American Urological Association - Diagnosis and Treatment Interstitial Cystitis/Bladder Pain Syndrome

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Home Guidelines Clinical Guidelines Interstitial Cystitis/Bladder Pain Syndrome (2011; Amended 2014)

Diagnosis and Treatment Interstitial Cystitis/Bladder Pain Syndrome

Published 2011; Amended 2014

The purpose of this clinical guideline is to provide a clinical framework for the diagnosis and treatment of interstitial cystitis/bladder pain syndrome (IC/BPS), including discussion of first through sixth line treatments and treatments that should not be offered.

Unabridged version of this Guideline [pdf]
Algorithm associated with this Guideline [pdf]

Panel Members

Philip M. Hanno, David Allen Burks, J. Quentin Clemens, Roger R. Dmochowski, Deborah Erickson, Mary Pat FitzGerald, John B. Forrest, Barbara Gordon, Mikel Gray, Robert Dale Mayer, Robert Moldwin, Diane K. Newman, Leroy Nyberg Jr., Christopher K. Payne, Ursula Wesselmann, Martha M. Faraday

Executive Summary

Amended 2014

Purpose

The purpose of this Guideline is to provide a clinical framework for the diagnosis and treatment of interstitial cystitis/bladder pain syndrome (IC/BPS).

Methods

A systematic review of the literature using the MEDLINE® database (search dates 1/1/83-7/22/09) was conducted to identify peer-reviewed publications relevant to the diagnosis and treatment of IC/BPS. Insufficient evidence was retrieved regarding diagnosis; this portion of the guideline, therefore, is based on Clinical Principles and Expert Opinion. The review yielded an evidence base of 86 treatment articles after application of inclusion/exclusion criteria. The AUA update literature review process, in which an additional systematic review is conducted periodically to maintain guideline currency with newly-published relevant literature, was conducted in July 2013. This review identified an additional 31 articles relevant to treatment. These publications were used to create the majority of the treatment portion of the guideline. When sufficient evidence existed, the body of evidence for a particular treatment was assigned a strength rating of A (high), B (moderate), or C (low). Additional treatment information is provided as Clinical Principles and Expert Opinion when insufficient evidence existed. See text and algorithm for definitions and detailed diagnostic, management, and treatment frameworks.

Guideline Statements

Diagnosis:

1. The basic assessment should include a careful history, physical examination, and laboratory examination to rule in symptoms that characterize IC/BPS and rule out other confusable disorders (see text for details). Clinical Principle

2. Baseline voiding symptoms and pain levels should be obtained in order to measure subsequent treatment effects. Clinical Principle

3. Cystoscopy and/or urodynamics should be considered as an aid to diagnosis only for complex presentations; these tests are not necessary for making the diagnosis in uncomplicated presentations. Expert Opinion

Treatment

4. Treatment strategies should proceed using more conservative therapies first, with less conservative therapies employed if symptom control is inadequate for acceptable quality of life; because of their irreversibility, surgical treatments (other than fulguration of Hunner's lesions) are appropriate only after other treatment alternatives have been exhausted, or at any time in the rare instance when an end-stage small, fibrotic bladder has been confirmed and the patient's quality of life suggests a positive risk-benefit ratio for major surgery. Clinical Principle

5. Initial treatment type and level should depend on symptom severity, clinician judgment, and patient preferences; appropriate entry points into the treatment portion of the algorithm depend on these factors. Clinical Principle

6. Multiple, simultaneous treatments may be considered if it is in the best interests of the patient; baseline symptom assessment and regular symptom level reassessment are essential to document efficacy of single and combined treatments. Clinical Principle

7. Ineffective treatments should be stopped once a clinically meaningful interval has elapsed. Clinical Principle

8. Pain management should be continually assessed for effectiveness because of its importance to quality of life. If pain management is inadequate, then consideration should be given to a multidisciplinary approach and the patient referred appropriately. Clinical Principle

9. The IC/BPS diagnosis should be reconsidered if no improvement occurs after multiple treatment approaches. Clinical Principle

Treatments that may be offered: Treatments that may be offered are divided into first-, second-, third-, fourth-, fifth-, and sixth-line groups based on the balance between potential benefits to the patient, potential severity of adverse events (AEs) and the reversibility of the treatment. See body of guideline for protocols, study details, and rationales.

First-Line Treatments (should be performed on all patients)

10. Patients should be educated about normal bladder function, what is known and not known about IC/ BPS, the benefits v. risks/burdens of the available treatment alternatives, the fact that no single treatment has been found effective for the majority of patients, and the fact that acceptable symptom control may require trials of multiple therapeutic options (including combination therapy) before it is achieved. Clinical Principle

11. Self-care practices and behavioral modifications that can improve symptoms should be discussed and implemented as feasible. Clinical Principle

12. Patients should be encouraged to implement stress management practices to improve coping techniques and manage stress-induced symptom exacerbations. Clinical Principle

Second-Line treatments

13. Appropriate manual physical therapy techniques (e.g., maneuvers that resolve pelvic, abdominal and/or hip muscular trigger points, lengthen muscle contractures, and release painful scars and other connective tissue restrictions), if appropriately-trained clinicians are available, should be offered to patients who present with pelvic floor tenderness. Pelvic floor strengthening exercises (e.g., Kegel exercises) should be avoided. Clinical Principle Standard (Evidence Strength Grade A)

14. Multimodal pain management approaches (e.g., pharmacological, stress management, manual therapy if available) should be initiated. Expert Opinion

15. Amitriptyline, cimetidine, hydroxyzine, or pentosan polysulfate may be administered as second-line oral medications (listed in alphabetical order; no hierarchy is implied). Options (Evidence Strength Grades B, B, C, and B)

16. DMSO, heparin, or lidocaine may be administered as second-line intravesical treatments (listed in alphabetical order; no hierarchy is implied). Option (Evidence Strength Grades C, C, and B)

Third-Line treatments

17. Cystoscopy under anesthesia with short-duration, low-pressure hydrodistension may be undertaken if first- and second-line treatments have not provided acceptable symptom control and quality of life or if the patient's presenting symptoms suggest a more invasive approach is appropriate. Option (Evidence Strength Grade C)

18. If Hunner's lesions are present, then fulguration (with laser or electrocautery) and/or injection of triamcinolone should be performed. Recommendation (Evidence Strength Grade C)

