Chronic Pelvic Pain Research Network Research Articles

Mediators of the association between childhood trauma and pain sensitivity in adulthood: a Multidisciplinary Approach to the Study of Chronic Pelvic Pain Research Network analysis.

Urologic chronic pelvic pain syndrome (UCPPS) is a complex, debilitating condition in which patients often report nonpelvic pain in addition to localized pelvic pain. Understanding differential predictors of pelvic pain only vs widespread pain may provide novel pathways for intervention. This study leveraged baseline data from the Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network's Symptom Pattern Study to investigate the impact of childhood sexual and nonsexual violent trauma on pelvic and nonpelvic pain sensitivity among adult patients with UCPPS, as well as potential mediators of this association. Study participants who met inclusion criteria for UCPPS completed questionnaires assessing childhood and recent trauma, affective distress, cognitive dysfunction, and generalized sensory sensitivity. Experimental pain sensitivity was also evaluated using standardized pressure pain applied to the pubic region and the arm. Bivariate analyses showed that childhood violent trauma was associated with more nonviolent childhood trauma, more recent trauma, poorer adult functioning, and greater pain sensitivity at the pubic region, but not pain sensitivity at the arm. Path analysis suggested that childhood violent trauma was indirectly associated with pain sensitivity at both sites and that this indirect association was primarily mediated by generalized sensory sensitivity. More experiences of recent trauma also contributed to these indirect effects. The findings suggest that, among participants with UCPPS, childhood violent trauma may be associated with heightened pain sensitivity to the extent that trauma history is associated with a subsequent increase in generalized sensory sensitivity.

PD05-01 DISTINCT PHENOTYPES OF BLADDER PAIN IDENTIFIED IN THE MULTIDISCIPLINARY APPROACH TO THE STUDY OF CHRONIC PELVIC PAIN RESEARCH NETWORK DATASET

You have accessJournal of UrologyCME1 Apr 2023PD05-01 DISTINCT PHENOTYPES OF BLADDER PAIN IDENTIFIED IN THE MULTIDISCIPLINARY APPROACH TO THE STUDY OF CHRONIC PELVIC PAIN RESEARCH NETWORK DATASET Oluwarotimi Nettey, Nicholas Jackson, and A. Lenore Ackerman Oluwarotimi NetteyOluwarotimi Nettey More articles by this author , Nicholas JacksonNicholas Jackson More articles by this author , and A. Lenore AckermanA. Lenore Ackerman More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003229.01AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Patients with chronic urologic pelvic pain present a unique challenge as their underlying condition is largely a diagnosis of exclusion. In the present analysis, we extend symptom cluster definitions from a pilot study evaluating bladder pain among ambulatory females to a multicenter prospectively recruited dataset using unsupervised machine learning techniques to assess the stability and reproducibility of these bladder pain phenotypes. METHODS: Unsupervised machine learning techniques were applied to patient reported symptoms extracted from the female Genitourinary Pain Index and Interstitial Cystitis Symptom and Problems Indices. Responses from 130 premenopausal female subjects without current opioid use enrolled in the Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) research network were analyzed. Symptom clusters generated from the MAPP multisite cohort (MC) were compared to previously published pilot data results to assess for alignment and concordance. RESULTS: Symptom clusters included a nonurological pelvic pain group with localized pain unrelated to the micturition cycle (NUPP-MC), a myofascial pelvic pain group (MFP-MC) with stranguria, sensation of incomplete bladder emptying, urinary urgency and high symptom bother/severity, and a bladder specific-pain group (BPS-MC) with pain worsened by bladder filling and relieved by bladder emptying.Cluster comparisons demonstrated concordance by subtype between local and multisite cohorts on various domains of bladder pain (Figure 1). MFP–MC patients had more pain severity (p<0.001), diffuse body pain involvement (p=0.02), pelvic floor tenderness (p=0.01), and increased number of flares (p=0.009). MFP-MC cluster assignation was associated with severe sexual dysfunction, impaired relationship scores as well as sleep and anxiety disturbances. CONCLUSIONS: Patient reported symptoms can be utilized to perform deep phenotyping and identify distinct subgroups of perceived bladder pain. Phenotypic clusters appear stable both in a single institutional pilot cohort and a larger multi-site study. Further validation of these phenotypes and their associations with response to therapy will clarify how to target treatment of bladder pain. Source of Funding: None © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e148 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Oluwarotimi Nettey More articles by this author Nicholas Jackson More articles by this author A. Lenore Ackerman More articles by this author Expand All Advertisement PDF downloadLoading ...

