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Breaking the Cycle of Pain in Interstitial Cystitis/Painful Bladder Syndrome
Toward Standardization of Early Diagnosis and Treatment Consensus Panel Recommendations John B. Forrest, M.D., and Daniel R. Mishell, Jr., M.D.
Chronic pelvic pain (CPP) affects about 15% of female adults in the United States. The source of this pain in many women is the bladder, specifically interstitial cystitis/painful bladder syndrome (IC/PBS). Despite the frequent occurrence of IC/PBS as a cause of CPP, there currently are no universally accepted guidelines for diagnosis and treatment of this disorder, and, consequently, many patients do not receive appropriate treatment in a timely manner. In an effort to develop a rational way to diagnose and treat patients with CPP, a panel of leaders in urology, gynecology, urogynecology and general women’s health met to review recent literature, reach consensus and formulate 2 algorithms, one for diagnosing and the other for managing IC/PBS. This article reflects the results of that meeting. (J Reprod Med 2009;54:3–14)
Keywords: cystitis, interstitial; painful bladder syndrome; pelvic pain; urinary bladder.
 The average time between the first
presentation of IC/PBS symptoms and a confirmed diagnosis has been estimated to be as long as 5 to 7 years. People with persistent pain cannot fully function and enjoy life, and they usually consult their physicians for help relieving the pain. The first step in relieving patients’ pain is identifying its cause(s). Confusion and controversy surround the issues of what causes chronic pelvic pain (CPP) and when the bladder should be considered the most likely source. Patients with CPP may consult various types of physicians, including urologists, gynecologists and family practitioners, all of whom need to be able to identify the causes of their patients’ pain and treat them appropriately. Thus, uniform, cross-disciplinary diagnostic criteria and therapies to manage patients with CPP, particularly those with interstitial cystitis/painful bladder syndrome (IC/PBS), are greatly needed. To develop methods to diagnose and treat IC/PBS, a panel of leaders in urology, gynecology, urogynecology and general women’s health met to review recent literature, reach consensus and formulate 2 algorithms, 1 for diagnosing and the other for managing IC/PBS. This article summarizes the panel’s recommendations.
A Common Syndrome
CPP affects approximately 15% of the adult female US population.1 The prevalence of CPP among women is comparable to that of other common chronic medical conditions, such as migraine headaches, asthma and back pain.2 Nonetheless, as many as two thirds of women with CPP neither receive the correct diagnosis nor are referred to specialists for evaluation and treatment.3
IC/PBS is a frequently underdiagnosed or misdiagnosed cause of CPP that is more prevalent than was previously believed,4 and the diagnosis of IC/PBS is often one of exclusion.5 Multiple definitions of IC/PBS exist, including those of the American Urological Association, the Interstitial Cystitis Association and the International Continence Society.6-8 IC/PBS is a disorder characterized by CPP and urinary symptoms. Because of a lack of prompt and accurate recognition of IC/PBS as a patient’s source of CPP, appropriate treatment is frequently delayed until an accurate diagnosis is made.
Several groups have published recommendations for the diagnosis and management of CPP and IC/PBS.3,9,10 There is wide variation among these recommendations, as well as in clinical practice. This variability may contribute substantially to delayed diagnosis, misdiagnosis and inappropriate treatment and to ongoing and unnecessary pain for many patients.
Psychosocial Impact of IC/PBS A number of factors that characterize IC/PBS can affect patients’ psychosocial functioning negatively, including the delay in diagnosis. The average time between the first presentation of IC/PBS symptoms and a confirmed diagnosis has been estimated to be as long as 5 to 7 years.11 A potential reason for the delay in the diagnosis is that not all patients with IC/PBS experience all of the symptoms of the condition.12 Clinicians’ suspicion of IC/PBS as a possible cause of the symptoms of CPP and thus the likelihood of early diagnosis and treatment may spare patients months to years of unnecessary adverse symptomology.
