{"paper_id":"4f758299-d2a6-47b7-87d1-0505c07892f4","body_text":"1 \nClinical profiling of subgroups of women with chronic pelvic pain \n \nAuthors:  \nLysia Demetriou1, Michal Krassowski 1, Pedro Abreu Mendes2, Kurtis Garbutt1, Allison F. Vitonis3ab, \nElizabeth Wilkins 1, Lydia Coxon 1, Lars Arendt-Nielsen4,5, Qasim Aziz 6, Judy Birch 7, Andrew W \nHorne8, Anja Hoffman 9, Lone Hummelshoj 10, Claire E Lunde 1,13ab, Jane Meijlink 11, Danielle Perro 1, \nNilufer Rahmioglu1, Kathryn L. Terry3ab, Esther Pogatzki-Zahn12, Christine B Sieberg13abc, Rolf-Detlef \nTreede14, Christian M Becker1, Franscisco Cruz 2, Stacey A Missmer15abcd, Krina T Zondervan1, Jens \nNagel16, Katy Vincent1 \n \nAuthors affiliations:  \n1. Oxford Endometriosis Centre, Nuffield Department of Women’s and Reproductive Health, University of \nOxford, UK \n2. IBMC/I3S and Faculty of Medicine of Porto/ Hospital S João, Porto, Portu \n3. a. Boston Center for Endometriosis, Brigham and Women ’s Hospital and Boston Children ’s Hospital, \nBoston, MA, USA and b. Department of Obstetrics and Gynecology, Brigham and Women’s Hospital and \nHarvard Medical School, Boston, MA, 02115, USA \n4. Center for Neuroplasticity and Pain (CNAP), SMI, Department of Health Science and Technology, School \nof Medicine, Aalborg University, Aalborg, Denmark \n5. Department of Medical Gastroenterology, Mech-Sense, Aalborg University Hospital, Aalborg, Denmark \n6. Centre for Neuroscience, Surgery and Trauma, Blizard Institute, Wingate Institute of \nNeurogastroenterology. Barts and The London School of Med icine and Dentistry, Queen Mary \nUniversity of London UK \n7. Pelvic Pain Support Network, Poole, UK   \n8. MRC Centre for Reproductive Health, University of Edinburgh, Edinburgh, UK \n9. Research & Development, Pharmaceuticals Experimental Medicine, Bayer AG, Berlin, Germany \n10. Endometriosis.org, UK \n11. International Painful Bladder Foundation \n . CC-BY-ND 4.0 International licenseIt is made available under a \nperpetuity. \n is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted October 4, 2022. ; https://doi.org/10.1101/2022.10.03.22280515doi: medRxiv preprint \nNOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice.\n\n 2 \n12. Department of Anesthesiology, Intensive Care and Pain Medicine, University Hospital Muenster, \nMuenster, Germany \n13. a. Biobehavioral Pediatric Pain Lab, Department of Psychiatry & Behavioral Sciences, Boston Children’s \nHospital, Boston, MA; b. Pain and Affective Neuroscience Center, Department of Anesthesiology, \nCritical Care, & Pain Medicine, Boston Children ’s Hospital, Boston, MA; c. Department of Psychiatry, \nHarvard Medical School, Boston, MA \n14. Department of Neurophysiology, Mannheim Center for Translational Neuroscience (MCTN), Heidelberg \nUniversity, Mannheim, Germany \n15. a. Department of Obstetrics, Gynecology, and Reproductive Biology; College of Human Medicine, \nMichigan State University, Grand Rapids, MI, USA. b. Department of Epidemiology, Harvard T.H. Chan \nSchool of Public Health, Boston, MA, USA. c. Division of Adolescent and Young Adult Medicine, \nDepartment of Pediatrics, Boston Children’s Hospital and Harvard Medical School, Boston, MA, USA. d. \nBoston Center for Endometriosis, Brigham and Women ’s Hospital and Boston Children ’s Hospital, \nBoston, MA, USA \n16. Pharmaceuticals Division, Research and Early Development, Therapeutic Area Endocrinology, \nMetabolism and Reproductive Health, Exploratory Pathobiology, Bayer AG, Wuppertal, Germany. \n \nWord Count: 4,167 \n \n  \n . CC-BY-ND 4.0 International licenseIt is made available under a \nperpetuity. \n is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted October 4, 2022. ; https://doi.org/10.1101/2022.10.03.22280515doi: medRxiv preprint \n\n 3 \nAbstract  \n \nStudy question \nDo subgroups of women with chronic pelvic pain (CPP) report different clinical symptoms and \ndiffering impact of pain on their quality of life? \n \nSummary answer \nClinical profiles of women with CPP show variability of clinical symptoms both within and \nbetween subgroups. However, there is an obvious negative impact of pain on the patients’ lives \nacross all subgroups  with the comorbid endometrio sis and bladder pain symptoms group \n(EABP) presenting with the higher pain intensities and the lower quality of life. \n \nWhat is known already \nCPP is a common condition affecting up to 26.6% of women, with many suffering for several \nyears before diagnosis and/or treatment. The clinical presentation of CPP is varied and there \nare frequently comorbid conditions both within and outside the pelvis.  Evidence from the \nliterature show that there is an overlap of symptoms in chronic pain conditions whatever the \nunderlying cause which suggests that chronic pain could be a condition itself. \n  \nStudy design, size, duration \nThe study is part of The Translational Research in Pelvic Pain (TRiPP) project \n(https://www.imi-paincare.eu/PROJECT/TRIPP/) which is a  cross-sectional observational \ncohort study. The present study includes 769 female participants sampled from  two existing \nendometriosis-focused cohort studies in Oxford , UK  and Boston , MA, USA  and newly \nrecruited from the Instituto de Biologia Molecular e Celular (IBMC)) in Porto. The participants \n . CC-BY-ND 4.0 International licenseIt is made available under a \nperpetuity. \n is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted October 4, 2022. ; https://doi.org/10.1101/2022.10.03.22280515doi: medRxiv preprint \n\n 4 \ncompleted an extensive set of question s derived from standardised WERF EPHect \nquestionnaires. Within this study population we defined  a control group (reporting no pelvic \npain, no bladder pain syndrome (BPS), and no endometriosis diagnosis, N=230) and four pain \ngroups: endometriosis-associated pain (EAP, N=237), (BPS, N=72), comorbid endometriosis-\nassociated pain and BPS (EABP, N=120), and pelvic pain only (PP, N=127). \n \nParticipants/materials, setting, methods \nAll participants were women of reproductive age (13 -50 years) and were recruited at three \ndifferent sites: Oxford  (University of Oxford) , Boston  (Boston Center for Endometriosis \n(BCE)) and Porto (Instituto de Biologia Molecular e Celular (IBMC)).  \nThe questionnaire included: demographics; reproductive history; pelvic pain intensity assessed \nusing 10 -point numerical rating scales (NRS) for dysmenorrhoea, non -cyclical pain, \ndyspareunia and bladder pain ; medical comorbidities ; factors relieving and worsening pain ; \nquality of life assessed using the SF-36 questionnaire; and pain catastrophising. \n \nMain results and the role of chance \nThe EAP (Mean:7.37) and EABP (Mean:7.88) groups scored higher on the pain intensity scales \nfor non -cyclical pelvic pain than the PP (Mean:6.82) group (p<0.001) and higher on the \ndysmenorrhoea scale than both the BPS and PP groups (p<0.001). The EABP (Mean:6.61)  and \nBPS (Mean:6.52) groups had significantly higher bladder pain scores than the EAP  \n(Mean:0.95) and PP (Mean:0.78) (p<0.001). The EABP group also had significantly higher \npain scores for dyspareunia (p<0.001), even though more than 50% of participants (who were \nsexually active) in each of the pain groups reported interrupting and/or avoiding sexual \nintercourse due to pain in the last 12 months.  \n \n . CC-BY-ND 4.0 International licenseIt is made available under a \nperpetuity. \n is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted October 4, 2022. ; https://doi.org/10.1101/2022.10.03.22280515doi: medRxiv preprint \n\n 5 \nExploring the factors reported to worsen or relieve pain found that across the pain groups the \nthree most reported factors for worsening pelvic pain were: stress (23.6%), full \nbladder/urinating (23.3%)  and exercising (20.2%). The most common factors for relieving \npelvic pain were: pain medication (31.4%), lying down (31.0%), and use of a heat pad (29.5%).  \n \nAnalysis of the quality-of-life questionnaire (SF-36) subscales revealed significant differences \nbetween the study groups across all SF-36 subscales (p<0.001). In line with the pain results the \nEABP group reported the negative highest impact across all the health measures while the PP \ngroup’s profile was closest to the control group’s profile. Significant effects were also observed \nbetween the pain groups for pain interference with their work (F(3,209)=9. 76, p<0.001) and \ndaily lives (F(3,244)=10.51, p<0.001), with the EABP suffering more compared to the EAP \nand PP groups (p<0.001). \n \nLimitations, reasons for caution \nData for this study were derived predominantly from existing cohorts where data have been \ncollected over time and thus different versions of questionnaires have been used. Thus , for \nsome questions only a subgroup may have had an opportunity to complete the measure of \ninterest. Recruitment of participants was impacted due to the COVID-19 pandemic. As a result, \nsample sizes overall were smaller than originally designed, and our BPS group was \npredominantly identified from gynaecological rather than urological clinics making it  \npotentially different from other published BPS cohorts. \n \nWider implications of the findings \nOverall, our results demonstrate the negative impact that chronic pain has on CPP patients ’ \nquality of life and suggests that further exploration of interventions targeting quality of more \n . CC-BY-ND 4.0 International licenseIt is made available under a \nperpetuity. \n is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted October 4, 2022. ; https://doi.org/10.1101/2022.10.03.22280515doi: medRxiv preprint \n\n 6 \nbroadly is important. Furthermore, it demonstrates the importance of dyspareunia in women \nwith CPP, highlighting the need for more research in this area. \n \nImportantly, we show significant differences between the sub -groups of CPP suggesting the \nneed for better patient stratification in future cl inical studies and trials. However, the marked \nvariability both within and between CPP sub -groups raises the question whether subgrouping \non the basis of clinical diagnosis is the most appropriate strategy or whether alternative \napproaches could be identified allowing prioritisation of treatments better suited to the \nindividual patient. \n \nStudy funding/competing interest(s) \nThis project has received funding from the Innovative Medicines Initiative 2 Joint \nUndertaking under grant agreement No 777500. This Joint Undertaking receives support \nfrom the European Union’s Horizon 2020 research and innovation programme and EFPIA \nCompanies.  Financial support was provided by the J. Willard and Alice S. Marriott \nFoundation for establishment of and baseline data collection within the A2A cohort - from \nwhich the Boston-based TRiPP population was sampled. \n \nTrial registration number \nNCT04001244 \n \n \n \n \n  \n . CC-BY-ND 4.0 International licenseIt is made available under a \nperpetuity. \n is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted October 4, 2022. ; https://doi.org/10.1101/2022.10.03.22280515doi: medRxiv preprint \n\n 7 \nIntroduction \nChronic pelvic pain (CPP) is common, affecting up to 26.6% of women (1–4), yet it remains \ndifficult to treat. For some women an associated pathology such as endometriosis can be \nidentified, but for many others diagnostic investigations will be n ormal and the label chronic \npelvic pain syndrome (CPPS) applied. However, even in those women where endometriosis is \nidentified the lack of correlation between measures of disease severity and pain symptoms (5,6) \nmakes it challenging to understand the extent to w hich symptoms are actually caused by \nendometriosis and to predict the benefit of treatments targeting the ectopic tissue. \n \nThere is increasing evidence that chronic pain conditions share many features whatever the \nunderlying cause (7,8), leading som e to suggest that chronic pain should be treated as a \ncondition in itself  (9,10). Whilst there i s relatively limited research on this in the context of \nchronic pelvic pain, studies that have looked at these features confirm similarities with other \nchronic pain conditions  such as irritable bowel syndrome (IBS), rheumatoid arthritis and \nfibromyalgia (11,12). However, current clinical practice guidelines are still relatively focussed \non the identification and treatment of underlying pelvic pathology (13).  \n \nThe Translational Research in Pelvic Pain (TRiPP) project ( https://www.imi-\npaincare.eu/PROJECT/TRIPP/) aims to better understand the mechanisms generating and \nmaintaining pelvic pain with a particular focus on endometriosis and interstitial cystitis/bladder \npain syndrome (IC/BPS)  (14). Here , we use the baseline data from th e TRiPP  project to \ndetermine whether different subgroups of women with CPP report different clinical features \nsymptoms and differing impacts of pain on their liv es. A better understanding of CPP would \nallow the development of refined clinical pathways and the prioritisation of specific subgroups \nof women for further research. Given the diversity of symptoms described by women with all \n . CC-BY-ND 4.0 International licenseIt is made available under a \nperpetuity. \n is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted October 4, 2022. ; https://doi.org/10.1101/2022.10.03.22280515doi: medRxiv preprint \n\n 8 \nforms of CPP we do not expect to see differences in specific clinical symptoms between those \nwith and without endometriosis or with and without IC/BPS (with the exception of bladder \nsymptoms themselves). However, we hypothesise that those women with comorbid pain and \nbladder symptoms will describe a poorer quality of life. \n \nMethods \nEthical Approval \nThe study has received ethical approval from Yorkshire & The Humber – South Yorkshire \nResearch Ethics Committee (19/YH/0030) with local site approvals and was being conducted \nin accordance with the principles of the Declaration of Helsinki and with relevant regulations \nand Good Clinical Practice. Informed consent was obtained from all the participants, and they \nwere informed that they are free to withdraw their data from the study at any time. \n \nStudy population \nAs described in the TRiPP protocol paper (14), participants were identified from two existing \nendometriosis cohort studies in Oxford (EndOX: A study to identify possible biomarkers in \nwomen with endometriosis, Oxford REC ref 09/H0604/58 ) (N=276) and Boston  (The \nWomen’s Health Study from Adolescence to Adulthood  (A2A), IRB -P00004267) (N=494) \nplus 16 BPS participants who were recruited at Hospital São João /Instituto de Biologia \nMolecular e Celular (IBMC) in Porto (Supplementary I).  \n \nThe study comprised of five study groups and participants were assigned according to specific \ninclusion and exclusion criteria for each study group  (14) (Table I): endometriosis-associated \npain (EAP: N=237), comorbid endometriosis associated- and bladder pain syndrome (EABP: \nN= 120 ), bladder pain syndrome  (BPS: N=72), pelvic pain only (PP: N=127 ) and controls \n . CC-BY-ND 4.0 International licenseIt is made available under a \nperpetuity. \n is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted October 4, 2022. ; https://doi.org/10.1101/2022.10.03.22280515doi: medRxiv preprint \n\n 9 \n(CON: N=230) ). All participants were women of reproductive age (13 -50 years). Pregnant, \nlactating or women planning pregnancy during the course of the study were not included as per \nthe study exclusion criteria. \n \nStudy design \nThe TRiPP study design is described in Supplementary I (and more fully elsewhere (14)), the \npresent report focuses on Phase I in which participants completed expanded World \nEndometriosis Research Foundation (WERF)  Biobanking Harmonisation Project (EPHect) \nquestionnaires (15). Here we explore a selected set o f outcomes as described below  that will \nalso be used in the analysis of phases II and III of the TRiPP project. \n \nStudy Data \nDemographics and Reproductive History \nDemographic information collected included participants’ age, body mass index (BMI), race, \neducation, work and relationship status. Information about the participants ’ gynaecological \nhistory consisted of: occurrence and frequency of pelvic pain, menstrual history (e.g. menarche \nand dysmenorrhoea onset), use of hormones in the last 3 months and information on fertility  \nand dyspareunia. Data from a number of questions were analysed to give a fuller picture of \nsexual activity, associated pain and functional impact. The questions on dyspareunia were not \nincluded in the  first version of the questionnaire that was completed by 67 participants in \nOxford and for participants younger than 18 years old (N=79) from the Boston cohort. \n \nPelvic pain \nPain was assessed using numerical rating scales (NRSs) for intensity ranging from 0 = “no \npain” to 10 = “worst imaginable pain ”. Participants were asked to complete NRS for the \n . CC-BY-ND 4.0 International licenseIt is made available under a \nperpetuity. \n is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted October 4, 2022. ; https://doi.org/10.1101/2022.10.03.22280515doi: medRxiv preprint \n\n 10 \nexperience of pelvic pain at its “worst” in the last three months (for non -cyclical pelvic pain), \nduring the last period (for dysmenorrhoea), worst bladder pain in the last 7 days and pain during \nand 24hours post sexual intercourse (for dyspareunia). \n \nThe pain catastrophising scale (PCS)  (16) was used to  assess pain-related worry. \nCatastrophizing is the single most important risk factor that impairs the effectiveness of pain -\nrelieving interventions (17,18), and it statistically mediates the prospective influence of factors \nsuch as anxiety on pain outcomes  (19). The PCS is  a validated/standardised 13-item \nquestionnaire that uses a 5-point scale ranging from 0 (not at all) to 4 (all the time), the total \nPCS score was computed by summing t he responses to all 13 items  (16). The scores for the \nthree subscales: Rumination (e.g.,“I can ’t stop thinking about how much it hurts .”),, \nMagnification (e.g., “I worry that something serious may happen.”)  