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ACCREDITATION STATEMENT This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education through the joint sponsorship of the Dannemiller Memorial Educational Foundation and SynerMed Communications. The Dannemiller Memorial Educational Foundation is accredited by the ACCME to provide continuing medical education for physicians. DESIGNATION OF CREDIT The Dannemiller Memorial Educational Foundation designates this educational activity for a maximum of 1 category 1 credit toward the AMA Physician’s Recognition Award. Each physician should claim only those credits that he/she actually spent in the activity. Vol. 23 No. 26 July 2005 ISSN 0264-6684 Release date: July, 2005 Expiration Date: July 31, 2006 EVOLVING ISSUES IN THE DIAGNOSIS AND MANAGEMENT OF INTERSTITIAL CYSTITIS Jointly sponsored by Dannemiller Memorial Educational Foundation and SynerMed® Communications. This program is made possible by an educational grant from Ortho Urology This newsletter provides the most current information on the following: METHOD OF PARTICIPATION This activity should take approximately 1 hour to complete. The participant should, in order, read the objectives and newsletter, answer the 10-question multiple-choice posttest, placing answers on the Registration/CME Posttest Answer Form/Evaluation on page 15, and complete the Program Evaluation on page 15. The evaluation form provides each participant with the opportunity to comment on the quality of the instructional process, the perception of enhanced professional effectiveness, the perception of commercial bias, and his or her views on future educational needs. To receive credit for this activity, follow the instructions provided on the posttest. NEEDS ASSESSMENT Chronic pelvic pain syndromes (CPPS) affect an estimated 9 to 15 million women in the United States, and while the cause of the chronic pelvic pain is often undiagnosed, at least one in seven women is affected by this condition. Studies have demonstrated that interstitial cystitis (IC) is the source of chronic pelvic pain in a large number of women. Urogenital syndromes affect an estimated 1 in 10 men in the United States. In the US, approximately 9% of men aged 40 to 79 years are diagnosed with prostatitis. The overwhelming majority of men with prostatitis have chronic nonbacterial prostatitis – classified as chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS). The true epidemiology and pathophysiology of CPPS, and particularly IC, remain unclear. There is no definitive test to identify IC. Moreover, a variety of therapeutic options have been employed to treat patients who suffer with this condition. Recent advances in both the diagnosis of IC, and available management alternatives, have enabled health care providers to more easily identify patients with this disease, and then provide effective treatment to positively impact their quality of life. Overview and Etiology of IC; Promising Clinical Markers; Challenges in the Diagnosis of IC in Men; Impact of CPP on Quality of Life; Differential Diagnosis of IC and CP/CPPS; Challenges in the Diagnosis of IC in Women; Differential Diagnosis of IC and Other Urologic and Gynecologic Conditions; Current Approach to Diagnosis of IC in Men and Women; Potassium Sensitivity Test; Symptom Questionnaires; Intravesical Anesthetic Challenge; Future Directions in the Diagnosis of IC; Patient Stratification for the Diagnosis and Treatment of IC; Current Approach to Treatment of IC; Conservative/Adjunctive Therapies; Pharmacologic Treatments Approved by the US Food and Drug Administration (FDA); Oral Pentosan Polysulfate Sodium; Intravesical Instillation With Dimethyl Sulfoxide (DMSO); Off-label Treatments for IC; Antihistamines; Antidepressants; Other Therapies for Pain Relief; Other Intravesical Solutions; Approaches to Multimodal Treatment of IC; Surgical Intervention. EDUCATIONAL OBJECTIVES 1. Review the epidemiology/prevalence of IC in men and women. 2. Differentiate between chronic pain of bladder and pelvic origin in men and women. 3. Examine the similarities between chronic nonbacterial prostatitis/chronic pelvic pain syndrome (CP/CPPS) and IC in clinical presentation, diagnostic evaluation, purported pathogenesis, and response to therapy. 4. Discuss the clinical presentation of IC and discuss its differential diagnosis in men and women; discuss the assessment of IC as a diagnosis of exclusion. 5. Explore traditional and emerging pharmacologic and nonpharmacologic treatment options for the management of IC. TARGET AUDIENCE This program is intended for urologists. FACULTY J. Curtis Nickel, MD Professor of Urology Queen’s University Kingston General Hospital Kingston, Ontario, Canada Jean L. Fourcroy, MD, PhD, MPH Assistant Professor/Urology Uniformed Services University Health Sciences Walter Reed Army Hospital Bethesda, Maryland Susan Keay, MD, PhD Professor of Medicine University of Maryland School of Medicine Veterans Affairs Medical Center Baltimore, Maryland Robert J. Evans, MD Chief of Surgery Moses Cone Health System Greensboro, North Carolina David M. Kaufman, MD Assistant Professor of Clinical Urology Columbia University College of Physicians and Surgeons St. Luke’s – Roosevelt Hospital New York, New York Diane K. Newman, RN, MSN Co-Director Penn Center for Continence and Pelvic Health Division of Urology University of Pennsylvania Medical Center Philadelphia, Pennsylvania DISCLOSURES In accordance with the Accreditation Council for Continuing Medical Education (ACCME), the Dannemiller Memorial Educational Foundation requires that any person who is in a position to control the content of a CME activity must disclose all relevant financial relationships they have with a commercial interest. Accordingly: • J. Curtis Nickel, MD reports that he has received research support, has been a consultant and has served on the speakers bureau for Ortho-McNeil Pharmaceutical, Inc. • Robert Evans, MD has received research support from Ortho-McNeil Pharmaceutical, Inc., and has served on the speakers bureau for Medtronic and Yamanouchi. • Jean Fourcroy, MD, PhD, MPH has been a consultant and has served on the advisory board for Ortho-McNeil Pharmaceutical, Inc. • David Kaufman, MD has received research support from Pfizer Inc., Watson Pharmaceutical, and Sanofi and has served on the speakers bureau for Ortho-McNeil Pharmaceutical, Inc. • Susan Keay, MD, PhD declares no financial interest or other relationship with the commercial supporter of this activity or any other manufacturer(s) of any commercial product(s) at this time. • Diane K. Newman, RN, MSN declares no financial interest or other relationship with the commercial support of this activity or any other manufacturer(s) of any commercial product(s) at this time. • The Dannemiller Memorial Educational Foundation staff that was involved in the development of this activity has no financial relationships with any commercial interests. • The SynerMed staff that was involved in the development of this activity has no financial relationships with any commercial interests. • In order to resolve conflict of interest, this activity was reviewed by Bernard Abrams, MD, Clinical Professor of Medicine, University of Missouri at Kansas City School of Medicine, who has no financial relationships with commercial interests. Disclosure of unlabeled/investigational use of drugs/devices will be made in the instructional text. Clinical Courier ® is a specialty newsletter reporting on clinical/biomedical issues. The publishers reserve copyright on all published materials, and such materials may not be reproduced in any form without the permission of SynerMed Communications.® This newsletter was developed, produced, and jointly sponsored by the Dannemiller Memorial Educational Foundation and SynerMed Communications.® The views presented herein are those of the faculty and not necessarily those of the publisher, grantor, or sponsor. This material is prepared based upon a review of multiple sources of information, but it is not exhaustive of the subject matter. Therefore, health care professionals and other individuals should review and consider other publications and materials on the subject matter before relying solely upon the information contained within this material. This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the FDA. The opinions expressed in the educational activity are those of the faculty. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications, and warnings. Further, attendees/participants should appraise the information presented critically and are encouraged to consult appropriate resources for any product or device mentioned in this program. ACCREDITATION STATEMENT This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education through the joint sponsorship of the Dannemiller Memorial Educational Foundation and SynerMed Communications. The Dannemiller Memorial Educational Foundation is accredited by the ACCME to provide continuing medical education for physicians. DESIGNATION OF CREDIT The Dannemiller Memorial Educational Foundation designates this educational activity for a maximum of 1 category 1 credit toward the AMA Physician’s Recognition Award. Each physician should claim only those credits that he/she actually spent in the activity. Vol. 23 No. 26 July 2005 ISSN 0264-6684 Release date: July 2005 Expiration Date: July 31, 2006 EVOLVING ISSUES IN THE DIAGNOSIS AND MANAGEMENT OF INTERSTITIAL CYSTITIS INTRODUCTION Interstitial cystitis (IC) is a clinical syndrome characterized by chronic pelvic pain (CPP) and severe urologic symptoms (urgency and frequency of urination, both day and night) in the absence of bacterial infection or other well-defined cause.1 The pathogenesis of IC is largely unknown, the diagnosis is primarily based on symptoms, and insight into effective treatment is still evolving. Prevalence studies have estimated that about 1 million people in the United States are affected by IC, with most cases being diagnosed in women.2 However, a recent study of patients diagnosed with IC in a managed care population found a prevalence of 197 cases per 100,000 women and 41 cases per 100,000 men, which is 10 times the numbers accepted 20 years ago.3 Some researchers believe that the true number of cases of IC could be even up to 100 times greater than those cited above, if IC is determined by screening populations for IC symptoms rather than for diagnosed cases.4 IC is a highly prevalent chronic pelvic pain syndrome whose pathogenesis is largely unknown; diagnosis is primarily based on symptoms, and insight into effective treatment is still evolving. For both men and women, IC is a disorder that exacts a tremendous physical and psychological toll, including dyspareunia and pelvic pain, depression, sexual dysfunction, missed work, and overall decrease in quality of life (QOL).5 In one epidemiologic study, 56% of patients with IC reported depression, 94% said that travel was difficult or impossible, and 70% reported a disruption in family relationships and responsibilities.6 For the clinician as well as the patient, IC is a frustrating disorder, posing both diagnostic and treatment challenges. Too often, patients are adequately identified only after a number of misdiagnoses, with a lost opportunity for early recognition that could afford the best chance for symptom resolution.7 IC patients frequently have overlapping symptoms related to the pelvic organs, which encompass urologic, gastrointestinal, gynecologic, pelvic floor, and prostate domains. This confusion can translate into a lengthy delay in diagnosis. One retrospective analysis found an average wait time of 7.8 years between symptom onset and correct diagnosis. That study found that IC was frequently misdiagnosed in women as urethral stricture, overactive bladder (OAB), recurrent cystitis, and endometriosis, and in men as prostatitis, bladder outlet obstruction, and benign prostatic hyperplasia (BPH). A presumptive diagnosis of IC may be made by looking for appropriate clinical criteria and after excluding other disorders such as urinary tract infection (UTI), bladder cancer, sexually transmitted diseases, neurologic disorders, kidney diseases, vaginal infections, or prostatitis. In the future, biomarkers may help identify patients