separately, and in total. This method of evaluation is standard in assessing treatment, along with the GRA ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "URL" : "", "accessed" : { "date-parts" : [ [ "2017", "11", "28" ] ] }, "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "0" ] ] }, "title" : "General IC Symptoms - Interstitial Cystitis Association", "type" : "webpage" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(\u201cGeneral IC Symptoms - Interstitial Cystitis Association\u201d n.d.)", "plainTextFormattedCitation" : "(\u201cGeneral IC Symptoms - Interstitial Cystitis Association\u201d n.d.)", "previouslyFormattedCitation" : "(\u201cGeneral IC Symptoms - Interstitial Cystitis Association\u201d n.d.)" }, "properties" : { }, "schema" : "" }(“General IC Symptoms - Interstitial Cystitis Association” n.d.). Other measurements can be used, including the Quality of Life index (HRQoL), Visual Analog Scale of Pain (VAS), voiding diaries reporting the voiding history for a minimum of three days, and cytoscopic evaluation, however the OSS and GRA surveys are considered to be the primary end- point evaluators for research involving IC/BPS ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "URL" : "", "accessed" : { "date-parts" : [ [ "2017", "11", "28" ] ] }, "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "0" ] ] }, "title" : "General IC Symptoms - Interstitial Cystitis Association", "type" : "webpage" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(\u201cGeneral IC Symptoms - Interstitial Cystitis Association\u201d n.d.)", "plainTextFormattedCitation" : "(\u201cGeneral IC Symptoms - Interstitial Cystitis Association\u201d n.d.)", "previouslyFormattedCitation" : "(\u201cGeneral IC Symptoms - Interstitial Cystitis Association\u201d n.d.)" }, "properties" : { }, "schema" : "" }(“General IC Symptoms - Interstitial Cystitis Association” n.d.).Public health significance and ObjectiveIC/BPS is highly prevalent in the population of women in the United States affecting up to 8 million women. This chronic pain condition can be extremely burdensome as symptoms are exacerbated by flare-ups associated with many aspects of life. Diet, physical activity, sexual activity, psychological state, and social interactions can all be affected and/or impacted by IC/BPS. This condition can be extremely bothersome and uncomfortable, with little immediate or long-term relief. Since there is no definitive evidence to support an autoimmune, inflammatory, structural or infectious etiology, treating patients is often challenging ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "URL" : "", "accessed" : { "date-parts" : [ [ "2017", "11", "28" ] ] }, "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "0" ] ] }, "title" : "Definition &amp; Facts of Interstitial Cystitis | NIDDK", "type" : "webpage" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(\u201cDefinition &amp; Facts of Interstitial Cystitis | NIDDK\u201d n.d.)", "plainTextFormattedCitation" : "(\u201cDefinition &amp; Facts of Interstitial Cystitis | NIDDK\u201d n.d.)", "previouslyFormattedCitation" : "(\u201cDefinition &amp; Facts of Interstitial Cystitis | NIDDK\u201d n.d.)" }, "properties" : { }, "schema" : "" }(“Definition &amp; Facts of Interstitial Cystitis | NIDDK” n.d.). Therefore, management of patient’s symptoms is the ultimate goal of treatment for improved quality of life. Understanding the literature surrounding the approved pharmacological treatments, as well as reviewing more recent research on newer diagnostic and treatment methods could allow for updated standards that may drastically improve the management of symptoms in patients with IC/BPS.This paper aims to evaluate the available literature on the efficacy and management of symptoms of two FDA approved pharmacological treatments, dimethyl sulfoxide (DMSO) and Elmiron/Pentosan polysulfate (PPS) compared to Onabotulinum toxin A, a non-FDA approved pharmacological treatment for IC/BPS. methodsThis paper is based on a literature review. Articles were located by searching online scientific resources such as PubMed and OVID databases between 1966 and October 21, 2017. The search strategy contained MeSH subheadings and word variations for IC/BPS and Methods of Treatment. Search terms included were (interstitial cystitis OR painful bladder syndrome OR bladder pain syndrome) AND (dimethyl sulfoxide OR dmso OR elmiron OR pentosane polysulfate OR botulinum toxin OR Onabotulinum toxin A OR OnabotulinumtoxinA OR botox) then filtered by “clinical trial” and “humans.” Exclusion criteria included studies that did not have measures or comparison of symptoms at baseline per treatment, research with combined therapies, and research with objectives that not include symptomatic analyses. Figure 1 illustrates the results from the database search. In total, 33 papers were found. Nine papers were found on the treatment method of DMSO. One paper was ruled ineligible because the treatment group receiving DMSO received a dose that also included heparin and corticosteroids. Two papers were ruled ineligible because there were no comparisons to baseline, and only to other drug arms. One paper was ruled ineligible because there was no English translation. One paper from the 1970s was ruled ineligible because at the time of publishing, the study was still ongoing and there was limited data to compare to baseline. In total, four papers were included in the critical review regarding intravesical DMSO treatment. Fourteen papers were included in the initial literature review of oral PPS therapy for IC/BPS. Three papers were excluded because details of the study were reviewed in another included paper, and the retrospective analyses of these data were not evaluating the symptomatic improvement. Two studies were excluded for no comparison of symptoms to baseline, and one other paper did not include the symptomatic improvement. In total, eight papers were evaluated for the review of literature on PPS treatment of IC/BPS symptoms. For the Onabotulinum toxin A review, one paper was excluded because it did not report baseline and follow-up symptom findings. Twenty-one papers met all criteria and were included in the literature review.-84455-606425013763914190528Excluded N=1200Excluded N=12Figure 1. Literature review search strategy and selection criteria of Pubmed articles (1966-November 1, 2017) on the efficacy and management of symptoms of dimethyl sulfoxide (DMSO), Elmiron/Pentosan polysulfate (PPS), and OnabotulinumtoxinA for the treatment of Interstitial Cystitis/Bladder Pain Syndrome.resultspentosan polysulfatePopulation and Definition of Interstitial Cystitis/Bladder Pain Syndrome Table 1 shows the results for studies involving PPS. Six studies were completed in the United States, and one study was completed in both the US and Canada, and one exclusively in Canada. Eighty-three percent of participants were women, and 17% were men. In 1987, the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) put forth a definition that includes 18 exclusion requirements, and three inclusion requirements, one of which is Hunner’s Ulcer or glomerulations on cystoscopic exam. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "URL" : "", "accessed" : { "date-parts" : [ [ "2017", "11", "28" ] ] }, "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "0" ] ] }, "title" : "Definition &amp; Facts of Interstitial Cystitis | NIDDK", "type" : "webpage" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(\u201cDefinition &amp; Facts of Interstitial Cystitis | NIDDK\u201d n.d.)", "plainTextFormattedCitation" : "(\u201cDefinition &amp; Facts of Interstitial Cystitis | NIDDK\u201d n.d.)", "previouslyFormattedCitation" : "(\u201cDefinition &amp; Facts of Interstitial Cystitis | NIDDK\u201d n.d.)" }, "properties" : { }, "schema" : "" }(“Definition &amp; Facts of Interstitial Cystitis | NIDDK” n.d.). None of the papers included in the review cited the NIDDK criteria for the definition of IC/BPS in diagnosis of participants. While criteria may still have been met, for some patients, this inclusion/exclusion criteria was not the standard definition for recruiting participants, and these studies did not evaluate the difference between Hunner’s and non-Hunner’s ulcer type patients. Definition of IC/BPS was based upon recurrence and severity of symptoms in all the included papers. Nickel et al. (2015) did not take cystoscopic evaluation into consideration during recruitment of participants, and actually excluded patients, if cystoscopy was performed within four weeks of the study. All participants were over the age of 18, and could not be pregnant or lactating. Ethnic differences in population were not addressed. An early study by Nickel et al (2005) allowed participants to remain on antidepressant and antihistamine therapy throughout the duration of the PPS therapy if an already an established treatment was in place. In a subsequent study by the same authors (Nickel et al 2015), they addressed this confounding effect by excluding participants who were taking any drug that could affect IC/BPS, including antidepressants or antihistamines MeasurementsThree of seven papers (Nickel et al 2015; Davis et al 2008; Nickel et al 2005) used the OSS, ICSI, and ICPI for evaluation of severity and symptoms (ICSI) and the bothersome burden for participants (Table 1). Four of seven papers (ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/j.juro.2014.09.036", "ISSN" : "00225347", "PMID" : "25245489", "abstract" : "PURPOSE We compared the efficacy and safety of the currently recommended dose of pentosan polysulfate sodium with a third of the daily dose and with placebo. MATERIALS AND METHODS In this multicenter, double-blind, randomized, placebo controlled study 368 adults with interstitial cystitis/bladder pain syndrome, defined as an ICSI total score of 8 or greater and a score of greater than 0 on the 4 ICSI component items, received pentosan polysulfate sodium 100 mg once daily or 3 times daily, or matching placebo for 24 weeks. Study eligibility was not based on cystoscopy findings. ICSI was administered at baseline, and at weeks 4, 8, 12, 18 and 24. Unblinded interim analysis performed at 6 years with 54% of the target number of 645 patients enrolled resulted in early study termination. RESULTS There was no statistically significant difference between the pentosan polysulfate sodium group and the placebo group or between the 2 pentosan polysulfate sodium groups for the primary end point, defined as responder achieving a 30% or greater reduction from the baseline ICSI total score at study end. This primary end point was achieved by 48 of 118 patients (40.7%) in the placebo group, and by 51 of 128 (39.8%) and 52 of 122 (42.6%) in the pentosan polysulfate sodium 100 mg once daily and 3 times daily groups, respectively. Pentosan polysulfate sodium was well tolerated with a similar percent of patients (range 10.2% to 13.3%) across the groups discontinuing due to an adverse event. CONCLUSIONS Results of this study in a broad population of patients with symptoms consistent with interstitial cystitis revealed no treatment effect vs placebo for pentosan polysulfate sodium at the currently established dose or at a third of the daily dose.", "author" : [ { "dropping-particle" : "", "family" : "Nickel", "given" : "J. Curtis", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Herschorn", "given" : "Sender", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Whitmore", "given" : "Kristene E.