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

This systematic literature review (SLR) was conducted as part of the Innovative Medicines Initiative (IMI) Pain Care Project (Improving the care of patients suffering from acute or chronic pain, Grant Agreement NR. 777500), following the Cochrane's methodology (Participants, Intervention, Comparator, Outcome, Study design) and in accordance with the Preferred Reporting Items for Systematic Reviews (PRISMA) 2009 guidelines. This SLR was pre-registered at the International Prospective Register of Systematic Reviews (PROSPERO) (Registration Number 147765, 12/2019, update 05/2021). The inclusion and exclusion criteria were defined following the PICOS criteria (P, population; I, intervention; C, comparison; O, outcome; S, study design 137 ). Only peer-reviewed, randomized controlled trials evaluating the effectiveness of pharmacological and nonpharmacological pain management for chronic pelvic pain associated with endometriosis were included. When screening studies for inclusion, particular attention was given to ensure that participants had experienced symptomatic pain related to endometriosis for a minimum duration of ≥3 months. Trials investigating primary surgery as an intervention were not considered because differentiation between diagnostic and treatment studies is difficult. Eligible interventions were systemic (oral and intravenous) or topical (eg, subcutaneous and cutaneous) medication, additionally, nonpharmacological treatments, such as acupuncture, physiotherapy, or psychotherapy were included if pain was a primary target of the intervention. All interventions were eligible if they either had a duration of ≥2 weeks or, for single administrations of drugs with long-term efficacy (such as hormonal depot application), if the follow-up was ≥2 weeks. According to the current International Association for the Study of Pain (IASP) and ICD-11 definition, chronic pelvic pain was defined as pain with a duration of 3 months or longer. 206 Only studies in English, French, or German language were included. Studies investigating less than 20 patients, patients younger than 18 years, or conditions other than chronic pelvic pain related to endometriosis without subgroup analysis were excluded. Ongoing studies, retrospective studies, and studies that were only published as abstracts were also excluded. The inclusion and exclusion criteria are summarized in Table 1 . Inclusion and exclusion criteria. mo, months; wk, weeks; y, years The MEDLINE, CENTRAL, and Embase electronic databases were electronically searched from the inception date of the respective database to July 2022. The database-specific search strings are shown in the supplemental digital content. Additional records were identified by an additional citation searching from the reference lists of included articles (“hand/citation search”). All identified possibly eligible studies were screened after exclusion of duplicates, using titles and abstracts by 5 independent reviewers (I.S., D.R., E.M., K.S., and F.F.) in a double-blinded manner by use of the RAYYAN program ( https://rayyan.qcri.org/ ). Thereby, every abstract was evaluated by at least 2 reviewers. Then, full-text screening, data extraction and grading of study quality was conducted by the same 4 reviewers with an overlap of ≥20% of studies extracted by more than one reviewer (differences in extraction were discussed and resulted in refinement of extraction criteria applied by all reviewers on all extractions). In case of disagreement during the process that could not be resolved by discussion, the principal investigator of this study (E.P.Z.) was involved for a final decision. The following data were gathered from the included studies: (1) study characteristics (first author, publication year, pharmaceutical funding, country of study conduction, study design, number of investigated patients, and a description of study population including mean disease duration, mean pain duration, and age), (2) information on interventions and comparators used (investigated treatment, comparators, methods, and duration of administration), and (3) all outcome parameters. A detailed list of extracted data is given in supplemental digital content (see Table 1, http://links.lww.com/PAIN/C69 ). All domains assessed with specific PROMs and the PROMs used (eg, completely used, short form, incompletely used, modified, self-constructed, description and reference article, and time points of assessment) were extracted. Patient-reported outcome measures were categorized and aggregated under their domains as recommended by the Core Outcome Measures in Effectiveness Trials (COMET) initiative (an initiative that fosters methodological research in this area 222 ) and, more recently, by Young et al. 228 Content wise, the domains recommended by IMMPACT for chronic pain (including pain, physical functioning , emotional functioning, participant ratings of improvement and satisfaction with treatment (short: improvement and satisfaction), and adverse events ) were considered a major guide for subgrouping PROMs. 