with IC more easily. This will lead to earlier and more accurate diagnosis and, consequently, more effective treatment. While there is currently no cure for IC, a multimodal management strategy helps greatly to alleviate symptoms and improve the QOL for these patients. Available diagnostic tools and treatment options are described in this report, along with the clinical experience of and discussion among key opinion leaders in the field of urology, who recently convened at a roundtable meeting to explore current and emerging IC diagnostic and treatment issues. TOWARD A DEFINITION OF IC J. Curtis Nickel, MD, FRCS stated that there is no unique known cause of IC and no specific diagnostic criteria, contributing to the difficulty of determining a precise definition of IC. The American College of Obstetricians and Gynecologists (ACOG) defines IC as a “chronic inflammatory condition of the bladder clinically characterized by irritable voiding symptoms or urgency and frequency, in the absence of objective evidence of another disease that could cause the symptoms.”8 In 1987 the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) established criteria to standardize the diagnosis of IC based on symptoms and cystoscopic findings with the patient under anesthesia; however, this diagnostic approach is considered more fitting for research than for clinical purposes.9 (TABLE 1) The National Institutes of Health IC Database Study found that the strict application of the NIDDK criteria would probably miss more than 60% of patients likely to have IC.10 ACOG defines IC as a “chronic inflammatory condition of the bladder clinically characterized by irritable voiding symptoms or urgency and frequency, in the absence of objective evidence of another disease that could cause the symptoms.” TABLE 1 DIAGNOSTIC CRITERIA FOR IC9 • Pelvic/perineal or bladder pain • Urinary urgency and/or frequency • Presence of glomerulations or ulcers on cystoscopic examination (hydrodistention under anesthesia) • Negative urine culture • Absence of genitourinary infections • Absence of prostatitis • Absence of bladder tumor • No history of chemical, tuberculosis, or radiation cystitis 1 The International Continence Society (ICS) prefers the term “painful bladder syndrome” (PBS) to define “the complaints of suprapubic pain related to bladder filling, accompanied by other symptoms such as daytime and nighttime frequency, in the absence of proven urinary infection or other previous pathology.” The ICS reserves the diagnosis of IC for patients with “typical cystoscopic and histological features,” without further specifying these.11,12 No matter how IC is defined, the essential symptomatology includes chronic pelvic or bladder pain and urinary symptoms of urgency and frequency. The pain may be relieved by voiding, usually in small amounts, but soon recurs when the bladder refills. This is often accompanied by an uncomfortable, constant urge to void that does not go away even after urination. The average patient with IC voids 16 times per day, though it is not uncommon for patients with severe disease to void 20, 40, or even 60 times daily.13,14 Along with treatment for the CPP, dietary changes and bladder training techniques, including the use of a bladder diary, are usually helpful in lengthening the time between voids and in monitoring progress. ETIOLOGY OF IC FIGURE 2 A PROPOSED MODEL FOR THE PATHOGENESIS OF IC Bladder insult More injury Epithelial layer damage Mast cell activation and histamine release Potassium leak Into interstitium Activation of C-fibers and release of substance P Courtesy of Robert J. Evans, MD. David M. Kaufman, MD indicated that effective diagnosis and treatment of IC will be influenced by a deepening understanding of the mechanisms of pathogenesis, which remain unclear. Most likely, there are multiple causes for the symptoms of IC in any one patient, including structural, neurologic, autoimmune, lymphatic, infectious, and psychological factors.5,15 It has been suggested that susceptible persons may have an underlying genetic defect, and may develop IC after some initial insult.16 When released, substance P causes an inflammatory cascade that leads to mast cell degranulation and activation of nearby nerve terminals. Patients with IC appear to have increased numbers of substance P-containing nerves (C-fibers) and increased concentration of substance P, which correlates with pain severity. 19 Increased production of inflammatory mediators such as leukotrienes and adenosine triphosphate have also been found in IC patients.20,21 A fundamental finding in IC is marked epithelial dysfunction that results in increased bladder epithelial permeability. (FIGURE 1) This may occur through a defect in the glycosaminoglycan (GAG) component of the mucin layer that covers and protects the bladder urothelium from noxious elements. Dysfunction of the GAG protective layer allows leakage and transvesical absorption of urinary solutes that can injure the bladder interstitium.14 Ongoing exposure to these toxic elements, including potassium, may cause inflammation, tissue irritation and injury, mast cell degranulation and sensory nerve depolarization, which may result in the urinary urgency, frequency and pain of IC (though pain can occur without somatic damage).17,18 (FIGURE 2) Abnormalities of mast cells (which contain histamine-rich granules) may also contribute to the development of IC. Patients with IC have increased levels of histamine and increased numbers of mast cells in the bladder wall, as well as increased urinary excretion of histamine metabolites. It is believed that degranulated mast cells abnormally release histamine, which in turn may cause the initial insult or damage to the GAG layer.14 Jean L. Fourcroy, MD, PhD, MPH commented that neurologic up-regulation and neurogenic inflammation are also important components in the pathogenesis of IC. Neuropeptide substance P—an inflammatory mediator that functions as a nociceptive neurotransmitter—may play a pivotal role. Referred pain and motor activity to the pelvic floor muscles and the pelvic organs may be other underlying causes of IC symptoms. Diane K. Newman, RN, MSN noted that the pelvic floor muscle tenderness and spasm known as pelvic floor dysfunction often occurs in conjunction with IC and is responsible for many of the symptoms that she sees in her patients.22 Three proposed contributors to the pathogenesis of IC are GAG layer abnormalities, mast cell activation, and neurogenic inflammation. FIGURE 1 ETIOLOGY OF IC: DEFECTIVE UROEPITHELIAL BARRIER Irritating Solutes Urothelium Irritated Nerve GAG Layer Inflammation The presence of glomerulations in the bladder has historically been one of the requisite criteria for formal diagnosis of IC. Tamaki et al recently concluded that angiogenic growth factors play a role in the pathogenesis of IC by promoting the neovascularization that apparently induces these glomerulations.23 Other researchers have found increased angiogenic factors in bladder tissue from IC patients, compared to controls, and suggest that these factors may be involved in the inflammatory process to cause the painful symptoms of IC.24 Robert J. Evans, MD concluded that he approaches treatment of his IC patients by targeting the 3 most likely and important contributors to the pathogenesis of IC: GAG layer abnormalities, mast cell activation, and neurogenic inflammation. Promising Clinical Markers A recent breakthrough in IC research has been the discovery of sensitive and specific biomarkers for IC, including antiproliferative factor (APF), heparinbinding epidermal growth factor-like growth factor (HB-EGF), epidermal 2 growth factor (EGF), and urinary glycoprotein (GP)51. Urine levels of all of these were found to be significantly different between patients with IC and asymptomatic controls.25-28 In a seminal study by Susan Keay, MD, PhD and colleagues, antiproliferative activity was found in 9% of urine specimens from subjects without IC and in 94% of urine specimens from patients with IC.29 APF appears to inhibit the growth of normal bladder epithelial cells. Dr. Keay commented that the demonstration of a difference in cell replication rates between IC cells, which produce APF, and normal cells, which do not appear to, may be evidence that the bladder epithelium is intrinsically abnormal in IC patients.30 GP51 is a urinary glycoprotein produced and secreted by the transitional epithelium of the genitourinary tract. Studies on the potential of using GP51 as a clinical marker for IC have found that low GP51 levels in the urine appear to be unique to the IC patient, compared to normal controls and to patients with other urinary tract diseases, supporting the potential usefulness of GP51 as another clinical marker for IC.28 APF appears to inhibit the normal growth of bladder cells. Antiproliferative activity was found in 9% of urine specimens from subjects without IC and in 94% of urine specimens from patients with IC. CHALLENGES IN THE DIAGNOSIS OF IC IN MEN Data are comparatively scarce regarding the prevalence of IC in men. Historically, IC has been thought to affect women disproportionately. In most studies of IC, only about 10% of patient cohorts are male. However, a recent study found a 1:5 male-to-female ratio of IC patients, accounting for a higher proportion of men with IC than has previously been recognized.3 (FIGURE 3) The study was based on a computer search of the Kaiser Permanente Northwest database of 206,470 (managed care) patients to find those patients assigned a diagnosis of IC by a clinician. Investigators noted that a significant FIGURE 3 No. per (100,000) GENDER-SPECIFIC PREVALENCE OF IC 220 200 180 160 140 120 100 80 60 40 20 0 197 158 41 Female ICD-9 Dx Male 28 Female Male ICD-9 + no excl. ICD-9 Dx = diagnosis of IC no excl. = no exclusion (after applying exclusion criteria derived from the NIDDK) Adapted from J Urol 2005;173(1):98-102, Clemens JQ, Meenan RT, Rosetti MC, et al. Prevalence and incidence of interstitial cystitis in a managed care population. Copyright © 2005, with permission from Lippincott Williams & Wilkins. number of both men and women had bladder-specific symptoms but did not receive a formal diagnosis of IC. They also found that half the men diagnosed with IC were additionally coded with a diagnosis of prostatitis. The roundtable participants concluded that a large number of men with bladder complaints and/or pelvic pain may have early IC that remains undiagnosed. IC should be suspected in a man with CPP and urinary symptoms, and he should be assessed and treated accordingly. IC should be suspected in a man with CPP and urinary symptoms, and he should be assessed and treated accordingly. Impact of CPP on Quality of Life IC, nonbacterial chronic prostatitis (CP), and chronic pelvic pain syndrome (CPPS) all adversely affect a man’s QOL. The QOL of male IC patients was found to be comparable to that of persons undergoing hemodialysis; the QOL of men diagnosed with CP/CPPS was found to be on par with severe congestive heart failure and diabetes and to have a sickness impact comparable to myocardial infarction, angina, and Crohn’s disease.31,32 For many men, sexual QOL is clearly compromised by IC and CP/CPPS. Rosen et al demonstrated the impact of lower urinary tract symptoms (LUTS) on male sexual dysfunction in a multinational survey of men aged 50 to 80 (12,815 men were deemed evaluable).33 The occurrence of sexual disorders, including ejaculatory loss, painful ejaculation, and erectile dysfunction, and their degree of “bothersomeness” (assessed by validated symptom scales) were strongly related to the severity of the urinary symptoms. Although 90% of the men included in Rosen’s survey had LUTS, only 19% had sought medical attention. The constellation of sexual problems with CP/CPPS and IC includes avoidance of intimacy and sexual dysfunction. Since men are often reluctant to report genitourinary symptoms to their health care providers, Dr. Fourcroy and Ms. Newman emphasized the importance of routinely questioning patients, especially men, about sexual activity and associated symptoms. Discussion with the patient can aid in early diagnosis and can encourage the patient with regard to the potential for improvement with treatment. Differential Diagnosis of IC and CP/CPPS