Characterization of Whole Body Pain in Urologic Chronic Pelvic Pain Syndrome at Baseline - A MAPP Research Network Study

METHODS

Participants

The MAPP Research Network enrolled 191 men and 233 women with UCPPS at six clinical sites across the United States. The study design, and inclusion and exclusion criteria have been described previously. 18 To meet IC/BPS symptom criteria males and females had to report an unpleasant sensation of pain, pressure or discomfort, perceived to be related to the bladder and/or pelvic region associated with lower urinary tract symptoms, for most of the time during the most recent 3 months. Males who met CP/CPPS criteria had to report pain or discomfort in any of the 8 Male Genitourinary Pain Index (GUPI) domains and these symptoms had to have been present for most of the time during any 3 of the previous 6 months. 19 Participants provided written informed consent following IRB-approved protocols.

Pain Assessment

The body map in Figure 1 was originally described by Margolis et al, 20 and used by two previous IC/BPS studies. 6,9 Participants were asked to check any of 45 body sites on the body map where they experienced pain in the past week. Participants reporting pain in sites 14, 15 or 16 only were considered to have "pelvic pain only". 7 Participants reporting pain in any of the 7 broader body regions (in color) in addition to sites 14, 15, or 16 were considered to have "pelvic pain and beyond". Our pelvic pain only versus pelvic pain and beyond nomenclature was similar to a previous mapping study by Nickel et al. 7 The pelvic pain and beyond group was further divided into two subgroups as shown in Figure 1: an "intermediate" group with 1-2 additional pain regions outside the pelvis, and the "widespread pain" group with 3-7 additional pain regions outside the pelvis. The threshold for "widespread pain" was operationalized to divide participants with pelvic pain and beyond into two subgroups with approximately equal numbers of patients.

Measures

The MAPP Network questionnaires have been described previously. 18 Urologic measures included: Interstitial Cystitis Symptom and Problem Indexes (ICSI, ICPI), Genitourinary Pain Index (GUPI), AUA Symptom Index (AUASI), RAND Interstitial Cystitis Epidemiology (RICE) instrument to assess bladder hypersensitivity, 21 numeric ratings of pelvic pain, frequency or urgency, MAPP Composite Pelvic Pain Score, MAPP Composite Urinary Score, and UCPPS flare assessment. 22 Non-urologic and psychosocial measures included: a numeric rating from 0-10 for non-urologic or -pelvic pain, fulfillment of standardized criteria of irritable bowel syndrome, fibromyalgia, chronic fatigue syndrome, migraine headache, or vulvodynia using the Complex Multiple Symptoms Inventory (CMSI) modules, 23 Brief Pain Inventory (BPI) for overall pain severity and pain interference, Hospital Anxiety and Depression Scale (HADS) for anxiety and depression, Positive and Negative Affect Scale (PNAS), Perceived Stress Scale (PSS) for psychological stress, Coping Strategies Questionnaires (CSQ) for pain catastrophizing, CMSI for somatic symptom burden, and PROMIS scales for fatigue and sleep disturbance. Quality of life measures included the SF-12 and GUPI. We limited our analyses to cross-sectional baseline data in this study.

Statistical Analyses

Few data were missing (<5%) for the reported outcomes. No imputations or adjustments were performed and the missing data were excluded from the analysis. Means and standard deviations were reported for continuous variables and relative frequencies for categorical variables. To test for a linear gradient effect in the 3 groups an ordinal value was assigned to each group, such that widespread pain = 2, intermediate pelvic pain and beyond = 1, and pelvic pain only = 0. The non-parametric Jonckheere-Terpstra trend test was used for the analysis of ordered progression of the measure across the 3 groups. 24 Analyses used SAS software 9.4(SAS Institute, Cary, NC).

RESULTS

Pain Localization Patterns and Duration of UCPPS Symptoms

Only one-quarter (25.5%) of UCPPS patients reported pelvic pain only, while three-quarters (74.5%) reported pelvic pain and beyond. The percentages of men and women in the pelvic pain only, intermediate, and widespread pain groups were shown in Table 1. Relative to men, women were more likely to experience more widespread pain (p-trend=0.039). There were no differences in the duration of UCPPS symptoms among the 3 pain groups (Table 1). Heat maps ( Figure 2) show the proportion of participants who had pain in a specific location in each of the 3 pain groups.