Stimulated whole-blood cytokine/chemokine responses are associated with interstitial cystitis/bladder pain syndrome phenotypes and features of nociplastic pain: a multidisciplinary approach to the study of chronic pelvic pain research network study.

Interstitial cystitis/bladder pain syndrome (IC/BPS) is a common and debilitating disease with poor treatment outcomes. Studies from the multidisciplinary approach to the study of chronic pelvic pain research network established that IC/BPS patients with chronic overlapping pain conditions (COPCs) experience poorer quality of life and more severe symptoms, yet the neurobiological correlates of this subtype are largely unknown. We previously showed that ex vivo toll-like receptor 4 (TLR4) cytokine/chemokine release is associated with the presence of COPCs, as well as widespread pain and experimental pain sensitivity women with IC/BPS. Here, we attempt to confirm these findings in the multisite multidisciplinary approach to the study of chronic pelvic pain Symptom Patterns Study using TLR4-stimulated whole blood (female IC/BPS patients with COPC n = 99; without n = 36). Samples were collected in tubes preloaded with TLR4 agonist, incubated for 24 hours, and resulting supernatant assayed for 7 cytokines/chemokines. These were subject to a principal components analysis and the resulting components used as dependent variables in general linear models. Controlling for patient age, body mass index, and site of collection, we found that greater ex vivo TLR4-stimulated cytokine/chemokine release was associated with the presence of COPCs ( P < 0.01), extent of widespread pain ( P < 0.05), but not experimental pain sensitivity ( P > 0.05). However, a second component of anti-inflammatory, regulatory, and chemotactic activity was associated with reduced pain sensitivity ( P < 0.01). These results confirm that the IC/BPS + COPCs subtype show higher levels of ex vivo TLR4 cytokine/chemokine release and support a link between immune priming and nociplastic pain in IC/BPS.

Clinical Phenotyping for Pain Mechanisms in Urologic Chronic Pelvic Pain Syndromes: A MAPP Research Network Study

Three categories of pain mechanisms are recognized as contributing to pain perception: nociceptive, neuropathic, and nociplastic (ie, central nervous system augmented pain processing). We use validated questionnaires to identify pain mechanisms in Urologic Chronic Pelvic Pain Syndrome (UCCPS) patients (n = 568, female = 378, male = 190) taking part in the Symptom Patterns Study of the Multidisciplinary Approach to the study of chronic Pelvic Pain Research Network. A cutoff score of 12 on the painDETECT questionnaire (-1 to 38) was used to classify patients into the neuropathic category while the median score of 7 on the fibromyalgia survey criteria (0–31) was used to classify patients into the nociplastic category. Categories were compared on demographic, clinical, psychosocial, psychophysical and medication variables. At baseline, 43% of UCPPS patients were classified as nociceptive-only, 8% as neuropathic only, 27% as nociceptive+nociplastic, and 22% as neuropathic+nociplastic. Across outcomes nociceptive-only patients had the least severe symptoms and neuropathic+nociplastic patients the most severe. Neuropathic pain was associated with genital pain and/or sensitivity on pelvic exam, while nociplastic pain was associated with comorbid pain conditions, psychosocial difficulties, and increased pressure pain sensitivity outside the pelvis. A self-report method classifying individuals on pain mechanisms reveals clinical differences that could inform clinical trials and novel targets for treatment. PerspectiveThis article presents differences in clinical characteristics based on a simple self-report method of classifying pain mechanisms for Urologic Chronic Pelvic Pain Syndrome patients. This method can be easily applied to other chronic pain conditions and may be useful for exploring pathophysiology in pain subtypes.

Is Pelvic Floor Muscle Tenderness a Distinct Urologic Chronic Pelvic Pain Syndrome Phenotype? Findings from the Multidisciplinary Approach to the Study of Chronic Pelvic Pain Research Network Symptom Pattern Study.