Urologists should consider CPP of bladder origin (IC) in the differential diagnosis of men with voiding disorders accompanied by irritative symptoms (urgency/frequency) and pelvic pain, especially in the absence of bacteria or following one or more courses of antibiotic therapy.34 The CPP associated with IC is often attributed to other genitourinary conditions, such as CP/CPPS. CP/CPPS is defined by the NIDDK of the National Institutes of Health (NIH) as genitourinary/pelvic pain or discomfort, for at least 3 of the last 6 months, in the absence of uropathogenic bacteria localized to prostate-specific specimens on culture.35 CP/CPPS and IC share similar clinical presentations and possibly similar etiologies.36 The clinical presentation of CP/CPPS includes CPP and urinary symptoms of urgency, frequency and nocturia. (TABLE 2, page 4) Ms. Newman suggested that questions about sexual activity should be included as part of the medical history, because CPP often manifests as testicular or penile pain, pain in the perineal area, or pain with or following ejaculation. The clinical presentation of both CP/CPPS and IC includes pelvic pain and urinary symptoms of urgency, frequency, and nocturia, with the absence of uropathogenic bacteria. Both CP/CPPS and IC can be associated with pain upon bladder filling, and both lack a bacterial etiology. Furthermore, other similarities are seen on physical examination and cystoscopy, including sensory bladder instability, 3 TABLE 2 FIGURE 4 SIMILARITY OF SYMPTOMS BETWEEN IC AND CP/CPPS IC 36 DIAGNOSTIC/TREATMENT ALGORITHM FOR CPP IN MEN CP/CPPS • Voiding symptoms (frequency, urgency, nocturia) • Voiding symptoms (frequency, urgency, nocturia) • Pain with intercourse • Pain with ejaculation, testicular pain • Referred pain (lower abdomen, urethra, lower back, medial thigh, perineum, postvoid) • Referred pain (urethral, perineal, lower abdomen, testicular, scrotal, rectal, postvoid) • Pain on bladder filling • Pain on bladder filling • Nonrelaxing pelvic floor (70%) • Nonrelaxing pelvic floor (50%) • Diet can exacerbate symptoms • Diet can exacerbate symptoms Chronic Pelvic Pain No urinary symptoms CP/CPPS? • Antimicrobial therapy (eg, levofloxacin) • Anti-inflammatory (eg, naproxen) • Alpha-blocker a non-relaxing pelvic floor muscle, and petechial hemorrhages with bladder hydrodistention.37 In several recent studies, 58% to 90% of men with CP/CPPS were found to have cystoscopically confirmed IC.34,38,39 There is emerging evidence that CP and IC, in fact, may be 2 conditions that are part of the same pathophysiologic spectrum, namely lower urinary epithelial dysfunction.40 Dr. Kaufman stated that his diagnostic protocol for a male patient who presents with CPP is to assign him to one of 2 categories: CPP with urinary symptoms or CPP without urinary symptoms. If results of the physical examination suggest pelvic floor dysfunction rather than prostatitis, and the patient does not have urinary symptoms, IC is not immediately indicated and initial treatment would consist of muscle relaxants and physical therapy. Dr. Kaufman considers a diagnosis of IC (with or without pelvic floor dysfunction) when the prostate seems normal to examination and the patient presents with CPP and urinary symptoms. He confirms that diagnosis with a potassium sensitivity test (PST, described below). Dr. Kaufman’s approach has been defined through his clinical experience. (FIGURE 4) In light of the many similarities in clinical presentation, IC should be suspected in all men presenting with the signs and symptoms of CP/CPPS and urinary symptoms. When IC in a male patient is misdiagnosed as CP/CPPS due to the similarity of symptoms, it is often managed inappropriately with antibiotics. In light of the many similarities between the conditions, IC should be suspected in all men presenting with signs and symptoms of CP/CPPS and urinary symptoms. When CP/CPPS is the probable diagnosis—based on genitourinary pain, pain on ejaculation, and substantial perineal discomfort, without irritative voiding symptoms—one could begin therapy for CP/CPPS and then assess response at 1 month. Dr. Evans noted that a multimodal treatment approach would typically involve an antibiotic, alpha-blocker, anti-inflammatory agent, diet modification and other supportive care. A lack of response at 1 month would lead to reassessment for IC. Ms. Newman cautioned that differentiation into 2 groups is not straightforward, especially when the patient has a history of UTI and occasional urinary frequency/urgency. Dr. Kaufman suggested that, in those questionable cases, a positive PST might support a diagnosis of IC. Dr. Evans recommended checking the post-prostatic massage urine specimen to rule out bacterial prostatitis (a small percentage of patients). His clinical experience indicates that a large percentage of his patients with CPP have pelvic floor muscle dysfunction associated with an underlying bladder or prostate pathology, and his treatment approach targets not just CP or IC, but also muscle rehabilitation. 4 No response IC? Urinary symptoms IC? PUF and PST Positive Negative Reassess IC treatment: • PPS • Amitriptyline • Hydroxyzine • Intravesical instillations • Supportive/adjunctive therapies Pelvic floor dysfunction? • Physical therapy • Muscle relaxant (eg, lorazepam) CHALLENGES IN THE DIAGNOSIS OF IC IN WOMEN It is estimated that as many as 1 in 3 American women experience pelvic pain at some point in their lives, and over 9 million have sought treatment for their pelvic pain.41 For many of these women, an accurate diagnosis of their complaints may be elusive for years. Clinicians often assume that CPP is caused by reproductive tract problems, such as unresolved endometriosis, pelvic adhesions, or vulvodynia. They also frequently diagnose OAB in the patient with urinary frequency/urgency without ascertaining pelvic discomfort, and prescribe anticholinergics with variable success. Recurrent UTI is another common misdiagnosis, and can lead to repeated and often futile courses of antibiotics.42,43 (TABLE 3) Of the approximately 9 million women with CPP, a substantial percentage have a disorder of bladder origin and may eventually be diagnosed with IC. Of the approximately 9 million women with CPP, a substantial percentage have a disorder of bladder origin and may eventually be diagnosed with IC. While the prevalence of IC is still not definitively established, the consensus is that IC affects a far greater number of women than the traditional figures have suggested. Previous estimates have largely been based on diagnosed cases, excluding women with likely IC who have not been definitively diagnosed. According to 2 recent studies, as many as 2 in 9 women may have IC.44 A 2004 study screened female medical students for IC symptoms and then evaluated the suspected cases, identifying probable IC in 30.6% and TABLE 3 DIFFERENTIAL DIAGNOSIS OF IC IN WOMEN42,43 Bladder or urinary tract infection Vulvar dermatoses Endometriosis Uterovaginal prolapse Overactive bladder Renal calculi Sexually transmitted infection Cystocele/Rectocele Chronic pelvic infection Urethral diverticula Vaginal infection Irritable bowel syndrome Vulvodynia Pelvic floor dysfunction documented IC in 10% of this young, unselected population.45 These data suggest the estimate of IC prevalence in the United States should be vastly increased from approximately 1.5 million to perhaps 25 to 30 million women and that IC is prevalent in young women.45 Earlier diagnosis would increase the likelihood of prompt and effective resolution of symptoms. Differential Diagnosis of IC and Other Urologic and Gynecologic Conditions All women who present with a history of urinary frequency and urgency along with pain or discomfort in the pelvis, bladder, or perineum should be evaluated for the presence of IC. The differential diagnosis can be extensive. Often, urologic and gynecologic symptoms occur together, further confounding the diagnosis. Chung et al, in fact, have labeled IC and endometriosis the “evil twins of chronic pelvic pain.”46 Their retrospective review of 60 patients with CPP found IC in 97% and endometriosis in 93%. All women who present with a history of urinary frequency and urgency along with pain or discomfort in the pelvis, bladder, or perineum should be evaluated for the presence of IC. The roundtable participants agreed that pelvic pain is a key presenting symptom in IC and should raise the suspicion of IC. Similarly, IC should be suspected in women reporting recurrent symptoms of UTI who have negative cultures. Because urinary frequency and urgency are also key symptoms of IC, the need to differentiate IC from OAB is an important goal of diagnosis. Ms. Newman emphasized that IC should be considered when patients diagnosed with OAB do not respond to anticholinergics/antimuscarinics and report pain or discomfort that is relieved by voiding. CURRENT APPROACH TO DIAGNOSIS OF IC IN MEN AND WOMEN The patient with signs and symptoms of IC should undergo a medical history and physical examination with urinalysis and/or culture, and should complete a voiding diary. These traditional assessments, however, do not provide enough information for a definitive diagnosis of IC. Many attempts have been made to establish objective criteria or a unique diagnostic test. Dr. Nickel offered the following perspective on currently employed diagnostic methods: • Testing for presence of Hunner’s ulcers – Found in fewer than 10% of patients • Testing for presence of glomerulations via cystoscopy and hydrostatic bladder dilation – Invasive, requires general anesthesia, no accepted criteria for identification, glomerulations may be present in only 50% of IC patients • Bladder capacity measurement under general anesthesia – Helpful but does not differentiate IC from other bladder diseases • Application of NIH/NIDDK criteria – Fails to diagnose at least 50% of patients • PST – Simple, inexpensive, generally safe and well-tolerated, provides objective assessment but fails to diagnose 25% of patients • Urine biomarkers – Exciting and promising but currently a research tool; not yet ready for clinical application None of the above methods has proved uniformly helpful, but some are more accurate than others. Two diagnostic approaches have recently become fairly well established for evaluating and perhaps diagnosing IC—the PST and the Pelvic Pain and Urgency/Frequency (PUF) Patient Symptom Scale. While neither is completely reliable alone as a definitive diagnostic tool, together (and along with a medical history, a physical examination, and appropriate urine testing) they may be considered sufficient to make a clinical diagnosis of IC and to initiate appropriate therapy. The PUF questionnaire and the PST are new diagnostic tools that allow clinicians to screen patients suspected of having IC easily and reliably. Potassium Sensitivity Test The PST can identify those patients who respond with pain or urgency to the instillation of an aqueous solution of potassium chloride (KCl) in the bladder, indicating a dysfunction of the uroepithelium. Because the test involves catheterization, it may not be readily employed in some primary care practices. The procedure may be accompanied by immediate pain and discomfort that quickly subside. Sterile, room temperature water (40 mL) is first slowly introduced via a thin catheter into the bladder to establish baseline levels of pain and urgency, using a point scale ranging from 0 to 5 (with 5 representing the most severe pain). The sterile water is generally retained in the bladder for approximately 5 minutes [Dr. Kaufman allows it to be retained for 1 minute], and then slowly drained through the catheter. (Dr. Kaufman mentioned that it may be necessary for men to void out the KCl solution in order to observe a positive response, which may be induced when the solution comes in contact with the urothelium of the prostatic urethra.) Then 40 mL of 0.4M KCl solution is instilled slowly into the bladder, and the patient is asked to re-evaluate the pain. An increase of 2 or more points is suggestive of abnormal epithelial function and IC is indicated. Patients who respond to the introduction of only the initial water solution are considered likely to have IC, as are those who report discomfort with the KCl solution. A patient has a clearly negative PST if he or she reports no pain or urgency response to any part of the procedure (except in certain situations, such as heavily medicated patients). 