Pelvic Pain and Urinary Symptom Severity

Men and women demonstrated no difference in the severity of pelvic pain, urinary symptom (frequency, urgency), and bladder hypersensitivity features (e.g., painful bladder filling and/or painful urgency) 21 among the 3 pain groups (p>0.05, Table 1). Women with a greater number of pain locations were more likely to report higher GUPI pain scores (p=0.033) and symptom flare at the time of visit (p=0.012).

Non-Pelvic Pain Severity and Chronic Overlapping Pain Conditions (COPC)

Men and women with a greater number of pain locations were more likely to report higher levels of non-pelvic pain severity (0-10 numeric ratings), and symptoms consistent with irritable bowel syndrome, fibromyalgia, and migraine headache (p<0.05, see Table 2). Women with a greater number of pain locations were also more likely to report higher pain interference scores (BPI), and symptoms consistent with chronic fatigue syndrome and multiple (≥2) COPC.

Psychosocial Health and Quality of Life

Men and women with greater number of pain locations had greater sleep disturbance (PROMIS), depression, anxiety (HADS), psychological stress (PSS), somatic symptom burden (CMSI), and negative affect scores (PANAS) (p<0.05, Table 2). Women with a greater number of pain locations were also more likely to report pain catastrophizing (CSQ) and fatigue (PROMIS), and a decrease in positive affect (PANAS). While the more general physical health and mental health domains of the SF-12 deteriorated across the gradient of increasing pain distribution, no trend was noted for urinary specific quality of life on the GUPI in either men or women.

Comparison of the Two Subgroups with Pelvic Pain and Beyond

Individuals commonly report pain in parts of their bodies from time to time (e.g., >40% of participants reported back pain or headache). To determine whether patients in the "intermediate" group with a limited distribution of pain outside the pelvis had a different presentation than those with "widespread pain", we performed additional comparisons of the two subgroups (Table 3). Men and women with widespread pain reported more severe nonpelvic pain, and were more likely to have fibromyalgia, depression, higher psychological stress, higher somatic symptom burden, and worse physical health (SF-12) than men and women in the intermediate group.. Men with widespread pain were additionally more likely to have migraine headache, anxiety, pain catastrophizing, more negative affect and less positive affect; while women with widespread pain were additionally more likely to have irritable bowel syndrome, chronic fatigue syndrome, multiple (≥2) COPC, sleep disturbance, fatigue, and worse mental health (SF-12) than their respective intermediate group. In both sexes, there was no difference in pelvic pain and urinary symptom severity between the two subgroups.

DISCUSSION

Despite being enrolled because of their UCPPS, most patients in this large multi-site study (75%) reported additional pain outside the pelvis/abdomen, and 38% reported a widespread pain distribution. In both men and women, increasing anatomic pain distribution was associated with greater non-pelvic pain severity, a higher prevalence of chronic overlapping pain conditions, poorer psychosocial health, and worse quality of life. In contrast, there was no difference in the severity of pelvic pain and urinary symptoms among the three pain subgroups. UCPPS patients with widespread pain appeared to be distinct from patients with more limited distribution of pain outside the pelvis (the intermediate group) as shown in Table 3.

Our overall findings were consistent with the previous studies: women with IC/BPS and systemic pain were more likely to have more severe overall pain, other pain syndromes, and worse quality of life than women who reported pelvic pain only. 6,9 Previous body pain mapping studies did not include men. 6,9 Here we studied a large cohort of men with IC/BPS or CP/CPPS, and demonstrated many similar findings in both sexes.

Body pain mapping may confer important information suggesting discrete UCPPS patient subgroups. Pain involving several body regions is likely to represent systemic pathophysiology characterized by centralized pain characteristics (e.g., driven by central sensitization and/or neuro-immune processes). Although the operational definitions of widespread pain varied between studies, literature from other chronic pain conditions suggests that the subgroup of patients with widespread pain may have more severe pain, decreased pain thresholds, and a centralized pain phenotype. [10][11][12][13][14][15][16] For instance, patients with temporomandibular disorders and widespread pain had reduced pressure pain thresholds in both cranial and extra-cranial regions compared to similar patients with more localized pain. 10 Patients with epicondylitis and multidisciplinary pain clinic patients with widespread pain also had lower pressure pain thresholds or increased central sensitization than similar patients with localized pain. 11,12 Here we have shown that a substantial proportion of UCPPS patients have widespread pain, and those with widespread pain have more intense whole body pain. Ongoing MAPP neuroimaging studies also suggest that UCPPS patients with widespread pain have altered brain structure and function. 25,26 In future studies we shall examine the pain thresholds and quantitative sensory testing data on these patients.

