Interstitial cystitis/bladder pain syndrome (IC/BPS) and chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) are defined by the hallmark symptom of chronic pain in the pelvis, urogenital floor, or external genitalia, and often accompanied by urinary symptoms such as urinary urgency or frequency.1,2 Historically, the bladder was thought to be the origin of IC/BPS, whereas the prostate was believed to be the source of CP/CPPS. However, this viewpoint has come under recent challenge, in large part from the observation that many IC/BPS and CP/CPPS patients exhibit symptoms, but do not have identifiable pathology in these organs.3 Therefore, the NIDDK funded the Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network to examine urological chronic pelvic pain syndrome (UCPPS) broadly to move beyond traditional bladder-focused and prostate-focused efforts.
Growing research suggests that UCPPS share demographic, clinical, and psychosocial features with other nonurological chronic overlapping pain conditions (COPCs), including fibromyalgia (FM), chronic fatigue syndrome (CFS), and irritable bowel syndrome (IBS) and frequently co-occur with these COPC.4 Many of the COPCs were previously thought to have organ-centric, local, or peripherally based pathology. However, substantial research now supports prominent central nervous system contributions (ie, central sensitization) to the pathophysiology of these conditions, prompting further exploration of common underlying pathophysiology instead of an organ-specific approach.5
Recognizing these emerging insights and the limitations of previous basic and clinical studies, the MAPP Research Network examined urological, nonurological, and psychosocial characteristics in men and women with UCPPS compared with sex-matched and age-matched healthy controls (HC) and positive control individuals with COPCs including FM, CFS, and IBS.6 One overarching goal of the MAPP Research Network was to use these comprehensive data to investigate the potential relationship between UCPPS and nonurological COPCs.
Despite longstanding clinical observation of the similarities between UCPPS and nonurological COPCs and the growing literature on the co-occurrence of these conditions, no studies to date have comprehensively examined the symptom-based and psychosocial similarities and differences between UCPPS and common COPCs. Better understanding these similarities and differences and the potential effects of co-occurrence on outcomes can help to illuminate shared pathophysiology, especially in the psychosocial domain, and have implications for testing interventions that can address potential underlying mechanisms. We used MAPP Research Network data to examine the similarities and differences in urological, nonurological, and psychosocial characteristics across individuals with UCPPS (with and without nonurological COPCs), individuals with nonurological COPCs (ie, FM, CFS, and IBS), and HC in a case-control study. The HC group was included to contextualize the findings in relation to a nonpain sample. We hypothesized that (1) participants with UCPPS would have the most urological symptoms and the HCs the least; (2) COPC participants would have more nonurological pain symptoms than the UCPPS and HC groups; and (3) across psychosocial characteristics, UCPPS participants would be more similar to COPC participants than HC participants. Given the limited literature on the potential symptom and psychosocial burden of UCPPS with co-occurring COPCs, we also conducted exploratory analyses to compare the UCPPS subgroups with and without COPCs and the COPC group on urological, nonurological, and psychosocial characteristics.
ROLE OF THE FUNDING SOURCE
The MAPP Research Network was funded by NIDDK through a series of research project cooperative agreements (U01) to conduct a multicenter epidemiology/phenotyping study. The study was designed with input from all centers and NIDDK program officers and was approved by an external advisory board of experts in UCPPS and COPCs.
MATERIALS AND METHODS
Participants and Procedures
UCPPS, nonurological COPCs, and HC participants were recruited by advertisement and from clinic attendees at 7 MAPP sites (Los Angeles, CA; Chicago, IL; St. Louis, MO; Iowa City, IA, Seattle, WA, Ann Arbor, MI, and Stanford) and 2 additional sites (Miami, FL; Birmingham, AL) provided support. Recruitment took place from February 14, 2009 to December 14, 2012 and required sample sizes for each group were established a priori based on power analyses. Participants were 18 years of age or older and could provide self-report data in English. All UCPPS participants met criteria for IC/BPS or CP/CPPS, with urological symptoms present a majority of the time during any 3 of the past 6 months (CP/CPPS) or the most recent 3 months (IC/BPS), and a response of at least 1 on a pain, pressure or discomfort scale (0 to 10 scale). Participants who met the established diagnostic criteria for FM, CFS, or IBS were recruited as positive controls.7–9 Potential UCPPS participants were referred to the study on the basis of bladder/urinary symptoms and/or chronic pelvic pain, but were assessed for COPCs during screening, whereas potential nonurological COPC potential participants were referred on the basis of a COPC diagnosis, but were also assessed for pelvic pain and urinary symptoms. Potential participants were evaluated according to the criteria for the group for which they were referred to the study and were enrolled into that group irrespective of criteria for the other study groups.