80% of IC patients have positive PST results, compared to 4% of asymptomatic controls. Eighty percent of IC patients have positive PST results, compared to 4% of asymptomatic controls. Patients with detrusor instability show a 25% false-positive rate and patients with UTI and radiation cystitis have a 100% false-positive rate.17 A positive PST result is seen in 85% of gynecologic patients with CPP, endometriosis, or vulvodynia.47 The PST seems to be appropriately negative in many urologic conditions, but the significant rate of positive results in others, including OAB and UTI, could confound the diagnosis of IC.40,44,47,48 5 While a positive PST does not conclusively diagnose IC, nor a negative PST rule it out, studies have found a sufficiently significant correlation between a positive PST result and presence of IC that it remains part of the diagnostic armamentarium for IC. (FIGURE 5) Positive PST results have been shown to correlate well with urodynamic findings, helping to confirm a diagnosis of IC. According to a study in 526 males and 25 females with LUTS, patients with a positive PST had urgency at significantly lower volumes, lower bladder capacity, and lower post-void residual than individuals with a negative PST— urodynamics that are characteristic of IC.49 Dr. Evans and Dr. Kaufman employ the PST in patients who present with CPP and urinary symptoms, and they consider a positive PST result suggestive of IC. Dr. Nickel and Ms. Newman generally depend on the medical history, a physical examination, appropriate urine testing, and other ancillary tests as indicated for a diagnosis of IC. FIGURE 5 PUF PATIENT SYMPTOM SCALE Patient’s Name:________________________________________ Today’s date: _________________________ Please circle the answer that best describes how you feel for each question. 1 How many times do you go to the bathroom during the day? 2 a. How many times do you go to the bathroom at night? 48 0 1 2 3 4 3-6 7-10 11-14 15-19 20+ 0 1 4+ 2 3 Never Occasionally bothers Usually Always Never Occasionally Usually Always Never Occasionally Usually Always Never Occasionally Usually Always Mild Moderate Severe b. Does your pain bother you? Never Occasionally Usually Always 7 Do you still have urgency after you go to the bathroom? Never Occasionally Usually Always Mild Moderate Severe Never Occasionally Usually Always b. If you get up at night to go to the bathroom, does it bother you? 100% 100% 84% 79% 79% 5 Do you have pain associated with your bladder or in your pelvis (vagina, labia, lower abdomen, urethra, perineum, penis, testes, or scrotum)? 8 a. If you have urgency, is it usually 55% BOTHER SCORE YES _____ NO _____ 4 a. IF YOU ARE SEXUALLY ACTIVE, do you now or have you ever had pain or symptoms during or after sexual activity? 6 a. If you have pain, is it usually b. Does your urgency bother you? SYMPTOM SCORE (1, 2a, 4a, 5, 6a, 7, 8a) 25% 24% BOTHER SCORE (2b, 4b, 6b, 8b) 16% TOTAL SCORE (Symptom Score + Bother Score) = Total score ranges are from 1 to 35. A total score of 10-14 = 74% likelihood of positive PST; 15-19 = 76%; 20+ = 91% Potassium Positive IC CPP CP/CPPS LUTS (women) (women) LUTS Urethral Acute Acute Radiation (men) syndrome detrusor bacterial cystitis instability cystitis Symptom Questionnaires The PUF is an 8-question symptom scale that measures the presence and severity of IC symptoms and the degree to which they are bothersome.44 It includes questions on the key symptoms of IC (pelvic pain and urinary frequency and urgency) and questions on symptoms that may manifest during or after sexual activity. It is easy to administer and score, and the patient can complete it in about 5 minutes. The maximum score is 35. High symptom, “bother,” and total scores (>10) can identify patients with a high likelihood of having IC and can help differentiate IC from other conditions that cause CPP. (TABLE 4) Parsons et al showed that patients with a PUF score higher than 10 had a 74% likelihood of having IC.44 The same study found that high PUF scores strongly correlated with a positive PST result, supporting the use of the PUF as an initial screening tool and allowing the more invasive PST to be reserved for patients with symptoms suggestive of IC but a lower (2-5) PUF score. (FIGURE 6) © 2000 C. Lowell Parsons, MD. Used with permission. FIGURE 6 HIGHER PUF SCORES CORRELATE WITH HIGHER LIKELIHOOD OF POSITIVE PST44 100 80 % PST Positive 110 100 90 80 70 60 50 40 30 20 10 0 SYMPTOM SCORE 3 Are you currently sexually active? b. If you have pain, does it make you avoid sexual activity? PST RESULTS IN POPULATIONS OF SYMPTOMATIC PATIENTS Patients With Positive PST Result (%) TABLE 4 60 40 20 0 0-4 (n=56) 5-9 (n=20) 10-14 (n=61) 15-19 (n=114) 20-24 (n=75) 25+ (n=56) PUF Score High scores on the PUF questionnaire strongly correlate with a positive PST result. Other symptom questionnaires can also be of benefit as diagnostic aids. One symptom scale commonly used is the O’Leary-Sant Interstitial Cystitis Symptom Index (ICSI), which evaluates IC symptom impact and treatmentrelated change in symptoms. The ICSI comprises a “symptom index” with 4 6 N = 334 patients urologic/gynecologic; 48 asymptomatic controls. questions about pain and urgency, and a “problem index” with 4 questions pertaining to the degree to which the patient experiences each symptom. Answers are assigned a score of 0 to 5, and a total score can range from 0 to 24 for both indices. Patients with IC typically score a total of 6 or more points on each index.50,51 Dr. Nickel commented that the PUF is highly sensitive but not specific for IC. Dr. Evans said he routinely uses the PUF, and finds that patients who score 15 or higher can be reliably diagnosed with IC. A diagnosis of IC indicated by a high PUF score may then be confirmed by the more invasive PST. Ms. Newman expressed her preference for the O’Leary-Sant ICSI, particularly for female patients. Dr. Nickel believes that either the ICSI or the PUF can be important in the initial assessment of patients because it can quantify their symptoms. He asks patients to fill out the PUF prior to diagnosis, but for monitoring patients he prefers the ICSI, which demonstrates treatmentrelated changes. Intravesical Anesthetic Challenge An emerging diagnostic procedure that may also give patients temporary symptomatic relief is the “intravesical anesthetic challenge.” Preliminary research has found that bladder instillation of an anesthetic lidocainebicarbonate solution leads to significant improvement in pain. Responders are likely to have pain of bladder origin indicative of IC.52 Although the PST has proven to be accurate and useful in clinical practice, the anesthetic challenge approach may be preferred as a diagnostic option because it alleviates rather than induces pain.53 Dr. Evans mentioned that he always uses a “rescue” solution that includes either pentosan polysulfate sodium (PPS) [dissolved in sterile water] or heparin plus lidocaine and bicarbonate after the PST when assessing a patient whose symptoms suggest a diagnosis of IC, and sometimes administers it even if he does not give the PST. Dr. Nickel said that after intravesical instillation of an anesthetic solution, which mutes bladder pain, pelvic pain associated with the bladder can be better isolated and defined.52 (FIGURE 7) FIGURE 7 DIAGNOSTIC ALGORITHM FOR IC Patient with CPP and urinary symptoms Physical Examination (Bladder neck tenderness on bimanual examination; pelvic floor dysfunction) History (Urgency, frequency, CPP, dyspareunia, flare-ups) Reassess Negative Positive PST Treat IC Urinalysis & Culture (negative) 24-hour voiding diary APF, which is associated with a greatly decreased rate of cell proliferation and decreased production of HB-EGF, compared to age-, race-, and gendermatched asymptomatic controls, and compared to patients with documented bacterial cystitis, clinically diagnosed vulvovaginitis, CP/CPPS, or other urogenital or pelvic organ dysfunction. (TABLE 5)26 In Dr. Keay’s subsequent study in men, patients with CPP were separated into IC and prostatitis cohorts based on the presence or absence of irritative voiding symptoms. In both studies, urinary APF activity was defined by the ability of the urine to inhibit tritiated thymidine incorporation in normal cells by greater than 2 standard deviations from controls. Male patients with IC (those with pain and irritative voiding symptoms) were differentiated from male patients with CPP (those without irritative voiding symptoms) by the presence of APF activity and abnormally low HB-EGF levels in their urine.54 TABLE 5 PREVALENCE OF URINE APF ACTIVITY Groups Number of Patients (positive/total) Percent of Patients Positive IC (206/219) 94% Asympt. Controls (10/113) 9% Overactive Bladder (2/32) 6% Bacterial Cystitis (7/58) 12% Micro Hematuria (2/19) 10% Stress Incontinence (1/10) 10% Neurogenic Bladder (0/11) 0% BPH (1/14) 7% Prostate Cancer (2/11) 18% Bladder Cancer (1/12) 8% Nonbact Prostatitis (1/16) 6% Vulvovaginitis (0/12) 0% Miscellaneous (1/16) 6% Adapted from Urology. 2001;57:9-14, Keay SK, Zhang CO, Shoenfelt J, et al. Sensitivity and specificity of antiproliferative factor, heparin-binding epidermal growth factor-like growth factor, and epidermal growth factor as urine markers for interstitial cystitis. Copyright © 2001, with permission from Elsevier. PUF Intravesical anesthetic solution Reassess or modify therapy No Symptoms improve after 4-6 months? Yes Continue or modify therapy Future Directions in the Diagnosis of IC The diagnosis of IC is currently dependent on clinical judgment based on symptoms in the absence of any other clearly defined pelvic disorder. Noninvasive urine tests for biomarkers specific for IC would greatly improve diagnostic accuracy. APF was recently shown in a multicenter blinded study to have the least overlap between IC and control groups of 13 putative biomarkers tested.27 Dr. Keay explained that the sensitivity and specificity of APF for identifying IC patients is over 90%, which provides encouragement that APF activity could become the foundation for an effective screening test. Dr. Keay and her colleagues discovered that there are inherent differences between bladder epithelial cells grown from IC patients and those grown from controls. The main difference seems to be that cells from IC patients produce The diagnosis of IC is currently dependent on clinical judgment based on symptoms in the absence of any other clearly defined pelvic disorder. Interestingly, the levels of APF significantly diminishes and the level of HB-EGF increases in the urine of IC patients who undergo cystoscopy and hydrodistention or percutaneous neurostimulation in a manner that correlates with symptom relief, thus suggesting a possible benefit in using APF and/or HB-EGF levels to monitor treatment success. Slobodov and colleagues evaluated other proteins involved with epithelial adhesion, cellular differentiation and bladder impermeability in 27 IC patients, specifically E-cadherin (which has a crucial role in urothelial differentiation), ZO-1 and uroplakin (which contribute to the impermeability of the bladder urothelium), and chondroitin sulfate (a component of the GAG layer).55 Normal marker patterns were found for only 3 of these proteins, upholding the hypothesis of abnormal cell differentiation in the IC bladder. 