The often excruciating pain of IC/PBS, as well as living with the fear of not being able to find a toilet when needed, can isolate patients and inhibit their activities. In addition, IC/PBS symptoms may be exacerbated by sexual intercourse, and, as a result, patients’ personal relationships may deteriorate.13 The more severe the symptoms, the more likely the patient is to experience decreases in physical and social functioning and vitality and increases in fatigue, anxiety and depression, which reduce functioning further.13,14 It is unfortunate that IC/PBS is often not correctly identified until patients are experiencing severe symptoms, as earlier diagnosis and treatment have been shown to result in improved quality of life.11,15
Prevalence of IC/PBS Approximately 90% of all patients with IC/PBS are women.16 CPP of bladder origin in men is frequently misdiagnosed as a prostatic disorder; therefore, the prevalence of IC/PBS among men may also be higher than originally estimated.17 One large study concluded that the prevalence of IC/PBS among both women and men was higher than previously believed and that the female-to-male ratio was approximately 5:1 rather than 9:1.18
Although it is difficult to assess without clear diagnostic criteria, estimates of the prevalence of IC/PBS among women have increased over time, and it has been proposed that between 0.5% and 12.5% of women in the US population may have IC/PBS.19 As shown in Figure 1, the incidence of clinically confirmed IC/PBS among women is about 0.2%.11,20,21 Leppilahti and colleagues estimated that about 0.5% of women had probable/ possible IC/PBS.21 In a Canadian urology practice audit, 7.9% of 2,675 female patients received a diagnosis of IC/PBS, a higher rate than originally expected.4 The increases in estimates over time probably are due more to higher awareness and improved diagnostic practices than to an actual increase in prevalence. The previously mentioned lack of uniform diagnostic criteria and inability to make a histologic diagnosis greatly reduce the number of patients correctly identified as having IC/PBS.
For example, if the research definition (requiring the presence of bladder ulcers seen during cystoscopy) established by the National Institute of Diabetes, Digestive and Kidney Diseases (NIDDK) were used exclusively, there would be more than a 60% underdiagnosis rate of IC/PBS among women.11,22 Similarly, the International Continence Society defines PBS as being characterized by “suprapubic pain” only, rather than by pain in any of several pelvic areas. A recent study, however, determined that this definition excluded approximately one third of patients with IC/PBS, none of whose symptoms were significantly different from those of patients who did receive this diagnosis. If the definition were amended to “pelvic pain,” including suprapubic, infrapubic, genital, rectal, or urethral, all of the patients in this study would qualify for a diagnosis of IC/PBS and be treated appropriately.23
It would also be erroneous to assume that IC/PBS is a condition that affects only middle-aged women. In the large Nurses’ Health Study, the prevalence of IC/PBS among women <50 years of age was actually higher than that among women ≥50 years of age.11
Patients with bladder pain may also have symptoms caused by multiple other conditions with symptoms similar to those of IC/PBS. Because there are so many potential overlapping pain generators and no histologic findings of IC/PBS, the diagnosis of IC/PBS is often one of exclusion.5 Findings indicating that IC/PBS is the cause of a major proportion of CPP suggest that the paradigm should change and diagnosis of IC/PBS be one of inclusion; i.e., IC/PBS should be considered at the same time as other common diagnoses rather than only when other causes of pain have been ruled out. In the Canadian practice audit, there was wide variation in the methods used to diagnose IC/PBS. Despite this lack of uniformity, the prevalence of IC/PBS was higher than the investigators expected.4
Some other conditions that cause similar symptoms commonly coexist with IC/PBS. In 1 retrospective study of patients eventually diagnosed with IC/PBS, urinary tract infection (UTI) preceded the diagnosis of IC/PBS in 60% of patients. All of the patients with initial diagnosis of UTI experienced only temporary symptom resolution with antibiotic treatment. When pain reemerged, urine cultures were negative, the diagnosis IC/PBS was made, targeted therapy was prescribed and symptom relief was reached.24 In another retrospective study, in which 89% of patients initially reported only 1 symptom of IC/PBS, 42% of patients had an initial diagnosis of UTI before being diagnosed with IC/PBS.12 Thus, clinicians should consider the possible presence of IC/PBS in patients with symptoms typical of recurrent UTI following successful antibiotic treatment, even without the full constellation of IC/PBS symptoms.24 Similarly, IC/PBS should be considered to be present in patients with symptoms of recurrent cystitis and consistently negative urine cultures.25