67 However, potential other domains were considered as well. The domain participant disposition 67 was addressed by extracting general information about the included studies (eg, recruitment and patients lost to follow-up) and evaluating this information in the context of risk of bias grading. To cover the different aspects of the domain pain , PROMs within this domain were further divided in the subdomains pain intensity scales , pain intensity other (ie, questionnaires rating p ain intensity by other measures, such as daily activity or analgesic intake ) and other aspects of pain . Accordingly, the domain physical functioning was subdivided into daily activity , sleep , and generic measures of health-related quality of life (HRQOL). Measures for health-related quality of life addressing physical functioning and emotional functioning specifically were assigned in these categories. Patient-reported outcome measures covering other aspects were also extracted, as well as questionnaires or scales to assess other symptoms, adverse events, and rescue medication. The risk of bias was evaluated for each study according to the GRADE guidelines 95 , 113 and rated as “fulfilled” (no limitation), “not fulfilled” (crucial limitation), and “not clear” (some limitation) for the criteria lack of allocation concealment, lack of blinding, incomplete accounting of patients and outcome events, selective outcome reporting bias, stopping early for benefit, use of nonvalidated outcome measures, and the carryover effect in cross over trials. The criteria for rating each item were defined precisely to guarantee that all reviewers graded as similarly as feasible (supplemental digital content, Table 2, http://links.lww.com/PAIN/C69 ). The quality of each study was then classified in 3 categories, “high,” “moderate,” and “low”. High quality was defined as a low risk of bias for all GRADE criteria. Moderate quality allows for either one crucial limitation for one criterion and/or some limitations for ≥ one criterion. Low quality was defined as a crucial limitation for more than one criterion or a crucial limitation for one criterion and some limitation for multiple criteria. Finally, to evaluate the quality of endometriosis-specific PROMs, the development process of PROMs used in around 10% of the trials or more was assessed according to the COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) initiative recommendation risk of bias checklist, box 1. 162 , 204 The checklist consists of 35 items, which were assessed by 2 independent raters (DCR and EPZ) for the Biberoglu and Behrman scale (used in ∼30% of all trials) and the Endometriosis Health Profile Questionnaire (EHP-30, used in ∼10% trials) by using the respective inauguration/development articles. 29 , 117 Data analysis was primarily descriptive as the aim of this SLR was to identify domains and PROMs used in clinical trials on chronic pelvic pain associated with endometriosis. First, all PROMs were listed within the appropriate domain. Second, for each study, the number of domains and PROMs per domain were listed. Third, PROMs and number of domains were compared for different study groups based on study quality and publication year (before or after publication of the IMMPACT recommendations for chronic pain trials). 67 Statistical analysis was performed using IBM SPSS statistics for Windows (version 23.0, NY).

