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Pharmacologic Management of Painful Bladder Syndrome/Interstitial CystitisA Systematic Review
Jordan Dimitrakov, MD, PhD;
Kurt Kroenke, MD;
William D. Steers, MD;
Charles Berde, MD, PhD;
David Zurakowski, PhD;
Michael R. Freeman, PhD;
Jeffrey L. Jackson, MD, MPH
Arch Intern Med. 2007;167(18):1922-1929.
ABSTRACT
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Background More than 180 different types of therapy have been used in the treatment and management of painful bladder syndrome/interstitial cystitis (PBS/IC), yet evidence from clinical trials remains inconclusive. This study aimed to evaluate the efficacy of pharmacologic approaches to PBS/IC, to quantify the effect size from randomized controlled trials, and to begin to inform a clinical consensus of treatment efficacy for PBS/IC.
Methods We identified randomized controlled trials for the pharmacologic treatment of patients wth PBS/IC diagnosed on the basis of National Institute of Diabetes and Digestive and Kidney Diseases or operational criteria. Study limitations include considerable patient heterogeneity as well as variability in the definition of symptoms and in outcome assessment.
Results We included a total of 1470 adult patients from 21 randomized controlled trials. Only trials for pentosan polysulfate sodium had sufficient numbers to allow a pooled analysis of effect. According to a random-effects model, the pooled estimate of the effect of pentosan polysulfate therapy suggested benefit, with a relative risk of 1.78 for patient-reported improvement in symptoms (95% confidence interval, 1.34-2.35). This result was not heterogeneous (P = .47) and was without evidence of publication bias (P = .18). Current evidence also suggests the efficacy of dimethyl sulfoxide and amitryptiline therapy. Hydroxyzine, intravesical bacille Calmette-Guérin, and resiniferatoxin therapy failed to demonstrate efficacy, but evidence was inconclusive owing to methodological limitations.
Conclusions Pentosan polysulfate may be modestly beneficial for symptoms of PBS/IC. There is insufficient evidence for other pharmacologic treatments. A consensus on standardized outcome measures is urgently needed.
INTRODUCTION
Painful bladder syndrome/interstitial cystitis (PBS/IC) is a poorly defined clinical condition characterized by 3 key symptoms: pelvic pain, urinary urgency, and urinary frequency.1 These symptoms significantly overlap with those of other common conditions and are not associated with any known pathognomonic tissue, serum, or urinary changes. The diagnosis of PBS/IC is therefore primarily one of exclusion.2 Further complicating diagnosis is the lack of a standard definition. In 1915, for example, Hunner3 described a form of bladder ulceration later designated classic IC. In 1978, Messing and Stamey4 proposed that glomerulations apparent with bladder distension were diagnostic of IC in the absence of Hunner ulcerations (ie, nonulcerative IC). Most recently, in 1987, the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) attempted to unify these contrasting approaches by developing a list of criteria to define IC.5 The NIDDK criteria, however, miss an estimated 60% of patients and, because of the criteria's restrictiveness, are currently recommended for research use only.6 Moreover, Waxman et al7 and others8-9 have called into question the specificity of the criteria by finding that 75% of healthy women show glomerulations even in the absence of symptoms. The term PBS is now often used to describe the broader spectrum of cases that meet a more inclusive, symptom-based definition, without the typical cystoscopic and histologic features that have traditionally been used to distinguish IC.2, 10
Prevalence estimates are highly variable, depending on what diagnostic criteria the epidemiologist is using. A number of surveys applying different methodologies have found IC incidence ranging from 1.611 to 15812 per 100 000 women. Self-reporting as part of the National Household Interview Survey found a rate of 450 per 100 000 women,13 and 3 studies that used the O’Leary-Sant Interstitial Cystitis Symptom Index (OLS-SI) or the O’Leary-Sant Problem Index (OLS-PI) scores found a prevalence of approximately 300 per 100 000 women.14-16
Treatment and management approaches vary widely. As of 1997, 183 different types of dietary, interventional, pharmacologic, and behavioral therapies had been used.17 This diversity continues to be reflected within the broad range of pharmacologic agents currently applied to the condition. Our aim was to synthesize and critically evaluate data from a wide range of current pharmacologic approaches to PBS/IC, to quantify the effect size from randomized controlled trials, and to begin to inform a clinical consensus of treatment efficacy for PBS/IC.