7 The roundtable participants suggested that determination of elevated urinary levels of APF (and abnormalities of other proteins), in combination with clinical signs, may allow for a simple, noninvasive, non-cystoscopic diagnosis of IC in the future. Patient Stratification for the Diagnosis and Treatment of IC The patient with severe IC, with unrelenting pain and frequency/urgency, is relatively easy to identify. Such cases were first recognized over 170 years ago and the clinical characterization of this disorder has remained essentially unchanged since that time. 56 The problem comes in recognizing the mild/intermittent and moderate cases, which appear to be more common. These patients often have vague, nonspecific urinary and pelvic complaints that can easily escape detection, escalating over time to a more refractory disorder. Differences in the presentation of IC indicate that it derives from a complex etiology, and stratifying patients according to certain characteristics may help in their diagnosis and treatment.57 Patients with mild/moderate cases of IC often have vague, nonspecific urinary and pelvic complaints that can easily escape detection, escalating over time to a more refractory disorder. Dr. Evans questioned the clinical relevance of stratifying patients with IC into subgroups, commenting that regardless of subclassification, treatment options remain the same. Dr. Nickel suggested that dividing patients into early onset, newly diagnosed, and chronic IC might be more helpful than some of the other proposed classifications, such as classic and non-ulcer. Two other possible means of patient stratification involve whether a patient has a positive or negative PST, or whether his or her pelvic pain is alleviated by an anesthetic intravesical cocktail. Urine biomarkers may provide a future means of identifying and classifying IC patients more simply and definitively. (TABLE 6) TABLE 6 APPROACHES TO PATIENT STRATIFICATION FOR DIAGNOSIS OF IC Differentiation History/Finding By disease course • Early onset • Newly diagnosed • Chronic By biomarkers • KCl + • KCl - By anesthetic cocktail • Pain ↓ with PPS, lidocaine, and bicarbonate By hydrostatic bladder dilation • Classic IC (ulcers) • Non-ulcer IC By symptoms • CPP • Urinary urgency/frequency 8 Because the etiology of IC is unknown, treatment is necessarily symptomdriven and empiric. Dr. Fourcroy stated that evidence-based treatment of IC remains problematic because of the lack of well-designed, randomized, placebo-controlled trials. Dr. Evans commented that a scientifically rational approach supports a multimodal strategy that targets the 3 key elements associated with IC: the damaged GAG layer of the uroepithelium, associated allergies, and neural up-regulation.18 (TABLE 7) Ms. Newman added that non-pharmacologic or conservative approaches, such as diet modification, physical therapy, and bladder retraining, can be used to enhance the benefits associated with drug treatment. TABLE 7 PHARMACOLOGIC TREATMENT OPTIONS FOR THE PRINCIPAL COMPONENTS OF IC18 Causative Factor Treatment GAG layer dysfunction PPS Mast cell activation Hydroxyzine hydrochloride Neurogenic up-regulation Amitriptyline Pelvic floor dysfunction Muscle relaxant/analgesic Because the etiology of IC is unknown, treatment is necessarily symptom-driven and empiric. The roundtable participants agreed that the ultimate approach to treatment of IC is first to understand the mechanisms of pathogenesis and to acknowledge that they may be interrelated. They concurred that crucial to successful treatment is diagnosis early in the disease process, when the patient first complains of urgency or frequency and the pain or discomfort is manageable. When a patient presents with long-standing IC, the treatment regimen will need to address not only initiating factors but also the chronic effects on the patient’s central and local nervous system and the psychological impact the IC symptoms have had on the patient’s life. Key to successful treatment of IC is diagnosis early in the disease process when the patient complains of a little urgency or frequency and discomfort. •APF ↑ • GP51 ↓ By PST test (epithelial dysfunction) CURRENT APPROACH TO TREATMENT OF IC Conservative/Adjunctive Therapies The benefits of pharmacologic agents can be enhanced with various adjunctive therapies, though they are rarely sufficient as monotherapy. A key component of multimodal treatment of IC is diet modification, because more than 50% of IC patients can identify foods that exacerbate symptoms or cause flare-ups.15 Ms. Newman said that foods high in acid (eg, alcohol, carbonated drinks, caffeine, spicy foods, tomatoes, vinegar) and arylalkylamines (tryptophan, tyrosine, tyramine, and phenylalanine) are particularly implicated in IC, as are artificial sweeteners and tobacco. Dr. Evans suggested that because not all patients are sensitive to the same foods, an elimination/challenge diet will help identify the offending items that should be avoided. Bladder training/behavioral modification can improve urinary frequency by teaching patients to void at designated times and gradually increase the time between voids. A program of manual physical therapy and pelvic floor exercises proved beneficial in the treatment of patients diagnosed with IC, with the greatest improvement seen in the indices of frequency and suprapubic pain, and less improvement in urgency and nocturia.58 Additionally, patients should spend adequate time in therapy and complete the recommended number of sessions in order to achieve maximum benefit. In addition to pelvic floor exercises, patients with pelvic floor dysfunction can be prescribed a muscle relaxant, such as lorazepam or baclofen. Diet modification, physical therapy, and bladder training are useful adjunctive treatments for IC. Pharmacologic Treatments Approved by the US Food and Drug Administration (FDA) Oral Pentosan Polysulfate Sodium A defective GAG bladder layer may be a contributing cause of IC. A multimodal treatment approach, therefore, might include repair of the GAG layer. PPS, a low molecular weight heparin-like compound, is the only oral drug approved by the US FDA for the relief of bladder pain or discomfort associated with IC.59 It is believed to act by replenishing the GAG layer, thus controlling cell permeability and preventing irritating solutes from reaching the uroepithelium.60 PPS may have a stabilizing effect on mast cells and antiinflammatory properties.61 It has no known drug-drug interactions, and can be administered together with antihistamines, analgesics, antidepressants and antispasmodics to provide enhanced pain and symptom relief to the patient with IC. PPS is well tolerated and is associated with infrequent, mild, and transient side effects such as minor gastrointestinal discomfort, headache, and reversible alopecia.59 PPS is a weak anticoagulant (1/15 the activity of heparin) and as such appears to have no effect on coagulation profiles. Slight liver function changes have been reported in about 1% of patients receiving PPS, but these changes resolved spontaneously and have not been associated with jaundice or other clinical signs or symptoms. Liver function tests are not routinely required in patients taking PPS. PPS is the only oral drug approved by the US FDA for relief of bladder pain or discomfort associated with IC. The FDA-recommended dose of oral PPS is 300 mg per day taken as one 100-mg capsule 3 times daily; an emerging off-label dose is 200 mg twice daily, which enhances patient compliance. The slow repair of the uroepithelial GAG layer facilitated by PPS requires several months of therapy before significant symptom resolution occurs, although patients diagnosed early in the disease process may experience pain relief as soon as 4 weeks.60,62 Neither doubling the dose nor giving PPS more frequently (TID) has been shown to improve or hasten the onset of efficacy.63 Clinicians have reported that prompt relief, however, may be achieved through a “jump start” method based on instillation of a PPS solution into the bladder (this approach is not FDAapproved). Dr. Kaufman uses a mixture of 200 mg PPS (2 tablets dissolved in saline), 10 mL of 2% lidocaine, and 5 mL of 8.4% sodium bicarbonate, administered intravesically 2 to 3 times a week, then once every 3 to 4 weeks until the effect of the oral PPS begins to be evident. In his clinical experience, patient and physician dedication to this strategy produces impressive results. Dr. Evans teaches his patients, who come to his office from a great distance, to do self-instillation of a PPS- or a heparin-lidocaine solution as needed. Several randomized controlled trials demonstrated that oral PPS produced significantly greater subjective improvement than did placebo on all 4 parameters of pain, urgency, frequency, and nocturia.60 A recent retrospective review of the charts of 260 patients with IC diagnosed at cystoscopy revealed a statistically significant improvement in frequency, urgency, and pain in the group treated with PPS compared to the IC patients without PPS treatment.64 (TABLE 8) The effect on symptoms is paralleled by a reduction in potassium sensitivity as measured by the PST, according to the results of a recent study, which showed that after 32 weeks of PPS therapy, 60% of patients had a significant improvement on the PST pain and urgency scales and 71% reported a 50% or greater improvement in symptoms (measured using the Patient Overall Rating of Improvement in Symptoms [PORIS] scale).63 The results of another study demonstrated that symptomatic improvement increases with duration of PPS therapy, regardless of study dose (300, 600, or 900 mg/d). The percentage of patients whose responses changed from “moderately improved” to “symptoms gone” (measured using PORIS-ICSI) more than doubled from the 4th to the 12th week of PPS therapy.62 (FIGURE 8, page 10) TABLE 8 IMPROVEMENT IN IC SYMPTOMS WITH PPS TREATMENT PPS-treated Group Control 15.3 16.4 Posttest 9.4 13.7 Change -5.9 -2.7 4.7 5.8 Parameter Frequency, No. of voids Pretest Nocturia, No. of voids Pretest Posttest 2.5 4.5 Change -2.2 -1.3 Urgency, severity*† Pretest 2.3 2.2 Posttest 1.4 1.6 Change -0.9 -0.6 Pretest 6.6 6.2 Posttest 3.3 4.7 Change -3.3 -1.5 Pain, severity* *Change in parameters over time † Scale of 1 to 6, from worst to total improvement or complete abatement of symptoms (or both) Adapted from J Am Osteopath Assoc. 2000;100:S13-S18, Waters MG, Suleskey JF, Finkelstein LJ, et al. Interstitial cystitis: a retrospective analysis of treatment with pentosan polysulfate and follow-up patient survey. Copyright © 2000. Reprinted with the consent of the American Osteopathic Association. Oral PPS treatment is associated with significant improvement in pain and urinary symptoms in patients diagnosed with IC. A recent study evaluating the efficacy and tolerability of PPS in men with category III CPPS found that significantly more patients receiving PPS (900 mg/d) experienced “moderate” to “marked” improvement as measured by the NIH-Chronic Prostatitis Symptom Index (CPSI), the Subjective Global Assessment, Symptom Severity Index, and Clinical Global Improvement assessment tools. The PPS was well tolerated even at the 900-mg daily dose, with diarrhea, nausea, and headache being the most common adverse events.65 9 FIGURE 8 IMPROVED RESOLUTION OF IC SYMPTOMS WITH DURATION OF PPS TREATMENT62 demonstrated objective improvement, compared with 35% of the placebo group; 53% of the DMSO group reported a marked improvement compared with 18% of the placebo group.70 (TABLE 9) Although DMSO rarely affords patients complete remissions, it can be combined with heparin and/or lidocaine to increase benefit.71 TABLE 9 40 34.3% DMSO TRIAL RESULTS 35 Percentage of Patients 30 24.3% 25 20 15 10 10.4% Findings for DMSO (RIMSO-50) IC/2 sessions of 4 treatments each (every 2 weeks)70 RIMSO-50 93% of subjects: Objective improvement 53%: Subjective improvement 3.2% 5 0 Baseline (n = 376) 4 (n = 346) 12 (n = 267) 32 (n = 137) Weeks of Treatment *ICSI scores scale: 0 = no symptoms; 20 = symptoms almost always Dr. Evans and Dr. Kaufman concurred that PPS, together with pain management, an antihistamine, diet modification, and a muscle relaxant (with pelvic muscle relaxation exercises or physical therapy, as required), can provide optimal benefit for most patients with IC. For the male patient who presents with CPP with or without urinary symptoms and fails a first round of antibiotic therapy (with supportive treatments), Dr. Evans will reassess for IC (usually with the PST) and will recommend PPS as part of a multimodal therapeutic regimen. Intravesical Instillation With Dimethyl Sulfoxide (DMSO) Prior to the approval of oral PPS, the only FDA-approved treatment for IC was DMSO for bladder instillation, and intravesical treatment is an option for those patients who do not respond to or cannot tolerate oral therapy. DMSO is an anti-inflammatory analgesic with muscle-relaxing properties that may prevent muscle contractions that can cause pain and urinary frequency/urgency. Its mechanism of action