The PRISMA flowchart of the literature search is shown in Figure 1 . In total, 1315 potentially eligible records were identified through database searching (MEDLINE, Embase, and CENTRAL). In addition, 57 articles were identified by hand/citation search. After removing all duplicates, 1286 abstracts were screened according to the predefined inclusion and exclusion criteria. After resolving all disagreements, 310 full-text articles were assessed for eligibility. Finally, 189 publications met the inclusion criteria and were included in the SLR. Two articles, comprising results of more than one study, were considered and extracted as 2 separate studies each. Thus, the final number of analyzed studies was 191. PRISMA Flowchart of included studies. A total of 191 studies were included in the analysis. Approximately half of these studies (101, 52.9%) were double-blinded RCTs with a parallel-group design. 83 studies (43.5%) had an open-label phase after randomization or single-blind (8, 4.6%) phase, mostly due to the form of intervention (eg, injections vs oral medication), whereas only 2 studies had a cross-over design and 4 studies had a different or not clearly defined study design. Almost half of the studies (78, 40.8%) were sponsored or initiated by a pharmacological company, and in 64 studies (33.5%), no conflict of interest was stated, whereas in 49 studies (25.7%), this information was missing. In 49 studies (25.7%), pain assessment was defined as the only primary outcome, further 20 studies (10.5%) defined it as one of the primary outcomes, while 27 studies (14.1%) assessed it as a secondary outcome. In 91 studies (47.6%), the primary outcome was not defined, and 4 studies (2.1%) defined primary and secondary outcomes, but pain assessment was not a part of it. Included patients were exclusively female and most frequently in the age group of 30 to 40 years (102, 53.4%), followed by 18 to 29 years (20, 10.5%). In 32 studies (16.8%), the intervention groups differed in age. Most of the patients included in the studies had previously undergone diagnostic (102, 53.4%) or therapeutic surgery (48, 25.1%) to confirm the diagnosis (endometriosis). 25 studies (13.1%) specifically defined chronic pelvic pain ≥3 months and 29 studies (15.2%) described the pain as “chronic” or “recurrent” for inclusion. In all other studies (137, 71.7%) for the included patients, a disease duration ≥3 months (including painful symptoms) was given. Most interventions studied in the trials were hormonal treatments, including GnRH receptor antagonists (162, 84.8%). Only 6 studies (3.1%) used analgesics, 10 (5.2%) used other drugs, and 21 (11.0%) used nonpharmacological treatments. Of 22 studies combining interventions, 20 were combined with hormonal treatment. In total, 69 studies (36.1%) were placebo-controlled, while 123 studies (64.4%) used a hormonal treatment or other pharmacological (2, 1.0%) or nonpharmacological comparators (8, 4.2). 42 studies (22.0%) had more than one comparator arm. A detailed list of study characteristics is given in supplemental digital content (see table 3, http://links.lww.com/PAIN/C69 ). All included studies were graded according to the risk of bias GRADE criteria 95 , 113 (supplemental digital content, Table 2, http://links.lww.com/PAIN/C69 ). More than half of the studies (113, 59.2%) were of a moderate-to-high methodological quality, while the rest (78, 40.8%) were of low methodological quality. GRADE for each study is shown in supplemental digital content (see Table 4, http://links.lww.com/PAIN/C69 ). The outcome assessment items (ie, PROMs) used within the included studies were sorted according to the IMMPACT domains pain (including the subdomains pain intensity [scales] , pain intensity other, pain relief, pain other aspects , and rescue medication ), emotional functioning , physical functioning (including generic measures of HRQOL, daily activity, sleep, and physical functioning other aspects ), improvement and satisfaction , and adverse events . 67 Table 2 summarizes the assessed domains for each individual study included in the analysis. The following section will focus first on domains across all included studies, followed by the PROMs used to assess the domains. IMMPACT—Core DOMAINs (Pain, Emotional Functioning, Physical Functioning, Satisfaction, and Adverse events) and subdomains assesses by each study included in this SLR ● Domain was assessed. The domain pain was assessed in almost every study (188, 98.4%) and the domain adverse events (and side effects) in almost 3/4 of the studies (144 studies, 73.8%). By contrast, other domains were assessed much less frequently (Figure 2 A, Table 2 ): physical functioning in only 57 studies (29.8%), improvement and satisfaction in only 27 studies (14.1%), and emotional functioning in only 13 studies (6.8%) (Figure 2 A, Table 2 ). Comparing the studies