Fourth-Line treatment

19. Intradetrusor botulinum toxin A (BTX-A) may be administered if other treatments have not provided adequate symptom control and quality of life or if the clinician and patient agree that symptoms require this approach. Patients must be willing to accept the possibility that post-treatment intermittent self- catheterization may be necessary. Option (Evidence Strength C)

20. A trial of neurostimulation may be performed and, if successful, implantation of permanent neurostimulation devices may be undertaken if other treatments have not provided adequate symptom control and quality of life or if the clinician and patient agree that symptoms require this approach. Option (Evidence Strength C)

Fifth-Line treatments

21. Cyclosporine A may be administered as an oral medication if other treatments have not provided adequate symptom control and quality of life or if the clinician and patient agree that symptoms require this approach. Option (Evidence Strength C)

Sixth-Line treatment

22. Major surgery (e.g., substitution cystoplasty, urinary diversion with or without cystectomy) may be undertaken in carefully selected patients for whom all other therapies have failed to provide adequate symptom control and quality of life (see caveat above in guideline statement #4). Option (Evidence StrengthC)

Treatments that Should Not be Offered

The treatments below appear to lack efficacy and/or appear to be accompanied by unacceptable AE profiles. See body of guideline for study details and rationales.

23. Long-term oral antibiotic administration should not be offered. Standard (Evidence StrengthB)

24. Intravesical instillation of bacillus Calmette-Guerin (BCG) should not be offered outside of investigational study settings. Standard (Evidence StrengthB)

25. High-pressure, long-duration hydrodistension should not be offered. Recommendation (Evidence Strength- C)

26. Systemic (oral) long-term glucocorticoid administration should not be offered. Recommendation (Evidence Strength- C)

Purpose

This guideline's purpose is to provide direction to clinicians and patients regarding how to: recognize interstitial cystitis (IC)/bladder pain syndrome (BPS); conduct a valid diagnostic process; and, approach treatment with the goals of maximizing symptom control and patient quality of life (QoL) while minimizing AEs and patient burden. The strategies and approaches recommended in this document were derived from evidence-based and consensus-based processes. IC/BPS nomenclature is a controversial issue; for the purpose of clarity the Panel decided to refer to the syndrome as IC/BPS and to consider these terms synonymous. There is a continually expanding literature on IC/BPS; the Panel notes that this document constitutes a clinical strategy and is not intended to be interpreted rigidly. The most effective approach for a particular patient is best determined by the individual clinician and patient. As the science relevant to IC/BPS evolves and improves, the strategies presented here will require amendment to remain consistent with the highest standards of clinical care.

Methodology

A systematic review was conducted to identify published articles relevant to the diagnosis and treatment of IC/BPS. Literature searches were performed on English-language publications using the MEDLINE database from January 1, 1983 to July 22, 2009 using the terms "interstitial cystitis," "painful bladder syndrome," "bladder pain syndrome," and "pelvic pain" as well as key words capturing the various diagnostic procedures and treatments known to be used for these syndromes. Studies published after July 22, 2009 were not included as part of the original evidence base considered by the Panel from which evidence-based guideline statements (Standards, Recommendations, Options) were derived. However, the guideline is regularly updated by additional systematic review searches conducted as part of the AUA's update literature review process (see below), and the evidence base is regularly updated based on the findings from the update reviews. Preclinical studies (e.g., animal models), pediatric studies, commentary, and editorials were eliminated. Review article references were checked to ensure inclusion of all possibly relevant studies. Studies using treatments not available in the US, herbal or supplement treatments, or studies that reported outcomes information collapsed across multiple interventions also were excluded. Studies on mixed patient groups (i.e., some patients did not have IC/BPS) were retained as long as more than 50% of patients were IC/BPS patients. Multiple reports on the same patient group were carefully examined to ensure inclusion of only nonredundant information. In a few cases, individual studies constituted the only report on a particular treatment. Because sample sizes in individual studies were small, single studies were not considered a sufficient and reliable evidence base from which to construct an evidence-based statement (i.e., a Standard, Recommendation, or Option). These studies were used to support Clinical Principles as appropriate.

IC/BPS Diagnosis and Overall Management. The review revealed insufficient publications to address IC/BPS diagnosis and overall management from an evidence basis; the diagnosis and management portions of the algorithm (see Figure 1), therefore, are provided as Clinical Principles or as Expert Opinion with consensus achieved using a modified Delphi technique if differences of opinion emerged.1 A Clinical Principle is a statement about a component of clinical care that is widely agreed upon by urologists or other clinicians for which there may or may not be evidence in the medical literature. Expert Opinion refers to a statement, achieved by consensus of the Panel, that is based on members' clinical training, experience, knowledge, and judgment for which there is no evidence.

IC/BPS Treatment. With regard to treatment, a total of 86 articles from the original literature searches met the inclusion criteria; an additional 31 relevant studies were retrieved as part of the update literature review process and also have been incorporated. The Panel judged that these were a sufficient evidence base from which to construct the majority of the treatment portion of the algorithm. Data on study type (e.g., randomized controlled trial, randomized crossover trial, observational study), treatment parameters (e.g., dose, administration protocols, follow-up durations), patient characteristics (i.e., age, gender, symptom duration), AEs, and primary outcomes (as defined by study authors) were extracted. The primary outcome measure for most studies was some form of patient-rated symptom scales, including the ICPS, ICSS, VAS scales, as available. In short supply are objective parameters and placebo controlled trials.

Quality of Individual Studies and Determination of Evidence Strength. Quality of individual studies that were randomized controlled trials (RCTs) or crossover trials was assessed using the Cochrane Risk of Bias tool.2 Because placebo effects are common in controlled trials conducted with IC/BPS patients, any apparent procedural deviations that could compromise the integrity of randomization or blinding resulted in a rating of increased risk of bias for that particular trial. Because there is no widely-agreed upon quality assessment tool for observational studies, the quality of individual observational studies was not assessed.

