Current developments in endometriosis-associated pain.

Endometriosis-associated pain is burdensome to both the individual and wider society. However, current treatment leaves many with persisting pain. Here, we highlight how recent work considering endometriosis in the context of chronic pain has altered our understanding and how this has the potential to improve clinical care.

Genome-wide association reveals a locus in neuregulin 3 associated with gabapentin efficacy in women with chronic pelvic pain.

Chronic pelvic pain (CPP) in women with no obvious pelvic pathology has few evidence-based treatment options. Our recent multicenter randomized controlled trial (GaPP2) in women with CPP and no obvious pelvic pathology showed that gabapentin did not relieve pain overall and was associated with more side effects than placebo. We conducted an exploratory genome-wide association study using eligible GaPP2 participants aiming to identify genetic variants associated with gabapentin response. One genome-wide significant association with gabapentin analgesic response was identified, rs4442490, an intron variant located in Neuregulin 3 (NRG3) (p = 2·11×10-8; OR = 18·82 (95% CI 4·86-72·83). Analysis of a large sample of UK Biobank participants demonstrated phenome-wide significant brain imaging features of rs4442490, particularly implicating the orbitofrontal cortex. NRG3 is expressed predominantly in central nervous system tissues and plays a critical role in nervous system development, maintenance, and repair, suggesting a neurobiologically plausible role in gabapentin efficacy and potential for personalized analgesic treatment.

Adolescent dysmenorrhoea in general practice: tensions and uncertainties.

This Perspectives article reflects on findings from our systematic review about adolescent dysmenorrhoea Q, drawing on sociology of diagnosis theory. We consider tensions and uncertainties between presentation with symptoms of dysmenorrhoea and processes of symptom categorisation and diagnosis in adolescents, tracing these through research and clinical guidance, considering possible implications for clinical practice. We argue that challenges in distinguishing between primary and secondary dysmenorrhoea in research translate into challenges in differentiation in clinical practice. We argue that framing this distinction as clear cut and straightforward belies the well-documented challenges in diagnosis of endometriosis, and that not recognising uncertainty and complexity inherent in this task may benefit neither clinicians nor patients.

What is known about adolescent dysmenorrhoea in (and for) community health settings?

Introduction: Dysmenorrhoea affects many adolescents with significant impacts on education and well-being. In the UK, most of the adolescents who seek care (and many never do), will do so through general practice (primary care). Knowing how best to care for adolescents reporting menstrual pain is an area where UK general practitioners would like better guidance and resources. Methods: This mixed-methods narrative synthesis collates community and specialist evidence from 320 papers about adolescent dysmenorrhoea, with a UK general practice community health perspective. Results: We report a narrative summary of symptoms, cause, consequences and treatments for adolescent dysmenorrhoea. We highlight areas of tension or conflicted evidence relevant to primary care alongside areas of uncertainty and research gaps identified through this synthesis with input from lived experience advisers. Discussion: There is little evidence about primary care management of adolescent dysmenorrhoea or specific resources to support shared-decision making in general practice, although there are evidence-based treatments to offer. Primary care encounters also represent potential opportunities to consider whether the possibility of underlying or associated health conditions contributing to symptoms of dysmenorrhoea, but there is little epidemiological evidence about prevalence from within community health settings to inform this. The areas where there is little or uncertain evidence along the care journey for adolescent dysmenorrhoea, including at the interface between experience and expression of symptoms and potential underlying contributory causes warrant further exploration. Systematic Review Registration: https://www.crd.york.ac.uk/PROSPEROFILES/256458_STRATEGY_20210608.pdf, identifier (CRD42021256458).

A systematic literature review on patient-reported outcome domains and measures in nonsurgical efficacy trials related to chronic pain associated with endometriosis: an urgent call to action.