IC/PBS and endometriosis may also have similar symptoms. In a study of 64 patients who underwent laparoscopy for CPP, 44 were found to have positive potassium sensitivity tests possibly consistent with a diagnosis of IC/PBS. The authors concluded that vulvar vestibulitis, endometriosis, pelvic adhesions and IC/PBS are independent risk factors for CPP, and the presence of 1 does not preclude the presence of another.26 In another study, 33% of women who underwent laparoscopy for CPP and were found to have endometriosis had concomitant IC/PBS, and 42% of those with negative laparoscopic findings were subsequently diagnosed as having IC/PBS.27
IC/PBS in men also shares symptoms with other common conditions. Men with chronic prostatitis generally complain of pain at any of several sites as well as urinary urgency and frequency, and almost half of men with chronic prostatitis experience pain with bladder filling, which also occurs with IC/PBS.28
The fact that many more patients than previously estimated may have IC/PBS further emphasized the need for guidelines to be used in diagnosing IC/PBS; therefore, the panel formulated Algorithm 1.
IC/PBS: A Diagnosis of Inclusion
As many as 92% of diagnostic laparoscopies for CPP reveal no evidence of pelvic pathology,29,30 suggesting that the bladder may be the origin of some patients with CPP. Several studies have concluded that nongynecologic causes should be considered initially in the diagnostic evaluation of women with CPP.27,31,32 The panel’s review supported the assertion that the bladder should be considered as a possible source of pain for every patient with CPP and should certainly be considered before female patients have potentially unnecessary gynecologic surgery such as laparoscopy or hysterectomy.
Clinical Presentation The presenting symptoms of IC/PBS are typically intermittent and frequently involve pain at sites other than the bladder. A database analysis of >600 patients with IC/PBS found that the lower abdominal area was the most frequent site of pain (80%), followed by the urethra (74%) and the lower back (65%). Patients with IC/PBS also frequently had concurrent conditions that might cause pain, such as arthritis, irritable bowel syndrome, migraine and fibromyalgia.33 Pain associated with sexual activity is common for both women and men with IC/PBS.
IC/PBS shares many symptoms—including generalized pelvic pain, urinary urgency and frequency, dyspareunia and menstrual exacerbation of pain—with pathologic conditions of gynecologic origin.34 Pain with bladder filling and relief with emptying frequently occurs with IC/PBS and can help differentiate this etiology from other conditions. The differential diagnosis must consider both gynecologic and nongynecologic sources of pain. Patients with IC/PBS frequently have sleep disturbances associated with nocturia and bladder pain. Table I shows the percentages of patients in several studies who were found to have conditions that might trigger bladder pain.26,35-40
 Etiology To be able to treat IC/PBS effectively, one needs to consider all potential causes of the pain. Although it is most likely that IC/PBS has a multifactorial etiology, it is proposed that the initiating factor is an insult to the bladder triggered by any of several associated events including recurrent UTI, childbirth, pelvic surgery, bladder trauma and introduction of bladder toxins such as chemotherapeutic agents. As a result of this insult, deficits occur in the glycosaminoglycan layer that normally lines the bladder urothelium. These deficits cause increased urothelial permeability, which leads to urinary solute diffusion into the bladder wall. Over time, this results in potential neural upregulation and subsequent bladder pain. It is also hypothesized that IC/PBS may have an autoimmune component.41,42 Additionally, more than half of all patients with IC/PBS have a history of allergies,43 particularly seasonal allergies. Antiproliferative factor has been identified in the urine of some patients with IC. This protein factor inhibits the reparative ability of the urothelium in patients with IC.44,45