The categorization of evidence strength is conceptually distinct from the quality of individual studies. Evidence strength refers to the body of evidence available for a particular question and includes consideration of study design, individual study quality, the consistency of findings across studies, the adequacy of sample sizes, and the generalizability of samples, settings, and treatments for the purposes of the guideline. AUA categorizes body of evidence strength as Grade A (well-conducted RCTs or exceptionally strong observational studies), Grade B (RCTs with some weaknesses of procedure or generalizability or generally strong observational studies), or Grade C (observational studies that are inconsistent, have small sample sizes, or have other problems that potentially confound interpretation of data). Because treatment data for this condition are difficult to interpret in the absence of a placebo control, bodies of evidence comprised entirely of studies that lacked placebo control groups (i.e., observational studies) were assigned a strength rating of Grade C.

Table 1: AUA Nomenclature
Linking Statement Type to Level of Certainty and Evidence Strength [Updated Version]
Standard: Directive statement that an action should (benefits outweigh risks/burdens) or should not (risks/burdens outweigh benefits) be taken based on Grade A (high quality; high certainty) or B (moderate quality; moderate certainty) evidence
Recommendation: Directive statement that an action should (benefits outweigh risks/burdens) or should not (risks/burdens outweigh benefits) be taken based on Grade C (low quality; low certainty) evidence
Option: Non-directive statement that leaves the decision regarding an action up to the individual clinician and patient because the balance between benefits and risks/burdens appears equal or appears uncertain based on Grade A (high quality; high certainty), B (moderate quality; moderate certainty), or C (low quality; low certainty) evidence
Clinical Principle: a statement about a component of clinical care that is widely agreed upon by urologists or other clinicians for which there may or may not be evidence in the medical literature
Expert Opinion: a statement, achieved by consensus of the Panel, that is based on members' clinical training, experience, knowledge, and judgment for which there is no evidence

AUA Nomenclature: Linking Statement Type to Evidence Strength. The AUA nomenclature system explicitly links statement type to body of evidence strength, level of certainty, and the Panel's judgment regarding the balance between benefits and risks/burdens.3 Standards are directive statements that an action should (benefits outweigh risks/burdens) or should not (risks/burdens outweigh benefits) be undertaken based on Grade A (high level of certainty) or Grade B (moderate level of certainty) evidence. Recommendations are directive statements that an action should (benefits outweigh risks/burdens) or should not (risks/burdens outweigh benefits) be undertaken based on Grade C (low level of certainty) evidence. Options are non-directive statements that leave the decision to take an action up to the individual clinician and patient because the balance between benefits and risks/burdens appears relatively equal or appears unclear; Options may be supported by Grade A (high certainty), B (moderate certainty), or C (low certainty) evidence. In the treatment portion of this guideline, most statements are Options because most treatments demonstrate limited efficacy in a subset of patients that is not readily identifiable a priori. The Panel interpreted these data to indicate that for a particular patient, the balance between benefits and risks/burdens is uncertain or relatively equal and whether to use a particular treatment is a decision best made by the clinician who knows the patient with full consideration of the patient's prior treatment history, current quality of life, preferences and values.

Limitations of the Literature. The Panel proceeded with full awareness of the limitations of the IC/BPS literature. These limitations include: poorly-defined patient groups or heterogeneous groups; small sample sizes; lack of placebo controls for many studies, resulting in a likely over-estimation of efficacy; short follow-up durations; and, use of a variety of outcome measures. With regard to measures, even though the most consistently used measure was some form of patient-rated improvement scale, the scales differed across studies in anchor points, number of gradations, and descriptors. Overall, these difficulties resulted in limited utility for meta-analytic procedures. The single metaanalysis reported here was used to calculate an overall effect size for data from randomized trials that evaluated pentosan polysulfate (PPS). No comparative procedures were undertaken.

Background

Definition. The bladder disease complex includes a large group of patients with bladder and/or urethral and/or pelvic pain, lower urinary tract symptoms, and sterile urine cultures, many with specific identifiable causes. IC/BPS comprises a part of this complex. The Panel used the IC/BPS definition agreed upon by the Society for Urodynamics and Female Urology (SUFU): "An unpleasant sensation (pain, pressure, discomfort) perceived to be related to the urinary bladder, associated with lower urinary tract symptoms of more than six weeks duration, in the absence of infection or other identifiable causes."4 This definition was selected because it allows treatment to begin after a relatively short symptomatic period, preventing treatment withholding that could occur with definitions that require longer symptom durations (i.e., six months). Definitions used in research or clinical trials should be avoided in clinical practice; many patients may be misdiagnosed or have delays in diagnosis and treatment if these criteria are employed.5

Epidemiology. Since there is no objective marker to establish the presence of IC/BPS, studies to define its prevalence are difficult to conduct. Population-based prevalence studies of IC/BPS have used three methods: surveys that ask participants if they have ever been diagnosed with the condition (self-report studies); questionnaires administered to identify the presence of symptoms that are suggestive of IC/BPS (symptom assessments); and, administrative billing data used to identify the number of individuals in a population who have been diagnosed with IC/BPS (clinician diagnosis). Not surprisingly, the use of different methods yields widely disparate prevalence estimates.

Self-Report Studies. Two large-scale studies in the United States have utilized self-report to estimate the prevalence of IC/BPS. The first was conducted as part of the 1989 National Health Interview Survey (NHIS), and the second was part of the third National Health and Nutrition Examination Surveys (NHANES III), which was conducted between 1988 and 1994. The same definition of IC/BPS was used in both studies. Participants were asked, "Have you ever had symptoms of a bladder infection (such as pain in your bladder and frequent urination) that lasted more than 3 months?" Those who gave a positive response were then asked, "When you had this condition, were you told that you had interstitial cystitis or painful bladder syndrome?" An affirmative answer to both questions was considered to define the presence of IC/BPS. The prevalence estimates obtained from these two studies were virtually identical. In the NHIS, the overall prevalence was 500 per 100,000 population, and the prevalence in women was 865 per 100,000.6

In NHANES III, the prevalence was 470 per 100,000 population, including 60 per 100,000 men and 850 per 100,000 women.6 This equals approximately 83,000 men and 1.2 million women across the US.