Of women with interstitial cystitis/bladder pain syndrome and men with chronic prostatitis/chronic pelvic pain syndrome 85% have concomitant pelvic floor muscle tenderness (PFT). The significance of this finding is incompletely understood. This study examines PFT among participants in the MAPP (Multidisciplinary Approach to the Study of Chronic Pelvic Pain) Research Network and its relationship with urologic chronic pelvic pain syndrome (UCPPS) symptom severity in order to determine whether this is a phenotypic predictor in UCPPS. Participants in the MAPP Network Symptom Patterns Study underwent a standardized pelvic examination (PEX). Trained examiners palpated 6 locations evaluating the pelvic musculature for PFT. Participants were assigned a 0 to 6 PEX score based on the number of areas with tenderness on PEX. Using regression tree models, PEX scores were divided into low (0, 1), mid (2, 3, 4, 5) and high (6). The relationship between PFT and UCPPS symptoms was examined using several validated questionnaires. The study cohort consisted of 562 UCCPS participants (375 females and 187 males) and 69 controls. Diagnoses included interstitial cystitis/bladder pain syndrome (397), chronic prostatitis/chronic pelvic pain syndrome (122), both (34) or no diagnosis (9). Of UCPPS participants 81% had PFT on PEX compared to 9% of controls: 107 (19%) low, 312 (56%) mid and 143 (25%) high. Participants with higher PFT scores had more severe disease burden (worse pelvic pain and urinary symptoms), worse quality of life and more widespread distribution of nonpelvic pain. UCPPS patients with more widespread PFT have severe pain and urinary symptoms, worse quality of life and a more centralized pain phenotype.

MP08-07 THE IMPORTANCE OF WIDESPREAD PAIN IN TREATMENT RESPONSE FOR PAIN AND URINARY SYMPTOMS IN INTERSTITIAL CYSTITIS/BLADDER PAIN SYNDROME (IC/BPS)

MP08-07 THE IMPORTANCE OF WIDESPREAD PAIN IN TREATMENT RESPONSE FOR PAIN AND URINARY SYMPTOMS IN INTERSTITIAL CYSTITIS/BLADDER PAIN SYNDROME (IC/BPS)

Does weather trigger urologic chronic pelvic pain syndrome flares? A case-crossover analysis in the multidisciplinary approach to the study of the chronic pelvic pain research network.

To investigate whether meteorological factors (temperature, barometric pressure, relative humidity, ultraviolet index [UVI], and seasons) trigger flares in male and female urologic chronic pelvic pain patients. We assessed flare status every 2 weeks in our case-crossover study of flare triggers in the Multidisciplinary Approach to the Study of Chronic Pelvic Pain 1-year longitudinal study. Flare symptoms, flare start date, and exposures in the 3 days preceding a flare or the date of questionnaire completion were assessed for the first three flares and at three randomly selected nonflare times. We linked these data to daily temperature, barometric pressure, relative humidity, and UVI values by participants' first 3 zip code digits. Values in the 3 days before and the day of a flare, as well as changes in these values, were compared to nonflare values by conditional logistic regression. Differences in flare rates by astronomical and growing seasons were investigated by Poisson regression in the full study population. A total of 574 flare and 792 nonflare assessments (290 participants) were included in the case-crossover analysis, and 966 flare and 5389 nonflare (409 participants) were included in the full study analysis. Overall, no statistically significant associations were observed for daily weather, no patterns of associations were observed for weather changes, and no differences in flare rates were observed by season. We found minimal evidence to suggest that weather triggers flares, although we cannot rule out the possibility that a small subset of patients is susceptible.

Changes in whole body pain intensity and widespreadness during urologic chronic pelvic pain syndrome flares-Findings from one site of the MAPP study.

To investigate changes in whole body pain during urologic chronic pelvic pain syndrome (UCPPS) flares. UCPPS participants at one site of the multidisciplinary approach to the study of chronic pelvic pain research network reported their daily flare status and pain levels in 7 pelvic/genital and 42 extrapelvic body areas (scale = 0-10) for 10 days at baseline and during their first flare. Linear mixed models and conditional logistic regression were used to investigate symptom changes during flares. Analyses were stratified by chronic overlapping pain condition (COPC) status. Fifty-five out of 60 participants completed the study, 27 of whom provided information on both nonflare (n = 281) and flare (n = 208) days. Pelvic/genital pain intensity (mean change = 3.20 of 10) and widespreadness (mean = 1.48) increased significantly during flares for all participants (all P interaction > .1), whereas extrapelvic pain intensity increased significantly only among participants with COPCs (mean = 2.09; P interaction < .0001). Pelvic/genital and extrapelvic pain also varied on nonflare days but symptom fluctuations were generally ≤1 point (80.0%-100% of participants). Increases of ≥2 points in pelvic/genital pain intensity (odds ratio (OR) = 22.0, 95% confidence interval (CI) = 4.0-118.6) and ≥1 point in urination-related pain (OR = 9.10, 95% CI = 1.74-47.7) were independently associated with flare onset for all participants. Our observations of extrapelvic pain increases during flares for patients with COPCs and our independent associations between pelvic/genital/urination-related pain intensity and flare onset may provide insight into mechanisms underlying flare development (eg, common biologic pathways between UCPPS phenotypes and flares), flare management (eg, local vs systemic therapies by COPC status), and patient flare definitions.