is unknown, but, in addition to its inherent antiinflammatory effects, it appears to inhibit mast cell secretion and to increase bladder capacity.60 DMSO treatments are administered in the clinician’s office once a week or once every 2 weeks for 6 to 8 weeks; motivated patients can self-catheterize at home. DMSO (RIMSO-50) is instilled into the bladder through a catheter and generally retained for 15 minutes before being expelled. (Dr. Kaufman instructs his patients to retain the DMSO for 1 hour.) The patient may experience moderately severe discomfort on administration, but this diminishes with repeated use. DMSO is generally well tolerated, but it can leave a garlic-like taste and odor on the breath or skin for up to 72 hours after treatment. Liver and renal function tests and complete blood count are recommended every 6 months during DMSO therapy.66 Intravesical treatment with DMSO is an option for those patients who do not respond to or cannot tolerate oral therapy. Clinical trials suggest that DMSO affords at least moderate symptom relief for most patients, with response to therapy reported within 3 to 4 weeks of the first 6- to 8- week cycle.67-69 In a placebo-controlled study of intravesical instillation of DMSO (every 2 weeks for 2 sessions) 93% of the DMSO recipients 10 Diagnosis/Treatment Chronic inflammatory bladder disease/ 3 treatments (every 2 weeks), then 3 more (every 4 weeks)67 80% of subjects: Satisfactory symptom relief No changes on endoscopy/ morphology IC/up to 236 treatments (every 2 weeks)9.958 pt 75% of subjects had good to excellent symptomatic relief ~80% had increased bladder capacity IC/3-6 treatments (at varying intervals)69 50%-77% of subjects had symptomatic relief Off-label Treatments for IC Antihistamines More than half of IC patients have reported a history of allergy or asthma.72 Mast cell activation has been shown to occur in patients with IC.73 When activated, mast cells release histamines and other inflammatory mediators. Mast cell activation is believed to have a role in the pathogenesis of IC, and antihistamines have been shown to be beneficial in its treatment, especially in patients with suspected allergic flares. In a study comparing the effect of hydroxyzine hydrochloride (75 mg/d for 3 months) on IC patients with or without a history of allergy, hydroxyzine hydrochloride reduced symptoms in 55% of those with a history of allergy and in 40% of those patients without allergy.74 In a recent study, the treatment response when hydroxyzine hydrochloride was administered with PPS was greater than the response for each agent administered alone.75 Dr. Evans has written that, when taken at night at a dose of 25 to 75 mg, hydroxyzine hydrochloride’s sedative properties can help alleviate nocturia and provide the patient a restful night.18 Antidepressants Antidepressants, particularly the tricyclic antidepressants (TCAs), can relieve pain by inhibiting histamine secretion from mast cells and decreasing norepinephrine and serotonin reuptake in the central and peripheral nervous systems. TCAs are useful in IC because, in addition to their antidepressant effects, they modify pain and have modest antihistamine and anticholinergic effects. In an early study, amitriptyline (25-75 mg/d taken nightly) provided mild to moderate central pain modulation in 60% to 90% of patients with IC.76 While few data have established the value of this agent in the treatment of IC, efficacy and safety were recently demonstrated in a prospective, randomized, placebo-controlled, double-blind study of 51 patients. Mean symptom score, pain and urgency intensity were significantly improved in the amitriptyline group (25-100 mg), along with frequency and functional bladder capacity, compared with the placebo group.77 Dr. Evans, Dr. Kaufman, and Ms. Newman include amitriptyline in their initial multimodal treatment regimen for their IC patients, but Dr. Kaufman stated that it is the first drug that he eliminates from the regimen once the patient begins to show improvement. Other Therapies for Pain Relief Pain symptoms in IC are often suggestive of a neuropathic component for which the long-acting opioids can be of benefit, especially before PPS therapy takes effect.78 Dr. Evans’ and Dr. Kaufman’s clinical experience with these agents in patients with severe IC shows that tolerance can develop over time but true addiction is rare. The anticonvulsant gabapentin has proved effective in neuropathic pain syndromes and has recently demonstrated efficacy in patients with IC and genitourinary pain.79 In a small study of patients with refractory genitourinary pain, 10 of 21 patients (including 5 of 8 with IC) reported improvement with 1200 mg per day of gabapentin.80 The current recommendation is to start with 100 mg at bedtime, and titrate to the most effective dose (the usual range is 300 to 2400 mg/d).18 To give immediate relief to patients with severe pain, Dr. Nickel reported success with short-term epidural anesthetic blockade. This approach may temporarily down-regulate the pain process, allow for treatment re-initiation, and provide much-needed sleep. This approach was validated by Sukiennik and colleagues, who found that urinary substance P levels initially increased, and then declined, in 5 patients who achieved pain control with a 3-day epidural infusion.81 Other Intravesical Solutions Although DMSO is the only FDA-approved intravesical agent indicated for IC, other agents have promoted pain relief and prolonged remission in some patients. Intravesical heparin (10,000-40,000 IU/d in 10 mL of water) or PPS (1 or 2 100-mg capsules dissolved in 10 mL buffered normal saline) can be administered daily or every other day (this is an off-label use) for more immediate relief than that afforded by oral PPS treatment.18,82 An early study of intravesical installation of hyaluronic acid, a GAG present in all connective tissues, including the GAG layer of the uroepithelium, at a dose of 40 mg weekly for 4 weeks and then monthly showed it improved symptoms in patients with IC refractory to other medical therapies. An initial 56% positive (complete plus partial) response rate at week 4 increased to 71% by week 12 and was maintained until week 20.83 Dr. Evans indicated that 2 recent placebocontrolled trials, however, failed to show any benefit. The unpublished results of these 2 trials, one of which included Dr. Evans as a principal investigator, were considered sufficient not to warrant additional studies on the use of intravesical hyaluronidase for treatment of IC. Patients with severe disease may derive immediate temporary relief from urgency and pain with adjunctive anesthetic intravesical solutions, or “rescue cocktails.” Patients with severe disease may derive immediate temporary relief from urgency and pain with adjunctive anesthetic intravesical solutions, or “rescue cocktails.” A recent study found that 85% of patients treated with rescue therapy 3 to 7 times weekly for 2 weeks or more experienced not only immediate but also sustained relief.84 The therapeutic rescue solutions utilize PPS (100-200 mg) or heparin (10,000-40,000 IU) as the foundation, plus 8.4% sodium bicarbonate (3 mL) and either 1% lidocaine (10 mL) or 2% lidocaine (16 mL) for a total volume of <25 mL. (The sodium bicarbonate greatly facilitates the absorption of the lidocaine.) The solution is retained in the bladder for 30 minutes. In one study, 41 of 55 patients (75%) experienced significant immediate symptom relief with a rescue solution utilizing PPS.85 Use of the solution 3 to 7 times per week for 2 or more weeks resulted in sustained pain relief in 85% of patients. Patients can be taught to perform the rescue instillations at home. Approaches to Multimodal Treatment of IC Because long-term multimodal therapy is key to resolution of IC, Dr. Fourcroy emphasized that prior to beginning a treatment regimen, the clinician should discuss with the patient the chronic nature of IC and realistic expectations of treatment outcome. Dr. Evans explains to his patients the 3 principal components to their disease: GAG layer abnormalities, mast cell dysfunction, and neurogenic up-regulation. He then recommends treatments to resolve each of those components: PPS (200 BID, an off-label dose), an antidepressant or other pain medication (perhaps amitriptyline 25-50 mg), and an antihistamine (hydroxyzine hydrochloride 25 mg). If pelvic floor dysfunction is a component of the disease, then rehabilitation (physical therapy), stress management, and pelvic floor exercises should be added to the regimen. (FIGURE 9) FIGURE 9 LONG-TERM MULTIMODAL THERAPY FOR IC Clinician : Confidence Pharmacotherapy • PPS (for GAG dysfunction) • Amitriptyline (for pain) • Hydroxyzine hydrochloride (for allergic patients; flare-ups) Narcotics for severe pain Patient : Empowerment Adjunctive Therapy • Diet modification • Physical therapy • Stress management • Bladder retraining Epidural to break severe pain cycle “Jump start” therapy with intravesical instillations of PPS or heparin with lidocaine and bicarbonate (every other day for 2 weeks) Once Dr. Kaufman has made a diagnosis of IC with a medical history, a physical examination, and a PST, he describes the disease as a manageable entity and engages the patient in a treatment contract, encouraging him or her to participate fully in the therapeutic process. He provides patients a brochure from the Interstitial Cystitis Association (ICA) that deals specifically with diet. The cornerstone of his treatment plan for his patients with IC is PPS. He recommends amitriptyline for the neuropathic pain (Elavil at 10 mg for women and 25 mg for men) and hydroxyzine hydrochloride (Atarax at the lowest dose of 10 mg) for patients who have a history of allergies. For immediate relief, Dr. Kaufman “jump starts” his patients on PPS by dissolving 1 or 2 100-mg tablets in saline and instilling that solution together with 10 mL of 2% lidocaine and 5 mL of sodium bicarbonate. He administers the jump-start solution 2 to 3 times per week for 2 weeks and then one instillation every 3-4 weeks, until the oral PPS shows benefit. He has found that intravesical PPS is more effective for pain relief and less expensive than heparin. He refers his patients with pelvic floor dysfunction to a physical therapist. Key to a successful outcome is engaging the patient to participate fully in the therapeutic process. Ms. Newman generally adds a pelvic floor muscle rehabilitation program to a pharmacologic treatment regimen, which can include PPS, amitriptyline, hydroxyzine hydrochloride, and a muscle relaxant. She offers a handout with information on adjunctive treatments, including dietary suggestions. She 11 administers intravesical instillations to patients with severe IC, and teaches them to self-administer treatment during flare-ups. Dr. Nickel recommends the short-term addition of muscle relaxants (baclofen or diazepam) for patients with documented pelvic floor spasm. When Dr. Nickel asked about the use of DMSO, Dr. Evans and Dr. Kaufman said they had used it in the past, but no longer included it in their treatment protocol because their patients generally do not tolerate it as well as PPS. All of the participants agreed that once patients begin to show improvement, they continue on the PPS but are slowly weaned off the other medications, beginning with the amitriptyline. Surgical Intervention A primary care clinician has the tools to diagnose and successfully manage the great majority of patients who present with the signs and symptoms of IC, but surgical intervention may be a last-resort approach for patients with severe, intractable disease. Dr. Evans noted that augmentation cystoplasty is not effective and surgery, such as cystectomy, is rarely indicated. The results of surgery for IC are variable and significant pain may persist after surgery.86 The current and preferred surgical intervention is that of sacral nerve root stimulation, a neuromodulation technique that is FDA-approved for the treatment of urinary frequency and urgency, urge incontinence, and urinary retention. Treatment with a permanently implanted device (InterStim; Medtronic) was found to significantly reduce the need for narcotics in 21 patients with refractory IC and to eliminate narcotic use completely in 4 of 18 chronic