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Forrest", "given" : "John B.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hu", "given" : "Peter", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Friedman", "given" : "Andrew J.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Baseman", "given" : "Alan S.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "The Journal of Urology", "id" : "ITEM-1", "issue" : "3", "issued" : { "date-parts" : [ [ "2015", "3" ] ] }, "page" : "857-862", "title" : "Pentosan Polysulfate Sodium for Treatment of Interstitial Cystitis/Bladder Pain Syndrome: Insights from a Randomized, Double-Blind, Placebo Controlled Study", "type" : "article-journal", "volume" : "193" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "DOI" : "10.1016/j.juro.2007.08.170", "ISSN" : "00225347", "PMID" : "18001798", "abstract" : "PURPOSE We examined the safety and the efficacy of a combination of intravesical and oral pentosan polysulfate sodium in comparison to only oral pentosan polysulfate sodium in treating interstitial cystitis. MATERIALS AND METHODS A total of 41 females diagnosed with interstitial cystitis were randomized to receive a combination of intravesical pentosan polysulfate sodium plus oral pentosan polysulfate sodium (21 in treatment group) or intravesical placebo plus oral pentosan polysulfate sodium (20 in placebo group) for 6 weeks. All subjects continued to receive oral pentosan polysulfate sodium for another 12 weeks. The primary outcome was the change in the O'Leary-Sant Interstitial Cystitis Symptoms/Problem Index from baseline to week 6, 12, and 18. Other outcomes included: the changes in Pelvic Pain and Urgency Frequency questionnaire, Health Related Quality of Life index: SF-36, pain scale, urgency scale, voiding log, patient global assessment, and sexual function scales. RESULTS The change in the total score of O'Leary-Sant Interstitial Cystitis Symptoms/Problems Index from baseline to week 12 among the treatment group (median -12 or approximately a 46% reduction) was significantly greater compared to the placebo group (median -5.5 or approximately a 24% reduction, p = 0.04). At week 18 the treatment group showed statistically significant improvement in all Health Related Quality of Life domains compared to the baseline (p < or = 0.01), while the placebo group showed significant improvement in only 3 Health Related Quality of Life domains, (p < or = 0.05) compared to the baseline. There were no significant differences within major categories of adverse events between treated and placebo groups. CONCLUSIONS The use of intravesical pentosan polysulfate sodium simultaneously with oral pentosan polysulfate sodium is a safe and effective therapeutic option. These findings will open a new option for patients with interstitial cystitis to reduce their severely devastating symptoms and to improve their quality of life and well-being.", "author" : [ { "dropping-particle" : "", "family" : "Davis", "given" : "Edward L.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Khoudary", "given" : "Samar R.", "non-dropping-particle" : "El", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Talbott", "given" : "Evelyn O.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Davis", "given" : "Josephine", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Regan", "given" : "Lisa J.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "The Journal of Urology", "id" : "ITEM-2", "issue" : "1", "issued" : { "date-parts" : [ [ "2008", "1" ] ] }, "page" : "177-185", "title" : "Safety and Efficacy of the Use of Intravesical and Oral Pentosan Polysulfate Sodium for Interstitial Cystitis: A Randomized Double-Blind Clinical Trial", "type" : "article-journal", "volume" : "179" }, "uris" : [ "" ] }, { "id" : "ITEM-3", "itemData" : { "ISSN" : "0090-4295", "PMID" : "9146008", "abstract" : "OBJECTIVES The long-term efficacy and safety of Elmiron (oral pentosan polysulfate sodium) in relieving recurring symptoms of interstitial cystitis (IC) were investigated in a long-term, open-label physician's usage study. METHODS Patients with diagnosed interstitial cystitis who met the study entry criteria received shipments of Elmiron for 3 months at a dose of 100 mg 3 times a day and for the consecutive 3-month periods, provided they completed and returned questionnaires about their disease symptoms, reported any adverse events, and had laboratory data collected before each new shipment. Patients were required to purchase the medication. Responses to questionnaires provided the data reported here. Several symptomatic parameters of the disease (overall improvement, overall improvement in pain and urgency, urinary frequency, and nocturia) were recorded in this way and used to evaluate efficacy. RESULTS Elmiron usage was correlated with improvements in some symptoms, and these improvements increased with duration of treatment. Some symptoms were improved within 5 months, although most continued to show improvements in both severity rating and in percentage of positive responders over 1 to 2 years. Populations of patients receiving extended treatment, some for > 90 months, showed no further improvement or worsening in symptom values. Forty-six percent of patients dropped out of the study within the first 3 months of Elmiron treatment. The frequency of adverse events was < 4%. The most notable adverse events were reversible alopecia, diarrhea, nausea, headache, and rash. CONCLUSIONS Elmiron appears to be an efficacious long-term treatment for reducing a constellation of debilitating symptoms associated with interstitial cystitis in some patients. Patients with a positive response to Elmiron appear to maintain this response over time.", "author" : [ { "dropping-particle" : "", "family" : "Hanno", "given" : "P M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Urology", "id" : "ITEM-3", "issue" : "5A Suppl", "issued" : { "date-parts" : [ [ "1997", "5" ] ] }, "page" : "93-9", "title" : "Analysis of long-term Elmiron therapy for interstitial cystitis.", "type" : "article-journal", "volume" : "49" }, "uris" : [ "" ] }, { "id" : "ITEM-4", "itemData" : { "ISSN" : "0022-5347", "PMID" : "7688432", "abstract" : "A randomized, prospective, double-blind, placebo-controlled study was conducted at 7 clinical centers on 148 patients. Patients received orally either 100 mg. pentosanpolysulfate (a synthetic polysaccharide) 3 times per day or a placebo. Of the patients on drug therapy 32% showed significant improvement compared to 16% of those on placebo (p = 0.01). This study provides a model to assess this disease quantitatively in a prospective manner using a method whereby the patients globally assess their symptoms as either worse or improved by 0, 25, 50, 75 or 100%. Patients on drug therapy also experienced a significant decrease in pain and urgency (p = 0.04 and 0.01) on analogue scales when compared to placebo and also more drug patients showed an average increase of more than 20 ml. in voided volume than did placebo patients (p = 0.02). All adverse effects were minor, with 7 in the drug group and 10 in the placebo group. The results support the concept that some patients with the interstitial cystitis syndrome may have abnormal bladder surface glycosaminoglycans.", "author" : [ { "dropping-particle" : "", "family" : "Parsons", "given" : "C L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Benson", "given" : "G", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Childs", "given" : "S J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hanno", "given" : "P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sant", "given" : "G R", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Webster", "given" : "G", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "The Journal of urology", "id" : "ITEM-4", "issue" : "3", "issued" : { "date-parts" : [ [ "1993", "9" ] ] }, "page" : "845-8", "title" : "A quantitatively controlled method to study prospectively interstitial cystitis and demonstrate the efficacy of pentosanpolysulfate.", "type" : "article-journal", "volume" : "150" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Nickel et al. 2015; Davis et al. 2008; P M Hanno 1997; Parsons et al. 1993)", "plainTextFormattedCitation" : "(Nickel et al. 2015; Davis et al. 2008; P M Hanno 1997; Parsons et al. 1993)", "previouslyFormattedCitation" : "(Nickel et al. 2015; Davis et al. 2008; P M Hanno 1997; Parsons et al. 1993)" }, "properties" : { }, "schema" : "" }(Nickel et al. 2015; Davis et al. 2008; P M Hanno 1997; Parsons et al. 1993) all used the Global Response Assessment (GRA) to measure the overall symptomatic improvement. For studies prior to the development of these standardized scales, analog pain and symptom scales were used. All studies had major components of self-reporting of symptoms as a measure of efficacy of the treatments (Table 1).Study Design and OutcomesTwo of eight papers concluded that pentosanepolysulfate is not an efficacious treatment for IC/BPS (ref for the two papers here). Nickel et al (2015). performed a multicenter, double-blind, randomized placebo controlled study on 368 adults with IC/BPS. Participants did not undergo cytoscopic evaluations, and were considered eligible based on having a total ICSI score of 8 or greater, and a score greater than 0 on each of the 4 ICSI component items. Although researchers were expecting a 30% or greater reduction from baseline in ICSI score in those who received the drug, no statistical difference was found between the PPS and placebo group ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/j.juro.2014.09.036", "ISSN" : "00225347", "PMID" : "25245489", "abstract" : "PURPOSE We compared the efficacy and safety of the currently recommended dose of pentosan polysulfate sodium with a third of the daily dose and with placebo. MATERIALS AND METHODS In this multicenter, double-blind, randomized, placebo controlled study 368 adults with interstitial cystitis/bladder pain syndrome, defined as an ICSI total score of 8 or greater and a score of greater than 0 on the 4 ICSI component items, received pentosan polysulfate sodium 100 mg once daily or 3 times daily, or matching placebo for 24 weeks. Study eligibility was not based on cystoscopy findings. ICSI was administered at baseline, and at weeks 4, 8, 12, 18 and 24. Unblinded interim analysis performed at 6 years with 54% of the target number of 645 patients enrolled resulted in early study termination. RESULTS There was no statistically significant difference between the pentosan polysulfate sodium group and the placebo group or between the 2 pentosan polysulfate sodium groups for the primary end point, defined as responder achieving a 30% or greater reduction from the baseline ICSI total score at study end. This primary end point was achieved by 48 of 118 patients (40.7%) in the placebo group, and by 51 of 128 (39.8%) and 52 of 122 (42.6%) in the pentosan polysulfate sodium 100 mg once daily and 3 times daily groups, respectively. Pentosan polysulfate sodium was well tolerated with a similar percent of patients (range 10.2% to 13.3%) across the groups discontinuing due to an adverse event. CONCLUSIONS Results of this study in a broad population of patients with symptoms consistent with interstitial cystitis revealed no treatment effect vs placebo for pentosan polysulfate sodium at the currently established dose or at a third of the daily dose.", "author" : [ { "dropping-particle" : "", "family" : "Nickel", "given" : "J. Curtis", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Herschorn", "given" : "Sender", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Whitmore", "given" : "Kristene E.