Adverse Childhood Experiences and Symptoms of Urologic Chronic Pelvic Pain Syndrome: A Multidisciplinary Approach to the Study of Chronic Pelvic Pain Research Network Study

Adverse Childhood Experiences (ACEs) such as sexual and physical violence, serious illness, and bereavement have been linked to number of chronic pain conditions in adulthood, and specifically to urologic chronic pelvic pain syndrome (UCPPS). We sought to characterize the prevalence of ACEs in UCPPS using a large well-characterized cohort in comparison with a group of healthy controls. We also sought to determine the association of ACE severity with psychological factors known to impact pain and to determine whether ACEs are associated with patterns of improvement or worsening of symptom over a year of naturalistic observation. For longitudinal analyses we used functional clusters identifying broad classes of (a) improved, (b) worsened, and (c) stable groups for genitourinary pain and urinary symptoms. We employed a mediation/path analysis framework to determine whether ACEs influenced 1 year outcomes directly, or indirectly through worse perceptions of physical well-being. ACE severity was elevated in UCPPS (n = 421) participants compared with healthy controls (n = 414; p < .001), and was most strongly associated with factors associated with complex chronic pain, including more diffuse pain, comorbid functional symptoms/syndromes, and worse perceived physical well-being (all p < .001). Finally, worse physical well-being mediated the relationship between ACE severity and less likelihood of painful symptom improvement (OR = .871, p = .007)) and a greater likelihood of painful symptom worsening (OR = 1.249, p = .003) at 1 year. These results confirm the association between ACEs and UCPPS symptoms, and suggest potential targets for therapeutic interventions in UCPPS. NCT01098279.

Brain signature and functional impact of centralized pain: a multidisciplinary approach to the study of chronic pelvic pain (MAPP) network study.

Chronic pain is often measured with a severity score that overlooks its spatial distribution across the body. This widespread pain is believed to be a marker of centralization, a central nervous system process that decouples pain perception from nociceptive input. Here, we investigated whether centralization is manifested at the level of the brain using data from 1079 participants in the Multidisciplinary Approach to the Study of Chronic Pelvic Pain Research Network (MAPP) study. Participants with a clinical diagnosis of urological chronic pelvic pain syndrome (UCPPS) were compared to pain-free controls and patients with fibromyalgia, the prototypical centralized pain disorder. Participants completed questionnaires capturing pain severity, function, and a body map of pain. A subset (UCPPS N = 110; fibromyalgia N = 23; healthy control N = 49) underwent functional and structural magnetic resonance imaging. Patients with UCPPS reported pain ranging from localized (pelvic) to widespread (throughout the body). Patients with widespread UCPPS displayed increased brain gray matter volume and functional connectivity involving sensorimotor and insular cortices (P < 0.05 corrected). These changes translated across disease diagnoses as identical outcomes were present in patients with fibromyalgia but not pain-free controls. Widespread pain was also associated with reduced physical and mental function independent of pain severity. Brain pathology in patients with centralized pain is related to pain distribution throughout the body. These patients may benefit from interventions targeting the central nervous system.

Evidence for the Role of Mast Cells in Cystitis-Associated Lower Urinary Tract Dysfunction: A Multidisciplinary Approach to the Study of Chronic Pelvic Pain Research Network Animal Model Study.