ABSTRACT: Endometriosis, a common cause for chronic pelvic pain, significantly affects quality of life, fertility, and overall productivity of those affected. Therapeutic options remain limited, and collating evidence on treatment efficacy is complicated. One reason could be the heterogeneity of assessed outcomes in nonsurgical clinical trials, impeding meaningful result comparisons. This systematic literature review examines outcome domains and patient-reported outcome measures (PROMs) used in clinical trials. Through comprehensive search of Embase, MEDLINE, and CENTRAL up until July 2022, we screened 1286 records, of which 191 were included in our analyses. Methodological quality (GRADE criteria), information about publication, patient population, and intervention were assessed, and domains as well as PROMs were extracted and analyzed. In accordance with IMMPACT domain framework, the domain pain was assessed in almost all studies (98.4%), followed by adverse events (73.8%). By contrast, assessment of physical functioning (29.8%), improvement and satisfaction (14.1%), and emotional functioning (6.8%) occurred less frequently. Studies of a better methodological quality tended to use more different domains. Nevertheless, combinations of more than 2 domains were rare, failing to comprehensively capture the bio-psycho-social aspects of endometriosis-associated pain. The PROMs used showed an even broader heterogeneity across all studies. Our findings underscore the large heterogeneity of assessed domains and PROMs in clinical pain-related endometriosis trials. This highlights the urgent need for a standardized approach to both, assessed domains and high-quality PROMs ideally realized through development and implementation of a core outcome set, encompassing the most pivotal domains and PROMs for both, stakeholders and patients.

Symptom flares in women with chronic pelvic pain: Questionnaire study within a cohort study (translational research in pelvic pain (TRiPP)).

OBJECTIVE: To quantify the variation, triggers and impact on quality of life of symptom flares in women with chronic pelvic pain (CPP). DESIGN: Cross-sectional questionnaire within the Translational Research in Pelvic Pain clinical cohort study. SETTING: Women with CPP, with subgroups of women with endometriosis (EAP), interstitial cystitis/bladder pain syndrome (BPS), comorbid endometriosis and interstitial cystitis/bladder pain syndrome (EABP), and those with pelvic pain without endometriosis or interstitial cystitis/bladder pain syndrome (PP). POPULATION OR SAMPLE: A total of 100 participants. METHODS: Descriptive and comparative analysis from flares questionnaire. MAIN OUTCOME MEASURES: The prevalence, characteristics and triggers of short, medium and long symptom flares in CPP. RESULTS: We received 100 responses of 104 questionnaires sent. Seventy-six per cent of women with CPP have ever experienced symptom flares of at least one length (short, medium and/or long). Flares are associated with painful and non-painful symptoms. There is large variation for the frequency, duration, symptoms and triggers for flares. Over 60% of participants reported flares as stopping them from doing things they would usually do, >80% reported thinking about symptoms of flares and >80% reported flares being bothersome. CONCLUSIONS: Flares are prevalent and clinically very important in CPP. More research is needed to elucidate the mechanisms and characteristics underlying flares. Clinical practice should include an enquiry into flares with the aim of finding strategies to lessen their burden.

Incidence of menstrual symptoms suggestive of possible endometriosis in adolescents: and variance in these by ethnicity and socio-economic status.

BACKGROUND: Dysmenorrhoea affects up to 94% of adolescents who menstruate; approximately one third miss school and activities. Dysmenorrhoea can occur without identified pelvic pathology (primary dysmenorrhoea) or in association with other conditions (secondary dysmenorrhoea). In adolescence, the commonest cause of secondary dysmenorrhoea is endometriosis. The incidence of symptoms in adolescence suggesting possible endometriosis has not been previously documented in GP records. AIM: To document incidence of adolescent endometriosis and symptoms associated with endometriosis in English GP records. METHOD: Data from the QResearch primary care database were used for adolescent females aged 10- 19 years between 1 January 2011 and 30 June 2021, reported using descriptive statistics. RESULTS: The population cohort included 2 843 347 female adolescents; 98 887 participants had coded dysmenorrhoea (3.48%) and 1994 (0.07%) had documented endometriosis. The cumulative incidence for the cohort who turned 10 years old in 2011 was 7.2% for dysmenorrhoea and 0.12% for endometriosis. The period prevalence of coded symptoms during adolescence potentially associated with dysmenorrhoea and endometriosis includes: heavy menstrual bleeding (3.73%), irregular menstrual bleeding (2.21%), pelvic pain (0.63%), dyspareunia (0.40%), premenstrual syndrome (PMS)/premenstrual dysphoric disorder (PMDD) (0.22%), cystitis (8.45%), and irritable bowel syndrome (IBS) (1.00%). Disparities in coding were observed for these variables by ethnicity and socioeconomic status. Incidence of prescribed hormonal medication, with and without coded dysmenorrhoea, varied by ethnicity. This was less apparent for non-steroidal anti-inflammatory medications. CONCLUSION: Prevalence of coded dysmenorrhoea in GP records is significantly lower than community surveys suggest; however, adolescent menstrual symptoms are commonly encountered in primary care, and deserve specific guidance and resources. There are demographic patterns, likely structural, that warrant further exploration.