IC/BPS Symptoms. Multiple studies have estimated the prevalence of IC/BPS symptoms, using a variety of different case definitions. A mailed questionnaire study to 1,331 Finnish women aged 17-71 identified probable IC/BPS symptoms in 0.45%.7 Another questionnaire mailing study to enrollees aged 25-80 in a managed care population in the US Pacific Northwest identified IC/BPS symptoms in 6-11% of women and 2–5% of men, depending on the definition used.8 Investigators in the Boston Area Community Health study conducted door-to-door interviews about urologic symptoms in a sample of Black, Hispanic and White individuals aged 30-79.9 They identified IC/BPS symptoms using six different definitions, which yielded prevalence estimates ranging from 0.6% to 2.0%. Across these definitions, symptoms were typically two to three times as common in women as men, but no clear variations were observed by race/ ethnicity. Questions about IC/BPS symptoms were included in the 2004 version of the US Nurses Health Study (NHS), which was administered to women aged 58 to 83 years.10 In this cohort of women, the prevalence of IC/BPS symptoms was 2.3%. The prevalence increased with age, from 1.7% of those younger than 65 years up to 4.0% in women aged 80 years or older. In a study of 981 Austrian women aged 19-89 at a voluntary health screening project in Vienna, the prevalence of IC/BPS symptoms was determined to be 0.3% (306 per 100,000).11

Further information is provided in three additional papers that reported data from the RAND Interstitial Cystitis Epidemiology (RICE) study.12-14 One of the RICE study objectives was to develop an IC/BPS case definition for use in epidemiological studies that had known sensitivity and specificity for use in epidemiological studies. Berry et al. (2010) report findings from a literature review, a structured expert panel process, and a telephone interview validation study to derive an IC/BPS definition.12 The authors note that none of the existing epidemiological definitions had high sensitivity or high specificity. As a result of this process, two definitions emerged – one with high sensitivity that correctly identified IC/BPS cases 81% of the time (with 54% specificity) and one with high specificity that correctly excluded non IC/BPS cases 83% of the time (with 48% sensitivity). The definitions are captured in an 11-item questionnaire. See Table 2 for definitions; the Panel notes that these are epidemiological case definitions and are not appropriate for use as diagnostic criteria.

Table 2: RICE BPS/IC Case Definitions13

High Sensitivity Definition
(sensitivity 81%, specificity 54% for BPS/IC v. endometriosis, vulvodynia and overactive bladder)

High Specificity Definition
(sensitivity 48%, specificity 83% for BPS/IC v. endometriosis, vulvodynia and overactive bladder)

Pain, pressure, or discomfort in the pelvic area
AND
Daytime urinary frequency 10+ or urgency due to pain, pressure, or discomfort, not fear of wetting
Pain, pressure, or discomfort in the pelvic area
AND
Daytime urinary frequency 10+ or urgency due to pain, pressure, or discomfort, not fear of wetting
AND
Symptoms did not resolve after treatment with antibiotics
AND
No treatment with hormone injection therapy for endometriosis
Exclusion criteria: bladder cancer, urethral diverticulum, spinal cord injury, stroke, Parkinson's disease, multiple sclerosis, spina bifida, cyclophosphamide treatment, radiation treatment to pelvic area, tuberculosis affecting the bladder, uterine cancer, ovarian cancer, vaginal cancer, genital herpes, pregnancy

Berry et al. (2011) used the questionnaire to determine prevalence of IC/BPS among adult females in the US.13 This study yielded prevalence estimates of from 2.7% to 6.53% (approximately 3.3 to 7.9 million US women age 18 or older). Only 9.7% of women who met the definitions reported having been given an IC/BPS diagnosis. Suskind et al. (2013) modified the case definition for use in men and used an additional case definition derived from the NIH-Chronic Prostatitis Symptom Index to assess the prevalence and overlap between IC/BPS and chronic prostatitis/chronic pelvic pain syndrome in men (CP/CPPS).14 This study yielded a prevalence estimate of from 2.9% to 4.2% for IC/BPS and a prevalence of 1.8% for CP/CPPS. The overlap between the two syndromes was approximately 17%. The authors note that these findings suggest that the prevalence of IC/BPS in men approaches its prevalence in women; therefore, it may be greatly under-diagnosed in the male population.

Clinician Diagnosis. Female participants in the NHS were asked by mailed questionnaires in 1994 and 1995 whether they had ever been diagnosed with 'interstitial cystitis (not urinary tract infection)'. In participants with a positive response, medical record reviews were performed to confirm a physician diagnosis, including cystoscopy performed by a urologist. Using these methods, the prevalence of IC/BPS was found to be 52/100,000 in the NHS I cohort, and 67/100,000 in the NHS II cohort.15 A subsequent study was performed using administrative billing data from the Kaiser Permanente Northwest managed care population in the Portland, Oregon metropolitan area.8 Patients with IC/BPS were identified by the presence of ICD-9 code 595.1 ('interstitial cystitis') in the electronic medical record, and the prevalence of the diagnosis was found to be 197 per 100,000 women and 41 per 100,000 men.

Typical Course and Comorbidities. IC/BPS is most commonly diagnosed in the fourth decade or after, although the diagnosis may be delayed depending upon the index of suspicion for the disease, and the criteria used to diagnose it.16 For instance, in European studies, where more strict criteria are typically used to make the diagnosis, the mean age is older than is typical for the US. A history of a recent culture-proven UTI can be identified on presentation in 18-36% of women, although subsequent cultures are negative.17,18 Initially it is not uncommon for patients to report a single symptom such as dysuria, frequency, or pain, with subsequent progression to multiple symptoms.19,20 Symptom flares, during which symptoms suddenly intensify for several hours, days, or weeks, are not uncommon. There is a high rate of prior pelvic surgery (especially hysterectomy) and levator ani pain in women with IC/BPS, suggesting that trauma or other local factors may contribute to symptoms.21 It is important to note, however, that the high incidence of other procedures such as hysterectomy or laparoscopy may be the result of a missed diagnosis and does not necessarily indicate that the surgical procedure itself is a contributing factor to symptoms. It is also common for IC/BPS to coexist with other unexplained medical conditions such as fibromyalgia, irritable bowel syndrome, chronic fatigue syndrome, Sjogren's syndrome, chronic headaches, and vulvodynia.22,23 These associations suggest that there may be a systemic dysregulation in some patients. Finally, patients with IC/BPS frequently exhibit mental health disorders such as depression and anxiety. While these symptoms may be reactive in some IC/BPS patients, there is also some evidence that there may be a common biologic mechanism involved. For instance, a link between IC/BPS and panic disorder has been suggested from genetic linkage studies.24,25

Conceptualizing IC/BPS. It is not known whether IC/BPS is a primary bladder disorder or whether the bladder symptoms of IC/BPS are a secondary phenomena resulting from another cause. Converging data from several sources suggest, however, that IC/BPS can be conceptualized as a bladder pain disorder that is often associated with voiding symptomatology and other systemic chronic pain disorders. Specifically, IC/BPS may be a bladder disorder that is part of a more generalized systemic disorder, at least in a subset of patients.