History and Physical Examination The diagnostic process begins with a thorough history and physical examination.46 The clinician should inquire about the patient’s previous diagnoses and about her pain and voiding histories. Of particular interest should be the duration of the patient’s symptoms, dietary triggers, allergy history and sexual dysfunction. It is helpful to have the patient keep a daily symptom diary.16 A pelvic examination should assess the presence of suprapubic tenderness, anterior vaginal wall and/or urethral or bladder-base tenderness, and rectal or levator muscle spasm.47
Symptom-Evaluation Tools Clinical scales are useful for grading and characterizing patients’ symptoms. These include the O’Leary-Sant IC Symptom and Problem Indexes, which assess urinary frequency and bladder discomfort but not dyspareunia or other types of bladder pain, and the University of Wisconsin Symptom Scale Questionnaire.48,49
One of the most frequently used scales is the Pelvic Pain and Urgency/Frequency Patient Symptom Scale (PUF). This questionnaire, which has been shown to have clinical utility for both initial assessment and follow-up, has been validated in both urologic and gynecologic practices.48-50 The PUF is a short, self-administered scale that takes approximately 5 minutes to answer (Figure 2).48 Although members of the panel differed in their preferences for screening tools, they all agreed that the PUF is useful, and 9 of the 10 panelists routinely use this questionnaire. Several agreed that the cutoff score for a definitive IC/PBS diagnosis based on the PUF should be at least 12 and possibly higher.
Laboratory Evaluation
Urinalysis is another mandatory first step in diagnosis, and urine culture should be performed.46 Bladder glomerulations visualized on cystoscopy are among the NIDDK criteria for inclusion in clinical trials of IC/PBS. It has been observed, however, that many patients who have IC/PBS would not be diagnosed with this disorder if the NIDDK criteria were applied strictly.51 Although cystoscopy is necessary to rule out malignancy in patients with microscopic or gross hematuria, it is not sufficient or always necessary to establish the diagnosis of IC/PBS.47,52 No universally accepted laboratory test has been developed that can diagnose IC/PBS, and no specific histologic abnormalities are present with this disorder. The potassium sensitivity test (PST) has been proposed by some as a clinical adjunct for the diagnosis of IC/PBS. This is based on the observation that patients with IC/PBS have an onset of pain in response to high concentrations of potassium chloride.48,53
The PST involves instilling water and then a potassium solution into the bladder and noting the patient’s onset of reaction and level of pain with each type of instillation; a rescue solution may be instilled following the potassium instillation to relieve pain caused by the test.53 The PST correlates very strongly with increased PUF scores.48,54 The PST has been observed to be positive in 78% of patients with IC/PBS and 81–85% of gynecologic patients with CPP, whereas the rate of positivity in healthy individuals is less than 3%.47 Although a positive PST indicates the presence of a bladder problem with relative certainty, a negative PST does not rule out bladder epithelial dysfunction.35 Despite some reluctance to use a test that actually caused patients more pain, the general opinion of the panelists was that they might use the PST in the presence of a low PUF score to enhance the probability of an accurate diagnosis. Nevertheless, it must be realized that the diagnosis of IC/PBS is mainly made by clinical history and physical examination, with the PST as an adjunct.
The diagnostic value of intravesical instillation of an anesthetic solution is still in question. A majority of patients experience symptomatic improvement following anesthetic instillation, and it is better tolerated than is the PST, relieving pain rather than inducing it. Although anesthetic instillation may help identify the bladder as the source of pain in patients with suspected IC/PBS, it does not necessarily support a diagnosis of urothelial dysfunction. Thus, it appears to be a valuable option, but it has not yet been validated as a diagnostic tool for IC/PBS.55
Establishing a diagnosis of IC/PBS may not require use of every available diagnostic test but rather a combination of results of physical examination, a symptom-evaluation tool such as the PUF, cystoscopy and, in some instances, the PST. If a definitive diagnosis cannot be made but IC/PBS seems likely, additional diagnostic testing or further clinical evaluation is warranted. Depending on the patient’s history and severity of symptoms, the clinician may consider initiating pharmacotherapy while continuing the diagnostic process.