Assessing the severity of pelvic pain, urinary symptoms (frequency, urgency), or bladder hypersensitivity (e.g., painful bladder filling, painful urgency) 21 alone cannot distinguish between the pelvic pain only group and the widespread pain group. Instead, the body map might identify patients who may have a more centralized pain syndrome possibly related to central sensitization. The body pain map may also be used to screen patients who may benefit from clinical evaluation for other chronic overlapping pain conditions (COPC). For example, among women with UCPPS in the widespread pain subgroup, 48% had irritable bowel syndrome, 26% had fibromyalgia, 31% had chronic fatigue syndrome, and 42% had migraine headaches. Among men with UCPPS in the widespread pain subgroup, these percentages were 34%, 13%, 5% and 24%, respectively. Women with widespread pain were more likely to have multiple (≥2) COPC. Despite widespreadness of pain being a cardinal component of fibromyalgia, it should be noted that relatively few UCPPS patients with widespread pain met the criteria for fibromyalgia (only 13% of men and 26% of women). 27 The difference being that besides widespread pain, fibromyalgia also requires other symptoms (e.g., fatigue, somatic symptoms). The body pain map might also be used to screen for patients with high psychosocial burden (depression, anxiety, psychological stress, negative affect, pain catastrophizing). The body pain map (Figure 1) is simple to use, and can be included in the evaluation of IC/BPS and CP/CPPS. Clinicians should consider the use of clinical phenotyping so they may tailor treatment to patients with UCPPS. It is possible that body pain mapping may be useful for categorization of the heterogeneous UCPPS population, and may inform more rational management strategies. For example, one might hypothesize that patients with bladder hypersensitivity features 21 and localized "pelvic pain only" may be more likely to benefit from bladdercentric treatments (e.g., intravesical instillation, or pentosanpolysulfate). One might also hypothesize that UCPPS patient subpopulations with widespread pain might be less likely to benefit from bladder/pelvic-directed treatments alone and might require systemic therapies for centrally mediated mechanisms (e.g., using tricyclic antidepressants, gabapentinoids, SNRI, or multidisciplinary pain management). Because many patients with widespread pain report increased psychosocial difficulties, they may also benefit from multi-modal and multidisciplinary therapies. Using a "one size fits all" approach to treat IC/BPS or CP/CPPS patients without regards for their discrete clinical characteristics (e.g., localized versus systemic pain) and pathogenesis may lead to treatment failures. In part, these hypotheses may explain why most prior randomized controlled trials failed to demonstrate clinically significant benefits of treating the entire UCPPS population using similar therapies. This is an important area for future translational studies because currently there is no high level evidence (randomized controlled trials) supporting this personalized approach to managing UCPPS. 28,29 There are potential weakness in this study: (1) we did not collect data on tobacco abuse, musculoskeletal trauma, myofascial pain, or medical conditions (e.g. osteoarthritis, rheumatoid arthritis) that may influence the distribution of pain; (2) It has been hypothesized that UCPPS patients might progress over time from localized pain to loco-regional pain to systemic pain (e.g. central sensitization). 1,4,30 Our data as well as those from Nickel et al 9 did not show a correlation between the duration of UCPPS symptoms and increased body pain distribution. However we cannot infer longitudinal trend from these cross-sectional data (e.g., there are risks of recall bias), longitudinal studies are needed to determine if there is temporal progression from one body pain pattern to another over time.

CONCLUSION

Three-quarters of men and women with UCPPS (IC/BPS or CP/CPPS) reported pain outside the pelvis. Widespread pain was associated with greater severity of non-pelvic pain symptoms, poorer psychosocial health and worse quality of life, but not worse pelvic pain or urinary symptoms.

Supplementary Material

Refer to Web version on PubMed Central for supplementary material. The numbers on the heat maps refer to the proportion of participants, within of the 3 defined subgroups, who experienced pain at that site. Table 1 Demographics, comparison of pelvic pain and urinary symptom severity. Comparison of non-pelvic pain severity, psychosocial, and quality of life measures. Table 3 Intermediate versus widespread pain subgroup comparison.

Table 2