Exclusion criteria for all participants included: symptomatic urethral stricture, neurological disease affecting bladder function, fistula, cystitis caused by tuberculosis, radiation therapy, or cytoxan/cyclophosphamide therapy, augmentation cystoplasty, cystectomy, Crohn disease, ulcerative colitis, systemic lupus erythematosis, rheumatoid arthritis, multiple sclerosis, human immunodeficiency virus infection, major psychiatric disorder (eg, bipolar disorder or schizophrenia), or severe cardiac, pulmonary, renal, or hepatic disease that in the study physician’s judgment would preclude participation. Males only were excluded for a history of isolated, unilateral orchalgia, transurethral microwave thermotherapy, transurethral needle ablation or balloon dilation of the prostate, prostate cryosurgery, or laser prostate procedure. HC participants were subject to the same exclusion criteria as UCPPS and nonurological COPCs and were additionally excluded if they reported any pain in the pelvic or bladder region or if they reported chronic pain in >1 nonurological body region.
Potential participants were initially screened by phone or in person for general interest and eligibility. If eligible, participants then completed the baseline questionnaire battery during an in-person visit, using a computerized testing procedure where responses were collected by the central MAPP Network Data Coordinating Core at University of Pennsylvania. Recruitment was monitored centrally by the Data Coordinating Core where the sex and age balance of the UCPPS and HC groups were monitored at the site level in a 2×3 cross classified table; sites were encouraged to recruit into a particular cell if it was lacking. Study procedures were approved by each site’s Institutional Review Board and participants provided written informed consent at their respective study sites.
Sociodemographic characteristics included age, sex, race/ethnicity, employment, and education collected by self-report. The extensive self-report assessment battery focused on the 3 domains of urological symptoms, nonurological pain symptoms, and psychosocial symptoms and traits as described in detail elsewhere.6 Measures are briefly described below. These baseline data were collected in office.
Urological measures were selected purposefully to assess symptoms historically related to CP/CPPS and IC/PBS, including: (1) Symptom and Health Care Utilization Questionnaire, a 12-item measure developed for this study to ask about pain, urgency, and frequency among other symptoms; (2) Genitourinary Pain Index, a 9-item instrument applicable to men and women to assess pain symptoms, urinary symptoms, and quality of life as separate subscales, and overall as a total score;10 (3) Interstitial Cystitis Symptom Index and Problem Index, 2 4-item questionnaires on urinary and pain symptoms and degree of bother associated with these symptoms in patients with IC/BPS;11 and (4) American Urological Association Symptom Index, a 7-item questionnaire that assesses voiding symptoms in both men and women.12 Across all participants, the correlation coefficients within this domain ranged from 0.72 to 0.90 (all Ps <0.0001).
Nonurological pain measures included established and standardized instruments used commonly in COPC and chronic pain research: (1) Brief Pain Inventory (BPI), a 15-item measure that results in scores for pain severity and pain interference;13 (2) A detailed body map used in epidemiological studies to better identify widespread pain by body regions;14 and (3) Complex Multi-Symptom Inventory (CMSI) containing a 41-item symptom checklist of past year illnesses specific to COPCs such as FM, CFS, and IBS. The CMSI was the tool used to determine presence of COPCs in study participants.15 Across all participants, the correlation coefficients within this domain ranged from 0.52 (no. of body map sites and BPI pain severity) to 0.81 (BPI pain severity and pain interference; all Ps<0.0001).
Psychosocial measures included a comprehensive battery of validated measures of state and trait indicators of mood, perceived stress, catastrophizing, and personality: (1) Hospital Anxiety and Depression Scale, a 14-item instrument assessing depressive and anxiety symptoms in nonpsychiatric settings;16 (2) Positive and Negative Affect Schedule, a 20-item measure of both positive and negative affect states;17 (3) Perceived Stress Scale, a 10-item measure of the degree to which situations are perceived as being unpredictable, uncontrollable, and overwhelming;18 (4) Catastrophizing subscale from the Coping Strategies Questionnaire, a 6-item measure of the perception that pain is overwhelmingly awful and the worst imaginable burden that one can endure;19 and (5) International Personality Item Pool short form, a public-domain, 120-item instrument developed to reflect the 5 personality domains of extraversion, neuroticism, agreeableness, conscientiousness, and openness to experience.20 Across all participants, the correlation coefficients within this domain ranged from −0.37 (extraversion and catastrophizing) to 0.81 (negative affect and anxiety symptoms; all Ps<0.0001).