Bladder inflammation frequently causes cystitis pain and lower urinary tract dysfunction (LUTD) such as urinary frequency and urgency. Although mast cells have been identified to play a critical role in bladder inflammation and pain, the role of mast cells in cystitis-associated LUTD has not been demonstrated. Interstitial cystitis/bladder pain syndrome (IC/BPS) is a chronic and debilitating inflammatory condition of the urinary bladder characterized by the hallmark symptoms of pelvic pain and LUTD. In this study we investigated the role of mast cells in LUTD using a transgenic autoimmune cystitis model (URO-OVA) that reproduces many clinical correlates of IC/BPS. URO-OVA mice express the membrane form of the model antigen ovalbumin (OVA) as a self-antigen on the urothelium and develop bladder inflammation upon introduction of OVA-specific T cells. To investigate the role of mast cells, we crossed URO-OVA mice with mast cell-deficient KitW-sh mice to generate URO-OVA/KitW-sh mice that retained urothelial OVA expression but lacked endogenous mast cells. We compared URO-OVA mice with URO-OVA/KitW-sh mice with and without mast cell reconstitution in response to cystitis induction. URO-OVA mice developed profound bladder inflammation with increased mast cell counts and LUTD, including increased total number of voids, decreased mean volume voided per micturition, and decreased maximum volume voided per micturition, after cystitis induction. In contrast, similarly cystitis-induced URO-OVA/KitW-sh mice developed reduced bladder inflammation with no mast cells and LUTD detected. However, after mast cell reconstitution URO-OVA/KitW-sh mice restored the ability to develop bladder inflammation and LUTD following cystitis induction. We further treated URO-OVA mice with cromolyn, a mast cell membrane stabilizer, and found that cromolyn treatment reversed bladder inflammation and LUTD in the animal model. Our results provide direct evidence for the role of mast cells in cystitis-associated LUTD, supporting the use of mast cell inhibitors for treatment of certain forms of IC/BPS.

Transgenic Mice Expressing MCP-1 by the Urothelium Demonstrate Bladder Hypersensitivity, Pelvic Pain and Voiding Dysfunction: A Multidisciplinary Approach to the Study of Chronic Pelvic Pain Research Network Animal Model Study.

Monocyte chemoattractant protein-1 (MCP-1) is one of the key chemokines that play important roles in diverse inflammatory and chronic pain conditions. Interstitial cystitis/bladder pain syndrome (IC/BPS) is a chronic and debilitating inflammatory condition of the urinary bladder characterized by the hallmark symptoms of pelvic pain and voiding dysfunction. To facilitate IC/BPS research, we used transgenic technology to develop a novel urothelial MCP-1 secretion mouse model (URO-MCP-1). A transgene consisting of the uroplakin II gene promoter and the mouse MCP-1 coding sequence with a secretory element was constructed and microinjected. URO-MCP-1 mice were found to express MCP-1 mRNA in the bladder epithelium and MCP-1 protein in the urine, and developed bladder inflammation 24 hours after intravesical administration of a single sub-noxious dose of lipopolysaccharide (LPS). The inflamed bladders of URO-MCP-1 mice exhibited elevated mRNAs for interleukin (IL)-1ß, IL-6, substance P precursor, and nerve growth factor as well as increased macrophage infiltration. In parallel with these phenotypic changes, URO-MCP-1 mice manifested significant functional changes at days 1 and 3 after cystitis induction. These functional changes included pelvic pain as measured by von Frey filament stimulation and voiding dysfunction (increased urinary frequency, reduced average volume voided per micturition, and reduced maximum volume voided per micturition) as measured by micturition cages. Micturition changes remained evident at day 7 after cystitis induction, although these changes were not statistically significant. Control wild-type C57BL/6 mice manifested no clear changes in histological, biochemical and behavioral features after similar cystitis induction with LPS. Taken together, our results indicate that URO-MCP-1 mice are hypersensitive to bladder irritants such as LPS and develop pelvic pain and voiding dysfunction upon cystitis induction, providing a novel model for IC/BPS research.