with high/moderate methodological quality to those with low quality, we found some differences related to domains assessed. Overall, an average (±SD) of 2.3 ± 0.9 domains were assessed, but the number of domains assessed was slightly higher (2.5 ± 0.9 domains) for studies of moderate-to-high methodological quality as compared with studies of low quality (2.0 ± 0.8 domains). Sixteen studies of high/moderate quality, but only 4 of low quality, investigated 4 or 5 domains. Similarly, of those studies using 3 domains or more (65 studies [34.0%]), 51 studies (45.1%) were of high/moderate quality and 14 (17.9%) of low quality (Figure 2 A and supplemental digital content, Fig. 1, http://links.lww.com/PAIN/C69 ). The subdomain pain intensity was used more frequently in studies of high quality than in studies of low quality (87.6% vs 57.7%). Physical functioning was used in 38.9% of all high/moderate-quality studies, but only in 16.7% of all low-quality studies. Emotional functioning was assessed in slightly more studies of high/moderate quality (8.0% vs 5.1%). For the subdomains sleep, daily activity , and other aspects , there were only slight differences as both were hardly used at all. Improvement and satisfaction was examined more frequently in high/moderate-quality studies compared with low-quality studies (20.4% vs 5.1%). Regarding adverse events , there was only a slight difference between high/moderate-quality and low-quality studies (80.5% vs 71.8%). (A) Occurrence of domains assessed in studies on management of endometriosis-related pain (n = 191) (% of studies, see indicator on the left side of the boxes [black triangle, upper number] for studies of moderate to high methodological quality [h/m] and indicator on the right side [empty triangle, lower number] for studies of low methodological quality [low]); (B) combinations of domains in these studies (% of studies [and total numbers]). For better readability, only studies of moderate to high methodological quality and combinations that were used more than once are included in graph (B). If a combination of three domains is congruent with a combination of four domains, only the combination of four domains is shown. For more details see Table 3. gmHRQoL, general measures of health related quality of life. Combinations of used domains varied widely between studies. The most frequent combinations were pain and adverse events (77.0% of all studies, 80.5% of high/moderate quality, and 71.8% of low methodological quality), followed by pain and physical functioning (29.8% of all studies, 38.9% of high/moderate quality, and 16.7% of low methodological quality; see Figure 2 B). The most frequent combinations of 3 domains assessed together were pain , adverse events , and physical functioning (47 studies, 24.6%, 33.6% of high/moderate quality, 11.5% of low methodological quality), as well as pain , adverse events , and improvement and satisfaction (25 studies, 13.1%, 18.6% of high/moderate quality, 5.1% of low methodological quality), followed by pain with emotional and physical functioning (12 studies, 6.3%, 7.1% of high/moderate quality, 5.1% of low methodological quality) and pain, improvement and satisfaction , and physical functioning (12 studies, 6.3%, 8.9% of high/moderate quality, 2.6% of low methodological quality) (Fig. 2B). Combination of 4 domains was rare. Pain, improvement and satisfaction, physical functioning , and adverse events were assessed in 12 studies together (6.3%, 8.9% of high/moderate quality, 2.6% of low methodological quality), followed by pain , emotional and physical functioning , and adverse events in 9 studies (4.7%, 6.9% of high/moderate quality, 2.6% of low methodological quality). Only 2 studies assessed all 5 domains (1 study of high/moderate quality and 1 of low methodological quality). A detailed overview of the distribution of the domains is summarized in Table 2 and combination of used domains over all studies is summarized in Table 3 . Combination of domains assessed within the same studies (n [%]). Patient-reported outcome measures used to assess the above-mentioned domains are summarized in Table 4 . Results will be presented for each domain separately here. Frequencies of PROMs that were used in the included studies according to the IMMPACT domains (n [%]). “Questionnaire,” “diary,” and “subjective scale” (if not mentioned above separately). See supplemental digital content (Table 5, http://links.lww.com/PAIN/C69 ) for an overview of PROMs specifically addressing endometriosis. These PROMs were used only partly (subanalysis for pain). For the domain pain (n = 188, 98.4%, Table 4 ), a variety of different PROMs were used (Table 4 ). To assess pain , in general, 129 studies (67.5%) used one PROM, 46 studies (24.1%) used 2 PROMs, 12 studies (6.3%) used 3 PROMs, and 2 studies (1.0%) used 4 PROMs. Most of these studies assessed pain through instruments, which can be categorized into the subdomain pain intensity (144, 75.4%). The most frequently used PROMs for pain intensity were visual analog scales (VAS; 98 studies, 51.3%), followed by verbal rating scales (VRS; 35 studies, 18.3%) and numeric rating scales (NRS; 16 studies, 8.4%). For pain intensity , 12 studies (6.3%) used 2 PROMs and 2 studies (1.0%) used 3 PROMs. Other PROMs that assessed pain intensity by using a scale that evaluates pain intensity through surrogate parameters were summarized as pain intensity other . These were used in 67 studies (35.1%; 10 studies [5.2%] used 2 PROMs). A prominent example of such composite measures specific for endometriosis is the Biberoglu and Behrman Scale (compare below, endometriosis-specific PROMs ). Similarly, PROMs assessing several aspects of pain not falling under the pain subdomain pain intensity (eg, composite measures) were categorized under pain-specific PROMs , other aspects . This was, however, rarely the case. For example, the painDETECT questionnaire was used by one study (0.5%) and the McGill Pain Questionnaire by 2 studies (1.0%). Seventeen studies (9.9%) used other PROMs for assessing pain , which were not specified (eg, “(symptom) diary” and “valid questionnaire”), 4 studies (2.1%) used self-constructed questionnaires, and 3 studies (1.6%) asked for “pain relief,” using a 4-point VRS scale. Rescue pain medication , allowed additionally to the investigated treatment, was assessed in 68 studies (35.6%), mostly using diaries (25 studies, 13.1%). Two studies used the Endometriosis Daily Impact Diary, while 35 studies (18.3%) did not indicate the used measure at all. PROMs for the assessment of emotional functioning were used in 13 studies (6.8%); 4 studies (2.1%) used 1 PROM, 8 studies (4.2%) used 2, and 1 study (0.5%) used 4 PROMs for this domain. The most frequently used PROMs for emotional functioning were the Hospital Anxiety and Depression Scale (used in 5 studies [2.6%]; 1 incompletely) and the State-Trait Anxiety Inventory (4 studies, 2.1%). Two studies used author-indicated PROMs for the assessment of emotional functioning , that is, the PROMs were used differently than intended (Woman Health Questionnaire, incompletely used, and Psychological general wellbeing questionnaire). Physical functioning was assessed in 57 studies (29.8%) by using different PROMs. 12 studies (6.3%) used 2, 3 studies (1.6%) used 3 PROMs, 1 study (0.5%) used 4, and 2 studies (1.0%) used 5 PROMs. Most studies assessed physical functioning through the subdomain generic measures of HRQOL (53 studies, 27.7%; 5 studies [2.6%] used 2 PROMs) (Table 4 ). For generic measures of HRQOL , the SF-36 (22 studies, 11.5%; 4 studies [2.1%] used the short form SF-12 and 2 [1.0%] used it incompletely), followed by the Endometriosis Health Profile Questionnaire (EHP-30) were used (19 studies, 9.9%; 6 [3.1%] used the short form EHP-5 and 9 used it incompletely). The subdomain daily activity was assessed in 8 studies (4.2%) and sleep in 5 studies (2.6%; one study used 2 PROMs); 11 studies (5.8%) used other PROMs to assess physical functioning , mostly addressing sexual function. The domain improvement and satisfaction was assessed in 27 studies (14.1%, 1 study [0.5%] used 2 PROMs; Table 4 ). The most frequently used PROMs for assessing this domain were the Patient Global Impression of Change (PGIC; 7 studies, 3.7%) and questionnaires without further specification asking for an “overall degree of satisfaction” (6 studies, 5.3%). In total, 147 studies (73.8%; 29 studies used 2 PROMs) assessed adverse events (and/or side effects) that occurred under the investigated treatment (Table 4 ). Although most studies (101; 52.9%) did not indicate how this was measured, 37 (19.4%) used a “diary” without further specification and only 15 studies used specific scales or questionnaires, for example, the Kuppermann Index (5, 2.6%). Two questionnaires for assessment of endometriosis-specific symptoms were mainly used: the Biberoglu and Behrman scale (used in 56 studies, 29.3%; 25 studies [13.1%] used it incompletely and 16 studies [8.4%] in a modified version) and the Andersch and Milsom questionnaire (used in 7 studies 4%; all used in modified versions). The Biberoglu and Behrman scale estimates pain intensity based on discomfort/need for analgesics for pelvic pain, loss in work efficiency for dysmenorrhea, and limitations regarding intercourse for dyspareunia. 