and Helplessness (e.g., \n“There is nothing I can do to reduce the intensity of my pain.”)  were computed by summing \nresponses of specific items as outlined in Sullivan (16). Scores above the “clinical cut -off \npoints” were c onsidered as clinically relevant levels of catastrophising (PCS Total: 30, \nRumination: 11, Magnification: 5, Helplessness: 13). \n \nMedical comorbidities \nParticipants were provided with a list of medical conditions and reported whether they had \nreceived a med ical diagnosis for any of those at any point in their live s. The list included \nautoimmune, gynaecological, mental health, chronic pain, endocrine and cardiovascular \ndisorders. \n \nFurthermore, given the prevalence of bowel symptoms in association with both endometriosis \nand IC/BPS, irritable bowel syndrome (IBS) was assessed based on the Rome III criteria using \n . CC-BY-ND 4.0 International licenseIt is made available under a \nperpetuity. \n is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted October 4, 2022. ; https://doi.org/10.1101/2022.10.03.22280515doi: medRxiv preprint \n\n 11 \na question about the participants’ bowel movements/stools when they experienced non-cyclical \npelvic pain in the last 3 months. The symptoms consisted of: a) pelvic pain getting worse/better \nafter bowel movement, b) more/less frequent bowel movement when pain started and c) \nlooser/harder stools when the pain started. Participants who reported having two or more bowel \nsymptoms for “most of the time” or “always” met the criteria for IBS.  \n \nQuality of life \nThe participants’ health status was assessed using the Short Form Health Survey (SF-36) which \nconsists of  36 questions covering eight health domains: physical functioning, physical role \nlimitations, bodily pain, general health, emotional role limitations and mental health. The \nquestionnaire was scored as per instructions  by Rand Corporation \n(https://www.rand.org/health-care/surveys_tools/mos/36-item-short-form/scoring.html) and \nBurholt et al. (20). A higher score indicates a better health status. \n \nTo assess pain interference with the participants’ lives we used a question assessing the impact \nof pain on six different aspects (work or school, daily activities at home, sleep, sexual  \nintercourse, exercise/sports and social activities). Participants had to rate the exten t of pain \ninterference using a 4-point Likert scale ranging from “Not at all” to “Extremely” for the last \n3 months. The scores were recoded into four groups: low, mediu m, high and no pain \ninterference or not applicable. Additionally, two NRSs were used to assess the severity of the \nimpact of pelvic pain on the participants’ work and personal daily activities productivity during \nthe past 4 weeks.  \n \n \n \n . CC-BY-ND 4.0 International licenseIt is made available under a \nperpetuity. \n is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted October 4, 2022. ; https://doi.org/10.1101/2022.10.03.22280515doi: medRxiv preprint \n\n 12 \nFactors worsening and relieving pain \nTwo multiple-choice questions were used to assess/identify factors that participants believe \nworsen or relieve their pelvic pain. Among others, the options included visceral functions such \nas bowel movement or bladder emptying; behavioural including exercising, standing/walking \nor sitting; wellbeing factors like stress and mediation ; or other factor s e.g. time of day and \nhaving a full meal. \n \nStatistical analysis \nThe data were entered into a REDCap database (21) and analysed using IBM SPSS Statistics \nsoftware, Version 27. The analysis was conducted in 2 phases. First, descriptive analysis was \nrun to identify the characteristics of each study group. Then, statistical testing was undertaken \nto investigate any effects between the study groups for the study outcomes.  Statistical testing \nfor the NRS pelvic and bladder pain did not include the control group since they were recruited \nbased on their NRS scores being <3/10. One-way ANOVAs and Bonferroni corrected post-hoc \ntests were used to compare between study groups for all the continuous variables  while \nfrequencies, percentages and non-parametric tests (chi-square, mann -whitney u tests) were \nemployed for all the categorical variables . Pearson’s correlations were run to explore \nrelationships between the variables . Bonferroni correction was used to account for mult iple \ncomparisons.  \n \nResults \nDemographics and Reproductive history \nA total of 785 participants were included in this phase of the study with a mean age of 27.6 \nyears (STD: 8.1) and mean BMI of 24. 8 (STD: 5.2) (Table II). A one-way ANOVA showed \nsignificant differences for age and BMI between groups (Age: F(4,781)=4.12, p=0.003, BMI: \n . CC-BY-ND 4.0 International licenseIt is made available under a \nperpetuity. \n is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted October 4, 2022. ; https://doi.org/10.1101/2022.10.03.22280515doi: medRxiv preprint \n\n 13 \nF(4, 757)=3.28, p=0.011) ; and post-hoc independent-samples t -tests showed that the BPS \ngroup was significantly older than the EABP (p=0.01) and Controls (p=0.04)  and had a \nsignificantly higher mean BMI than the Controls (p=0.008) (Table II). \n \nThe mean age at menarche (mean=12.2 years) range d from 8 to 16 years old (One -way \nANOVA: F(4,768)=0.715, p=0.582) and did not significantly differ among groups (Table II). \nLikewise, the age at which dysmenorrhoea commenced was similar among all study groups  \n(mean=14.3 years, F(4,631)=1.10, p=0.356 ) (Table II). On average, patients suffered for \napproximately 8 years with non-cyclical pelvic pain, and there were no significant differences \nbetween the patient groups, even though the PP  group had the lowest mean number of years \n(mean=4.6 years), while the EABP and BPS  groups had the highest mean number of years \n(EABP: mean=9.7 years, BPS: mean=9.9 years ) (F(4,204)=3.906, p=0. 004). A Pearson’s \ncorrelation showed that  the number of years suffering with pelvic pain positively correla ted \nwith the age of the participants (r=0.411, p<0.001).  \n \nMore participants in the PP (90.5%) and Controls (92.6%) group reported having periods \nduring the last three months than participants in the EAP (76.9%), EABP (63.9%) and BPS \n(71.8%) (Table III). Of the participants who reported having periods, more than 53.8% of the \ncontrols and 35 .0% of the pain groups reported having periods whilst using exogenous \nhormones in the last 3 months.  The most common reason for not having periods across the \ngroups was taking hormones continuously  (91.8%). Regardless of whether they had periods, \nmany participants reported using exogenous hormones in the last three months (EAP: 52.7%, \nEABP: 61.7%, BPS: 61.1%, PP: 39.4%, Controls: 57%) (Table III). \n \n \n . CC-BY-ND 4.0 International licenseIt is made available under a \nperpetuity. \n is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted October 4, 2022. ; https://doi.org/10.1101/2022.10.03.22280515doi: medRxiv preprint \n\n 14 \nPelvic pain \nThe mean pain rating for non -cyclical pain at its worst during the last three months was \nsignificantly higher in the EAP and EABP compared to the PP group (Table IV). When asked \nabout dysmenorrhoea at its worst the EABP and EAP groups had a significantly higher mean \nscore on pain severity compared to both the BPS and PP groups (p<0.001). Results for the NRS \nscale on bladder pain during the last seven days revealed significantly higher mean pain scores \nfor the BPS and EABP groups compared to the EAP and PP groups (p<0.001) (Figure I). \n \nRegarding questions on dyspareunia, there were missing responses for more than 50% of our \nparticipants, because: a) 4.8% of all the participants did not wish to respond to the questions , \nb) 7.5% of all the participants reported never having sexual intercourse or c) these questions \nwere not available to 10.1% of the participants as described in the methods section above. \n \nFrom the available data sexual intercourse data however, most participants in each of the pain \ngroups (>58%) reported that they have experienced pain during intercourse or in the 24 hours \nfollowing vaginal sexual intercourse (Table V). Of  those, more than 60% experienced \ndyspareunia during the last month across all the pain groups. Almost half of those participants \n(49.2%) in the EABP group said that they had always experience d dyspareunia during \nintercourse in the last 12 months as opposed to the BPS and PP groups in which most \nparticipants reported occasional dyspareunia in the last year. In the EAP group  >77% of \nparticipants reported experiencing dyspareunia often, usually or always (Table V).  \n \nConcerning the location of dyspareunia, most participants in each pain group reported feeling \npain deep inside the vagina, the second most common location was in the abdomen/pelvis \nexcept for the  PP group in which 50.9% reported feeling pain at the entrance of the vagina.  \n . CC-BY-ND 4.0 International licenseIt is made available under a \nperpetuity. \n is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted October 4, 2022. ; https://doi.org/10.1101/2022.10.03.22280515doi: medRxiv preprint \n\n 15 \nWhen asked whether they have been avoiding or interrupting sexual intercourse during the last \n12 months due to pelvic pain, more than half of the participants (>54%) in all four pain groups \nsaid that they have interrupted sexual intercourse while more than half (>51%) of the \nparticipants in the EAP, EABP and BPS groups reported avoiding it. \n \nFurther analysis showed effects between the groups for the two dyspareunia NRS scales (pain \nduring intercourse: F(4,240)=12.77, p<0.001, pain in the 24hrs post -intercourse: \nF(4,242)=12.33, p<0.001) (Figure I). The EABP group had significantly higher mean ratings \non the NRS scales than all other pain groups (p<0.001) for the pain felt during intercourse, and \nsignificantly higher mean rating for pain severity in the 24hours after the sexual intercourse \nthan the EAP and PP groups (Table IV and Figure I). \n \nMedical comorbidities \nAcross all pain groups the most common comorbidities were depression, anxiety, migraine, \nasthma, and irritable bowel syndrome  (IBS) (Table V I). Within the EAP, EABP and BPS \ngroups there were higher percentages of depression, anxiety  and migraine diagnosis (>28%) \nthan in the PP group (<22%), while the frequency of asthma ranged between 20% - 27% across \nall pain groups (Table VI).  Statistical analysis using Mann-Whitney U tests revealed than when \ncompared to the control group  only the EABP group has significantly higher frequency of \nanxiety and depression diagnosis (anxiety: (U(NEABP=114, N CON=221)=10510, z= -3.39, \np<0.001), depression: (U(NEABP=120, N CON=230)=10855, z= -4.36, p<0.001)) . However, \nstatistical analysis for migraine showed that it was significantly more common in EAP (28.7%), \nEABP (34.2%) and BPS  (40.2%) groups than the control group  (9.6%) ((U(NEAP=237, \nNCON=230)=22042, z=-5.23, p<0.001), (U(NEABP=120, NCON=230)=10405, z=-5.68, p<0.001), \n(U(NBPS=72, NCON=230)=5737, z=-6.60, p<0.001)) groups. Similarly, IBS diagnosis was also \n . CC-BY-ND 4.0 International licenseIt is made available under a \nperpetuity. \n is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted October 4, 2022. ; https://doi.org/10.1101/2022.10.03.22280515doi: medRxiv preprint \n\n 16 \nsignificantly more common in the EAP (18.6%), EABP (24.2%) and BPS (20.8%) groups when \ncompared to the control group  (4.8%) ((U(NEAP=237, NCON=229)=23402, z=-4.60, p<0.001), \n(U(NEABP=120, NCON=230)=11079, z= -5.39, p<0.001), (U(NBPS=72, NCON=229)=6922, \nz=-4.22, p<0.001)).  \n \nIBS diagnosis was also less common in the PP group (10%) compared to the EAP, EABP and \nBPS groups (>18%). Correlation analysis between the participants ’ age and the different \ncomorbidities showed only a weak but significant  positive correlation between age and \noccurrence of spinal problems excluding scoliosis (r=0.014, p=0.001). \n \nFurther analysis of the bowel symptoms revealed that more than 11% of the participants in the \npain groups met the criteria for IBS regardless of whether they reported having a medical \ndiagnosis for it in the comorbidities question. The EABP and PP groups had the higher \npercentages of participants meeting the IBS criteria (>20%) (Table VI). \n \nQuality of life  \nAnalysis of the SF -36 questionnaire using a one -way ANOVA revealed significant effects \nbetween the five study groups across all eight SF-36 domains (p<0.001). Specifically, the \nEABP group suffered the most while the control group had the best scores across all sub-scales \n(p<0.001) (Table VII). Significant effects were also observed between the four pain groups for \npain interference with activities at work and daily life  (work: F(3,209)=9.76, p<0.001; daily \nactivities: F(3,244)=10.51, p<0.001) (Figure II). Post-hoc tests revealed that the EABP group \nhad significantly higher pain interference scores than the EAP and PP groups at both scales \n(p<0.001) (Table IV). \n \n . CC-BY-ND 4.0 International licenseIt is made available under a \nperpetuity. \n is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted October 4, 2022. ; https://doi.org/10.1101/2022.10.03.22280515doi: medRxiv preprint \n\n 17 \nPain Catastrophising \nPain catastrophising was higher in the EABP group both in the mean total score and in the \nmean scores of all three subscales (p<0.001). The EAP and BPS groups also had a higher pain \ncatastrophising score th an both the PP and Controls groups (p<0.001). According to the \nclinical-cut-offs more than 19% of the participants in the EAP, EABP and BPS had clinical \nlevels of pain catastrophising. The EABP group had the highest percentage of people above \nthe clinical cu t-off (36.0%) (Table VII). A Pearson ’s correlation between all the pain \ncatastrophising and all the NRS pain scales across all CPP patients revealed strong positive \ncorrelations (p<0.001). \n \nFactors worsening and relieving pain \nOn average, participants from all groups chose three to four factors that either relieve or worsen \ntheir pelvic pain. Across the four pain groups the three most common factors for worsening \npelvic pain were: stress (23.6%), full bladder/urinating (23.3%)  and exercising (20.2%). The \nmost frequently reported factors for relieving pelvic pain were: pain medication (31.4%), lying \ndown (31.0%) and heating pad (29.5%) (Table IX). Analysis of bowel movement and bladder \nemptying as visceral factors, shows that less people in the EAP and the PP groups report these \nfactors as relieving (bowel movement: EAP: 19.8% and PP 15.7%; emptying bladder: EAP: \n9.3% and PP 4.7%)  or worsening  (bowel movement: EAP: 6.7% and PP 2.5% ; emptying \nbladder: EAP: 24.1% and PP 10.2% ), while in the EABP and BPS groups more participants \nreport visceral factors as worsening (bowel movement: EABP: 27.7% and BPS 9.5%; emptying \nbladder: EABP: 65.8% and BPS 44.4%) rather than relieving (bowel movement: EABP: 32.5% \nand BPS 20.8%; emptying bladder: EAP: 34.2% and BPS 23.6%).  \n \n \n . CC-BY-ND 4.0 International licenseIt is made available under a \nperpetuity. \n is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted October 4, 2022. ; https://doi.org/10.1101/2022.10.03.22280515doi: medRxiv preprint \n\n 18 \nDiscussion \nThis study phenotypically describes the clinical profiles of women with CPP and contrasts \nthem with controls.  In line with existing literature, we have demonstrated that regardless of \nthe aetiology, CPP has a negative impact on the lives of people who suffer with it. However,  \nour results show that there are important differences between different clinical subgroups of \nthose with CPP and those with comorbid endometriosis and bladder pain syndrome  (EABP) \nare particularly severely affected. The heterogeneity in factors exacerbating and relieving \npelvic pain, highlights the complexity of the condition but suggests that there may be a variety \nof different underlying pain mechanisms contributing to the  similar clinical presentation. \nFurther evaluation of these underlying mechanisms may provide more clinically relevant \napproaches to patient stratification.  \n \nImportantly, we highlight how common painful sexual intercourse is in women with CPP and \nthat half of those who answered these questions reported interrupting or avoiding it due to pain. \nThis is an important issue for women and their partners and it can have a negative effect on \nmore than one aspect of a woman’s life, including mental health, body image, relationship with \ntheir partner and fertility (22,23). Dyspareunia is a commonly described symptom of \nendometriosis, but there is less of  a focus on this issue in BPS. It is therefore particularly \nnotable that the highest dyspareunia scores were reported by those with bladder symptoms in \nour cohort. A better understanding of the mechanisms underlying dyspareunia in all women \nwith CPP not just those with deep endometriosis is clearly an important future need and will \nultimately improve the clinical care of those suffering with this important symptom (24). \n \nIt is perhaps unsurprising that those with comorbid endometriosis and bladder pain symptoms \nscored highly on NRSs for all types of pelvic pain (non -cyclical pelvic pain, bladder pai n, \n . CC-BY-ND 4.0 International licenseIt is made available under a \nperpetuity. \n is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted October 4, 2022. ; https://doi.org/10.1101/2022.10.03.22280515doi: medRxiv preprint \n\n 19 \ndysmenorrhoea and dyspareunia). However, our data demonstrate that these women also have \npoorer quality of life and report greater pain interference . Whilst there are studies exploring \nthe prevalence and comorbidity of endometriosis and subsequent diagnosis of IC/BPS (25–27), \nfew studies focus on those with comorbid symptoms, either in terms of exploring clinical \nfeatures or considering specific treatment regimes. Moreover, for many clinical studies the \npresence of a comorbidity is an exclusion criteria and thus very limited data exists , this is \nparticularly true for clinical trials. Our findings suggest this may be a priority group to consider \nin future work. \n \nGiven that viscero-visceral referral is a relativ ely well understood phenomenon (28) and that \nvisceral pain conditions are often comorbid (29), we had expected to see higher rates of IBS in \nthose with bladder symptoms. This was the case when questioning previous diagnosis of IBS \n(EABP 24% and BPS 21% vs EAP 19% and PP 10%) . However, considering the answers to \nthe questions comprising the Rome IV criteria, a higher proportion of those in the EABP and \nPP groups would be considered to meet IBS criteria  than in the other groups . It is of course \ndifficult to know whether this reflects ongoing effective treatment in at least a proportion of \nthose with a past diagnosis of IBS. Nonetheless, the high rates of IBS across the cohort as a \nwhole highlight the importance of assessing symptoms from all abdominopelvic organs in \nwomen with CPP.  \n \nInterestingly the impact of visceral function (bladder and bowel emptying specificall y) on \npelvic pain appears to be very variable. For some participants these visceral functions worsened \ntheir pain, whilst for others they could be relieving. In fact, there was wide variability in the \nfactors identified as either worsening or relieving pel vic pain even within diagnostic groups \nand it would be interesting to consider whether patterns within these data may reflect \n . CC-BY-ND 4.0 International licenseIt is made available under a \nperpetuity. \n is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted October 4, 2022. ; https://doi.org/10.1101/2022.10.03.22280515doi: medRxiv preprint \n\n 20 \nunderlying pain mechanisms rather than for example the presence or absence of endometriosis \nor bladder symptoms. Whilst it can feel challenging in a clinical consultation to raise the topics \nof mental health and the stressors of daily life, particularly when women may have had a long \njourney to get their pain taken seriously, stress was the most commonly identified worsening \nfactor whereas relaxation was one of the most frequent relieving factors. Moreover, anxiety \nand depression were commonly reported comorbidities and those in the EAP, EABP and BPS \ngroups all scored significantly lower than controls on the emotional function dimension on the \nquality of life questionnaire. This evidence suggest that patients could benefit from treatments \nfocusing on managing their stress and developing better coping mechanisms for their pelvic \npain.  \n \nWhilst not an assessment of psychological wellbeing, catastrophic thinking about pain has been \nshown to be an important predictor of outcomes both in the transition to chronic pain after an \nacute injury and in the response to a variety of therapeutic options  (30,31). In line with other \nstudies (32,33) we observed that the chronic pain groups (EAP, EABP and BPS) scored higher \nin pain catastrophising compared to the control group with  a particularly high percentage of \nEABP patients meeting clinical levels of catastrophising.  This highlights the need to include \nbehavioural interventions that specifically target pain-related worry in the management of CPP \nin the same way as they are cons idered essential to the management of other chronic pain \nconditions (34,35). \n \nStrengths and weakness \nThere are a number of strengths to the TRiPP cohort which include the size of the sample and \nthe detailed phenotypic information available for these participants. Moreover , our study \nfocuses on chronic pelvic pain and therefore includes women with a variety of underlying \n . CC-BY-ND 4.0 International licenseIt is made available under a \nperpetuity. \n is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted October 4, 2022. ; https://doi.org/10.1101/2022.10.03.22280515doi: medRxiv preprint \n\n 21 \ndiagnoses rather than studying only a single condition such as endomet riosis. This strategy \nallows us to compare the similarities between different clinical subgroups but also to \nunderstand differences between them. We have a particular interest in IC/BPS and therefore \nthis cohort is relatively unusual in allowing the comparison between endometriosis and IC/BPS \nas well as those with comorbid symptoms. Unfortunately, our BPS group is smaller than we \ninitially planned. Neither of the original cohorts from which the TRiPP sample was formed had \nspecifically recruited IC/BPS patie nts (although many did meet the diagnostic criteria) and \ntherefore we had planned to expand these with a large number of new recruits from specialist \ncentres. However, the COVID-19 pandemic halted our ability to recruit to the study. Overall , \nwe still consider our sample size sufficient to draw meaningful conclusions (192 participants \nwith bladder pain, 120 of whom have coexisting endometriosis). \n \nA further strength of our study is that participants were recruited from three different centres \nrather than a single site. However, the duration of recruitment to the original cohorts has meant \nthat the baseline questionnaires have been reviewed and updated such that not all participants \ncompleted the same version. This has reduced the number of variables we could analyse across \nthe full cohort. Nonetheless the EPHect questionnaire is very comprehensive and the data we \ndo have available allows us to phenotypically charact erise our participants in a very detailed \nmanner. \n \nConclusion \nOverall, our results demonstrate the negative impact that chronic pain has on the lives of those \nwith CPP and particularly the importance of dyspareunia. Whilst we do see similarities across \nthe clinical subgroups that we explored our data highlight the difference between these groups \nand importantly illustrate how severely impacted the group with comorbid endometriosis and \n . CC-BY-ND 4.0 International licenseIt is made available under a \nperpetuity. \n is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted October 4, 2022. ; https://doi.org/10.1101/2022.10.03.22280515doi: medRxiv preprint \n\n 22 \nIC/BPS are. The heterogeneity seen in many of our measures , especially the factors \nexacerbating and relieving pain suggests that multiple different mechanisms may under lie the \nsimilar clinical presentations and emphasise the importance of better characterising those with \nCPP to identify clinically meaningful methods of patient stratification. Further studies within \nthe TRiPP project will explore these mechanisms in greater detail towards this aim.  \n . CC-BY-ND 4.0 International licenseIt is made available under a \nperpetuity. \n is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted October 4, 2022. ; https://doi.org/10.1101/2022.10.03.22280515doi: medRxiv preprint \n\n 23 \nAuthor’s roles \nLD and KV drafted the manuscript. All other authors contributed to the original design of the \nproject and reviewed and edited the manuscript. \n \nFunding \nThe study was funded by Innovative Medicines Initiative 2 Joint Undertaking (JU) under \ngrant agreement No 777500. The JU receives support from the European Union’s Horizon \n2020 research and innovation programme and EFPIA. Financial support was provided by the \nJ. Willard and Alice S. Marriott Foundation for establishment of and baseline data collection \nwithin the A2A cohort - from which the Boston-based TRiPP population was sampled. \n \nConflict of interest \nLD, MK, EW, LC, DP, NR, AVF, LAN, QA, JB, AH, LH, CEL, JM, CS, PAM, KG: declare \nno competing interests \nAWH: : reports grant funding from the MRC, NIHR, CSO, Wellbeing of Women, Roche \nDiagnostics, Astra Zeneca, Ferring, Charles Wolfson Charitable Trust and Standard Life. His \nemployer has received consultancy fees from Roche Diagnostics, AbbVie, Nordic Pharma \nand Ferring, outside the submitted work. In addition, AWH has a patent for a serum \nbiomarker for endometriosis pending. \nAH: Employee of Bayer AG, Germany \nEPZ: received financial support from Grunenthal and Mundipharma for research activities \nand advisory and lecture fees from Grünenthal, Novartis and Mundipharma. In addition, she \nreceives scientific support from the German Research Foundation (DFG), the Federal \nMinistry of Education and Research (BMBF), the German Federal Joint Committee (G-BA) \nand the Innovative Medicines Initiative (IMI) 2 Joint Undertaking under grant agreement No \n . CC-BY-ND 4.0 International licenseIt is made available under a \nperpetuity. \n is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted October 4, 2022. ; https://doi.org/10.1101/2022.10.03.22280515doi: medRxiv preprint \n\n 24 \n777500. This Joint Undertaking receives support from the European Union’s Horizon 2020 \nresearch and innovation programme and EFPIA. All money went to the institution E.M.P.-Z. \nis working for. \nRDT: Ad board for BAYER, IASP task force on chronic pain classification \nCMB: Research Grants from Bayer Healthcare, MDNA Life Sciences, Roche Diagnostics, \nEuropean Commission, NIH. His employer has received consulancy fees from Myovant and \nObsEva for work outside of this project \nFC: Consultant and/or investigator for Allergan (Abbvie), Astellas, Bayer, Ipsen and \nRecordati \nSAM: has been an advisory board member for AbbVie and Roche and receives research \nfunding from the National Institutes of Healt h, the US Department of Defense, the J. Willard \nand Alice S. Marriott Foundation, and AbbVie; none are related to the presented work ; the J. \nWillard and Alice S. 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CC-BY-ND 4.0 International licenseIt is made available under a \nperpetuity. \n is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted October 4, 2022. ; https://doi.org/10.1101/2022.10.03.22280515doi: medRxiv preprint \n\n . CC-BY-ND 4.0 International licenseIt is made available under a \nperpetuity. \n is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted October 4, 2022. ; https://doi.org/10.1101/2022.10.03.22280515doi: medRxiv preprint \n\n . CC-BY-ND 4.0 International licenseIt is made available under a \nperpetuity. \n is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted October 4, 2022. ; https://doi.org/10.1101/2022.10.03.22280515doi: medRxiv preprint \n\n . CC-BY-ND 4.0 International licenseIt is made available under a \nperpetuity. \n is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted October 4, 2022. ; https://doi.org/10.1101/2022.10.03.22280515doi: medRxiv preprint \n\n . CC-BY-ND 4.0 International licenseIt is made available under a \nperpetuity. \n is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted October 4, 2022. ; https://doi.org/10.1101/2022.10.03.22280515doi: medRxiv preprint \n\n . CC-BY-ND 4.0 International licenseIt is made available under a \nperpetuity. \n is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted October 4, 2022. ; https://doi.org/10.1101/2022.10.03.22280515doi: medRxiv preprint \n\n . CC-BY-ND 4.0 International licenseIt is made available under a \nperpetuity. \n is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted October 4, 2022. ; https://doi.org/10.1101/2022.10.03.22280515doi: medRxiv preprint \n\n . CC-BY-ND 4.0 International licenseIt is made available under a \nperpetuity. \n is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted October 4, 2022. ; https://doi.org/10.1101/2022.10.03.22280515doi: medRxiv preprint \n\n . CC-BY-ND 4.0 International licenseIt is made available under a \nperpetuity. \n is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted October 4, 2022. ; https://doi.org/10.1101/2022.10.03.22280515doi: medRxiv preprint \n\n . CC-BY-ND 4.0 International licenseIt is made available under a \nperpetuity. \n is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted October 4, 2022. ; https://doi.org/10.1101/2022.10.03.22280515doi: medRxiv preprint \n\n . CC-BY-ND 4.0 International licenseIt is made available under a \nperpetuity. \n is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted October 4, 2022. ; https://doi.org/10.1101/2022.10.03.22280515doi: medRxiv preprint \n\n . CC-BY-ND 4.0 International licenseIt is made available under a \nperpetuity. \n is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted October 4, 2022. ; https://doi.org/10.1101/2022.10.03.22280515doi: medRxiv preprint","source_license":"CC0","license_restricted":false}