Multimodal Management for Optimal Outcomes Multiple treatment strategies are available for patients with IC/PBS, including oral medications, intravesical instillations, psychological counseling and dietary modification.56,57 In the Canadian practice audit, a large amount of variation was also found in approaches to treatment for IC/PBS, again emphasizing the need for guidelines based on evolving evidence.4 Therefore, the panel formulated Algorithm 2 to guide clinicians in therapeutic decision making.
Principles of IC/PBS Treatment
Relief of pain and improvement in patient quality of life are the primary goals of therapy for IC/PBS; the following 2 principles address those goals.
Treat Early. In a retrospective chart review of a large urology practice, the factor most strongly correlated with therapeutic response was duration of symptoms. Fifty percent of patients who had been symptomatic for <2.5 years achieved a 75% response within 3 months of therapy, whereas 65% of those who had been symptomatic for >4 years required 6 months to achieve the same level of relief. Thus, early recognition and treatment of IC/PBS are likely to result in positive outcomes.15
Treat All Sources of Pain. The pain of IC/PBS is often complex, comprising neuropathic, nociceptive and visceral aspects.56 Because the delay between symptom onset and diagnosis is typically long, most patients will have such severe symptoms that multimodal, long-term therapy will be necessary.58
Oral Therapy Pentosan polysulfate (PPS) is a heparinoid substance that coats the defects in the bladder surface mucin. PPS is one of the few oral treatments for IC/PBS that have undergone prospective, randomized, placebo-controlled trials.59 In a double-blind trial, 38% of patients with IC/PBS who were treated with PPS for 3 months rated themselves as having 50% improvement in pain, vs. 18% of those on placebo (p=0.005).60 In a dose-ranging study, the percentages of patients experiencing at least 50% improvement on the Patient’s Overall Rating of Symptoms Index increased with increasing duration of therapy with all 3 PPS dosages studied (300, 600 and 900 mg/day), whereas there was no significant between-dosage difference in improvement.59
PPS, given at a dosage of 100 mg, 3 times daily, is the only oral medication approved by the US Food and Drug Administration (FDA) for IC/PBS56; however, several other agents, some of which are shown in Table II, are also of benefit.56 The tricyclic antidepressant amitriptyline is used frequently to treat IC/PBS as it has neuromodulatory, antihistamine and serotonergic effects. It has been observed to decrease urinary frequency and nocturia, thus improving sleep.50,56 The antihistamine hydroxyzine has been observed to reduce IC/PBS symptoms substantially, particularly in patients with history of allergy, perhaps by reducing mast cell histamine and substance P release.50,56Additionally, cyclosporine A was recently found in a randomized, comparative trial to be superior to PPS in reducing several symptoms of IC/PBS. Cyclosporine A, which is not approved by the FDA for treating IC/PBS, should be used with caution, however, as it has the potential for nephrotoxicity.61
 Intravesical Therapy As with oral therapy, only one agent, dimethyl sulfoxide (DMSO), is approved by the FDA for bladder instillation to treat IC/PBS. DMSO (50 mL of a 50% solution) is placed in the bladder via a catheter and left there for 15 minutes. This therapy has provided at least partial relief to patients with IC/PBS within a few weeks after treatment initiation. DMSO is administered in the office at 1- to 2-week intervals for 4–8 treatments, with maintenance therapy every 1 or 2 months as needed. Intravesical heparin (10,000–40,000 U), sometimes used with DMSO, also provides symptomatic relief but does not have FDA approval for treating IC/PBS.58
Intravesical instillations of anesthetic “cocktails” can provide prompt relief during flares of IC/PBS, relieve the discomfort patients develop following the PST and, by selectively relieving pain of bladder origin, help the clinician make a differential diagnosis. These cocktails typically consist of an anesthetic such as 8 mL of 1% or 2% lidocaine accompanied by 3 mL 8.4% sodium bicarbonate or 1–2% lidocaine diluted in 8.4% sodium bicarbonate to enhance the anesthetic’s action; PPS (a 100- to 200-mg capsule) or heparin (40,000 U) is added to help restore bladder mucus overlying the urothelium; an antibiotic (e.g., 80 mg gentamycin) is used if infection is present; and a corticosteroid (e.g., 100 mg hydrocortisone) may be added to control inflammation.47,62,63