users.87 Other studies have also demonstrated high rates of clinical improvement using a similar approach that included percutaneous third sacral nerve stimulation, with concomitant normalization of the biomarkers APF and HB-EGF, that could indicate a benefit occurring at the tissue level.88 CONCLUSIONS Although IC can be a challenging disease to diagnose, the PUF questionnaire and the PST are simple and reliable tools available to the clinician. Because the CPP associated with IC is often accompanied by depression, anxiety, and a lowered QOL, it is vital that the clinician take a thorough history and suspect IC if the pain is accompanied by urinary symptomatology. Misdiagnosis may occur when clinicians lack adequate knowledge about the etiology of IC and the availability of treatment options, or when they lack the time that is required to follow the patient through to a successful outcome. Men and women with IC should be managed by clinicians who can recognize and differentiate the symptoms of IC from those of other urogenital disorders, and who are committed to long-term management approaches and convey encouragement and optimism to their patients. As Dr. Fourcroy noted, it is crucial to build confidence in the patient and empower him or her to participate fully in the treatment process. With commitment from both the patient and the health care provider, most cases of IC can be accurately diagnosed and satisfactorily resolved. IC may be far more prevalent among both men and women than previously believed. Largely because of the many similarities between IC and other urologic and gynecologic conditions, identification of IC can be delayed for many years. Men may be misdiagnosed as having chronic prostatitis. Women are often thought to have a gynecologic disorder, OAB, or recurrent UTI. Inappropriate or inadequate treatment may allow IC to progress to a severe and refractory condition. Delay in diagnosis and treatment adversely affects prognosis. Patients with long-standing disease are a treatment challenge, usually requiring longer, more intensive treatment. Those who receive a timely diagnosis early in their disease course, on the other hand, may improve with several months of multimodal therapy, and can often taper or withdraw some of the interventions over time. New diagnostic measures, such as the PST, the PUF symptom questionnaire, and the intravesical anesthetic challenge, have enhanced diagnosis and facilitated earlier treatment. Several biomarkers, particularly APF, have shown utility in the diagnosis of IC in the research setting. Understanding the reasons for their altered levels in IC should help to clarify the pathogenesis of this condition and may provide a dependable tool for diagnosis and a simple measure of therapeutic efficacy. The mechanisms by which IC develops on a cellular level may become better elucidated by understanding the gene regulation that occurs during the neurogenic inflammation of the bladder. These and other areas of research may lead to novel targeted therapies for IC. Newer treatments and a multimodal treatment strategy have improved outcomes and QOL. For many years, bladder instillation with DMSO was the only FDA-approved treatment for IC. The FDA approval of oral PPS has made available a safe, effective, and more convenient therapy that now serves as the foundation for the multimodal treatment strategy that typically includes antihistamines, antidepressants, and when indicated, physiotherapy. An intensive “jump start” approach with intravesical instillation of a PPS or heparin solution may hasten treatment response. In conjunction with oral PPS, occasional intravesical “rescue treatment” with PPS or heparin plus lidocaine and sodium bicarbonate can be incorporated as needed for immediate pain relief. Nonpharmacologic adjunctive approaches, such as diet modification, although not sufficient alone, can enhance treatment. Finally, a critical component of therapy is an empathetic, devoted clinician who will work with the IC patient to reverse this challenging, but ultimately modifiable, condition. SUMMARY • IC is far more prevalent in men and women than previously believed • IC may be misdiagnosed as chronic prostatitis (CP/CPPS) in men and urogenital infection in women • Absence of a precise definition and a definitive diagnostic test for IC complicates its management • Early diagnosis might be key to “cure” or reversal of IC pathogenesis • APF is a promising clinical marker for IC • The PUF questionnaire is a noninvasive diagnostic tool that has been shown to correlate significantly with a likelihood of a positive PST score • Multimodal treatment of the 3 principal components of IC (GAG abnormalities, mast cell activation, and neurogenic up-regulation) is key to symptomatic improvement • Research trials and clinical experience have shown that PPS, the only oral agent approved by the US FDA for the relief of pain and bladder symptoms associated with IC, has proven safe and effective in men and women with IC symptoms REFERENCES 1. Simon L, Landis J, Erickson D, et al. The Interstitial Cystitis Data Base Study: Concepts and Preliminary Baseline Descriptive Statistics. Urology. 1997;49:64-75. 2. Ratner V, Taylor N. Re: Epidemiology of interstitial cystitis: a population based study. J Urol. 1999;162:500-503. 12 3. Clemens JQ, Meenan RT, Rosetti MC, et al. Prevalence and incidence of interstitial cystitis in a managed care population. J Urol. 2005;173:98-102; discussion 102. 4. Parsons CL. Interstitial cystitis: a chronic disease with ever-increasing recognition and prevalence. J Urol. 2005;173:6. 5. Burkman R. Chronic pelvic pain of bladder origin: epidemiology, pathogenesis and quality of life. J Reprod Med. 2004;49:225-229. 27. Erickson DR, Xie SX, Bhavanandan VP, et al. A comparison of multiple urine markers for interstitial cystitis. J Urol. 2002;167:2461-2469. 6. Koziol JA, Clark DC, Gittes RF, et al. The natural history of interstitial cystitis: a survey of 374 patients. J Urol. 1993;149:465-469. 28. Byrne DS, Sedor JF, Estojak J, et al. The urinary glycoprotein GP51 as a clinical marker for interstitial cystitis. J Urol. 1999;161:1786-1790. 7. Teichman JMH, Ottem D. Diagnosis and Misdiagnosis Given to IC Patients. Available at: http://www.urologyrounds.com/files/PDF/May-19-2004-04.pdf. Accessed April 29, 2005. 29. Keay S, Zhang CO, Hise MK, et al. A diagnostic in vitro urine assay for interstitial cystitis. Urology. 1998;52:974-978. 8. ACOG Committee on Practice Bulletins - Gynecology. ACOG Practice Bulletin No. 51. Chronic pelvic pain. Obstet Gynecol. 2004;103:589-605. 9. Gillenwater JY, Wein AJ. Summary of the National Institute of Arthritis, Diabetes, Digestive and Kidney Diseases Workshop on Interstitial Cystitis, National Institutes of Health, Bethesda, Maryland, August 28-29, 1987. J Urol. 1988;140:203-206. 10. Hanno PM, Landis JR, Matthews-Cook Y, et al. The diagnosis of interstitial cystitis revisited: lessons learned from the National Institutes of Health Interstitial Cystitis Database study. J Urol. 1999;161:553-557. 11. Abrams P, Cardozo L, Fall M, et al. The standardisation of terminology of lower urinary tract function: report from the Standardisation Sub-committee of the International Continence Society. Neurourol Urodyn. 2002;21:167-178. 30. Keay S, Zhang CO, Shoenfelt JL, et al. Decreased in vitro proliferation of bladder epithelial cells from patients with interstitial cystitis. Urology. 2003;61:1278-1284. 31. McNaughton Collins M, Pontari MA, O’Leary MP, et al. Quality of life is impaired in men with chronic prostatitis: the Chronic Prostatitis Collaborative Research Network. J Gen Intern Med. 2001;16:656-662. 32. Wenninger K, Heiman JR, Rothman I, et al. Sickness impact of chronic nonbacterial prostatitis and its correlates. J Urol. 1996;155:965-968. 33. Rosen R, Altwein J, Boyle P, et al. Lower urinary tract symptoms and male sexual dysfunction: the multinational survey of the aging male (MSAM-7). Prog Urol. 2004;14:332-344. 34. Novicki DE, Larson TR, Swanson SK. Interstitial cystitis in men. Urology. 1998;52:621-624. 12. Hanno P, Baranowski AP, Fall M, et al. Painful Bladder Syndrome (including interstitial cystitis). Report from Committee 21 of the 3rd International Consultation on Incontinence - June 26-29, 2004. Monte Carlo, Monaco. 35. Schaeffer AJ. Classification (traditional and National Institutes of Health) and demographics of prostatitis. Urology. 2002;60:5-6. 13. Parsons CL, Koprowski PF. Interstitial cystitis: successful management by increasing urinary voiding intervals. Urology. 1991;37:207-212. 36. Forrest JB, Schmidt S. Interstitial cystitis, chronic nonbacterial prostatitis and chronic pelvic pain syndrome in men: a common and frequently identical clinical entity. J Urol. 2004;172:2561-2562. 14. Metts JF. Interstitial cystitis: urgency and frequency syndrome. Am Fam Physician. 2001;64:1199-1206. 15. Marshall K. Interstitial cystitis: understanding the syndrome. Altern Med Rev. 2003;8:426-437. 16. Warren JW, Jackson TL, Langenberg P, et al. Prevalence of interstitial cystitis in first-degree relatives of patients with interstitial cystitis. Urology. 2004;63:17-21. 17. Parsons CL, Greenberger M, Gabal L, et al. The role of urinary potassium in the pathogenesis and diagnosis of interstitial cystitis. J Urol. 1998;159:1862-1866. 18. Evans R. Treatment approaches for interstitial cystitis: multimodal therapy. Rev Urol. 2002;4:S16-S20. 19. Chen Y, Varghese R, Lehrer J, et al. Urinary substance P is elevated in women with interstitial cystitis. J Urol. 1999;161:(4S):26. 20. Bouchelouche K, Kristensen B, Nordling J, et al. Increased urinary leukotriene E4 and eosinophil protein X excretion in patients with interstitial cystitis. J Urol. 2001;166:2121-2125. 21. Sun Y, Chai TC. Up-regulation of P2X3 receptor during stretch of bladder urothelial cells from patients with interstitial cystitis. J Urol. 2004;171:448-452. 22. Lukban JC, Parkin JV, Holzberg AS, et al. Interstitial cystitis and pelvic floor dysfunction: a comprehensive review. Pain Med. 2001;2:60-71. 23. Tamaki M, Saito R, Ogawa O, et al. Possible mechanisms inducing glomerulations in interstitial cystitis: relationship between endoscopic findings and expression of angiogenic growth factors. J Urol. 2004;172:945-948. 37. Eisenberg ER, Moldwin RM. Etiology: where does prostatitis stop and interstitial cystitis begin? World J Urol. 2003;21:64-69. 38. Miller JL, Rothman I, Bavendam TG, et al. Prostatodynia and interstitial cystitis: one and the same? Urology. 1995;45:587-590. 39. Berger RE, Miller JE, Rothman I, et al. Bladder petechiae after cystoscopy and hydrodistension in men diagnosed with prostate pain. J Urol. 1998;159:83-85. 40. Parsons CL, Albo M. Intravesical potassium sensitivity in patients with prostatitis. J Urol. 2002;168:1054-1057. 41. Mathias SD, Kuppermann M, Liberman RF, et al. Chronic pelvic pain: prevalence, health-related quality of life, and economic correlates. Obstet Gynecol. 1996;87:321-327. 42. Dell J. Chronic pelvic pain of bladder origin: a focus on interstitial cystitis. Int J Fertil Womens Med. 2003;48:154-162. 43. Parsons CL, Dell J, Stanford EJ, et al. The prevalence of interstitial cystitis in gynecologic patients with pelvic pain, as detected by intravesical potassium sensitivity. Am J Obstet Gynecol. 2002;187:1395-1400. 44. Parsons CL, Dell J, Stanford EJ, et al. Increased prevalence of interstitial cystitis: previously unrecognized urologic and gynecologic cases identified using a new symptom questionnaire and intravesical potassium sensitivity. Urology. 2002;60:573-578. 45. Parsons CL, Tatsis V. Prevalence of interstitial cystitis in young women. Urology. 2004;64:866-870. 24. Ueda T, Tamaki M, Ogawa O, et al. Over expression of platelet-derived endothelial cell growth factor/thymidine phosphorylase in patients with interstitial cystitis and bladder carcinoma. J Urol. 2002;167:347-351. 46. Chung MK, Chung RR, Gordon D, et al. The evil twins of chronic pelvic pain syndrome: endometriosis and interstitial cystitis. JSLS. 2002;6:311-314. 25. Keay S, Kleinberg M, Zhang CO, et al. Bladder epithelial cells from patients with interstitial cystitis produce an inhibitor of heparin-binding epidermal growth factor-like growth factor production. J Urol. 2000;164:2112-2118. 