29 The Andersch and Milsom scale, developed to assess dysmenorrhea, claims to assess pain severity based on questions related to work performance, systematic symptoms, and analgesic use. 16 Only a few studies used other specifically endometriosis-related pain scales, such as the VRS-based endometriosis daily impact eDiary (2 studies, 1.0%) to assess pain . Regarding other domains, only a few endometriosis-specific PROMs were used, such as the Endometriosis Health Profile Questionnaire (EHP-30) and its short form (used in 19 studies [9.9%] and 6 studies [3.1%], respectively, compare supplemental digital content, Table 5, http://links.lww.com/PAIN/C69 ) were used as generic measures of HRQOL . The structured extraction of the assessment of bleeding patterns was difficult because this aspect was hardly described explicitly. Only 44 studies (23.0%) described the assessment of bleeding patterns at all, 24 of these among the adverse events assessment. 13 studies (6.8%) described this assessment using calendars or diaries. For a detailed overview of the different endometriosis-specific PROMs used, see supplemental digital content (see Table 5, http://links.lww.com/PAIN/C69 ). Self-constructed questionnaires were indicated in a minority of all studies; 4 studies used 1 self-constructed instrument for pain and 1 study used a self-constructed instrument for generic measures of HRQOL . However, it has to be considered that many used scales and questionnaires, for example, 3 to 11 “point-scales” or “Likert-scales,” were not further described and had no references and thus are likely to be self-constructed, too. In addition, many questionnaires were used in modified and/or incomplete versions (Table 4 ). Comparing the use of PROMs between studies of moderate-to-high vs low methodological quality revealed differences between these categories. Regarding pain intensity , more studies of moderate-to-high quality used VAS (65.5% vs 30.8%) and VRS (23.9% vs 10.3%), while studies of low methodological quality used more PROMs that were not clearly described (11.5% vs 0.9%) and self-constructed scales (0.9% vs 5.1%). Rescue medication was assessed more frequently in studies of moderate-to-high quality (45.1% vs 21.8%). Approximately one-third of all studies of moderate-to-high quality used PROMs of the subdomain generic measures of HRQOL (vs 16.7% of the low-quality studies). Here, the most frequently used PROMs, the SF-36 and SF-12, as well as the endometriosis-specific EHP-30 and EHP-5 were mainly used in studies of moderate-to-high methodological quality (30.9% vs 15.4%). For the assessment of improvement and satisfaction , the PGIC was only used in studies of moderate-to-high quality (7 studies, 6.2%) but not in low-quality studies. For the assessment of adverse events , almost all designated (eg, Ferriman and Gallway Score) and clearly described PROMs (eg, VAS or “diary”) were used in studies of moderate-to-high quality, while the fraction of instruments that were not described clearly was larger in low-quality studies (17.9% vs 10.6%). However, both groups had a high proportion of studies that did not describe at all how adverse events were assessed (high/moderate: 56.6% vs low-quality: 42.3%). The use of PROMs developed specifically for patients with endometriosis is highly relevant to address their specific needs. Characteristics of endometriosis-specific PROMs are listed in supplemental digital content (see Table 6, http://links.lww.com/PAIN/C69 ). Whereas the overall rating of the EHP-30 questionnaire (a questionnaire assessing HRQOL in patients with endometriosis) was adequate (subscales were rated “doubtful” to “very good”), the overall rating for the Biberoglu and Behrman scale (a scale used to assess pain levels in patients with endometriosis) development study was inadequate, as were all subscales (see supplemental digital content, Table 7, http://links.lww.com/PAIN/C69 ). In fact, the scale was basically used in an interventional study without any description of the development process.