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Forrest", "given" : "John B.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hu", "given" : "Peter", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Friedman", "given" : "Andrew J.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Baseman", "given" : "Alan S.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "The Journal of Urology", "id" : "ITEM-1", "issue" : "3", "issued" : { "date-parts" : [ [ "2015", "3" ] ] }, "page" : "857-862", "title" : "Pentosan Polysulfate Sodium for Treatment of Interstitial Cystitis/Bladder Pain Syndrome: Insights from a Randomized, Double-Blind, Placebo Controlled Study", "type" : "article-journal", "volume" : "193" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Nickel et al. 2015)", "plainTextFormattedCitation" : "(Nickel et al. 2015)", "previouslyFormattedCitation" : "(Nickel et al. 2015)" }, "properties" : { }, "schema" : "" }(Nickel et al. 2015). Holm-Bentzen et al 1987 also performed a prospective double-blind multicenter trial of pentosane polysulfate but divided participants into two protocols for randomization after cytoscopic evaluation. IC patients with specified histological findings (28 or more mast cells per mm squared in the detrusor muscle) were allocated to protocol A and symptomatically diagnosed participants with unspecified histological findings were assigned to Protocol B. To ensure the degree of severity in the second protocol group, participants had to have 3 or more voidings each night, and more than 10 points on the defined symptom score scale at baseline ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "ISSN" : "0022-5347", "PMID" : "2442415", "abstract" : "Painful bladder disease, sensory bladder disease, chronic abacterial cystitis and interstitial cystitis are ill-defined conditions of unknown etiology and pathogenesis, and, therefore, they are without any rational therapy. Pathogenetic theories concerning defects in the epithelium and/or mucous surface coat (including glycosaminoglycans) of the bladder, and theories concerning immunological disturbances predominate. Sodium pentosanpolysulfate (Elmiron) acts by substituting a defective glycosaminoglycan layer and inhibits complement reactions in inflammatory processes. We compared sodium pentosanpolysulfate versus placebo in a prospective double-blind, clinically controlled multicenter trial of 115 patients with painful bladder disease. Two protocols were used. Protocol A included 43 patients with clinically and pathologically anatomically verified interstitial cystitis (28 or more mast cells per mm.2), and protocol B included 72 patients with a painful bladder and unspecific histological findings. The patients were randomized to receive either sodium pentosanpolysulfate (200 mg. twice daily) or placebo capsules for 4 months. Before and after the trial the patients were evaluated with symptom grading, urodynamics and cystoscopy with distension and deep bladder biopsies. The results showed no difference between the pre-trial and post-trial values in the sodium pentosanpolysulfate and placebo groups in both protocols in regard to symptoms, urodynamic parameters, cystoscopic appearance and mast cell counts. A significant increase in the cystoscopically determined bladder capacity in the sodium pentosanpolysulfate group in protocol A was found. We conclude that no statistically or clinically significant effect of sodium pentosanpolysulfate was found compared to placebo in patients with painful bladder disease.", "author" : [ { "dropping-particle" : "", "family" : "Holm-Bentzen", "given" : "M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Jacobsen", "given" : "F", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Nerstr\u00f8m", "given" : "B", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lose", "given" : "G", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kristensen", "given" : "J K", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Pedersen", "given" : "R H", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Krarup", "given" : "T", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Feggetter", "given" : "J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bates", "given" : "P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Barnard", "given" : "R", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "The Journal of urology", "id" : "ITEM-1", "issue" : "3", "issued" : { "date-parts" : [ [ "1987", "9" ] ] }, "page" : "503-7", "title" : "A prospective double-blind clinically controlled multicenter trial of sodium pentosanpolysulfate in the treatment of interstitial cystitis and related painful bladder disease.", "type" : "article-journal", "volume" : "138" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Holm-Bentzen et al. 1987)", "plainTextFormattedCitation" : "(Holm-Bentzen et al. 1987)", "previouslyFormattedCitation" : "(Holm-Bentzen et al. 1987)" }, "properties" : { }, "schema" : "" }(Holm-Bentzen et al. 1987). Researchers found no difference between treatment group and placebo groups in participants allocated to both protocols with regard to symptoms, urodynamic parameters, and cystoscopic appearances. However, significant increase in the cystoscopically determined bladder capacity was found in the Protocol A treatment group. Ultimately, the findings of the study did not confirm the efficacy of PPS for the treatment of IC/BPS. Six of eight papers reported finding PPS to be successful and effective in treating the symptoms of IC/BPS (Table 1). Nickel et al (2005) compared three dosages of PPS to evaluate symptom responses. Participants were randomized to receive either the standard dose of 100 mg oral PPS, three times daily, or 200 mg or 300 mg of oral PPS, three times daily. Results showed that mean baseline of ICSI scores improved after 32 weeks for all dosages (p<0.01), however there was no significant difference between dosage groups, therefore rejecting their hypothesis that response to treatment was dose dependent. Davis et al. (2008) saw a 46% reduction (p<0.05) in ICSI over 18 weeks, along with a significant improvement of HRQoL in those treated with oral PPS. An open-label physician’s usage study Hanno (1997) evaluated the long-term efficacy and safety of PPS for the treatment of IC/BPS symptoms. Similar to Davis et al (2008) patient assessments of overall change in IC symptoms showed that 42% to 62% experienced moderate or better improvement compared to symptoms prior to PPS therapy ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "ISSN" : "0090-4295", "PMID" : "9146008", "abstract" : "OBJECTIVES The long-term efficacy and safety of Elmiron (oral pentosan polysulfate sodium) in relieving recurring symptoms of interstitial cystitis (IC) were investigated in a long-term, open-label physician's usage study. METHODS Patients with diagnosed interstitial cystitis who met the study entry criteria received shipments of Elmiron for 3 months at a dose of 100 mg 3 times a day and for the consecutive 3-month periods, provided they completed and returned questionnaires about their disease symptoms, reported any adverse events, and had laboratory data collected before each new shipment. Patients were required to purchase the medication. Responses to questionnaires provided the data reported here. Several symptomatic parameters of the disease (overall improvement, overall improvement in pain and urgency, urinary frequency, and nocturia) were recorded in this way and used to evaluate efficacy. RESULTS Elmiron usage was correlated with improvements in some symptoms, and these improvements increased with duration of treatment. Some symptoms were improved within 5 months, although most continued to show improvements in both severity rating and in percentage of positive responders over 1 to 2 years. Populations of patients receiving extended treatment, some for > 90 months, showed no further improvement or worsening in symptom values. Forty-six percent of patients dropped out of the study within the first 3 months of Elmiron treatment. The frequency of adverse events was < 4%. The most notable adverse events were reversible alopecia, diarrhea, nausea, headache, and rash. CONCLUSIONS Elmiron appears to be an efficacious long-term treatment for reducing a constellation of debilitating symptoms associated with interstitial cystitis in some patients. Patients with a positive response to Elmiron appear to maintain this response over time.", "author" : [ { "dropping-particle" : "", "family" : "Hanno", "given" : "P M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Urology", "id" : "ITEM-1", "issue" : "5A Suppl", "issued" : { "date-parts" : [ [ "1997", "5" ] ] }, "page" : "93-9", "title" : "Analysis of long-term Elmiron therapy for interstitial cystitis.", "type" : "article-journal", "volume" : "49" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(P M Hanno 1997)", "plainTextFormattedCitation" : "(P M Hanno 1997)", "previouslyFormattedCitation" : "(P M Hanno 1997)" }, "properties" : { }, "schema" : "" }(P M Hanno 1997) Similar findings were reported for pain (Table 1). Length of treatment varied by participant due to the nature of this study design.Parsons et al. (1993) conducted a randomized prospective double-blind placebo controlled study with a definition of IC/BPS based upon bladder capacity, voiding eight times per day or more, a small average voided volume and nocturia (Table 1). If a patient did not meet one or two of these inclusion criteria, they could enter the study but had to have pain and/or moderate urgency and negative urine cultures. A follow-up questionnaire was administered to confirm the efficacy of the treatment compared to placebo. After 3 months, Thirty two percent of patients taking PPS showed significant improvement compared to 16% in the placebo group (p=0.01). Further, participants receiving drug therapy also experienced at least a 50% improvement in symptoms of pain (p=0.04) and urgency p=0.01) when compared to placebo. PPS treated patients showed an average increase of more than 20 mL in voided volume than the placebo patients (p=0.02). These findings are similar to the earlier study by Parson et al (1987) where follow up was longer, but non-standardized scales were used to measure treatment efficacy (Table 1).Lastly, Parsons and Mulholland (1987) published a multi-centered double-blind study, where patients were enrolled and treated for 3 months with PPS at the recommended dose of 100 mg oral PPS, three times daily (Table 1). At three months, there was a 26% improvement in the treatment group (p=0.03) based on the investigators review of voiding profiles, pain and urgency survey responses. Similarly, patients self-evaluated their overall improvement in symptoms as 28% (p=0.04). When evaluating pain alone, 46% of participants (p=0.07) reported improvement. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "ISSN" : "0022-5347", "PMID" : "2442417", "abstract" : "Sodium pentosanpolysulfate (Elmiron) is a synthetic, sulfated polysaccharide available in an oral form that is excreted into the urine. This drug was used in a double-blind fashion to evaluate its efficacy in the management of symptoms of interstitial cystitis. A dose of 100 mg. 3 times daily was used for a minimum of 4 months and was continued for longer than 18 months in some individuals. A total of 62 patients was evaluated from 2 different medical centers. Subjective improvements were greater in all parameters when the drug was compared to placebo therapy, with significant improvement in pain, urgency, frequency and nocturia. Objective improvement in average voided volumes was greater with the drug than with placebo (p equals 0.009). No significant difference was found between drug and placebo groups in the average number of daily voiding episodes.", "author" : [ { "dropping-particle" : "", "family" : "Parsons", "given" : "C L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mulholland", "given" : "S G", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "The Journal of urology", "id" : "ITEM-1", "issue" : "3", "issued" : { "date-parts" : [ [ "1987", "9" ] ] }, "page" : "513-6", "title" : "Successful therapy of interstitial cystitis with pentosanpolysulfate.", "type" : "article-journal", "volume" : "138" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Parsons and Mulholland 1987)", "plainTextFormattedCitation" : "(Parsons and Mulholland 1987)", "previouslyFormattedCitation" : "(Parsons and Mulholland 1987)" }, "properties" : { }, "schema" : "" }(Parsons and Mulholland 1987)Dimethyl SulfoxidePopulation and Definition of Interstitial Cystitis/Bladder Pain SyndromeTable 2 shows the results of the papers evaluating DMSO for the treatment of IC/BPS. In the studies evaluating the effects of dimethyl sulfoxide (DMSO), the recruitment criteria were similar, but not entirely standard for each paper. A majority of the participants in studies were women (96%). Studies were completed in: Belgium, Italy, Sweden, and Canada – none in the US. Peeker et al (20xx) defined IC/BPS according to the NIDDK definition, and all other papers utilized their own definitions and criteria based on cytoscopic findings and symptomology. Peeker et al (20xx) was also the only group to look at a comparison of Hunner’s vs. non-ulcerative IC/BPS, and all other papers did not evaluate the differences. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "ISSN" : "0022-5347", "PMID" : "3288775", "abstract" : "To evaluate the effectiveness of dimethyl sulfoxide in the treatment of patients with biopsies suggestive of interstitial cystitis, 33 patients underwent a controlled crossover trial. Patients were allocated randomly to receive 50 per cent dimethyl sulfoxide or placebo (saline). The medication was administered intravesically every 2 weeks for 2 sessions of 4 treatments each. Response was assessed urodynamically and symptomatically. Thirty women and 3 men (mean age 48 years and mean duration of symptoms 5.5 years) were entered into the study. No significant side effects to dimethyl sulfoxide were noted. When assessed subjectively, 53 per cent of dimethyl sulfoxide treated patients were markedly improved compared to 18 per cent of the placebo treated patients. Of the dimethyl sulfoxide group 93 per cent had objective improvement versus 35 per cent of the placebo group. Thus, dimethyl sulfoxide proved to be superior to placebo in the objective and subjective improvement of patients with interstitial cystitis.", "author" : [ { "dropping-particle" : "", "family" : "Perez-Marrero", "given" : "R", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Emerson", "given" : "L E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Feltis", "given" : "J T", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "The Journal of urology", "id" : "ITEM-1", "issue" : "1", "issued" : { "date-parts" : [ [ "1988", "7" ] ] }, "page" : "36-9", "title" : "A controlled study of dimethyl sulfoxide in interstitial cystitis.", "type" : "article-journal", "volume" : "140" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Perez-Marrero, Emerson, and Feltis 1988)", "plainTextFormattedCitation" : "(Perez-Marrero, Emerson, and Feltis 1988)", "previouslyFormattedCitation" : "(Perez-Marrero, Emerson, and Feltis 1988)" }, "properties" : { }, "schema" : "" }(Perez-Marrero, Emerson, and Feltis 1988) reported that all participants met criteria of 18 mast cells per mm squared, but no ulcers were found. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1002/nau.23091", "ISSN" : "07332467", "author" : [ { "dropping-particle" : "", "family" : "Cervigni", "given" : "Mauro", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sommariva", "given" : "Monica", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Tenaglia", "given" : "Raffaele", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Porru", "given" : "Daniele", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ostardo", "given" : "Edoardo", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Giamm\u00f2", "given" : "Alessandro", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Trevisan", "given" : "Silvia", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Frangione", "given" : "Valeria", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ciani", "given" : "Oriana", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Tarricone", "given" : "Rosanna", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Pappagallo", "given" : "Giovanni L.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Neurourology and Urodynamics", "id" : "ITEM-1", "issue" : "4", "issued" : { "date-parts" : [ [ "2017", "4", "1" ] ] }, "page" : "1178-1186", "title" : "A randomized, open-label, multicenter study of the efficacy and safety of intravesical hyaluronic acid and chondroitin sulfate versus dimethyl sulfoxide in women with bladder pain syndrome/interstitial cystitis", "type" : "article-journal", "volume" : "36" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Cervigni et al. 2017)", "plainTextFormattedCitation" : "(Cervigni et al. 2017)", "previouslyFormattedCitation" : "(Cervigni et al. 2017)" }, "properties" : { }, "schema" : "" }(Cervigni et al. 2017) required that participants should have tried, but were unsuccessful with oral treatment of PPS, cyclosporine – A, antihistamines, antidepressant and antiepileptics, with a minimum of three months since previous treatment, authors excluded participants who had received any other type of intravesical treatment. Tutolo et al (20xx) excluded participants if they had been receiving therapies or medications that could affect IC/BPS including antidepressants, antihistamines, intravesical treatments, investigational treatments, antispasmodics or anticholinergics. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1590/S1677-5538.IBJU.2016.0302", "ISSN" : "1677-6119", "PMID" : "28124536", "abstract" : "OBJECTIVE To compare effectiveness of intravesical chondro\u00eftin sulphate (CS) 2% and dimethyl sulphoxide (DMSO) 50% in patients with painful bladder syndrome/interstitial cystitis (PBS/IC). MATERIALS AND METHODS Patients were randomized to receive either 6 weekly instillations of CS 2% or 50% DMSO. Primary endpoint was difference in proportion of patients achieving score 6 (moderately improved) or 7 (markedly improved) in both groups using the Global Response Assessment (GRA) scale. Secondary parameters were mean 24-hours frequency and nocturia on a 3-day micturition dairy, changes from baseline in O'Leary-Sant questionnaire score and visual analog scale (VAS) for suprapubic pain. RESULTS Thirty-six patients were the intention to treat population (22 in CS and 14 in DMSO group). In DMSO group, 57% withdrew consent and only 6 concluded the trial. Major reasons were pain during and after instillation, intolerable garlic odor and lack of efficacy. In CS group, 27% withdrew consent. Compared with DMSO group, more patients in CS group (72.7% vs. 14%) reported moderate or marked improvement (P=0.002, 95% CI 0.05-0.72) and achieved a reduction in VAS scores (20% vs. 8.3%). CS group performed significantly better in pain reduction (-1.2 vs. -0.6) and nocturia (-2.4 vs. -0.7) and better in total O'Leary reduction (-9.8 vs. -7.2). CS was better tolerated. The trial was stopped due to high number of drop-outs with DMSO. CONCLUSIONS Intravesical CS 2% is viable treatment for PBS/IC with minimal side effects. DMSO should be used with caution and with active monitoring of side effects. More randomized controlled studies on intravesical treatments are needed.", "author" : [ { "dropping-particle" : "", "family" : "Tutolo", "given" : "Manuela", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ammirati", "given" : "Enrico", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Castagna", "given" : "Giulia", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Klockaerts", "given" : "Katrien", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Plancke", "given" : "Hendrik", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ost", "given" : "Dieter", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Aa", "given" : "Frank", "non-dropping-particle" : "Van der", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ridder", "given" : "Dirk", "non-dropping-particle" : "De", "parse-names" : false, "suffix" : "" } ], "container-title" : "International braz j urol : official journal of the Brazilian Society of Urology", "id" : "ITEM-1", "issue" : "1", "issued" : { "date-parts" : [ [ "2017" ] ] }, "page" : "134-141", "publisher" : "Brazilian Society of Urology", "title" : "A prospective randomized controlled multicentre trial comparing intravesical DMSO and chondro\u00eftin sulphate 2% for painful bladder syndrome/interstitial cystitis.", "type" : "article-journal", "volume" : "43" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Tutolo et al. 2017)", "plainTextFormattedCitation" : "(Tutolo et al. 2017)", "previouslyFormattedCitation" : "(Tutolo et al. 2017)" }, "properties" : { }, "schema" : "" }(Tutolo et al. 2017) and ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1002/nau.23091", "ISSN" : "07332467", "author" : [ { "dropping-particle" : "", "family" : "Cervigni", "given" : "Mauro", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sommariva", "given" : "Monica", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Tenaglia", "given" : "Raffaele", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Porru", "given" : "Daniele", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ostardo", "given" : "Edoardo", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Giamm\u00f2", "given" : "Alessandro", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Trevisan", "given" : "Silvia", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Frangione", "given" : "Valeria", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ciani", "given" : "Oriana", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Tarricone", "given" : "Rosanna", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Pappagallo", "given" : "Giovanni L.