Age was summarized by means and SD and binary comparisons between groups were evaluated by Student t test. Categorical demographic variables were summarized by frequencies and percentages and compared among groups by χ2 tests. Groups were compared by multivariable linear regression models, adjusted for those demographic factors (age, sex, race, and employment status) that differed significantly for any 2 groups at the 0.05 level. An overall test was conducted using a 3-level dummy variable for group, and subsequent pairwise tests were conducted for variables that differed significantly across all the 3 groups. To reduce the likelihood of false positives, overall group differences were declared significant at the 0.01 level and pairwise tests among groups were conducted at the 0.003 level of significance. Further, Cohen effect sizes (d) for adjusted group differences were calculated as an indicator of practical or clinical difference between groups. To explore the role of comorbidity on urological symptoms, nonurological pain, and psychosocial symptoms and traits, post hoc analyses explored differences between the UCPPS subgroups with and without COPCs and the COPC group.
Demographics and Prevalence of COPCs
The final comparison groups included 424 UCPPS (233 females and 191 males) 200 nonurological COPC control (156 females and 44 males) and 415 HC (233 females and 182 males) participants. Demographic characteristics of the 3 participant groups are described in Table 1. Participants had a mean age in the 40s and were predominantly females, white, of non-Hispanic ethnicity, employed, and with college or graduate education. The UCPPS participants were, on average, older than HCs and were more likely to be white than the other 2 groups. The percentage of women in the COPC group was higher than in the other 2 groups. Participants in both UCPPS and COPC groups were less likely to be employed than HC participants. There were no other group differences among demographic characteristics.
Based on the CMSI follow-up assessment modules, 162 (38.2%) of 424 UCPPS participants met criteria for at least 1 additional COPC, including 15 (4%) with FM; 13 (3%) with CFS; 93 (22%) with IBS; and 41(10%) with multiple COPCs. Of the 200 participants in the COPC group, 13 (6.5%) had FM alone, 12 (6.0%) had CFS alone, 95 (47.5%) had IBS alone, and 80 (40.0%) met criteria for multiple conditions.
The 3-level overall tests of group differences were significant for each of the examined variables; Table 2 provides information on the pair-wise comparison of the 3 groups for urological, nonurological pain, and psychosocial symptoms and traits. Individuals with UCPPS and those with nonurological COPCs had more urinary symptoms across all measures (P<0.001) than HCs, yielding large Cohen effect size values (UCPPS vs. HC, d=1.92 to 3.85; COPC vs. HC, d=0.67 to 1.19), indicating both statistical and clinical differences. Individuals with UCPPS also had more urinary symptoms across all measures (P<0.001) than those with COPCs, with large effect sizes (d=1.07 to 2.22).
Across nonurological pain symptoms, UCPPS and COPC groups reported more nonurological pain symptoms than the HC group (all Ps<0.001) with large Cohen effect sizes (UCPPS vs. HC, d=0.87 to 2.28; COPC vs. HC, d=1.42 to 1.74). Differences between the UCPPS and COPC groups were significant, but smaller in magnitude, with the UCPPS group showing slightly higher ratings across pain severity (P<0.001; d=0.52) and interference (P=0.004; d=0.36), and the COPC group reporting more widespread pain on the body map with a large Cohen effect size (P<0.001; d=0.63). The UCPPS and COPC groups reported greater levels of multiple symptoms on the CMSI than the HC group, but did not differ from each other (P=0.225; d=0.11).
On psychosocial symptoms and traits, UCPPS and COPC participants reported higher levels of anxiety, depression, negative affect, perceived stress, and catastrophizing symptoms, and lower levels of positive affect compared with the HC group (all Ps<0.001; UCPPS vs. HC, d=0.85 to 1.46; COPC vs. HC, d=0.81 to 1.07). UCPPS and COPC participants also reported higher neuroticism and lower extraversion than HC individuals, with medium effects sizes (all Ps <0.001; d=0.41 to 0.71). With the exception of pain catastrophizing symptoms, where the UCPPS group had higher scores than the COPC group (P<0.001; d=0.51), both groups had similarly worse scores on all other measures than HC that were not significantly different from each other.