Initial observations suggesting this conceptualization were made by Clauw and colleagues (1997). He noted among chronic pelvic pain patients that other chronic pain disorders such as interstitial cystitis, irritable bowel syndrome, chronic fatigue syndrome, and fibromyalgia tended to co-occur.26 He suggested that there might be a common central pathogenesis and pathophysiology for these disorders. Self-report data collected by the Interstitial Cystitis Association corroborated Clauw's findings and showed an association between IC/BPS and other chronic pain disorders.27 Aaron and Buchwald (2001) analyzed a co-twin control study and supported the findings previously reported by Clauw and colleagues (1997).28, Additional epidemiologic studies support these data and suggest that if the IC patient is properly assessed during the diagnostic evaluation, many of these somatic symptoms are also present.

Considering these data, it has been suggested that IC/BPS is a member of a family of hypersensitivity disorders which affects the bladder and other somatic/visceral organs, and has many overlapping symptoms and pathophysiology.29,30 An additional hypothesis is that IC/BPS might be just a part of the continuum of painful v. non-painful overactive bladder syndrome (OAB).31,32

Challenge to Patient and Clinician: Impact on Psychosocial Functioning and Quality of Life (QoL)

The effects of IC/BPS on psychosocial functioning and QoL are pervasive and insidious, damaging work life, psychological well-being, personal relationships and general health.9 QoL is poorer in IC/BPS patients than in controls.9,33,34 Rates of depression are also higher.33-35 In addition, IC/BPS patients have significantly more pain, sleep dysfunction, catastrophizing, depression, anxiety, stress, social functioning difficulties and sexual dysfunction than do non-IC/BPS age-matched women.36,37 The impact of IC/BPS on QoL is as severe as that of rheumatoid arthritis and end- stage renal disease.9,38 Health-related QoL in women with IC/BPS is worse than that of women with endometriosis, vulvodynia or overactive bladder.39 Given that IC/BPS causes considerable morbidity over the course of a patient’s life and loss of work during the most productive years of work and family life significant negative psychological and QoL impacts are not surprising.9

Sexual dysfunction has an especially important impact on the QoL of IC/BPS patients. In IC/BPS patients, sexual dysfunction is moderate to severe40 and occurs at high rates compared with controls.41,42 In women with treatment-refractory IC/BPS, poor sexual function is a primary predictor of poor mental QoL.43 Pain appears to mediate sexual dysfunction and its associated effects on QoL. Adult women with IC/BPS report rates of intercourse, desire, and orgasm frequency in their adolescence that are similar to those reported by controls, but rates diverge in adulthood, when IC/BPS patients report significantly more pain and fear of pain with intercourse and more sexual distress.41

The strong link between IC/BPS symptoms and psychosocial functioning and QoL make clear the critical importance of optimizing treatment of IC/BPS symptoms. Successful treatment of the medical condition clearly brings improvement in functioning and QoL. Response to therapy is associated with improved overall QoL.44 In addition, response to therapy is associated with improved sexual function and sleep, with concomitant improvements in QoL.36,40

Cost. Quantifying the economic burden of IC/BPS on the American health care system is difficult because of the lack of an objective marker for diagnosis, resulting in uncertainty regarding its true prevalence. Direct costs associated with IC/BPS are incurred through physician visits, prescription medications, outpatient procedures, and hospitalization. These costs are greater than the mean annual per-person direct costs of diabetes mellitus, depression, hypertension, and asthma.45

They are also more consistent across geographic regions of the United States than other urologic conditions.46 Because of the chronicity of the condition, these costs typically persist over years. The indirect costs of IC/BPS, including time away from work and lost productivity while working, are particularly significant since the condition primarily affects working age adults, and especially women aged 25-50 years. The psychosocial costs such as social, educational and career related activities not pursued, as well as the emotional distress, depression, social isolation, and diminished QoL have not been measured, but are almost certainly substantial. 

Analysis of data extracted from multiple databases, including the Centers for Medicare and Medicaid Services, National Center for Health Statistics, Medical Expenditure Panel Survey, National Health and Nutrition Examination Survey, Department of Veterans Affairs, National Association of Children's Hospitals and Related Institutions, and various private data sets between 1994 and 2000 revealed an increase of 29% from $37 to $66 million among persons with a formal diagnosis of IC/BPS. Similarly, the direct annual costs associated with BPS rose from $481 million to $750 million (amounts standardized to 1996-1998 values).46 Between 1992 and 2001 the rate of visits to physician's offices increased three-fold and the rate of visits to hospital outpatient visits increased two-fold.46 Only the rate of ambulatory surgery visits declined during this period, which may be attributed to a shift to diagnosis based on a symptom-based approach rather than the more traditional procedure- based diagnostic evaluation.46 While these findings are thought to reflect an increased awareness and diagnosis of IC/BPS, existing evidence reveals that more than 92% of office visits among patients with a diagnosis of IC/ BPS were to urologists.46 In contrast, visits attributed to IC/BPS are found under a variety of less specific codes including urinary frequency, other specified symptoms associated with female genital organs, or other unspecified symptoms associated with the female genital organs.46 These findings suggest that misdiagnosis and under-diagnosis remain common, especially in the primary care setting.