A lack of sociodemographic participant diversity in endometriosis evidence risks unrepresentative clinical guidance: a structured review of the evidence contributing to a NICE guideline.

BACKGROUND: Women who are black are less likely to be diagnosed with endometriosis than white women. There is no confirmed biological basis, so this likely represents structural barriers around health care. There is a lack of evidence exploring the interface between ethnicity and symptoms or experience of care and treatment. AIM: To map recording of sociodemographic diversity in the evidence informing an endometriosis guideline. METHOD: Inclusion of study setting, ethnicity, age, and socioeconomic status was documented within the evidence cited in National Institute for Health and Care Excellence (NICE) NG73 (2017) Endometriosis diagnosis and management. Included were 44 studies with 43 sample groups from the chapters: 'Signs and Symptoms', 'Information and Support', and 'Diagnosis'. Data were extracted independently by two researchers. RESULTS: No studies were conducted in primary care. The evidence cited in 'Signs and Symptoms' and 'Diagnosis' was exclusively from tertiary care. 'Information and Support' included 9/16 studies from tertiary care, and 7/16 recruited through community and advocacy networks. For ethnicity, 4/44 studies formally reported participant ethnicity (three from 'Information and Support', one from 'Diagnosis'). In these, 93%, 90%, 60%, and 75% of participants were white/Caucasian (mean 79.5%). For age, 3/44 studies included adolescents. Many studies excluded women who were deemed outside reproductive age. For socioeconomic status, eight studies, all from 'Information and Support', reported socioeconomic status in some form. The majority of participants were tertiary educated. CONCLUSION: These results highlight the missing demographics within evidence cited in a national guideline for endometriosis. These align with documented inequities in diagnosis of endometriosis and warrant urgent attention.

Uncovering moderators of pain perception by women with endometriosis from Latin America and Spain: the roles of sociodemographics, racial self-identity, and pain catastrophizing.

ABSTRACT: A cross-sectional multinational collaborative study on women with endometriosis from Latin America and Spain uncovered high levels of painful symptomatology and high pain catastrophizing scores. Associations between pain perception/catastrophizing and race/ethnicity have been documented. This study was conducted to uncover factors moderating pelvic pain severity, including socioeconomic variables, self-identified race, and pain catastrophizing in women with endometriosis from Latin America and Spain, a population encompassing diverse racial and sociocultural contexts. Self-reported data on demographics, clinical history, Ob-Gyn history, pelvic pain intensity, and pain catastrophizing were collected with the Spanish World Endometriosis Research Foundation (WERF) Endometriosis Phenome Project (EPhect) Clinical Questionnaire (ECQ). Multiple logistic regression was conducted to analyze effects of self-identified race, demographic clusters (defined as countries with similar racial population distribution), socioeconomic factors, and pain catastrophizing on reporting severe vs moderate-mild levels of dysmenorrhea, dyspareunia, and pelvic pain. Self-identified race did not affect the likelihood of reporting severe pelvic pain; however, there were significant differences in reporting severe dysmenorrhea at worst among demographic clusters. Older age was associated with severe dyspareunia at worst and recent pelvic pain. Pain catastrophizing score was highly predictive of reporting most types of severe pelvic pain, regardless of race and demographic cluster. These results negate a role of racial categories as moderator of pain in women from Latin America and Spain and support integration of pain catastrophizing assessments and psychological interventions into the pain management plan to enhance therapeutic outcomes and QoL for patients with endometriosis.