Other Therapies An integrated, multimodal treatment program should always include a behavioral component. Patients may use several self-care techniques that help reduce the severity of symptoms, including smoking cessation if applicable, bladder retraining, relaxation techniques and pelvic floor exercises. Patients should be cautioned not to reduce fluid intake as this could make voiding more painful because of a higher concentration of irritating components, as well as potentially causing dehydration.57,64 Certain foods may exacerbate IC/PBS symptoms. Table III provides a partial list of foods to avoid.65 A survey of 104 patients with IC evaluated 175 foods and beverages for their effects on IC symptoms. More than 90% of the patients reported that certain foods and vegetables exacerbated their IC symptoms. Those patients, who tended to have higher scores on symptom questionnaires, identified 35 items, including spicy foods, artificial sweeteners, certain fruits and juices and alcoholic, carbonated and caffeinated beverages as particularly worsening their symptoms.66
 Sacral nerve root stimulation has been shown to relieve pain, urgency and frequency, thereby improving quality of life.67,68 Manual therapy, consisting of massage and myofascial release, can correct the pelvic floor tension experienced by many patients with IC/PBS, reducing urinary urgency and frequency. This type of physical therapy carries very little risk and may help reduce stress, another contributory factor for IC/PBS flares.5,69,70 Surgery, specifically cystectomy, should be the last option for patients with intolerable symptoms for whom other forms of treatment have failed.57
Conclusion The prevalence of IC/PBS is much greater than previously believed, and many women are symptomatic for longer than necessary because of missed or late diagnoses. The physical and psychosocial effects of living with unrelieved persistent pelvic pain can be devastating and disabling. Therefore, it is imperative that clinicians consider the bladder, specifically the presence of IC/PBS, as a potential source of CPP early in the diagnostic process rather than after the alternatives have been ruled out.
Once IC/PBS is diagnosed, it is important to treat promptly and target all sources of pain with a multimodal strategy. Whatever treatment is used, behavioral techniques, including diet modification and, possibly, physical and psychological therapy, should be integrated into the regimen. The chief goals of treatment for IC/PBS are to break the cycle of chronic pain and provide patients with improved quality of life. For these goals to be achieved, clear diagnostic criteria must be identified, consistent treatment strategies developed and uniform standards of care applied across disciplines. There remains a pressing need for diagnosis and treatment guidelines that can be used in all settings to ensure optimal outcomes for patients with IC/PBS. It is the hope of the panel members whose consensus is reflected herein that this report and the algorithms will provide uniform recommendations for the diagnosis and treatment of IC/PBS.
Acknowledgments The authors would like to acknowledge the other members of the expert panel for their invaluable contributions to the consensus meeting and to the development of the 2 algorithms: Charles Butrick, M.D., Overland Park Regional Hospital, Robert J. Evans, M.D., Moses Cone Health Center, Fred M. Howard, Jr., M.D., University of Rochester School of Medicine and Dentistry, J. Curtis Nickel, M.D., FRCS, Queen’s University, Lee P. Shulman, M.D., Northwestern University Feinberg School of Medicine, Diane A. Smith, MSN, CRNP, UroHealthcare LLC, Edward J. Stanford, M.D., MS, Center for Advanced Pelvic Surgery, and Kristene E. Whitmore, M.D., Drexel University.
References
From Urologic Specialists of Oklahoma, University of Oklahoma Health Sciences Center, Tulsa, Oklahoma, and the Department of Obstetrics and Gynecology, Keck School of Medicine, University of Southern California, Los Angeles, California.
Address correspondence to: John B. Forrest, M.D., 10901 East 48th Street South, Tulsa, OK 74146 (jforrest@sjmc.org). Financial Disclosure: Dr. Forrest has received grant/research support from, has been a consultant for and has served on the speakers bureau for Ortho-McNeil Pharmaceuticals, Inc. Dr. Mishell is a Consultant for Ortho-McNeil Pharmaceuticals.
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