The economic burden of IC/BPS for the individual patient is even greater than the impact on the health care system at large. The mean annual health care costs following a diagnosis of IC/BPS are 2.0 to 2.4 times higher than age matched controls.45,46 A study of 239 women diagnosed with IC and cared for in a managed care setting found a mean cost of $6,614, including $1,572 for prescription medications, and $3,463 for outpatient medical services.45,47 In addition, a woman who is diagnosed with IC/BPS will incur a higher mean cost than a male patient diagnosed with the same condition.46 A cross-sectional study of 43 women cared for in an outpatient urology center found that the annual direct cost associated with a diagnosis of IC/BPS based on Medicare rates was $3,631 per person, while the estimated costs based on non-Medicare rates was nearly twice that amount.47 Indirect individual costs were estimated by querying lost wages due to symptoms within a three month period. Nineteen percent of patients with IC/BPS reported lost wages, resulting in a mean annual cost of $4,216. The magnitude of these indirect costs was greatest among women with severe symptoms as compared to those with mild symptoms.47 Although clearly substantial, these additional costs fail to reflect the economic burden associated with commonly occurring coexisting conditions.48

Patient Presentation

Symptoms. Pain (including sensations of pressure and discomfort) is the hallmark symptom of IC/BPS. Typical IC/BPS patients report not only suprapubic pain (or pressure, discomfort) related to bladder filling but pain throughout the pelvis—in the urethra, vulva, vagina, rectum—and in extragenital locations such as the lower abdomen and back.18,42,49 Warren and colleagues (2006) found that by using "pelvic pain" as the key descriptor that 100% of his population fit the case definition.50 It is important that the term "pain" encompass a broad array of descriptors. Many patients use other words to describe symptoms, especially “pressure” and may actually deny pain.49,51 Finally, pain that worsened with specific foods or drinks and/or worsened with bladder filling and/or improved with urination contributed to a sensitive case definition of IC/BPS.18

The prototypical IC/BPS patient also may present with marked urinary urgency and frequency but because these symptoms may indicate other disorders, they do not exclusively indicate the presence of IC/BPS. Voiding frequency is almost universal (92% of one population),42 but does not distinguish the IC/ BPS patient from other lower urinary tract disorders. Change in urinary frequency is valuable to evaluate response to therapy but is of little help in diagnosis. Urinary urgency is also extremely common (84% of the same population),42 but urgency is considered to be the characteristic symptom of overactive bladder and thus it can actually confound the diagnosis. There may, however, be qualitative differences in the urgency experienced by IC/BPS patients compared to OAB patients; IC/BPS patients may experience a more constant urge to void as opposed to the classic ICS definition of a "compelling need to urinate which is difficult to postpone."52,53 Typically IC/BPS patients void to avoid or to relieve pain; OAB patients, however, void to avoid incontinence. Symptoms of urinary urgency and frequency may precede symptoms of pain.20 Median time to the development of a full symptom complex of frequency, urgency, and pain was reported to be two years in one study.20

Presentation of Male IC Patients. Historically, IC/BPS in men has been considered relatively unusual with a female to male ratio of 10:1.54,55 However, uncontrolled clinical series over the past two decades have suggested the incidence of male IC/BPS may be higher than previously observed.8,56 IC/BPS in men is diagnosed by identifying the same symptom complex that makes the diagnosis in women. That is, if the man fulfills the criteria established by the definition of IC/BPS, he can be assumed to have the disorder. Early clinical symptoms may begin with mild dysuria or urinary urgency. Mild symptoms may progress to severe voiding frequency, nocturia, and suprapubic pain. The presence or absence of glomerulations on endoscopy can be considered supporting information, but is too nonspecific to make the diagnosis of the disease in anyone who does not fit the symptom complex as defined.

Clinical findings mirror those of the female IC/BPS patient. On examination, suprapubic tenderness is common along with external (perineal) tenderness and internal (levator muscle) tenderness/spasticity. Cystoscopy with hydraulic distention of the bladder in men with IC/BPS commonly demonstrates diffuse glomerulations.56 Some data suggest that Hunner's ulcers are more common in male IC/BPS patients.57

Male IC/BPS v. Chronic Prostatitis. Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS), or NIH Type III prostatitis58 is characterized by pain in the perineum, suprapubic region, testicles or tip of the penis.59

The pain is often exacerbated by urination or ejaculation. Voiding symptoms such as sense of incomplete bladder emptying and urinary frequency are also commonly reported, but pain is the primary defining characteristic of CP/CPPS. It is clear that the clinical characteristics which define CP/CPPS are very similar to those previously described for IC/BPS. In general, the Panel believes that the diagnosis of IC/BPS should be strongly considered in men whose pain is perceived to be related to the bladder. However, it is also quite clear that certain men have symptoms which meet criteria for both conditions (IC/BPS and CP/CPPS). In such cases, the treatment approach can include established IC/BPS therapies as well as other therapies that are more specific to CP/ CPPS. It is interesting to note that some studies of patients with CP/CPPS have high rates of bladder glomerulation under anesthesia.60 Additionally, empiric IC/BPS strategies in those CP/CPPS patients have demonstrated clinical symptomatic improvement.57,60,61

Diagnosis

The Diagnostic Approach. The diagnosis of IC/BPS can be challenging. Patients present with a wide spectrum of symptoms, physical exam findings, and clinical test responses. This complexity causes significant misdiagnosis, under-diagnosis and delayed diagnosis.62 Insufficient literature was identified to constitute an evidence base for diagnosis of IC/BPS in clinical practice. The lack of evidence is not surprising given the many definitions of the disorder employed and the focus of most trials on NIDDK diagnostic criteria (note that the NIDDK diagnostic criteria are not appropriate for use outside of clinical trials).63,64 For this reason, the section below titled Diagnosis is based on Clinical Principles or Expert Opinion with consensus achieved using a modified Delphi technique when differences of opinion emerged. This section is intended to provide clinicians and patients with a framework for determining whether a diagnosis of IC/BPS is appropriate; it is not intended to replace the judgment and experience of the individual clinician faced with a particular patient.