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Neurourology and Urodynamics", "id" : "ITEM-1", "issue" : "4", "issued" : { "date-parts" : [ [ "2017", "4", "1" ] ] }, "page" : "1178-1186", "title" : "A randomized, open-label, multicenter study of the efficacy and safety of intravesical hyaluronic acid and chondroitin sulfate versus dimethyl sulfoxide in women with bladder pain syndrome/interstitial cystitis", "type" : "article-journal", "volume" : "36" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Cervigni et al. 2017)", "plainTextFormattedCitation" : "(Cervigni et al. 2017)", "previouslyFormattedCitation" : "(Cervigni et al. 2017)" }, "properties" : { }, "schema" : "" }(Cervigni et al. 2017) excluded pregnant and lactating mothers as well, because DMSO can be excreted in milk and cross the placenta. MeasurementsAll measurements of efficacy were related to the reduction of pain intensity and symptoms. Seventy-five percent of studies used the Visual Analog Scale of pain (VAS) to measure the outcome, and 50% of papers used the OSS and the GRA as well. All studies evaluated self-report voiding diaries, and video-urodynamic analyses were not performed on any patients. Study Design and OutcomesThe studies evaluated can be found in Table 2. The most recent study, Tutolo et al (2015) compared the effectiveness of intravesical chondroitin sulphate (CS) and DMSO in the treatment of symptoms for patients with IC/BPS. This prospective single-blind randomized multicentered trial randomized patients to receive 6 weekly instillations of CS 2% or DMSO 50%, and measured the changes from baseline in the OSS and VAS. No significant changes in any of the symptomatic or pain scales were found, and the study was halted early ended early due to the high drop-out rate of DMSO. The study concluded that DMSO should be used with caution and involve active monitoring of side effects. The three other studies that were considered for this review found DMSO to be an effective method of treatment. Cervigni et al (2017) completed a randomized open-label multicenter study for evaluating the safety and efficacy of hyaluronic acid and chondroitin sulfate versus DMSO where female participants were randomized for 13 weekly instillations of the medication. Participants were evaluated at baseline, after the final treatment at 13 weeks, and six months post treatment. Compared to baseline, a significant reduction (at least 50%) in pain intensity was observed at six months (p<0.0001). Significant improvements in urination frequency, and in all categories of the ICSI, ICPI, PUF were found at three months and six months when compared to baseline in the DMSO group (p<0.0001). Peeker et al (2000) compared intravesical bacillus Calmette- Guerin (BCG) and DMSO for treatment of ulcerative and nonulcerative IC/BPS in a prospective, randomized double-blind study in Sweden (Table 2). Twenty-one patients randomly underwent treatments for six weeks, and if were not successful with first assigned treatment, crossed-over to the other substance after a washout period. The study found that there was no significant increase in maximal functional capacity in either subtype following DMSO, but there was a significant pain reduction (from a score of 6 to 4) measured by VAS in both classic and non-ulcer IC/BPS (p<0.05), and significant reduction in urgency in the ulcerative group. In 1985, Perez-Marrero et al. completed a controlled cross-over trial, which was the only study that evaluated DMSO at three months and six months compared with a true placebo of normal saline solution intravesically every two weeks for two sessions of four treatments each (Table 2). There was a four-week washout period in between treatments. The evaluators who provided the objective response were blinded to treatment group. When assessed subjectively, 53% of DMSO treated patients were markedly improved vs. 18% of placebo patients. When assessed objectively using voiding diaries, 93% of the DMSO group had improvement vs. 35% of placebo group. Researchers confirmed their hypothesis that DMSO was superior to the placebo in symptomatic improvement in patients with IC/BPS.Onabotulinum toxin a Population and Definition of Interstitial Cystitis/Bladder Pain SyndromeTable 3 shows the results of the papers evaluating onabotulinum toxin A. In these studies, 90.7% of participants were women, and 9.3% of participants were men. Eighty-eight percent of studies used the NIDDK definition of IC/BPS, and three out of eight studies compared results of ulcer versus non-ulcer IC/BPS. One study was completed in the United States, one in Poland, two studies were completed in Italy, four in Taiwan, one in Australia, and one in Japan. All studies were conducted within the past 15 years. Recruitment criteria for all studies included lack of response to previous oral and intravesical treatments. MeasurementsThe GRA was used as a measure of efficacy in four of the papers reviewed (Table 3). Four studies used the OSS, ICPI and ICSI as a measure of efficacy for treatment of symptoms (Table 3). Seven studies used a VAS and all eight studies included a self-reporting voiding diary from participants. One study (Giannantoni et al 2010) also evaluated depression and other psychological functioning with administration of the Hamilton Anxiety and Hamilton Depression rating scale. Study Design and OutcomesThe studies evaluated can be found in Table 3. Two studies reported partially successful findings on the use of Onabotulinum toxin A as a treatment of symptoms for IC/BPS. First, Manning et al (20xx) completed a multicenter prospective randomized double-blind study on women, who were referred from medical centers to receive either hydrodistenstion and injection of normal saline, or hydrodistention and injection of Onabotulinum toxin A. If patients had no improvement to initial treatment, they could choose to withdraw themselves and have access to Onabotulinum toxin A at minimum of 3 months post-initial injection. Significant improvements (mean score change 3.64) were seen in the ICPI at three months in the Onabotulinum toxin A group in comparison to the control group. Twelve patients had a proven urinary tract infection detected and treated sometime after injection. These authors were concerned that presence of a UTI (of indeterminable origin) may have confounded the findings. Nonetheless, after excluding those with UTIs, and there was still an overall improvement in the Onabotulinum toxin A group in all measurements including total OSS score (p=0.02), ICSI (p=0.008), ICPI (p=0.08) and question 4 of the ICPI addressing the problem of bladder pain (p=0.02) (Table 3). A paper by ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "ISSN" : "2150-1149", "PMID" : "23511677", "abstract" : "BACKGROUND Ulcer type and non-ulcer type interstitial cystitis/bladder pain syndromes (IC/BPS) are considered different disease entities. Thus, intravesical botulinum toxin A (BoNT-A) treatment outcomes could differ for each entity. OBJECTIVES To evaluate and compare the treatment outcomes of BoNT-A injections for treatment of each IC/BPS type. STUDY DESIGN Prospective interventional study. SETTING Tertiary medical center affiliated with Buddhist Tzu Chi General Hospital and Tzu Chi University, Taiwan. METHODS Forty-four consecutive patients with IC/BPS for whom conventional treatments failed were prospectively enrolled in this study. Patients were classified as having ulcer (n = 10) or non-ulcer (n = 30) IC/BPS based on their previous cystoscopic findings. INTERVENTION All patients received 4 sets of intravesical BoNT-A injections (100 U in 40 suburothelial injections) every 6 months. The primary end-point was the global response assessment (GRA) 6 months after the fourth set of BoNT-A injections. Secondary end-points included the O'Leary-Sant score (OSS) including symptom indexes (ICSI) and problem indexes (ICPI), visual analog scale (VAS) pain score, voiding diary, and urodynamics variables. RESULTS After 4 sets of BoNT-A injections, 15 patients with non-ulcer IC/BPS had GRA scores >= 2, while the other 15 had GRA scores < 2. All 10 patients with ulcer IC/BPS had GRA scores < 2 at the study end-point (treatment failure). At baseline, patients with ulcer IC/BPS had significantly higher daytime frequency, nocturia, smaller functional bladder capacity, smaller voided volume, greater VAS, smaller maximal bladder capacity, and greater glomerulation grade than did patients with non-ulcer IC/BPS. After 4 sets of BoNT-A injections, patients with non-ulcer IC/BPS and GRA scores >= 2 or < 2 all had significantly decreased ICSI, ICPI, OSS, VAS pain scores, frequency episodes, and increased functional bladder capacity. However, patients with ulcer IC/BPS showed no significant change in any clinical or urodynamic variable. After failure of repeated BoNT-A injections, all 10 patients with ulcer IC/BPS underwent transurethral electrocauterization of their ulcers, which resulted in immediate pain relief. LIMITATIONS Lack of a control arm in this study. CONCLUSION Repeated intravesical BoNT-A injections provided effective treatment outcomes at the end-point in half of the patients with non-ulcer IC/BPS, but did not benefit any patient with ulcer type IC/BPS. Ulcer ty\u2026", "author" : [ { "dropping-particle" : "", "family" : "Lee", "given" : "Cheng-Ling", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kuo", "given" : "Hann-Chorng", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Pain physician", "id" : "ITEM-1", "issue" : "2", "issued" : { "date-parts" : [ [ "2010" ] ] }, "page" : "109-16", "title" : "Intravesical botulinum toxin a injections do not benefit patients with ulcer type interstitial cystitis.", "type" : "article-journal", "volume" : "16" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Lee and Kuo 2010)", "plainTextFormattedCitation" : "(Lee and Kuo 2010)", "previouslyFormattedCitation" : "(Lee and Kuo 2010)" }, "properties" : { }, "schema" : "" }(Lee and Kuo 2010) evaluated the efficacy of Onabotulinum toxin A injections by diagnoses type. Participants received 4 sets of intravesical Onabotulinum toxin A injections every 6 months, and were followed in an outpatient clinic two weeks post-injection to evaluate symptoms and turn in voiding diaries. When comparing the ulcer-type group to the non-ulcer groups – improvements in the non-ulcer groups, regardless of GRA response, was significant in the OSS total score, ICSI, and ICPI (p<0.05 for all). When comparing the non-ulcer groups, the GRA success group had significant increases in the OSS (p=0.004), ICSI (p=0.007) and ICPI (p=0.016), but not the VAS (p=0.14) when compared to GRA failure. When comparing each non-ulcer group to baseline individually, both the GRA success and GRA failure group had significant improvements from baseline in OSS, ICSI, ICPI and VAS. Changes in both in day time and nighttime urinary frequency were significant when compared to baseline as well. Overall, this study found that Onabotulinum toxin A was not successful in patients with refractory ulcer-type IC/BPS, however, while half of patients with non-ulcer IC/BPS did not have significant improvement as measured by GRA, symptom scores were still significant in all non-ulcer type participants ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "ISSN" : "2150-1149", "PMID" : "23511677", "abstract" : "BACKGROUND Ulcer type and non-ulcer type interstitial cystitis/bladder pain syndromes (IC/BPS) are considered different disease