To assess the potential effects of comorbidity on outcomes, exploratory analyses compared UCPPS individuals with and without COPCs to the COPC control group (Table 3). As expected, the UCPPS with COPCs subgroup reported worse urological, nonurological pain, and psychosocial symptoms and traits than the UCPPS without COPCs subgroup across measures. More importantly, individuals with UCPPS and COPCs also reported worse nonurological pain severity and interference, greater level of multiple symptoms, more negative affect, and increased catastrophizing compared with those with nonurological COPCs (all Ps <0.001; d=0.45 to 0.68). UCPPS participants without COPCs also had a higher catastrophizing score than the nonurological COPC group (P<0.001; d=0.43).
To better understand the pathophysiology of UCPPS, we evaluated similarities and differences between UCPPS individuals and controls across the urological, pain, and psychological domains. Three participant groups (UCPPS, nonurological COPCs, and HC) were compared across comprehensive measures targeting urological symptoms, nonurological pain, and psychological characteristics and symptoms. Our data support the hypothesis that UCPPS participants had the most urological symptoms and the HC group the least, but also found that those with nonurological COPCs also had significantly elevated urological symptoms compared with HC. Our data also provide partial support for the hypothesis that both the UCPPS and COPC groups showed higher levels of nonurological pain symptoms compared with HC. However, differences between the UCPPS and nonurological COPC groups were less pronounced for pain severity and interference. Results across psychological symptoms and characteristics also supported the hypothesis that UCPPS and nonurological COPC participants had similarly elevated psychosocial symptoms than HC. Exploratory subgroup analyses found a higher burden of nonurological pain and negative affect in UCPPS plus COPCs, but both UCPPS with and without COPC participants had higher catastrophizing compared with COPCs alone.
To our knowledge this is the first large-scale study to examine the similarities and differences between UCPPS and nonurological COPCs (FM, CFS, and IBS). Regardless of their clinical diagnosis or the anatomical site of primary symptoms, individuals with UCPPS and those with COPCs reported elevated levels of urological, nonurological, and psychosocial symptoms and traits; although as expected those with UCPPS had more urological symptoms than those with nonurological COPCs. Thus, our results suggest that these conditions share many characteristics across multiple physical and psychosocial domains. In addition, we found substantial co-occurrence of these conditions (ie, UCPPS, FM, CFS, or IBS) even though participants were recruited based on meeting criteria for a primary set of symptoms. The next step in this line of research is to conduct latent class or other cluster analyses to empirically establish groups with similar characteristics and to examine those groups in relation to clinical and other outcomes.
The link between UCPPS and COPCs may be complex and multifactorial. Although this study did not examine mechanisms underlying the shared characteristics, the findings are supportive of the hypothesis that UCPPS and COPCs may be linked through partially shared mechanisms or pathophysiology. For example, recent studies suggest that genetic factors may underlie the relationship between urological and somatic syndromes and within chronic pain conditions.21,22 Central nervous system-mediated hypersensitivity or central sensitization might partially account for the similarities between UCPPS and COPCs. Central sensitization has been implicated in FM, CFS, IBS, and a number of other COPCs.5,23,24 There is also growing evidence that central sensitization plays a role in chronic pelvic pain and urological conditions.25,26 Alternately, a recent study from the MAPP Research Network found brain white matter abnormalities unique to UCPPS in comparison with IBS,27 suggesting that other mechanisms may also be important in the pathophysiology of UCPPS. In addition, the similar presentations in UCPPS and COPCs could be a consequence of experiencing any sort of chronic pain condition. Future studies should examine these and other shared and unique mechanisms and pathophysiology to guide treatments that may more comprehensively address these conditions.