Guideline Statements

Guideline Statement 1

The basic assessment should include a careful history, physical examination, and laboratory examination to document symptoms and signs that characterize IC/BPS and exclude other disorders that could be the cause of the patient's symptoms. Clinical Principle

Discussion


Guideline Statement 2

Baseline voiding symptoms and pain levels should be obtained in order to measure subsequent treatment effects. Clinical Principle

Discussion


Guideline Statement 3

Cystoscopy and/or urodynamics should be considered when the diagnosis is in doubt; these tests are not necessary for making the diagnosis in uncomplicated presentations. Expert Opinion

Discussion


First-Line Treatment Statements

Issues to Consider. The published literature regarding the typical course of IC/BPS is conflicting. Some studies suggest that IC/BPS is a chronic condition with a waxing and waning course with, on average, little improvement over time while other studies suggest that most patients seem to improve over time.91-93

Conflicting information is not surprising given that studies have been conducted on different patient populations and have had different purposes (e.g., documenting disease course v. treating the disease in the context of a controlled trial). It is clear, however, that there is a limited understanding of IC/BPS pathophysiology and that most treatments are targeted at symptom control. In addition, treatment studies suggest that no single treatment works well over time for a majority of patients. Until more definitively effective therapies are identified, the treatment approach should be tailored to the specific symptoms of each patient in order to optimize quality of life. To optimally treat patients with a more complex presentation and/or when standard treatment approaches are ineffective, urologists may need to partner with other clinicians such as primary care providers, nurse practitioners, registered dietitians, physical therapists, pain specialists, gastroenterologists, and/or gynecologists.

Overall Management. The information presented on Overall Management of IC/BPS in this section is based on Clinical Principles or Expert Opinion with consensus achieved using a modified Delphi technique. This section is offered to provide clinicians and patients with a framework and strategy for determining optimal treatment approaches (see Figure 1); it is not intended to replace the judgment and experience of the individual clinician faced with a particular patient. The framework for overall management includes the following:

Guideline Statement 4

Treatment strategies should proceed using more conservative therapies first with less conservative therapies employed if symptom control is inadequate for acceptable quality of life; because of their irreversibility, surgical treatments (other than fulguration of Hunner's lesions) are generally appropriate only after other treatment alternatives have been exhausted or at any time in the rare instance when an end-stage small, fibrotic bladder has been confirmed and the patient's quality of life suggests a positive risk-benefit ratio for major surgery. Clinical Principle

Discussion


Guideline Statement 5

Initial treatment type and level should depend on symptom severity, clinician judgment, and patient preferences; appropriate entry points into the treatment portion of the algorithm depend on these factors. Counseling patients with regard to reasonable expectations for treatment outcomes is important. Clinical Principle

Discussion


Guideline Statement 6

Multiple, concurrent treatments may be considered if it is in the best interests of the patient; baseline symptom assessment and regular symptom level reassessment are essential to document efficacy of single and combined treatments. Clinical Principle

Discussion


Guideline Statement 7

Ineffective treatments should be stopped once a clinically-meaningful interval has elapsed. Clinical Principle

Discussion


Guideline Statement 8

Pain management should be continually assessed for effectiveness because of its importance to quality of life. If pain management is inadequate, then consideration should be given to a multidisciplinary approach and the patient referred appropriately. Clinical Principle

Discussion


Guideline Statement 9

The IC/BPS diagnosis should be reconsidered if no improvement occurs after multiple treatment approaches. Clinical Principle

Discussion


Guideline Statement 10

Patients should be educated about normal bladder function, what is known and not known about IC/BPS, the benefits v. risks/burdens of the available treatment alternatives, the fact that no single treatment has been found effective for the majority of patients, and the fact that acceptable symptom control may require trials of multiple therapeutic options (including combination therapy) before it is achieved. Clinical Principle

Discussion


Guideline Statement 11

Self-care practices and behavioral modifications that can improve symptoms should be discussed and implemented as feasible. Clinical Principle

Discussion


Guideline Statement 12

Patients should be encouraged to implement stress management practices to improve coping techniques and manage stress-induced symptom exacerbations. Clinical Principle

Discussion


Second-Line Treatments

Guideline Statement 13

Appropriate manual physical therapy techniques (e.g., maneuvers that resolve pelvic, abdominal and/or hip muscular trigger points, lengthen muscle contractures, and release painful scars and other connective tissue restrictions), if appropriately-trained clinicians are available, should be offered to patients who present with pelvic floor tenderness. Pelvic floor strengthening exercises (e.g., Kegel exercises) should be avoided. [Clinical Principle] Standard

Discussion


Guideline Statement 14

Multimodal pain management approaches (e.g., pharmacological, stress management, manual therapy if available) should be initiated. Expert Opinion

Discussion


Guideline Statement 15

Amitriptyline, cimetidine, hydroxyzine, or pentosan polysulfate may be administered as second-line oral medications (listed in alphabetical order; no hierarchy is implied). Options

Discussion


Guideline Statement 16

DMSO, heparin, or lidocaine may be administered as second-line intravesical treatments (listed in alphabetical order; no hierarchy is implied). Option

Discussion


Third-Line Treatments

Guideline Statement 17

Cystoscopy under anesthesia with shortduration, low-pressure hydrodistension may be undertaken if firstand secondline treatments have not provided acceptable symptom control and quality of life or if the patient's presenting symptoms suggest a more invasive approach is appropriate. Option

Discussion


Guideline Statement 18

If Hunner's lesions are present, then fulguration (with laser or electrocautery) and/or injection of triamcinolone should be performed. Recommendation

Discussion


Fourth-Line Treatments

Guideline Statement 19

Intradetrusor botulinum toxin A (BTX-A) may be administered if other treatments have not provided adequate symptom control and quality of life or if the clinician and patient agree that symptoms require this approach. The patient must be willing to accept the possibility that intermittent self-catheterization may be necessary post-treatment. Option

Discussion


Guideline Statement 20

A trial of neurostimulation may be performed and, if successful, implantation of permanent neurostimulation devices may be undertaken if other treatments have not provided adequate symptom control and quality of life or if the clinician and patient agree that symptoms require this approach. Option

Discussion


Fifth-Line Treatments

Guideline Statement 21

Cyclosporine A may be administered as an oral medication if other treatments have not provided adequate symptom control and quality of life or if the clinician and patient agree that symptoms require this approach. Option

Discussion


Sixth-Line Treatments

Guideline Statement 22

Major surgery (substitution cystoplasty, urinary diversion with or without cystectomy) may be undertaken in carefully selected patients for whom all other therapies have failed to provide adequate symptom control and quality of life (see caveat above in Guideline Statement 4). Option

Discussion


Treatments that Should Not be Offered

The treatments below appear to lack efficacy and/or appear to be accompanied by unacceptable AE profiles.

Guideline Statement 23

Long-term oral antibiotic administration should not be offered. Standard

Discussion


Guideline Statement 24

Intravesical instillation of bacillus Calmette-Guerin (BCG) should not be offered outside of investigational study settings. Standard

Discussion


Guideline Statement 25

High-pressure, long-duration hydrodistension should not be offered. Recommendation.