METHODS
SEARCH STRATEGY
A search strategy was developed for the purposes of the present review. The following databases were searched: PubMed (1966-2007), EMBASE (1988-2007), CINAHL (1982-2007), Healthstar (1975-2000), Current Contents (2000-2007), Web of Science (1980-2007), PsychInfo (1967-2007), Science Citation Indexes (1996-2007), and Cochrane Collaboration Reviews (1993-2007). The exploded Medical Subject Headings interstitial cystitis and painful bladder syndrome were combined with truncated keywords that described the type of publication, such as random, double-blind, random allocation, placebo, clinical trial, and comparative study and were limited to English-language studies in humans. Additional studies were identified through a manual search of the bibliographies of retrieved articles, recent reviews, monographs, and the Interstitial Cystitis Task Force—a National Institutes of Health (NIH)/NIDDK initiative on the epidemiology and definition of PBS/IC.1
INCLUSION CRITERIA
Articles on clinical trials were included if they met all of the following 6 inclusion criteria18: a controlled clinical trial involving the pharmacologic treatment of PBS/IC; study population of adult patients; administration of a pharmacologic intervention to more than 10 patients; inclusion of a control group that received placebo therapy for PBS/IC; outcome measures of global status or individual PBS/IC symptoms (or both); and use of a randomized, double-blind, parallel-group or crossover design.
DATA EXTRACTION
The study characteristics, patient demographic information, enrollment criteria, therapy allocation, adverse effects, outcomes, and reasons for dropout were extracted independently by 2 of us (J.D. and K.K.). We focused on the efficacy of treatment for PBS/IC compared with placebo or active controls. Continuous measures included assessment of specific symptoms (pain and urinary frequency and urgency) as well as OLS-SI and OLS-PI scores.19 Our dichotomous measure was patient-reported global improvement with treatment. Given the large placebo effect seen in IC trials, we provide only qualitative information about randomized controlled trials (RCTs).
QUANTITATIVE ASSESSMENT
Only trials for treatment of PBS/IC with pentosan polysulfate sodium had sufficient numbers to allow a pooled analysis of effect using a random-effects model.20 Heterogeneity was assessed using Q and I2 statistics, and publication bias was assessed using the Egger test.21 For the remaining treatment modalities, we decided not to attempt to pool the data because of the wide variety of designs; the small sample sizes; the many different treatments, with few studies on each specific treatment; the broad classes of medications, raising the question of whether drugs within these broad classes can be pooled; the different modes of drug administration (oral vs intravesical); and the considerable variation in the reporting of statistical details, such as exact P values and standard deviations.
For all trials, an attempt was made to abstract the data as a standardized mean difference, which produces measures of effect for each treatment trial on a similar metric. By convention, these standardized mean differences, also known as effect sizes, are considered small if they are less than 0.2, moderate if they are between 0.5 and 0.8, and large if they are greater than 0.8.22 For many trials, abstracting the data as a standardized mean difference was not possible, and the study results were classified simply as a positive or a negative outcome, in terms of efficacy.
For some study-specific characteristics, such as duration of studies or number of patients included, the t test was used to compare continuous variables, and the  ² test was used to compare binary variables between certain study subgroups. The Mann-Whitney U test was used to compare median sample sizes between positive and negative study results and between high- and low-quality study results, as sample sizes were skewed.
RESULTS
Of 278 RCTs identified using our search criteria, 21 met the requirements for inclusion in our final analysis. Those excluded (n = 257) did not address treatment of PBS/IC or did not report global or symptom-specific outcomes (n = 77); did not use a randomized, double-blind, placebo-controlled design (n = 55); included patients without a diagnosis of PBS/IC (n = 57); were incomplete or duplicate publications (n = 7); were not published in English (n = 34); or involved fewer than 10 patients (n = 27).
The 21 RCTs that we analyzed are shown in the Table.23-43 A single agent was evaluated in 18 RCTs, and a combination of 2 agents was evaluated in 3 RCTs. The 21 RCTs spanned 1987 to 2006, reporting on a total of 1470 adult patients. The studies enrolled an average of 70 patients each (range, 16-265 patients), with ages ranging from 18 to 80 years (mean age, 46.87 years); 90% of the patients were women. Eleven RCTs (52%) were conducted in North America and 10 (48%) in Europe. All studies were conducted in urological settings, either single (63%) or multiple (37%) practices. Three trials (14%) were published before 1989, 6 (29%) between 1990 and 1999, and 12 (57%) between 2000 and 2007.