entities. Thus, intravesical botulinum toxin A (BoNT-A) treatment outcomes could differ for each entity. OBJECTIVES To evaluate and compare the treatment outcomes of BoNT-A injections for treatment of each IC/BPS type. STUDY DESIGN Prospective interventional study. SETTING Tertiary medical center affiliated with Buddhist Tzu Chi General Hospital and Tzu Chi University, Taiwan. METHODS Forty-four consecutive patients with IC/BPS for whom conventional treatments failed were prospectively enrolled in this study. Patients were classified as having ulcer (n = 10) or non-ulcer (n = 30) IC/BPS based on their previous cystoscopic findings. INTERVENTION All patients received 4 sets of intravesical BoNT-A injections (100 U in 40 suburothelial injections) every 6 months. The primary end-point was the global response assessment (GRA) 6 months after the fourth set of BoNT-A injections. Secondary end-points included the O'Leary-Sant score (OSS) including symptom indexes (ICSI) and problem indexes (ICPI), visual analog scale (VAS) pain score, voiding diary, and urodynamics variables. RESULTS After 4 sets of BoNT-A injections, 15 patients with non-ulcer IC/BPS had GRA scores >= 2, while the other 15 had GRA scores < 2. All 10 patients with ulcer IC/BPS had GRA scores < 2 at the study end-point (treatment failure). At baseline, patients with ulcer IC/BPS had significantly higher daytime frequency, nocturia, smaller functional bladder capacity, smaller voided volume, greater VAS, smaller maximal bladder capacity, and greater glomerulation grade than did patients with non-ulcer IC/BPS. After 4 sets of BoNT-A injections, patients with non-ulcer IC/BPS and GRA scores >= 2 or < 2 all had significantly decreased ICSI, ICPI, OSS, VAS pain scores, frequency episodes, and increased functional bladder capacity. However, patients with ulcer IC/BPS showed no significant change in any clinical or urodynamic variable. After failure of repeated BoNT-A injections, all 10 patients with ulcer IC/BPS underwent transurethral electrocauterization of their ulcers, which resulted in immediate pain relief. LIMITATIONS Lack of a control arm in this study. CONCLUSION Repeated intravesical BoNT-A injections provided effective treatment outcomes at the end-point in half of the patients with non-ulcer IC/BPS, but did not benefit any patient with ulcer type IC/BPS. Ulcer ty\u2026", "author" : [ { "dropping-particle" : "", "family" : "Lee", "given" : "Cheng-Ling", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kuo", "given" : "Hann-Chorng", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Pain physician", "id" : "ITEM-1", "issue" : "2", "issued" : { "date-parts" : [ [ "2010" ] ] }, "page" : "109-16", "title" : "Intravesical botulinum toxin a injections do not benefit patients with ulcer type interstitial cystitis.", "type" : "article-journal", "volume" : "16" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Lee and Kuo 2010)", "plainTextFormattedCitation" : "(Lee and Kuo 2010)", "previouslyFormattedCitation" : "(Lee and Kuo 2010)" }, "properties" : { }, "schema" : "" }(Lee and Kuo 2010)Akiyama et al. (2015) completed a single-center prospective open-labeled randomized comparative study, where participants were divided into two groups: immediate injection (group A) and 1-month delayed injection (group B) of Onabotulinum toxin A after allocation. At one-month analyses, the GRA (p=0.01), ICSI (p=0.04), ICPI (p=0.03), VAS (p=0.01) and QoL indexes (p=0.03) were all significantly higher in the group that had received the injection in comparison to the group that had delayed injection ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1111/iju.12833", "ISSN" : "09198172", "author" : [ { "dropping-particle" : "", "family" : "Akiyama", "given" : "Yoshiyuki", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Nomiya", "given" : "Akira", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Niimi", "given" : "Aya", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Yamada", "given" : "Yukio", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Fujimura", "given" : "Tetsuya", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Nakagawa", "given" : "Tohru", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Fukuhara", "given" : "Hiroshi", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kume", "given" : "Haruki", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Igawa", "given" : "Yasuhiko", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Homma", "given" : "Yukio", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "International Journal of Urology", "id" : "ITEM-1", "issue" : "9", "issued" : { "date-parts" : [ [ "2015", "9", "1" ] ] }, "page" : "835-841", "title" : "Botulinum toxin type\u00a0A injection for refractory interstitial cystitis: A randomized comparative study and predictors of treatment response", "type" : "article-journal", "volume" : "22" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Akiyama et al. 2015)", "plainTextFormattedCitation" : "(Akiyama et al. 2015)", "previouslyFormattedCitation" : "(Akiyama et al. 2015)" }, "properties" : { }, "schema" : "" }(Akiyama et al. 2015). Univariate analysis was completed to show that exposure to past hydrodistension more than three times, and disease duration longer than 6 years were significant factors for better response. There was no significant difference between patients with and without Hunner’s ulcers. Two studies completed in Taiwan evaluated the effects of multiple injections of Onabotulinum toxin A on IC/BPS, as measured primarily by the GRA and secondarily by the OSS, ICPI, ICSI, voiding diaries, and other clinical measures ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1111/ijcp.12113", "ISSN" : "13685031", "author" : [ { "dropping-particle" : "", "family" : "Kuo", "given" : "H.-C.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "International Journal of Clinical Practice", "id" : "ITEM-1", "issue" : "5", "issued" : { "date-parts" : [ [ "2013", "5", "1" ] ] }, "page" : "427-434", "title" : "Repeated intravesical onabotulinumtoxinA injections are effective in treatment of refractory interstitial cystitis/bladder pain syndrome", "type" : "article-journal", "volume" : "67" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "PMID" : "23340540", "abstract" : "Background: Onabotulinumtoxin-A (BoNT-A) is effective for the treatment of interstitial cystitis/painful bladder syndrome (IC/PBS). However, long-term follow-up does not show successful outcome after a single injection.", "author" : [ { "dropping-particle" : "", "family" : "Kuo", "given" : "Hann-Chorng", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Pain Physician", "id" : "ITEM-2", "issued" : { "date-parts" : [ [ "2013" ] ] }, "page" : "E15-E23", "title" : "Repeated Onabotulinumtoxin-A Injections Provide Better Results than a Single Injection Treatment of Painful Bladder Syndrome.", "type" : "article-journal", "volume" : "16" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(H.-C. Kuo 2013; Hann-Chorng Kuo 2013)", "plainTextFormattedCitation" : "(H.-C. Kuo 2013; Hann-Chorng Kuo 2013)", "previouslyFormattedCitation" : "(H.-C. Kuo 2013; Hann-Chorng Kuo 2013)" }, "properties" : { }, "schema" : "" }(H.-C. Kuo 2013; Hann-Chorng Kuo 2013) Methods were exactly the same in each study, one study compared the effectiveness of a single injection, and the other simply evaluated the efficacy of four repeated injections compared to baseline. Significant improvements were seen in all measurements of ICSI, ICPI, OSS, VAS and GRA when compared to baseline for both studies (p≤0.05 for all) ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "PMID" : "23340540", "abstract" : "Background: Onabotulinumtoxin-A (BoNT-A) is effective for the treatment of interstitial cystitis/painful bladder syndrome (IC/PBS). However, long-term follow-up does not show successful outcome after a single injection.", "author" : [ { "dropping-particle" : "", "family" : "Kuo", "given" : "Hann-Chorng", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Pain Physician", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2013" ] ] }, "page" : "E15-E23", "title" : "Repeated Onabotulinumtoxin-A Injections Provide Better Results than a Single Injection Treatment of Painful Bladder Syndrome.", "type" : "article-journal", "volume" : "16" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "DOI" : "10.1111/ijcp.12113", "ISSN" : "13685031", "author" : [ { "dropping-particle" : "", "family" : "Kuo", "given" : "H.-C.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "International Journal of Clinical Practice", "id" : "ITEM-2", "issue" : "5", "issued" : { "date-parts" : [ [ "2013", "5", "1" ] ] }, "page" : "427-434", "title" : "Repeated intravesical onabotulinumtoxinA injections are effective in treatment of refractory interstitial cystitis/bladder pain syndrome", "type" : "article-journal", "volume" : "67" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Hann-Chorng Kuo 2013; H.-C. Kuo 2013)", "plainTextFormattedCitation" : "(Hann-Chorng Kuo 2013; H.-C. Kuo 2013)", "previouslyFormattedCitation" : "(Hann-Chorng Kuo 2013; H.-C. Kuo 2013)" }, "properties" : { }, "schema" : "" }(Hann-Chorng Kuo 2013; H.-C. Kuo 2013) Giantonni et al (2008) evaluated the 1-year efficacy and tolerability of Onabotulinum toxin A at 1-month, 3-month, 6 month, and one-year post injection. Significant improvements in pain relief were seen in 86% of patients at three months when compared to baseline. The beneficial effect lasted about 5 months in 30% of cases, but pain had recurred in all participants at the 1-year follow-up. However, the treatment was still determined to be effective.ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/j.juro.2007.10.032", "ISSN" : "00225347", "PMID" : "18206941", "abstract" : "PURPOSE We evaluated the 1-year efficacy and tolerability of botulinum A toxin intravesically injected in patients with painful bladder symptoms associated with increased urinary frequency, refractory to conventional treatments. MATERIALS AND METHODS Three men and 12 women were prospectively included in the study. Under short general anesthesia the patients were given injections of 200 U commercially available botulinum A toxin diluted in 20 ml 0.9% NaCl. Injections were performed submucosally in the bladder trigone and lateral walls under cystoscopic guidance. A voiding chart and the visual analog scale for pain were used, and urodynamics were performed before treatment, and 1, 3, 5 and 12 months later. RESULTS Overall 13 patients (86.6%) reported subjective improvement at the 1 and 3-month followups. The mean visual analog scale score, and daytime and nighttime urinary frequency were significantly decreased (p <0.05, <0.01 and <0.05, respectively). At the 5-month followup the beneficial effects persisted in 26.6% of cases but increased daytime and nighttime urinary frequency, and an increased visual analog scale score were observed compared to baseline. At 12 months after treatment pain recurred in all patients. Nine patients complained of dysuria 1 month after treatment. Dysuria persisted in 4 cases at the 3-month followup and in 2 at the 5-month followup. CONCLUSIONS Intravesically injected botulinum toxin A is effective for short-term management of refractory painful bladder syndrome. The beneficial effects decreased progressively within a few months after treatment. Thus, repeat injections of the neurotoxin are required for efficacious treatment in patients with the disease.", "author" : [ { "dropping-particle" : "", "family" : "Giannantoni", "given" : "Antonella", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Porena", "given" : "Massimo", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Costantini", "given" : "Elisabetta", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Zucchi", "given" : "Alessandro", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mearini", "given" : "Luigi", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mearini", "given" : "Ettore", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "The Journal of Urology", "id" : "ITEM-1", "issue" : "3", "issued" : { "date-parts" : [ [ "2008", "3" ] ] }, "page" : "1031-1034", "title" : "Botulinum A Toxin Intravesical Injection in Patients With Painful Bladder Syndrome: 1-Year Followup", "type" : "article-journal", "volume" : "179" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Giannantoni et al. 2008)", "plainTextFormattedCitation" : "(Giannantoni et al. 2008)", "previouslyFormattedCitation" : "(Giannantoni et al. 2008)" }, "properties" : { }, "schema" : "" }(Giannantoni et al. 2008) In a later study by Giantonni et al (2010) improvements in psychological function in both anxiety and depression studies were also found, with the exception of weight and sleep disorders in the Hamilton Depression questionnaire (p<0.01 for all) (Table 3) ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "ISSN" : "1875-5704", "PMID" : "20950262", "abstract" : "INTRODUCTION To assess the impact of intravesically injected botulinum A toxin (BoNT/A) upon bladder pain, urological complaints, symptoms of anxiety and depression, and Quality of Life (QoL) in patients with painful bladder symptoms (PBS) refractory to conventional treatment. PATIENTS AND METHODS In this prospective study 14 patients received one injection of BoNT/A (200 U diluted in 20 ml 0.9% NaCl), under cystoscopic guidance. At pre- and 3 months post- treatment all patients underwent an urological assessment (voiding diary, urodynamics), a pain quantification on a visual analog scale (VAS), an evaluation with the 14-item Hamilton Anxiety Rating Scale (HAM-A) to assess symptoms of psychic and somatic anxiety, an evaluation with the Hamilton Depression Rating Scale (HAM-D) to assess depression, and the 36-item Medical Outcomes Study Short Form (SF-36) to assess QoL. Results. At pre-treatment all 14 patients had increased daytime and nighttime urinary frequency and high VAS scores. Nine patients had pathological HAM-A scores and all had pathological HAM-D scores. At the 3-month follow-up 10/14 patients reported a subjective improvement in pain. Mean VAS score, mean daytime and nighttime urinary frequency decreased significantly (p <0.01, <0.01 and <0.01, respectively). All domains in SF-36 and HAM-A significantly improved (p<0.01). All domains, except weight and sleep disorders, significantly improved in HAM-D, particularly somatoform symptoms (p<0.01), cognitive performance (p<0.01), and circadian variations (p<0.01). CONCLUSION In patients with refractory PBS with symptoms of anxiety, depression and poor QoL, BoNT/A intravesical treatment reduced bladder pain, improved psychological functioning, and well-being.", "author" : [ { "dropping-particle" : "", "family" : "Giannantoni", "given" : "Antonella", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cagini", "given" : "Roberta", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Zingaro", "given" : "Michele", "non-dropping-particle" : "Del", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Proietti", "given" : "Silvia", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Quartesan", "given" : "Roberto", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Porena", "given" : "Massimo", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Piselli", "given" : "Massimiliano", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Current drug delivery", "id" : "ITEM-1", "issue" : "5", "issued" : { "date-parts" : [ [ "2010", "12" ] ] }, "page" : "442-6", "title" : "Botulinum A toxin intravesical injections for painful bladder syndrome: impact upon pain, psychological functioning and Quality of Life.", "type" : "article-journal", "volume" : "7" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Giannantoni et al. 2010)", "plainTextFormattedCitation" : "(Giannantoni et al. 2010)", "previouslyFormattedCitation" : "(Giannantoni et al. 2010)" }, "properties" : { }, "schema" : "" }(Giannantoni et al. 2010). DiscussionThis paper compared two FDA approved pharmacological treatments for IC/BPS compared to Onabotulinum toxin A, a non-FDA approved treatment. Overall, results were mixed. Generally, the FDA approved treatments showed modest improvements in sympotology in the papers reviewed, whereas the Onabotulinum toxin A treatments seemed to confer better subjective and objective outcomes for patients impacted by IC/BPS. Comparison of the findings are difficult due to inconsistencies in reported information, differing dosages, varying outcome measures and study designs.PPS is the FDA approved, oral medication standard for treatment of IC/BPS. However, there are some limitations to the research reviewed for this treatment. The improvement in symptoms and pain were measured using various methods. Older studies evaluating the drug and comparing to a placebo utilized symptom scales that were not directly associated with IC/BPS. Nickel et al (2015) found no significance in the use of PPS compared to a third of the dose of PPS, and a placebo group. However, the recruitment criteria were weak as the definition of IC/BPS required an ICSI total score of 8 or greater, and could not be associated to UTI. Further standardization of the diagnosis was not included. Davis et al. (2008) compared intravesical PPS and oral PPS with oral PPS alone, with one limitation of this study being no true placebo. By double-blinding and randomizing the treatments, and having strong exclusion criteria, the strengths of this study are apparent. The methods of evaluation of symptom response were measured by the standard OSS, ICSI, ICPI and VAS pain scale. The trial also became underpowered because of the completion rate only reaching 60%, therefore lacking generalizability. In Hanno’s (1997) open-label physician usage study, the sample size was large, but the study selects out drug responders for analysis which thereby magnifies the overall response rate. This could have an effect on the conclusion that the improvement of symptoms continues throughout three years, as the responders are those who are receiving the treatment. Parsons et al. noted that patients are not all alike in the manner in which they evaluate and report individual symptoms. Some patients may report a decrease in urgency, or perhaps pain, when the number of days that these symptoms are present is significantly reduced, while other patients with similar reduction because the urgency or pain is still severe on the days that either is present This self-reporting can be a limitation of those studies that do not utilize the standardized questionnaires specifically designed for IC/BPS as they attempt to eliminate this bias by asking questions regarding the severity and timeliness of the of symptoms and problems. By choosing patients who had failed previous methods of treatment, there is a strength associated with the studies, but a better understanding of the treatment effect of PPS may be gained by studying patients at an early stage of the disease, after first-line drugs have failed.Overall, there was only one study evaluating the effects of DMSO compared to a true placebo. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "ISSN" : "0022-5347", "PMID" : "3288775", "abstract" : "To evaluate the effectiveness of dimethyl sulfoxide in the treatment of patients with biopsies suggestive of interstitial cystitis, 33 patients underwent a controlled crossover trial. Patients were allocated randomly to receive 50 per cent dimethyl sulfoxide or placebo (saline). The medication was administered intravesically every 2 weeks for 2 sessions of 4 treatments each. Response was assessed urodynamically and symptomatically. Thirty women and 3 men (mean age 48 years and mean duration of symptoms 5.5 years) were entered into the study. No significant side effects to dimethyl sulfoxide were noted. When assessed subjectively, 53 per cent of dimethyl sulfoxide treated patients were markedly improved compared to 18 per cent of the placebo treated patients. Of the dimethyl sulfoxide group 93 per cent had objective improvement versus 35 per cent of the placebo group. Thus, dimethyl sulfoxide proved to be superior to placebo in the objective and subjective improvement of patients with interstitial cystitis.", "author" : [ { "dropping-particle" : "", "family" : "Perez-Marrero", "given" : "R", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Emerson", "given" : "L E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Feltis", "given" : "J T", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "The Journal of urology", "id" : "ITEM-1", "issue" : "1", "issued" : { "date-parts" : [ [ "1988", "7" ] ] }, "page" : "36-9", "title" : "A controlled study of dimethyl sulfoxide in interstitial cystitis.", "type" : "article-journal", "volume" : "140" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Perez-Marrero, Emerson, and Feltis 1988)", "manualFormatting" : "(Perez-Marrero et al. 1988)", "plainTextFormattedCitation" : "(Perez-Marrero, Emerson, and Feltis 1988)", "previouslyFormattedCitation" : "(Perez-Marrero, Emerson, and Feltis 1988)" }, "properties" : { }, "schema" : "" }(Perez-Marrero et al. 1988) As previously discussed, people self-report pain in different manners which can be a limitation of the reporting. None of the other studies evaluating DMSO had a true placebo, which limits the findings. Peeker et al. (2000) had a small sample size of 20 participants, but was double-blinded which reduced bias. Cervigni et al. (2017) required failure of other treatments for comparing the efficacy of DMSO and Chondroitin. The study had small sample size did not have a placebo or control arm and a short follow-up time. This could be due to the disease. Tutolo et al. (2017)completed a single blinded randomized trial comparing DMSO and Cervigni et. al (2017) both used the OSS, ICSI, ICPI and GRA as measures of efficacy which assist in self-reporting bias. Overall, the literature supporting Onabotulinum toxin A as a treatment of symptoms in IC/BPS shows the strongest associations. Six out of eight articles found highly significant decreases in symptoms including bladder pain, severity of pain, urgency, and frequency of urination in participants (Table 3). The other two studies ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1007/s00192-013-2267-8", "ISSN" : "0937-3462", "author" : [ { "dropping-particle" : "", "family" : "Manning", "given" : "Jane", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Dwyer", "given" : "Peter", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Rosamilia", "given" : "Anna", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Colyvas", "given" : "Kim", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Murray", "given" : "Christine", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Fitzgerald", "given" : "Elizabeth", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "International Urogynecology Journal", "id" : "ITEM-1", "issue" : "5", "issued" : { "date-parts" : [ [ "2014", "5", "26" ] ] }, "page" : "593-599", "publisher" : "Springer London", "title" : "A multicentre, prospective, randomised, double-blind study to measure the treatment effectiveness of abobotulinum A (AboBTXA) among women with refractory interstitial cystitis/bladder pain syndrome", "type" : "article-journal", "volume" : "25" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "ISSN" : "2150-1149", "PMID" : "23511677", "abstract" : "BACKGROUND Ulcer type and non-ulcer type interstitial cystitis/bladder pain syndromes (IC/BPS) are considered different disease entities. Thus, intravesical botulinum toxin A (BoNT-A) treatment outcomes could differ for each entity. OBJECTIVES To evaluate and compare the treatment outcomes of BoNT-A injections for treatment of each IC/BPS type. STUDY DESIGN Prospective interventional study. SETTING Tertiary medical center affiliated with Buddhist Tzu Chi General Hospital and Tzu Chi University, Taiwan. METHODS Forty-four consecutive patients with IC/BPS for whom conventional treatments failed were prospectively enrolled in this study. Patients were classified as having ulcer (n = 10) or non-ulcer (n = 30) IC/BPS based on their previous cystoscopic findings. INTERVENTION All patients received 4 sets of intravesical BoNT-A injections (100 U in 40 suburothelial injections) every 6 months. The primary end-point was the global response assessment (GRA) 6 months after the fourth set of BoNT-A injections. Secondary end-points included the O'Leary-Sant score (OSS) including symptom indexes (ICSI) and problem indexes (ICPI), visual analog scale (VAS) pain score, voiding diary, and urodynamics variables. RESULTS After 4 sets of BoNT-A injections, 15 patients with non-ulcer IC/BPS had GRA scores >= 2, while the other 15 had GRA scores < 2. All 10 patients with ulcer IC/BPS had GRA scores < 2 at the study end-point (treatment failure). At baseline, patients with ulcer IC/BPS had significantly higher daytime frequency, nocturia, smaller functional bladder capacity, smaller voided volume, greater VAS, smaller maximal bladder capacity, and greater glomerulation grade than did patients with non-ulcer IC/BPS. After 4 sets of BoNT-A injections, patients with non-ulcer IC/BPS and GRA scores >= 2 or < 2 all had significantly decreased ICSI, ICPI, OSS, VAS pain scores, frequency episodes, and increased functional bladder capacity. However, patients with ulcer IC/BPS showed no significant change in any clinical or urodynamic variable. After failure of repeated BoNT-A injections, all 10 patients with ulcer IC/BPS underwent transurethral electrocauterization of their ulcers, which resulted in immediate pain relief. LIMITATIONS Lack of a control arm in this study. CONCLUSION Repeated intravesical BoNT-A injections provided effective treatment outcomes at the end-point in half of the patients with non-ulcer IC/BPS, but did not benefit any patient with ulcer type IC/BPS. Ulcer ty\u2026", "author" : [ { "dropping-particle" : "", "family" : "Lee", "given" : "Cheng-Ling", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kuo", "given" : "Hann-Chorng", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Pain physician", "id" : "ITEM-2", "issue" : "2", "issued" : { "date-parts" : [ [ "2010" ] ] }, "page" : "109-16", "title" : "Intravesical botulinum toxin a injections do not benefit patients with ulcer type interstitial cystitis.", "type" : "article-journal", "volume" : "16" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Manning et al. 2014; Lee and Kuo 2010)", "plainTextFormattedCitation" : "(Manning et al. 2014; Lee and Kuo 2010)", "previouslyFormattedCitation" : "(Manning et al. 2014; Lee and Kuo 2010)" }, "properties" : { }, "schema" : "" }(Manning et al. 2014; Lee and Kuo 2010) significant decreases in symptoms as well. The confounding urinary tract infection skewed the data supporting the treatment in the research by Manning et al., but when removing those participants, results were significant in supporting Onabotulinum toxin A. This is not the only study that associated urinary tract infections with Onabbotulinum toxin A. Cui et. Al (2015) also found that the main side effect of onabotulinum toxin A injections was localized to urinary tract infections. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1002/nau.22598", "ISSN" : "07332467", "PMID" : "24676791", "abstract" : "AIM We carried out a systematic review and meta-analysis to assess the efficacy and safety of the drug for treating idiopathic OAB. METHODS A literature review was performed to identify all published randomized double-blind, placebo-controlled trials of onabotulinumtoxinA for the treatment of idiopathic OAB. The search included the following databases: MEDLINE, EMBASE, and the Cochrane Controlled Trials Register. The reference lists of the retrieved studies were also investigated. RESULTS Eight publications involving a total of 1,320 patients were used in the analysis, including six RCTs that compared onabotulinumtoxinA with placebo. OnabotulinumtoxinA significantly decreased the mean number of urinary incontinence (UI) per day -2.77 versus -1.01 (the standardized mean difference (SMD)\u2009=\u2009-1.68, 95% CI\u2009=\u2009-2.06 to -1.31, P\u2009<\u20090.00001); the mean number of micturitions per day -1.61 versus -0.87 (SMD\u2009=\u2009-1.82, 95% CI\u2009=\u2009-2.61 to -1.02, P\u2009<\u20090.00001); maximum cystometric capacity (MCC) 91.39 versus 32.32 (SMD\u2009=\u200963.82, 95% CI\u2009=\u200938.14 to 89.50, P\u2009<\u20090.00001) and volume voided 44.29 versus 7.36 (SMD\u2009=\u200933.05, 95% CI\u2009=\u200922.45 to 43.66, P\u2009<\u20090.00001) versus placebo and 29.20% versus 7.95% of patients became incontinence-free (odds ratio [OR]\u2009=\u20094.89, 95% confidence interval [CI]\u2009=\u20093.11 to 7.70, P\u2009<\u20090.00001). Safety assessments primarily localized to the urinary tract indicated onabotulinumtoxinA were often associated with complications resulting from postvoid residuals (PVR; P\u2009<\u20090.00001), urinary tract infections (UTI; P\u2009<\u20090.00001) and clean intermittent catheterization (CIC; P\u2009<\u20090.00001). CONCLUSION This meta-analysis indicates that onabotulinumtoxinA to be an effective treatment for idiopathic overactive bladder symptoms with side effects primarily localized to urinary tract.", "author" : [ { "dropping-particle" : "", "family" : "Cui", "given" : "Yuanshan", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Zhou", "given" : "Xin", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Zong", "given" : "Huantao", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Yan", "given" : "Huilei", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Zhang", "given" : "Yong", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Neurourology and Urodynamics", "id" : "ITEM-1", "issue" : "5", "issued" : { "date-parts" : [ [ "2015", "6" ] ] }, "page" : "413-419", "title" : "The efficacy and safety of onabotulinumtoxinA in treating idiopathic OAB: A systematic review and meta-analysis", "type" : "article-journal", "volume" : "34" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Cui et al. 2015)", "plainTextFormattedCitation" : "(Cui et al. 2015)", "previouslyFormattedCitation" : "(Cui et al. 2015)" }, "properties" : { }, "schema" : "" }(Cui et al. 2015) Lee et al. also had significant results supporting Onabotulinum toxin A as a treatment, with the exception of Hunner’s ulcer participants, who ended up removing the ulcers with laser treatment post study, and found relief from all symptoms. Ultimately, all eight reports supported the use of Onabotulinum toxin A to reduce symptoms and improve the quality of life in those suffering from IC/BPS. A primary limitation of these studies is not having a true placebo or control arm. Kuo et al. (2013) reported that the lack of placebo was due to the ethical considerations of the human subjects ethics board. Due to the lack of control arm, participants were also not randomized to treatments with the exception of Akiyama et al. randomizing a delay of injection. The inability to compare results to a comparator group rather than baseline limits the research. A strength of Onabotulinum toxin A studies is the methods of detection, in that the majority of the studies used the standard OSS, ICPI, ICSI and GRA measurements as efficacy assessments. Research has been completed in recent years, with the oldest study in 2004. The relevance or external validity of these data could be in question because the populations studied were all refractory patients, whereas they were required to have failure in other treatment methods, likely due to the cost and lack of FDA approval for this method of treatment. Akiyama et al (2015) were the only researchers to compare groups with the delayed interjection group, but only allotted a short observational period of one month to compare groups. Double-blind, placebo controlled, multi-center randomized trials with larger sample sizes are warranted to overcome all of the study limitations. The success of the reported studies so far, and the number of studies expressing interest in this treatment method should encourage researchers to examine efficacies in other populations to provide effective and safe symptomatic relief in patients suffering from IC/BPS. Overall, the nature of all the papers evaluated was generally lacking relevant details to directly compare across studies. This included missing relevant information on age and racial breakdown of patients, making it difficult to decipher if there is an age or race effect on treatment improvement by modality, and lack of information on the magnitude of the change in the key symptomatology outcome measures. However, these studies still gleaned valuable information to preliminarily compare their effectiveness and is a first step towards designing better trials to evaluate this problem.In conclusion, there is limited research on DMSO, with most recent findings unsupportive of the treatment. Orally administered PPS has the best-designed studies, with multiple placebo controlled, randomized clinical trials supporting the efficacy of symptom treatment, but findings indicated limited success in symptom reduction. While Onabotulinum toxin A is considered to be a treatment that is administered at a later point of disease treatment, there is a substantial amount of published research that uses updated methods of pain and symptom evaluation which leads to a belief of efficacy. Given the stronger findings for Onabotulinum toxin A, future research should be directed to determine if this modality should be considered as the primary intravesical treatment method of IC/BPS treatment despite its possible side effect of increasing UTIs. The public health implications of the existing and future work could allow for quicker and more effective relief of symptoms of IC/BPS for the millions of adults suffering from this painful condition.bibliographyADDIN Mendeley Bibliography CSL_BIBLIOGRAPHY “4 to 12 Million May Have IC - ICA - McLean, VA.” n.d. 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