This systematic literature review revealed profound heterogeneity in both, domain assessment and PROMs used to evaluate symptoms in pain-related efficacy trials in endometriosis. The identified 5 domains (and subdomains) were categorized in accordance with the IMMPACT's outcome assessment recommendations for trials on chronic pain. 67 Although nearly all studies assessed the domain pain intensity , and approximately three-quarters assessed adverse events , other domains, such as emotional functioning (6.8%), physical functioning (29.8%), and improvement and satisfaction (14.1%) were considerably less frequently appraised. Despite the substantial impact that pain-related symptoms, such as those related to emotional functioning , exert on patients' quality of life, their assessment in the context of endometriosis is surprisingly inconsistent. 7 , 116 , 117 Chronic pain, acknowledged as a multidimensional entity and recognized as a disease by the WHO, 207 is overlooked in most clinical interventional trials related to endometriosis-associated pain. Merely one-third of studies assessed more than 3 domains, with pain , physical functioning, and adverse events as the predominant combination of domains. This neglects pain-related psychosocial symptoms, although it is well-established that pain severity alone is insufficient to evaluate how a patient's life is affected. 50 , 151 , 235 Alignment of perspectives from healthcare professionals and patients remains a challenge in numerous chronic pain conditions, including endometriosis, 71 but also other entities of chronic pelvic pain, 86 , 87 postsurgical pain, 30 , 131 chronic low back pain, 50 or fibromyalgia. 63 As recommended by COMET, the initial step toward achieving this alignment is defining the domains that warrant evaluation. 222 In addition to domains, this review explores PROMs used to assess the domains in pain-related efficacy trials in endometriosis. This not only guided to identify the assessed domains as advised by COMET and Young et al. 222 , 228 but also highlights heterogeneity in assessment strategies when different PROMs are used for the same (sub-)domain. Mirroring the diversity in domain usage, our results show a vast variety of used PROMs even within a single (sub-)domain, further complicating study comparison, restricting data for meta-analysis and recommendations, and hindering the evaluation of therapeutic effectiveness. Furthermore, many instruments lacked detailed descriptions, contributing to a high proportion categorized as “other” within the respective domains. Heterogeneity and insufficient PROM description, along with the use of incomplete or modified versions, further impede comparability. Approximately 73% of studies using the Biberoglu and Behrman scale (41/56) used modified or incomplete versions, often without any explanations for the nature and extent of modifications. Furthermore, the quality of PROMs used to assess a specific domain is critical. Here, guidance by COSMIN and COMET is essential to determine suitable instruments to measure defined outcome domains. 82 , 222 For pain intensity assessment, various unidimensional scales, such as NRS, VRS, and VAS, and—even within one form of scale—different anchors as descriptors of extremity were used, which might affect outcomes and hamper comparability. 107 However, following the IMMPACT recommendations and Hjermstad and colleagues, NRS, VRS, and VAS are still considered the most sensitive and suitable PROMs for pain intensity in trials in chronic pain and other types of pain. 67 , 107 Notably, many of the identified endometriosis-specific PROMs differ markedly from recommended scales in the pain field, with the most frequently used Biberoglu and Behrman scale deemed inadequately developed based on the COSMIN recommendations. 163 , 204 Thus, this instrument cannot be recommended for assessing pain in endometriosis clinical trials. 31 , 84 In addition, none of the endometriosis-specific PROMs differentiate appropriately between nociceptive and neuropathic pain. 174 Owing to evidence of both forms in patients with endometriosis, alongside tremendously different treatment options, 111 , 235 questionnaires for differentiation of neuropathic and nociceptive pain should be considered. 17 , 174 Presenting the vast diversity of outcome assessment in efficacy trials for chronic endometriosis-related pain, our comprehensive analysis of all domains and their respective PROMs reveals a devastating gap in addressing bio–psycho–social aspects crucial for patients with chronic pain in general and endometriosis in particular. Our results underscore the urgent need to define prioritized domains in clinical studies on pain-related interventions for endometriosis. Defining a core outcome set (COS) of domains and corresponding PROMs would improve study comparability, clinical and patient relevance, and thereby facilitate evaluation of treatment options. Moreover, it might improve communication between patients and health professionals through reflection and focusing on the experience of the patients and thus improve patient centred health care. 93 In addition, an inclusive consideration of the holistic bio–psycho–social framework encourages exploration of more comprehensive multimodal approaches to ascertain efficacy in the future. A very recent COS initiative, the INTEGRATE initiative, developed an overarching COS of domains for all chronic pain entities including the domains pain , activities of daily living , and HRQOL . 33 Ideally, a COS representing a minimum of domains to be assessed in all clinical trials on endometriosis-related chronic pain should be developed with healthcare professionals and patients together. Such a process aligns closely with the recommendations outlined by the COMET and the COSMIN initiative. 