Reframing pain: the power of individual and societal factors to enhance pain treatment.

The effectiveness of analgesics can be increased if synergistic behavioural, psychological, and pharmacological interventions are provided within a supportive environment.

World Endometriosis Research Foundation Endometriosis Phenome and Biobanking Harmonization Project: V. Physical examination standards in endometriosis research.

OBJECTIVE: The World Endometriosis Research Foundation established the Endometriosis Phenome and Biobanking Harmonisation Project (EPHect) to create standardized documentation tools (with common data elements) to facilitate the comparison and combination of data across different research sites and studies. In 2014, 4 data research standards were published: clinician-reported surgical data, patient-reported clinical data, and fluid and tissue biospecimen collection. Our current objective is to create an EPHect standard for the clinician-reported physical examination (EPHect-PE) for research studies. DESIGN: An international consortium involving 26 clinical and academic experts and patient partners from 11 countries representing 25 institutions and organizations. Two virtual workshops, followed by the development of the physical examination standards underwent multiple rounds of iterations and revisions. SUBJECTS: N/A MAIN OUTCOME MEASURE(S): N/A RESULT(S): The EPHect-PE tool provides standardized assessment of physical examination characteristics and pain phenotyping. Data elements involve examination of back and pelvic girdle; abdomen including allodynia and trigger points; vulva including provoked vestibulodynia; pelvic floor muscle tone and tenderness; tenderness on unidigital pelvic examination; presence of pelvic nodularity; uterine size and mobility; presence of adnexal masses; presence of incisional masses; speculum examination; tenderness and allodynia at an extra-pelvic site (e.g., forearm); and recording of anthropometrics. CONCLUSION(S): The EPHect-PE standards will facilitate the standardized documentation of the physical examination, including the assessment and documentation of examination phenotyping of endometriosis-associated pelvic pain.

Developing consensus on core outcome sets of domains for acute, the transition from acute to chronic, recurrent/episodic, and chronic pain: results of the INTEGRATE-pain Delphi process.

Background: Pain is the leading cause of disability worldwide among adults and effective treatment options remain elusive. Data harmonization efforts, such as through core outcome sets (COS), could improve care by highlighting cross-cutting pain mechanisms and treatments. Existing pain-related COS often focus on specific conditions, which can hamper data harmonization across various pain states. Methods: Our objective was to develop four overarching COS of domains/subdomains (i.e., what to measure) that transcend pain conditions within different pain categories. We hosted a meeting to assess the need for these four COS in pain research and clinical practice. Potential COS domains/subdomains were identified via a systematic literature review (SLR), meeting attendees, and Delphi participants. We conducted an online, three step Delphi process to reach a consensus on domains to be included in the four final COS. Survey respondents were identified from the SLR and pain-related social networks, including multidisciplinary health care professionals, researchers, and people with lived experience (PWLE) of pain. Advisory boards consisting of COS experts and PWLE provided advice throughout the process. Findings: Domains in final COS were generally related to aspects of pain, quality of life, and physical function/activity limitations, with some differences among pain categories. This effort was the first to generate four separate, overarching COS to encourage international data harmonization within and across different pain categories. Interpretation: The adoption of the COS in research and clinical practice will facilitate comparisons and data integration around the world and across pain studies to optimize resources, expedite therapeutic discovery, and improve pain care. Funding: Innovative Medicines Initiative 2 Join Undertaking; European Union Horizon 2020 research innovation program, European Federation of Pharmaceutical Industries and Associations (EFPIA) provided funding for IMI-PainCare. RDT acknowledges grants from Esteve and TEVA.

What are important areas where better technology would support women's health? Findings from a priority setting partnership.