Inflammation and Symptom Change in Interstitial Cystitis or Bladder Pain Syndrome: A Multidisciplinary Approach to the Study of Chronic Pelvic Pain Research Network Study

To explore inflammatory factors that influence symptom changes in interstitial cystitis or bladder pain syndrome (IC or BPS). This longitudinal, prospective study examined the association of inflammation elicited by Toll-like receptor (TLR) stimulation in peripheral blood mononuclear cells (PBMCs) and diurnal cortisol rhythms with changes in painful and urinary symptoms of IC or BPS and symptom flares over a 48-week period. Participants were 24 women meeting criteria for IC or BPS who supplied blood for isolation of PBMCs and 3 days of salivary cortisol samples prior to a baseline visit. Participants completed the Genitourinary Pain Index (pain and urinary subscales) and reported symptom flares every 2 weeks for 48 weeks. Mixed effects longitudinal and regression models were used to determine if inflammatory variables were associated with the changes in IC or BPS symptoms (time × variable interactions), and the probability of a symptom flare. Elevated TLR-4 inflammation (P = .031) and elevated TLR-2 inflammation (P = .045) from PBMCs, and flattened diurnal cortisol slope (P = .012) were each associated with less improvement in genitourinary pain over time. Additionally, elevated TLR-4 inflammation was associated with less improvement in urinary symptoms (P = .018), whereas TLR-2 inflammation and cortisol slopes were not (both P > .16). In contrast, no inflammatory measure was associated with an increased likelihood of reporting a symptom flare (all P > .25). TLR-mediated inflammation and diurnal cortisol slope may be useful as markers of symptom changes in IC or BPS.

Animal Models of Urologic Chronic Pelvic Pain Syndromes: Findings From the Multidisciplinary Approach to the Study of Chronic Pelvic Pain Research Network

To describe the approach taken by the Multidisciplinary Approach to the Study of Chronic Pelvic Pain Research Network investigators to advance the utility of urologic chronic pelvic pain syndromes (UCPPS) animal models. A multidisciplinary team of investigators representing basic science and clinical expertise defined key phenotypic criteria for rodent models of UCPPS. UCPPS symptoms were prioritized based on their clinical significance. Methods for quantifying animal correlates to patient symptoms were developed. The methods were implemented across proposed rodent models for evaluation and comparison of animals for phenotypic characteristics relevant to human symptomatology. Pelvic pain and urinary frequency were deemed primary features of human UCPPS and were prioritized for assessment in animals. Nociception was quantified using visceromotor response to bladder distention and by applying von Frey filaments to the lower abdomen (referred tactile allodynia). Micturition activity was assessed as free voiding using micturition cages or blotting pad assays and in response to bladder filling by cystometry. Models varied in both depth of characterization and degree of recapitulating pelvic pain and urinary frequency characteristics of UCPPS. Rodent models that reflect multiple key characteristics of human UCPPS may be identified and provide enhanced clinical significance to mechanistic studies. We have developed a strategy for evaluating current and future animal models of UCPPS based on human symptomatology. This approach provides a foundation for improved translation between mechanistic studies in animals and clinical research and serves as a validation strategy for assessing validity of models for symptom-driven disorders of unknown etiology.

Widespread Psychosocial Difficulties in Men and Women With Urologic Chronic Pelvic Pain Syndromes: Case-control Findings From the Multidisciplinary Approach to the Study of Chronic Pelvic Pain Research Network

To determine the extent, severity, and sex differences of psychosocial deficits in men and women with urologic chronic pelvic pain syndromes (UCPPS), which in the past have been considered separate bladder (interstitial cystitis-painful bladder syndrome) and prostate (chronic prostatitis-chronic pelvic pain syndrome) disorders. Evaluations of men and women separately suggest UCPPS is associated with increased anxiety and depression. However, studies directly testing deficits in broader psychosocial domains such as cognitive processes, intimate relationships, and trauma history, or tests of sex differences in the pattern of difficulties associated with UCPPS have not been performed. A total of 233 female and 191 male UCPPS patients and 235 female and 182 male healthy controls (HCs) were recruited from 6 academic medical centers in the United States and evaluated with a comprehensive battery of symptom, psychosocial, and illness impact measures. Primary comparisons of interest were between UCPPS patients and HCs and between men and women with UCPPS. In addition to greater negative effect, male and female UCPPS patients show higher levels of current and lifetime stress, poorer illness coping, increased self-report of cognitive deficits, and more widespread pain symptoms compared with sex- and education-matched HCs. Similar problems were found in male and female UCPPS patients although female UCPPS patients showed increased self-report of childhood adversity and more widespread symptoms of pain and discomfort. Given the significance of psychosocial variables in prognosis and treatment of chronic pain conditions, the results add substantially to our understanding of the breath of difficulties associated with UCPPS and point to important areas for clinical assessment.