Discussion


Guideline Statement 26

Systemic (oral) long-term glucocorticoid administration should not be offered. Recommendation.

Discussion


Future Research

Patients with IC/BPS constitute a previously under-recognized and underserved population in need of adequate medical management. Over the last 20 years, there have been significant efforts directed at understanding the etiology and the therapeutic challenges of this disease. These efforts were spearheaded by US patient support groups that have urged the National Institutes of Health to fund research studies to better understand IC/BPS pathophysiology and to fund clinical studies to identify valid treatment approaches.

Treating IC/BPS patients presents a significant challenge in clinical practice. Treatment approaches may be local (directed to the bladder) or systemic, range from behavioral to pharmacological, and may include many types of adjunctive therapy approaches intended to optimize quality of life. Although there are evidenced-based data supporting certain treatment approaches for patients in clinical studies, the unsolved question in clinical practice remains: "Who is the ideal patient for a given treatment approach?" Thus, treatment of IC/BPS often requires a trial and error approach.

IC/BPS, which was originally considered to be a bladder disease, has now been recognized as a chronic pain syndrome.28,212-214 There is a growing body of literature demonstrating that different visceral pain syndromes, as well as pain syndromes in other body regions, and other systemic diseases often occur together in the same patient. Thus, efforts to understand the pathophysiology and to design therapeutic modalities have recently shifted from an organ-based approach to a more global approach.92 Reflecting this new paradigm, the NIDDK has funded the Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network (www.mappnetwork.org). The MAPP network is focused on a broader approach to the study of IC/BPS and CP/CPPS than previously undertaken. A wide range of scientific discovery projects, moving beyond the previous traditional bladder- and prostate-focused efforts, are being conducted at six Discovery Sites. Investigations include the relationship between IC/BPS, CP/CPPS and other chronic pain conditions (fibromyalgia, chronic fatigue syndrome, and irritable bowel syndrome), innovative epidemiological studies, search for clinically important biomarkers, investigation of bacterial, viral and other infectious causative/exacerbating agents, novel brain imaging studies and animal studies to better understand the pathophysiology of these often disabling syndromes.

As the definition of IC/BPS has expanded, clinical trial design for this condition is becoming more complex and challenging. Early clinical trials have enrolled participants based on NIDDK research criteria for IC.215 However, this approach resulted in two-thirds of potential subjects being excluded at the outset.5,30

Further, IC/BPS patients with comorbidities have typically been excluded in clinical trials.195 While there is a need in clinical research to enroll a more homogeneous patient population, this approach raises concerns about the clinical relevance of such studies for the truly heterogeneous IC/BPS population. Two strategies may be useful to move the field forward. First, entry criteria for these trials could be as broad as possible to both improve the ability to generalize the results and permit subgroup analysis.196 Second, clinically-important subgroups could be identified a priori and evaluated for treatment responses. In future trials it will be important to keep track of comorbidities for clinical trial design, either for the purpose of post hoc subgroup analysis or a priori subgroup recruitment, since the neuroathophysiological mechanisms in IC/ BPS patients with different co-morbidities are likely to be different.26,33,35,216,217

A key issue for future clinical trial design will be to identify clinically relevant objective criteria for patient enrollment, and this remains a challenge, which has delayed a more aggressive approach of the pharmaceutical industry to identifying new treatment avenues for this condition. A validated urine marker for IC/BPS would be a major advantage in this disorder since it would provide an objective criterion for participant enrollment and allow subclassification of various subgroups of BPS.

The second major challenge in clinical trial design remains the selection of outcome measures.195 Many patients have periods of flares and remission. In other patients, symptoms become more severe and frequent over time. Thus it is difficult to establish a baseline for the symptoms over a longer observation period. It has been suggested by some investigators to circumvent this problem by evaluating the response to an evoked painful visceral stimulus, such as bladder distension, either in normal volunteers, or in subjects with visceral pain.218 Conceptually, however, it is not clear, if studies evaluating the response to an evoked visceral stimulus can be used to predict the response to spontaneous visceral pain, since the neurophysiological mechanisms are likely to be different. In the past questionnaires have been used to assess a global response or individual symptoms related to IC/BPS. However, as the definition of IC/BPS appears to be expanding from a bladder disease to a chronic pain syndrome, reliable new outcome measures will have to be developed. Again, a biomarker would be an ideal outcome measure, if it would measure the presence of IC/BPS and changes in the biomarker would reflect a response to treatment. Many IC/BPS patients suffer from other chronic pain conditions as well. Outcome measures in clinical trials will have to track these comorbidities, so that different subgroups of IC/BPS patients can be identified and responders versus non-responders categorized appropriately.

IC has only been recognized as a highly prevalent health problem in the last 20 years. Data regarding disease progression, remission, and prevention are very limited and we know very little about risk factors for development of associated symptoms over time. Patients are currently treated with a variety of different medications and other treatment interventions on an empirical basis by different clinicians. There is an urgent need for a long-term registry for these patients following them over several decades prospectively. Such a registry will provide information about the natural course of the disease and information about treatment interventions found to be effective could provide a basis for future clinical trials.219

Although progress in developing specific IC/BPS treatments has been slow, these are exciting times for the development of new treatment targets.220 Modulation of visceral nociceptive pathways can occur at peripheral, spinal and supraspinal sites and a wide variety of potential drug targets exists. Compounds that hit several targets might be the best option for a successful approach in the short term, carefully evaluating the benefits of each sequentially. However, there is emerging evidence that a more refined approach may be achievable.221 In addition, research is needed on antiproliferative factors (APF) as a possible therapeutic pathway for treatment of IC/BPS. APF is a frizzled 8 protein secreted by the bladder epithelial cells of patients with IC/BPS. It inhibits uroepithelial cell proliferation by decreasing heparin binding epidermal growth factor-like growth factor (HB-EGF).221 APF has been shown to be a sensitive and specific biomarker for IC/BPS v. controls.222 It has been speculated that APF suppression of uroepithelial cell proliferation after bladder injury may result in clinical IC/BPS, and inhibition of APF may be an effective treatment or prevention,223 but further research is needed.

Tools and Resources

For Patients

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