BACKGROUND: Women's health has historically lacked investment in research and development. Technologies that enhance women's health ('FemTech') could contribute to improving this. However, there has been little work to understand which priority unmet needs should be a focus for women's health technology development. The voices of clinicians and those who experience and utilise these technologies (including those used at home or encountered in clinical settings) are needed to ensure that device development aligns with need, without risking exacerbating or creating health inequities. METHOD: We undertook a priority setting partnership project exploring unmet needs in women's health and well-being where physical technologies or innovations could help. This comprised gathering feedback from: patients and clinicians using both qualitative surveys and discussions; collating and publishing these responses and asking for feedback; evidence checking unmet needs identified, and holding a partnership priority setting event to agree a top 10 and top 20 list of priorities. RESULTS: We generated a 'longlist' of 54 suggestions for areas where better kit, devices or equipment could support women's health. For three, we found evidence of existing technologies which mitigated against that need. We took the remaining 51 suggestions to a partnership priority setting meeting which brought together clinicians and service users. Through discussion as this group, we generated a list of the top 10 areas identified as priorities for technological development and improvement. These included better devices to manage examination, diagnosis and treatment of pelvic pain (including endometriosis), prolapse care, continence (treatment and prevention, related to pregnancy and beyond), menstruation, vaginal pain and vaginismus, point of care tests for common infections, and nipple care when breastfeeding. CONCLUSION: The top priorities suggest far-reaching areas of unmet need across women's life course and across multiple domains of health and well-being, and opportunities where innovation in the devices that people use themselves or encounter in health settings could potentially enhance health and healthcare experiences.

Endometriosis - a painful disease.

PURPOSE OF REVIEW: This review looks to overview advances in endometriosis-associated pain, both in understanding the pain mechanisms involved and increasing treatment options with well designed clinical trials and meta-analyses. RECENT FINDINGS: Our understanding of endometriosis-associated pain has progressed from a purely nociceptive model to an awareness that both neuropathic and nociplastic mechanisms can be present for some people with endometriosis. Clinical trials and meta-analyses have demonstrated efficacy of surgical treatments and hormonal therapies. It is notable that currently, the basic science and clinical trials are not cross-fertilising. SUMMARY: Following growth in other areas of chronic pain, there have been significant advances in our understanding of endometriosis-associated pain. However, there remains lots to explore and we are currently a long way from our goal of timely personalized holistic multidisciplinary treatment for all sufferers of endometriosis-associated pain.

Clinical profiling of specific diagnostic subgroups of women with chronic pelvic pain.

Introduction: Chronic pelvic pain (CPP) is a common condition affecting up to 26.6% of women, with many suffering for several years before diagnosis and/or treatment. Its clinical presentation is varied and there are frequently comorbid conditions both within and outside the pelvis. We aim to explore whether specific subgroups of women with CPP report different clinical symptoms and differing impact of pain on their quality of life (QoL). Methods: The study is part of the Translational Research in Pelvic Pain (TRiPP) project which is a cross-sectional observational cohort study. The study includes 769 female participants of reproductive age who completed an extensive set of questions derived from standardised WERF EPHect questionnaires. Within this population we defined a control group (reporting no pelvic pain, no bladder pain syndrome, and no endometriosis diagnosis, N = 230) and four pain groups: endometriosis-associated pain (EAP, N = 237), interstitial cystitis/bladder pain syndrome (BPS, N = 72), comorbid endometriosis-associated pain and BPS (EABP, N = 120), and pelvic pain only (PP, N = 127). Results: Clinical profiles of women with CPP (13-50 years old) show variability of clinical symptoms. The EAP and EABP groups scored higher than the PP group (p < 0.001) on the pain intensity scales for non-cyclical pelvic pain and higher than both the BPS and PP groups (p < 0.001) on the dysmenorrhoea scale. The EABP group also had significantly higher scores for dyspareunia (p < 0.001), even though more than 50% of sexually active participants in each pain group reported interrupting and/or avoiding sexual intercourse due to pain in the last 12 months. Scores for the QoL questionnaire (SF-36) reveal that CPP patients had significantly lower QoL across all SF-36 subscales (p < 0.001). Significant effects were also observed between the pain groups for pain interference with their work (p < 0.001) and daily lives (p < 0.001), with the EABP suffering more compared to the EAP and PP groups (p < 0.001). Discussion: Our results demonstrate the negative impact that chronic pain has on CPP patients' QoL and reveal an increased negative impact of pain on the comorbid EABP group. Furthermore, it demonstrates the importance of dyspareunia in women with CPP. Overall, our results demonstrate the need for further exploration of interventions targeting QoL more broadly and suggest that novel approaches to classifying women with CPP are needed.