47. Parsons CL, Bullen M, Kahn BS, et al. Gynecologic presentation of interstitial cystitis as detected by intravesical potassium sensitivity. Obstet Gynecol. 2001;98:127-132. 26. Keay SK, Zhang CO, Shoenfelt J, et al. Sensitivity and specificity of antiproliferative factor, heparin-binding epidermal growth factor-like growth factor, and epidermal growth factor as urine markers for interstitial cystitis. Urology. 2001;57:9-14. 48. Parsons CL. Prostatitis, interstitial cystitis, chronic pelvic pain, and urethral syndrome share a common pathophysiology: lower urinary dysfunctional epithelium and potassium recycling. Urology. 2003;62:976-982. 13 49. Bernie JE, Hagey S, Albo ME, et al. The intravesical potassium sensitivity test and urodynamics: implications in a large cohort of patients with lower urinary tract symptoms. J Urol. 2001;166:158-161. 50. O’Leary MP, Sant GR, Fowler FJ, Jr, et al. The interstitial cystitis symptom index and problem index. Urology. 1997;49:58-63. 51. Lubeck DP, Whitmore K, Sant GR, et al. Psychometric validation of the O’Leary-Sant interstitial cystitis symptom index in a clinical trial of pentosan polysulfate sodium. Urology. 2001;57:62-66. 52. Henry R, Patterson L, Avery N, et al. Absorption of alkalized intravesical lidocaine in normal and inflamed bladders: a simple method for improving bladder anesthesia. J Urol. 2001;165:1900-1903. 68. Stewart BH, Shirley SW. Further experience with intravesical dimethyl sulfoxide in the treatment of interstitial cystitis. J Urol. 1976;116:36-38. 69. Stout L, Gerspach JM, Levy SM, et al. Dimethyl sulfoxide does not trigger urine histamine release in interstitial cystitis. Urology. 1995;46:653-656. 70. Perez-Marrero R, Emerson LE, Feltis JT. A controlled study of dimethyl sulfoxide in interstitial cystitis. J Urol. 1988;140:36-39. 71. Moldwin RM, Sant GR. Interstitial cystitis: a pathophysiology and treatment update. Clin Obstet Gynecol. 2002;45:259-272. 72. Theoharides TC, Kempuraj D, Sant GR. Mast cell involvement in interstitial cystitis: a review of human and experimental evidence. Urology. 2001;57:47-55. 53. Teichman JM. Potassium sensitivity testing in the diagnosis and treatment of interstitial cystitis. Infect Urol. 2003;16:87-94. 73. Theoharides TC, Sant GR, el-Mansoury M, et al. Activation of bladder mast cells in interstitial cystitis: a light and electron microscopic study. J Urol. 1995;153:629-636. 54. Keay S, Zhang CO, Chai T, et al. Antiproliferative factor, heparin-binding epidermal growth factor-like growth factor, and epidermal growth factor in men with interstitial cystitis versus chronic pelvic pain syndrome. Urology. 2004;63:22-26. 74. Theoharides TC, Sant GR. Hydroxyzine therapy for interstitial cystitis. Urology. 1997;49:108-110. 55. Slobodov G, Feloney M, Gran C, et al. Abnormal expression of molecular markers for bladder impermeability and differentiation in the urothelium of patients with interstitial cystitis. J Urol. 2004;171:1554-1558. 56. Parsons JK, Parsons CL. The historical origins of interstitial cystitis. J Urol. 2004;171:20-22. 75. Sant GR, Propert KJ, Hanno PM, et al. A pilot clinical trial of oral pentosan polysulfate and oral hydroxyzine in patients with interstitial cystitis. J Urol. 2003;170:810-815. 76. Hanno PM. Amitriptyline in the treatment of interstitial cystitis. Urol Clin North Am. 1994;21:89-91. 57. Peeker R, Fall M. Toward a precise definition of interstitial cystitis: further evidence of differences in classic and nonulcer disease. J Urol. 2002;167:2470-2472. 77. van Ophoven A, Pokupic S, Heinecke A, et al. A prospective, randomized, placebo controlled, double-blind study of amitriptyline for the treatment of interstitial cystitis. J Urol. 2004;172:533-536. 58. Lukban J, Whitmore K, Kellogg-Spadt S, et al. The effect of manual physical therapy in patients diagnosed with interstitial cystitis, high-tone pelvic floor dysfunction, and sacroiliac dysfunction. Urology. 2001;57:121-122. 78. Theoharides TC, Sant GR. New agents for the medical treatment of interstitial cystitis. Expert Opin Investig Drugs. 2001;10:521-546. 59. ELMIRON® - 100 mg (pentosan polysulfate sodium) [package insert]. Raritan, NJ; Ortho-McNeil Pharmaceutical, Inc. 2002. 79. Hansen HC. Interstitial cystitis and the potential role of gabapentin. South Med J. 2000;93:238-242. 60. Dell JR, Parsons CL. Multimodal therapy for interstitial cystitis. J Reprod Med. 2004;49:243-252. 80. Sasaki K, Smith CP, Chuang YC, et al. Oral gabapentin (neurontin) treatment of refractory genitourinary tract pain. Tech Urol. 2001;7:47-49. 61. Chiang G, Patra P, Letourneau R, et al. Pentosan polysulfate inhibits mast cell histamine secretion and intracellular calcium ion levels: an alternative explanation of its beneficial effect in interstitial cystitis. J Urol. 2000;164:2119-2125. 81. Sukiennik A, Carr D, Bonney I, et al. The effect of short-term epidural local anesthetic blockade on urinary levels of substance P in interstitial cystitis. Anesth Analg. 2004;98:846-850. 62. Nickel JC, Barkin J, Forrest J, et al. Randomized, double-blind, dose-ranging study of Pentosan polysulfate Sodium (PPS) for interstitial Cystitis (IC). Urol, 65:654-658. 2005. 82. Parsons CL, Housley T, Schmidt JD, et al. Treatment of interstitial cystitis with intravesical heparin. Br J Urol. 1994;73:504-507. 63. Parsons CL, Forrest J, Nickel JC, et al. Effect of pentosan polysulfate therapy on intravesical potassium sensitivity. Urology. 2002;59:329-333. 64. Waters MG, Suleskey JF, Finkelstein LJ, et al. Interstitial cystitis: a retrospective analysis of treatment with pentosan polysulfate and follow-up patient survey. J Am Osteopath Assoc. 2000;100:S13-S18. 65. Nickel JC, Forrest JB, Tomera K, et al. Pentosan polysulfate sodium therapy for men with chronic pelvic pain syndrome: a multicenter, randomized, placebo controlled study. J Urol. 2005;173:1252-1255. 66. RIMSO-50® (brand of dimethyl sulfoxide irrigation, U.S.P.) [package insert]. Irvine, CA; Edwards Lifesciences. 2004. 67. Barker SB, Matthews PN, Philip PF, et al. Prospective study of intravesical dimethyl sulphoxide in the treatment of chronic inflammatory bladder disease. Br J Urol. 1987;59:142-144. 14 83. Morales A, Emerson L, Nickel JC, et al. Intravesical hyaluronic acid in the treatment of refractory interstitial cystitis. J Urol. 1996;156:45-48. 84. Parsons CL. Evidence-based strategies for recognizing and managing IC. Contemporary Urology. 2003:22-35. 85. Parsons CL, Davis EL. Pentosan polysulfate sodium intravesical instillation: end-organ therapy. Practice Building Today. 2003;September:18-22. 86. Baskin LS, Tanagho EA. Pelvic pain without pelvic organs. J Urol. 1992;147:683-686. 87. Peters KM, Konstandt D. Sacral neuromodulation decreases narcotic requirements in refractory interstitial cystitis. BJU Int. 2004;93:777-779. 88. Chai TC, Zhang C, Warren JW, et al. Percutaneous sacral third nerve root neurostimulation improves symptoms and normalizes urinary HB-EGF levels and antiproliferative activity in patients with interstitial cystitis. Urology. 2000;55:643-646. EVOLVING ISSUES IN THE DIAGNOSIS AND MANAGEMENT OF INTERSTITIAL CYSTITIS (04-762) Release Date: July 2005 Expiration Date for Credit: July 31, 2006 CME REGISTRATION/POSTTEST/ANSWER FORM/EVALUATION Instructions: This activity should take approximately 1 hour to complete. The participant should, in order, read the objectives and newsletter, answer the 10-question multiple-choice Posttest below, and complete the registration/evaluation form. If you wish to receive CME credit and a certificate, please mail/fax a copy of your completed form to: Dannemiller Memorial Educational Foundation Attention: 04-762 5711 Northwest Parkway, Suite 100, San Antonio, TX 78249-3360 Phone (210) 641-8311 Fax (210) 697-9318 POSTTEST/SELF-ASSESSMENT (Circle the single most appropriate answer below.) 1. One theory regarding the pathogenesis of IC is based on: a. The presence of undetectable bacteria/unusual pathogens b. Immunologic abnormalities c. Dysfunction of the mucosal glycosaminoglycan (GAG) barrier that allows toxins to be absorbed d. Inflammatory processes 2. Which one of the following statements about diagnosis of IC is TRUE? a. Cystoscopy with hydrodistention is the gold standard diagnostic tool for IC b. IC currently remains a diagnosis of exclusion c. A positive PST result correlates well with low PUF scores d. A positive PST result is seen only in patients with IC, never in patients with other urogenital disorders 3. Which one of the following biomarkers shows the least overlap between IC patients and control groups? a. Glycoprotein (GP)51 b. Vascular endothelial growth factor (VEGF) c. Antiproliferative factor (APF) d. Epidermal growth factor (EGF) 4. When used alone, which of the following can conclusively diagnose IC: a. Cystoscopy with hydrodistention b. PST c. PUF questionnaire d. None of these 5. What is considered by some to be an appropriate first-line management of IC: a. Antibiotic treatment b. Antispasmodic treatment c. Laser therapy d. Multimodal therapy which includes oral PPS 6. The clinical presentation that is common to chronic prostatitis, chronic pelvic pain syndrome, and IC is: a. Genitourinary pelvic pain for 3 of the last 6 months, without uropathic bacteria b. Genitourinary pelvic pain for 3 of the last 6 months, with uropathic bacteria detected c. Pain on ejaculation consistently occurring for at least 3 months, without uropathic bacteria d. Irritative voiding, genitourinary pain for at least 6 months, with or without uropathic bacteria 7. Women with IC are often misdiagnosed as having: a. Endometriosis d. Overactive bladder b. Recurrent UTI e. Any of the above c. Vulvodynia 8. Pelvic floor dysfunction often accompanies IC and is best treated by: a. Oral PPS with intravesical “jump start” b. Bed rest c. Physical therapy d. Epidural blockade 9. Which one of the following statements about the use of PPS in the treatment of IC is TRUE? a. Onset of symptom relief is immediate b. PPS is one of several oral treatments approved by the US FDA for IC c. Efficacy can be enhanced by increasing the dose and frequency d. “Jump-starting” with intravesical delivery several times a week for several weeks may facilitate treatment response 10. For most patients, which one of the following interventions is not part of a longterm rational treatment strategy for IC: a. PPS d. Antidepressant b. Short-acting opioid e. Diet modification c. Antihistamine PROGRAM EVALUATION Full Name________________________________ MD/DO/Other________________ Street ____________________________________________________________ City ______________________________________ State ______ ZIP Code ________ PHYSICIANS: Are you licensed in the US? (circle) YES or NO Email Address __________________________ @ ________________________ I certify that I completed this CME activity: The actual amount of time I spent in this activity was: _____hours _____minutes Signature ________________________________ Date Completed____________ The Dannemiller Memorial Educational Foundation would appreciate your comments regarding the quality of the information presented. Later, via email, we would also like to send you a website link to a follow-up survey regarding the material presented. May we contact you? (Please check one.) ___ Yes, via Email. © 2005 SynerMed® Communications 1. The program objectives were fully met. Strongly Agree Agree Disagree Strongly Disagree 2. The quality of the educational process (method of presentation and information provided) was satisfactory and appropriate. Strongly Agree Agree Disagree Strongly Disagree 3. The educational activity has enhanced my professional effectiveness to treat patients. Strongly Agree Agree Disagree Strongly Disagree 4. The educational activity will result in a change in my practice behavior. Strongly Agree Agree Disagree Strongly Disagree 5. The information presented was without promotional or commercial bias. Strongly Agree Agree Disagree Strongly Disagree 6. Comments/suggestions regarding this material. ____________________________ ______________________________________________________________ 7. Recommendations for topics of future presentations. ________________________ ______________________________________________________________ ___ No, please do not contact me. LGOP313a All rights reserved Printed in USA 15