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Table. Randomized Controlled Trials for the Treatment of Painful Bladder Syndrome/Interstitial Cystitis
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PATIENT POPULATION
Seventeen RCTs used the 1987 NIH/NIDDK research criteria for diagnosing IC (Table). Four studies based the diagnosis on operational criteria. All trials reported an adequate workup to exclude organic disease, including medical history, physical examination findings, and the results of laboratory, radiologic, and cystoscopic evaluation.
STUDY DESIGN
Of the 21 RCTs, 17 used a parallel design and 4 used a crossover design. The length of the intervention ranged from a single treatment procedure to 36 weeks of treatment, with a mean of 15 weeks and a median of 12 weeks. Symptom severity, as assessed within each individual trial, was similar at baseline between the intervention and control groups in all of the parallel RCTs. Treatment adherence was reported in only 4 RCTs and was measured by pill counts or patient interview. Adherence was similar between the intervention and the control groups in these 4 trials, although actual adherence rates were not provided. Cointerventions, such as concurrent use of other medications to relieve IC symptoms and dietary changes during the intervention period, were assessed in 4 of the RCTs. In these 4 trials, patients were simply advised to avoid use of other medications. Despite the relatively short trials, with few patients enrolled, none of the trials with negative outcomes reported power analyses.
OUTCOME ASSESSMENT
Both global and individual symptom improvement was reported in all of the studies. The definition of symptoms, such as pain and urinary urgency and frequency, varied considerably across the trials. Data were collected by a daily voiding diary maintained by the patient. A standardized symptom questionnaire (OLS19) was used in 11 RCTs and was reportedly validated in 1 trial.44
TREATMENT EFFICACY
The Table shows the evidence for treatment efficacy of each pharmacologic agent in their respective RCT(s). Outcomes most frequently assessed—pain, urinary urgency and frequency, and the OLS-SI scores—are itemized for each trial. The specific symptoms assessed and the measures used varied considerably among the different studies. Therefore, we viewed global improvement as the common metric across treatments, which was usually reported as the number of patients reporting self-improvement in each group. The mean frequency of global improvement was 19% (range, 4%- 40%) among control groups and 49% (range, 28%-89%) among treatment groups for all RCTs that reported this outcome. The effect size for the magnitude of improvement for pain, urinary urgency and frequency, and the OLS-SI scores was generally small among the studies reporting these outcomes (Figures 1,2,3, and 4).
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Figure 1. Effect on patient-reported pain. CI indicates confidence interval; SMD, standardized mean difference.
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Figure 2. Effect on patient-reported urinary frequency. CI indicates confidence interval; SMD, standardized mean difference.
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Figure 3. Effect on patient-reported urinary urgency. CI indicates confidence interval; SMD, standardized mean difference.
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Figure 4. Effect on patient-reported O’Leary-Sant Interstitial Cystitis Symptom Index. CI indicates confidence interval; SMD, standardized mean difference.
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FINDINGS ON SPECIFIC AGENTS
Six RCTs29, 31, 36-39 and 1 meta-analysis45 examined treatment with oral pentosan polysulfate (Table, Figures 1, 2, 3, 4 through Figure 5). The reported overall response rate varied between 15% and 67% at the 300-mg dose recommended by the Food and Drug Administration. An industry-sponsored dose-ranging 3-arm study comparing 300 mg, 600 mg, and 900 mg failed to show dose-related efficacy; the duration of administration was more important than the dosage itself, although adverse effects were dose related.46 The most rigorous NIDDK-supported trial by the Interstitial Cystitis Clinical Trials Group failed to demonstrate the superiority of pentosan polysulfate over placebo, although the study was underpowered.31 Our pooled analysis (Figure 5) suggested benefit, with a relative risk of 1.78 for patient-reported improvement in symptoms (95% confidence interval, 1.34-2.35). This result was not heterogeneous (Q = 3.53; I2 = 0%; P = .47) and was without evidence of publication bias (Egger P = .18).
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Figure 5. Relative risk (RR) of overall improvement with pentosan polysulfate sodium treatment. CI indicates confidence interval.
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Intravesical 50% dimethyl sulfoxide therapy, the only Food and Drug Administration–approved intravesical treatment for IC, proved beneficial in 2 crossover RCTs.26, 30 One trial demonstrated a 93% objective improvement and a 53% subjective improvement compared with 35% and 18%, respectively, with saline solution.30 Symptom alleviation has been demonstrated in up to 80% of patients with the usual treatment schedule of 6 weekly bladder instillations of 50% dimethyl sulfoxide, followed by maintenance therapy every 2 to 4 weeks and then every 2 to 3 months. One important caveat is that saline cannot really be considered an appropriate "placebo" in dimethyl sulfoxide trials because the latter causes prominent adverse effects (in taste and smell). Furthermore, in these early studies, dimethyl sulfoxide was administered once every 2 weeks rather than weekly, as is usually the case today.