Toll-like receptor 4 and comorbid pain in Interstitial Cystitis/Bladder Pain Syndrome: a multidisciplinary approach to the study of chronic pelvic pain research network study.

Interstitial Cystitis/Bladder Pain Syndrome (IC/BPS) is a condition characterized by pelvic pain and urinary symptoms. Some IC/BPS patients have pain confined to the pelvic region, while others suffer widespread pain. Inflammatory processes have previously been linked to pelvic pain in IC/BPS, but their association with widespread pain in IC/BPS has not been characterized. Sixty-six women meeting criteria for IC/BPS completed self-report measures of pain as part of the Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP), collected 3days of saliva for cortisol assays, and provided blood samples. Peripheral blood mononuclear cells (PBMCs) were stimulated with Toll-like Receptor (TLR) 2 and 4 agonists and cytokines were measured in supernatant; IL-6 was also measured in plasma. Associations between inflammatory variables and the likelihood of endorsing extra-pelvic pain, or the presence of a comorbid syndrome, were tested by logistic regression and General Linear Models, respectively. A subset of patients (n=32) completed Quantitative Sensory Testing. A one standard deviation increase in TLR-4 inflammatory response was associated with a 1.59 greater likelihood of endorsing extra-pelvic pain (p=.019). Participants with comorbid syndromes also had higher inflammatory responses to TLR-4 stimulation in PBMCs (p=.016). Lower pressure pain thresholds were marginally associated with higher TLR-4 inflammatory responses (p=.062), and significantly associated with higher IL-6 in plasma (p=.031). TLR-4 inflammatory responses in PBMCs are a marker of widespread pain in IC/BPS, and should be explored in other conditions characterized by medically unexplained pain.

Alterations in Resting State Oscillations and Connectivity in Sensory and Motor Networks in Women with Interstitial Cystitis/Painful Bladder Syndrome

The pathophysiology of interstitial cystitis/painful bladder syndrome remains incompletely understood but is thought to involve central disturbance inthe processing of pain and viscerosensory signals. We identified differences inbrain activity and connectivity between female patients with interstitial cystitis/painful bladder syndrome and healthy controls to advance clinical phenotyping and treatment efforts for interstitial cystitis/painful bladder syndrome. We examined oscillation dynamics of intrinsic brain activity in a large sample of well phenotyped female patients with interstitial cystitis/painful bladder syndrome and female healthy controls. Data were collected during 10-minute resting functional magnetic resonance imaging as part of the Multidisciplinary Approach to the Study of Chronic Pelvic Pain Research Network project. The blood oxygen level dependent signal was transformed to the frequency domain. Relative power was calculated for multiple frequency bands. Results demonstrated altered frequency distributions in viscerosensory (post insula), somatosensory (postcentral gyrus) and motor regions (anterior paracentral lobule, and medial and ventral supplementary motor areas) in patients with interstitial cystitis/painful bladder syndrome. Also, the anterior paracentral lobule, and medial and ventral supplementary motor areas showed increased functional connectivity to the midbrain (red nucleus) and cerebellum. This increased functional connectivity was greatest inpatients who reported pain during bladder filling. Findings suggest that women with interstitial cystitis/painful bladder syndrome have a sensorimotor component to the pathological condition involving an alteration in intrinsic oscillations andconnectivity in a cortico-cerebellar network previously associated with bladder function.