Comprehensive quantitative sensory testing shows altered sensory function in women with chronic pelvic pain: results from the Translational Research in Pelvic Pain (TRiPP) Study.

ABSTRACT: Chronic pelvic pain (CPP), despite its high prevalence, is still relatively poorly understood mechanistically. This study, as part of the Translational Research in Pelvic Pain (TRiPP) project, has used a full quantitative sensory testing (QST) paradigm to profile n = 85 women with and without CPP (endometriosis or bladder pain specifically). We used the foot as a control site and abdomen as the test site. Across 5 diagnostically determined subgroups, we found features which are common across different aetiologies, eg, gain of function in pressure pain threshold (PPT) when assessing responses from the lower abdomen or pelvis (referred pain site). However, disease-specific phenotypes were also identified, eg, greater mechanical allodynia in endometriosis, despite there being large heterogeneities within diagnostic groups. The most common QST sensory phenotype was mechanical hyperalgesia (>50% across all the groups). A "healthy' sensory phenotype was seen in <7% of CPP participants. Specific QST measures correlated with sensory symptoms assessed by the painDETECT questionnaire (pressure-evoked pain [painDETECT] and PPT [QST] [ r = 0.47, P < 0.001]; mechanical hyperalgesia (painDETECT) and mechanical pain sensitivity [MPS from QST] [ r = 0.38, P = 0.009]). The data suggest that participants with CPP are sensitive to both deep tissue and cutaneous inputs, suggesting that central mechanisms may be important in this cohort. We also see phenotypes such as thermal hyperalgesia, which may be the result of peripheral mechanisms, such as irritable nociceptors. This highlights the importance of stratifying patients into clinically meaningful phenotypes, which may have implications for the development of better therapeutic strategies for CPP.

Effectiveness of laparoscopic removal of isolated superficial peritoneal endometriosis for the management of chronic pelvic pain in women (ESPriT2): protocol for a multi-centre randomised controlled trial.

BACKGROUND: Endometriosis affects 190 million women and those assigned female at birth worldwide. For some, it is associated with debilitating chronic pelvic pain. Diagnosis of endometriosis is often achieved through diagnostic laparoscopy. However, when isolated superficial peritoneal endometriosis (SPE), the most common endometriosis subtype, is identified during laparoscopy, limited evidence exists to support the common decision to surgically remove it via excision or ablation. Improved understanding of the impact of surgical removal of isolated SPE for the management of chronic pelvic pain in women is required. Here, we describe our protocol for a multi-centre trial to determine the effectiveness of surgical removal of isolated SPE for the management of endometriosis-associated pain. METHODS: We plan to undertake a multi-centre participant-blind parallel-group randomised controlled clinical and cost-effectiveness trial with internal pilot. We plan to randomise 400 participants from up to 70 National Health Service Hospitals in the UK. Participants with chronic pelvic pain awaiting diagnostic laparoscopy for suspected endometriosis will be consented by the clinical research team. If isolated SPE is identified at laparoscopy, and deep or ovarian endometriosis is not seen, participants will be randomised intraoperatively (1:1) to surgical removal (by excision or ablation or both, according to surgeons' preference) versus diagnostic laparoscopy alone. Randomisation with block-stratification will be used. Participants will be given a diagnosis but will not be informed of the procedure they received until 12 months post-randomisation, unless required. Post-operative medical treatment will be according to participants' preference. Participants will be asked to complete validated pain and quality of life questionnaires at 3, 6 and 12 months after randomisation. Our primary outcome is the pain domain of the Endometriosis Health Profile-30 (EHP-30), via a between randomised group comparison of adjusted means at 12 months. Assuming a standard deviation of 22 points around the pain score, 90% power, 5% significance and 20% missing data, 400 participants are required to be randomised to detect an 8-point pain score difference. DISCUSSION: This trial aims to provide high quality evidence of the clinical and cost-effectiveness of surgical removal of isolated SPE. TRIAL REGISTRATION: ISRCTN registry ISRCTN27244948. Registered 6 April 2021.