Individuals with COPCs reported significantly greater urological symptoms than HC participants across multiple measures. These findings are striking in that the mean American Urological Association Symptom Index score in this group, as an indicator of lower urinary tract symptoms, was higher than what has been reported in the general population, and even higher than groups in which urological disorders are common (eg, men and women in their 70s).28 Our findings are consistent with a small, but growing literature suggesting comorbidity between UCPPS and various COPCs,4 and extends those findings by suggesting that the overlap is not limited to pain, but may include urinary symptoms as well.29 We also found that individuals with UCPPS reported similar, if not higher, levels of nonurological pain than those with COPCs, suggesting that the experience of UCPPS may also extend beyond pain associated with urinary symptoms. Individuals with UCPPS and nonurological COPCs typically present to different clinics and specialists. Our findings indicate that patients with any of these conditions may benefit from a comprehensive and multidimensional assessment regardless of treating clinic and specialist. These findings also support previous recommendations to evaluate pain and urinary symptoms separately in UCPPS.30
The subgroup analyses validate previous findings from the same sample that individuals with UCPPS and COPCs have more symptoms and morbidity than those with UCPPS alone.31 Here, we extend those findings by comparing UCPPS with and without COPCs with the nonurological COPC group. Individuals with UCPPS with and without COPCs reported similarly elevated distress and other psychological symptoms and characteristics compared with individuals with nonurological COPCs on nearly all measures. Catastrophizing (ie, negative cognitive-affective perceptions or appraisal of the pain experience) was a notable exception suggesting that UCPPS regardless of comorbid COPCs appears to lead to significantly worse catastrophizing than COPCs. Several previous studies have shown that individuals with UCPPS exhibit more catastrophizing than HCs,32–34 but ours is the first to document that catastrophizing in UCPPS is even worse than in others with chronic pain conditions. One potential reason for increased catastrophizing in UCPPS is the greater burden of urological and nonurological pain in those with UCPPS. Future studies can examine the interaction of pain and pain catastrophizing to better understand the experience of pain in UCPPS and inform treatments.
Longitudinal studies also can help shed light on the potential role of catastrophizing as a dispositional or outcome factor in relation to urological and other symptoms in UCPPS. Increased catastrophizing has been associated with poorer quality of life and appears to mediate the relationship between pain and quality of life in at least some UCPPS conditions.35,36 Findings from the MAPP Research Network also indicate that greater pain catastrophizing is associated with poorer pain outcomes over a 1-year period.37 As with COPCs and chronic pain in general, pharmacotherapy with noradrenergic antidepressants and behavioral treatments such as cognitive- behavioral therapy, acceptance and commitment therapy, or mindfulness-based interventions might improve functioning and quality of life in UCPPS.24,38–40 There is some evidence that high levels of catastrophizing may limit the benefits of antidepressants in pain.41 Psychosocial interventions, on the other hand, are well suited for addressing cognitive distortions such as catastrophizing. Intervention research should focus on large-scale clinical trials that specifically focus on reducing catastrophizing in UCPPS.
This is the largest and most comprehensive comparison of UCPPS with COPCs. We used a cross-sectional case-control design to examine urological, nonurological, and psychosocial characteristics across individuals with UCPPS, nonurological COPCs, and HCs. Nonetheless, this study has limitations. The predominantly white sample was recruited from clinics and community advertising, not from a representative population sample. Enrollment did not target specific COPC such that separate COPC comparisons are limited by sparsity. The composition of the nonurological COPC group did not allow us to examine comparisons across sex. The sex and age matching was specific to the UCPPS and HC groups and did not include COPCs. We chose to include a nonpain HC groups so it is possible that differences with the HC group are larger than would be expected in the general population. However, one would argue that as pain is part of the definition for UCPPS and COPCs, this difference is not a bias and rather a manifestation of the conditions being compared with HC. Further, we did not evaluate the COPC group for UCPPS diagnoses and relied on symptom-based urinary measures and did not evaluate the UCPPS group for COPC diagnoses and relied on the CMSI. Despite these limitations, our findings make an important contribution to understanding the similarities and differences between UCPPS and nonurological COPCs.
In conclusion, this study provides evidence that UCPPS and nonurological COPCs are similar across multiple measures of nonurinary pain symptoms and psychological symptoms and characteristics, supporting the potential for common underlying biopsychosocial mechanisms. Regardless of primary diagnosis, individuals with UCPPS and COPCs exhibit a variety of urological, nonurological, and psychosocial symptoms. Thus, the clinical assessment of these conditions should be comprehensive and multidimensional. Finally, individuals with UCPPS appear to have worse catastrophizing than those with nonurological COPCs. The heightened role of catastrophizing in UCPPS should be examined further to inform future psychosocial clinical trials and improve patient care.
The authors are grateful for the collaboration within the MAPP Research Network. The attached Appendix (Supplemental Digital Content 1, http://links.lww.com/CJP/A599) provides a list of all MAPP Network investigators.
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