Amitriptyline, a tricyclic antidepressant, provided symptomatic relief for 15 of 24 patients in 1 RCT, although the study did not provide details regarding the use of active or inactive placebo.23 The median preferred dose was 75 mg in a range of 25 to 150 mg taken at dinner time rather than bedtime. As is the case with fibromyalgia and chronic fatigue syndrome, it is generally recommended that patients start at the lowest possible dose (10 mg) and titrate up to the dose that provides optimal symptom relief.47-49
The efficacy of intravesical bacille Calmette-Guérin for the treatment of IC was evaluated in 3 RCTs.25-27 Sixty percent of the bacille Calmette-Guérin–treated patients and 27% of the placebo-treated patients reported at least moderate improvement in 1 trial (P = .06).25 The most recent NIDDK-sponsored RCT further supports those findings, demonstrating benefit in 21% of the bacille Calmette-Guérin–treated patients compared with 12% improvement in the placebo group (P = .06).27 In a crossover trial of treatment with bacille Calmette-Guérin compared with dimethyl sulfoxide, none of the patients improved with bacille Calmette-Guérin as the first treatment, whereas 7 patients improved with dimethyl sulfoxide therapy (2 when dimethyl sulfoxide was the first treatment, and 5 when dimethyl sulfoxide therapy was followed by treatment with bacille Calmette-Guérin).26 The findings from the crossover study pose a special challenge to interpretation in light of the fact that there was no a priori outcome or, as a result, no estimated sample size for power calculation. Furthermore, the authors failed to observe an optimal washout period before changing the patient's treatment from bacille Calmette-Guérin to dimethyl sulfoxide. Thus, if treatment with bacille Calmette-Guérin is followed by dimethyl sulfoxide therapy, the reported benefit might actually be a delayed bacille Calmette-Guérin effect. Hydroxyzine, an H1 blocker, failed to show efficacy as a single agent in a recent NIH/NIDDK study, although the combination with pentosan polysulfate approached statistical significance (P = .06).31 However, the study lacked the power to detect significant differences.
COMMENT
Evaluation of treatment efficacy in PBS/IC is challenging owing to the short duration of trials, the heterogeneity of the disease, and the lack of knowledge of the natural history of the disease. The RCTs we analyzed did not take into consideration the variability of symptoms over time and regression to the mean. Most trials were short, with a mean duration of 15 weeks, which might not be optimal given the chronic nature of PBS/IC symptoms. As reflected in results from the largest observational IC study to date, the Interstitial Cystitis Database, patients who began with the most severe symptoms demonstrated the greatest initial improvement (ie, their symptom scores moved toward the population mean).50 Conversely, the condition of patients who began with mild symptoms was more likely to worsen. Appropriately designed RCTs would have minimized such bias. Also, the short duration of trials limits the generalizability of the findings.
Inadequate blinding (eg, saline as placebo in dimethyl sulfoxide trials26, 30), a small number of patients (eg, certain studies involving treatment with pentosan polysulfate,36-38 hydroxyzine,31 or amitriptyline23), and nonstandardized outcome measures (eg, bladder biopsy findings28) present additional challenges to analyzing treatment efficacy for PBS/IC. While most trials used the NIDDK diagnostic criteria for IC, very limited information was presented about participants who were ineligible or about symptomatic patients without bladder glomerulations (eg, patients with PBS). It is well known that strict use of NIDDK criteria would exclude 60% of patients with PBS/IC.6 Therefore, it is difficult to extrapolate how the findings from IC trials might relate to the larger majority of patients across the spectrum of PBS/IC symptoms.
The definition of symptoms—such as pain and urinary urgency and frequency—varied considerably across the trials. The symptoms were measured using several different scales, making it inappropriate to pool the data for specific pharmacologic interventions investigated in more than 1 trial as well as making it difficult to compare the findings in a qualitative synthesis. Consequently, it is not clear whether a positive result based on the pain scale of the OLS-SI, for example, is as good as, better than, or worse than a positive result on a different scale. Outcomes such as "global improvement," in which participants were asked to rate themselves as better or worse than they were before the intervention began, were frequently reported. However, as has been shown to be the case with chronic fatigue syndrome and other chronic pain syndromes, the patients may feel better able to cope with symptoms because they have reduced their expectations of what they should achieve, rather than because they have made any recovery as a result of the intervention. A more objective measure of the effect of any intervention would be whether participants have increased their working or waking hours, returned to work or school, or increased their physical or sexual activities.