A Watershed Year for Interstitial Cystitis

A watershed is occurring in our understanding of interstitial cystitis (IC). Recent publications in The Journal of Urology® and others have added explanations of genetic1 and epigenetic2 influences, documented the time course of the appearance of comorbid disorders3 and shown again how much systemic involvement occurs in most patients.4 A disorder once described as “a hole in the air” may be yielding to investigators looking beyond the bladder to consider the whole individual. The most recent contributions to this expanded view of IC as a problem affecting the bladder rather than as a bladder problem include contributions to an expanded view of phenotyping of IC cases. A recent group concluded, “(Clinically relevant) domains that function outside of the bladder (psychosocial, neurological, tenderness) predict a significant impact on symptoms.”4 A new review added additional evidence for an overlap between urological and nonurological unexplained clinical conditions.5 The article by Ogawa et al (page 1206) in this issue of The Journal focuses on the ulcerative form of IC, which may be different from the nonulcerative form in its extent of systemic involvement. Although their gene expression studies are limited to urothelium, others have reported increased circulating chemokines in patients with IC.6 Concurrent events also are under way at the National Institute of Diabetes, Digestive and Kidney Diseases (NIDDK), which recently established the Multidisciplinary Approach to the Study of Chronic Pelvic Pain research network (http://www. mappnetwork.org). The network is charged to take a new look at urological chronic pelvic pain and is undertaking comprehensive phenotyping activities in patients with these syndromes. Another recently reported systemic biomarker may eventually assist in diagnosing IC in humans and animals.7 However, new knowledge cannot always be accepted and integrated easily. For example, revision of the nosology of the syndrome has been under way for some time. Although IC no longer captures the extent of the problem, if it ever did, it is less clear what the most appropriate name may be. A number of suggestions have been offered, including painful bladder syndrome, bladder pain syndrome and bladder hypersensitivity syndrome. They remain focused on the end organ, still reflecting the perspective of the specialty rather than current understanding of the syndrome. Feinstein recently concluded, “An important principle in naming apparently new ailments is to avoid etiologic titles until the etiologic agent has been suitably demonstrated. A premature causal name can impair a patient’s recovery from the syndrome and impede research that may find the true cause.”8 Regardless of the name eventually chosen, we have reached a time when the description of patients with IC (and these 2 letters may be name enough for the time being) in research and clinical presentations and publications may no longer be restricted to urinary symptoms. A research implication of this new view is the choice of appropriate animal models for studying IC. Acute bladder injury in otherwise healthy animals cannot adequately model the systemic aspects of IC. Fortunately various models in other disciplines are available that exploit the effects of early adverse experience on adult physiology and behavior.9 Although to my knowledge reports of the effects of these maneuvers on voiding function have not yet appeared, the results of evaluating other organs suggest that isolated abnormalities are unlikely. Collaboration with groups that have established these models could rapidly screen for influences on bladder function using relatively simple methods. What has also occurred recently is the retirement of a major driving force behind this renaissance of knowledge about IC, Dr. Lee Nyberg. Leroy M. Nyberg, M.D. and Ph.D., was Director of Urology Programs at NIDDK from 1989 until retirement in September 2009. His portfolio included directing basic and clinical research into IC, and he led NIDDK efforts to understand its etiopathogenesis. Doctor Nyberg was instrumental in developing research programs, mentoring and collaborating with investigators, and speaking at conferences around the world about IC. As an indicator of his influence, there were 317 IC citations in PubMed® from 1929 to the end of 1989 and from 1989 to the end of 2009 a total of 1,678 were added (53 vs 839 per decade), a 16-fold increase. Because of his efforts and those of many others, new leaders in IC research and treatment will emerge. They and their patients have Doctor Nyberg’s determination and persistence to thank for getting us to this new place in the evolution of our understanding of IC.

Painful Myofascial Trigger Points and Pain Sites in Men With Chronic Prostatitis/Chronic Pelvic Pain Syndrome

A combination of manual physiotherapy and specific relaxation training effectively treats patients with chronic prostatitis/chronic pelvic pain syndrome. However, little information exists on myofascial trigger points and specific chronic pelvic pain symptoms. We documented relationships between trigger point sites and pain symptoms in men with chronic prostatitis/chronic pelvic pain syndrome. We randomly selected a cohort of 72 men who underwent treatment with physiotherapy and relaxation training from 2005 to 2008. Patients self-reported up to 7 pelvic pain sites before treatment and whether palpation of internal and external muscle trigger points reproduced the pain. Fisher's exact test was used to compare palpation responses, ie referral pain, stratified by reported pain site. Pain sensation at each anatomical site was reproduced by palpating at least 2 of 10 designated trigger points. Furthermore, 5 of 7 painful sites could be reproduced at least 50% of the time (p <0.05). The most prevalent pain sites were the penis in 90.3% of men, the perineum in 77.8% and the rectum in 70.8%. Puborectalis/pubococcygeus and rectus abdominis trigger points reproduced penile pain more than 75% of the time (p <0.01). External oblique muscle palpation elicited suprapubic, testicular and groin pain in at least 80% of the patients at the respective pain sites (p <0.01). This report shows relationships between myofascial trigger points and reported painful sites in men with chronic prostatitis/chronic pelvic pain syndrome. Identifying the site of clusters of trigger points inside and outside the pelvic floor may assist in understanding the role of muscles in this disorder and provide focused therapeutic approaches.