The appropriate duration and follow-up of interventions used in the management of PBS/IC remains unknown. Given the fluctuation of symptoms and the relapsing nature of PBS/IC, we suggest that follow-up should continue for at least an additional 6 to 12 months after the intervention period has ended to confirm that any improvement observed was attributable to the intervention itself and not just to a naturally occurring fluctuation in the course of the illness or regression to the mean. High dropout rates may be important indicators of the unacceptability of an intervention. This appears to be the case with studies involving treatment with cyclosporine,29 dimethyl sulfoxide,26, 30 and antibiotics,24 which had dropout rates of 55%, 19%, and 26%, respectively. High dropout rates may also indicate that the trial protocol is too rigid to accommodate any but a very specific group of participants, as might be the case with those receiving cyclosporine and dimethyl sulfoxide. Again, this limits the generalizability of the findings.
Finally, many of the treatment response differences in IC clinical trials may be related to the heterogeneity of this illness. Identifying patient subsets based on response to specific treatments and biologic variables is one of the most challenging tasks in IC research. Patients with Hunner ulcer on cystoscopy form one such subgroup. This group, however, is relatively small, as an ulcer is present in only about 15% of patients with IC. Patients with Hunner ulcer, therefore, should probably be enrolled as an isolated subset of patients with IC.
Scant data are available from RCTs to confirm the efficacy of current pharmacologic approaches to PBS/IC. What data do exist emerge from inadequately designed trials characterized by high dropout rates, restrictive protocols, variation in outcomes measures, and definitional vagueness. Moreover, PBS/IC is a multifactorial and heterogeneous clinical symptom complex, yet, to our knowledge, RCTs designed to test pharmacologic agents have not taken into consideration the variability of symptoms over time or regression to the mean. Determining the optimal treatment strategy therefore remains elusive. Future treatments for PBS/IC will certainly be better informed by further unraveling the pathophysiologic mechanisms underlying the disease. Meanwhile, the key to developing evidence-based therapies is to establish a consensus on standardized outcome measures and then to design and conduct appropriate RCTs that use those standards.
AUTHOR INFORMATION
Correspondence: Jordan Dimitrakov, MD, PhD; Harvard Urological Diseases Research Center, Children's Hospital Boston, Harvard Medical School, Enders Research Bldg, Room 1061, 300 Longwood Ave, Boston, MA 02115 (Jordan.Dimitrakov{at}childrens.harvard.edu).
Accepted for Publication: May 29, 2007.
Author Contributions: Study concept and design: Dimitrakov and Berde. Acquisition of data: Dimitrakov. Analysis and interpretation of data: Dimitrakov, Kroenke, Steers, Zurakowski, Freeman, and Jackson. Drafting of the manuscript: Dimitrakov, Steers, and Zurakowski. Critical revision of the manuscript for important intellectual content: Dimitrakov, Kroenke, Steers, Berde, Freeman, and Jackson. Statistical analysis: Zurakowski and Jackson. Obtained funding: Dimitrakov. Administrative, technical, and material support: Dimitrakov and Freeman. Study supervision: Kroenke and Steers. Editing and analysis of manuscript: Berde.
Financial Disclosure: None reported.
Funding/Support: This work was supported in part by NIH/NIDDK grant R01 DK 065990 (Dr Dimitrakov).
Additional Contributions: Russell Reich and Michael D. Smith assisted in the preparation of the manuscript.
Author Affiliations: Harvard Urological Diseases Research Center (Drs Dimitrakov and Freeman) and Departments of Anesthesiology, Perioperative and Pain Medicine (Dr Berde) and Orthopaedic Surgery (Dr Zurakowski), Children's Hospital Boston and Harvard Medical School (Drs Dimitrakov, Berde, Zurakowski, and Freeman), Boston, Massachusetts; Department of Medicine, Indiana University School of Medicine, Regenstrief Institute, Indianapolis, Indiana (Dr Kroenke); Department of Urology, University of Virginia, Charlottesville (Dr Steers); and Department of Medicine, Uniformed Services University of the Health Sciences, Bethesda, Maryland (Dr Jackson).
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