163 , 222 , 223 After consenting on a COS of domains (ie, the next step in forming a COS for endometriosis-related pain 222 ), corresponding PROMs need to be searched and assessed for psychometric properties. Particularly pain-related PROMs seem lacking in development or validation in patients with endometriosis-related pain. 31 Additional evaluation of the development process of the Biberoglu and Behrman scale following COSMIN guidelines for assessing quality of a PROM 163 , 204 revealed an inadequate development process, indicating it unsuitable for recommendation within in a COS. By contrast, our analysis indicates a rather good quality of the development process of the HRQOL questionnaire EHP-30 based on the COSMIN risk of bias checklist. This finding aligns with a previous review on HRQOL measures for patients with endometriosis. 32 To the best of our knowledge, this is the first and most comprehensive systematic literature research on the use of all domains and corresponding PROMs in clinical trials on chronic pelvic pain related to endometriosis in adults. One strength is its comprehensiveness, encompassing nearly 200 articles, extracting domains and PROMs, and performing analysis according to IMMPACT and study quality. To ensure accuracy, 4 reviewers were trained in data extraction, and ≥ 20% of studies were reviewed by multiple reviewers until a high level of agreement was reached. One limitation might be the exclusion of studies in adolescents and the search in only the large databases MEDLINE, CENTRAL, and Embase without considering databases such as PSychINfo or CONAHL. The results are largely consistent with previous literature reviews 31 , 87 , 149 , which have described and evaluated outcome measures in patients with chronic pelvic pain (CPP), including endometriosis. However, their focuses differed, studying outcome assessment in CPP in general without considering endometriosis separately, 87 the use of PROMs in endometriosis populations, but mainly the subdomain pain intensity , 31 or analysing PROMs regarding their applicability and validity in endometriosis populations without performing comprehensive analysis of the status quo in the current literature. 149 Although some PROMs were developed specifically for patients with endometriosis, encompassing various domains beyond pain , some lack validation for this population. 31 , 149 Yet, none of these reviews considered all IMMPACT domains, thus overlooking the psychosocial aspects of pain-related symptoms. We aimed to categorize domains in alignment with IMMPACT classifications as closely as possible. However, we acknowledge that categorizing certain PROMs, not referenced in literature, or applicable to multiple domains, might be debatable. 67 Furthermore, the classification of PROMs' short-forms, incomplete versions, or modifications was based on descriptions in the original publications. Various levels of precision in these descriptions of the content and intention of the used PROMs may have resulted in minor misclassifications.

This SLR identified an important variability in outcome domains and outcome measures (PROMs) used in endometriosis-related pain trials. Our findings provide evidence for a notable disparity between the assessment of pain intensity (almost all studies) and the assessment of other bio–psycho–social pain-related aspects (scarcely used). This basically ignores the fact that CPP related to endometriosis is a bio–psycho–social disease with multiple facets for patients. The measures used to assess these domains are heterogeneous across studies, with endometriosis-specific PROMs frequently used in incomplete or modified forms, hampering comparability. Particularly, the frequently used Biberoglu and Behrman scale lacks an adequate development process. To address these challenges, there is an urgent need to define and implement a common COS of domains, and successively one of high-quality PROMs for studies on endometriosis-related pain, relevant to all stakeholders including patients. This initiative is critical to improve study comparability and thus the reliability of meta-analysis, recommendations, and finally, patient care.

Endometriosis, affecting approximately 10% of women of reproductive age worldwide, is a chronic inflammatory disease of uncertain etiology and a common cause of chronic pelvic pain (CPP). 105 , 180 , 235 The prevalence may be underestimated because symptoms are very heterogeneous and complex, and surgical confirmation is necessary for definitive diagnosis with severity of symptoms not being related to the extent or location of disease found at surgery. 54 , 210 Hence, patients often face diagnostic delays of up to 7 to 9 years. 151 , 168 , 235 Typical symptoms, such as chronic noncyclical pelvic pain, dysmenorrhea, dyspareunia, and many other associations (including infertility), drastically affect physical and mental function, quality of life, as well as social and sexual well-being in the affected women. 151 , 185 , 235 Treatment options, both medical and surgical, are often insufficient or even fail in up to 50% of patients. 22 , 168 Ineffective treatment of chronic pain contributes to the burden of suffering for those affected. When studying the efficacy of interventions for pain in general, the assessment of pain-related symptoms is crucial. Particularly chronic pain is inherently a bio–psycho–social disease. 164 Consequently, a variety of pain-related outcomes for trials have been recommended several years ago already as a minimum to be assessed, 67 and a very recent update can be found here. 33 However, in most pain-related studies, the domain pain (particularly the subdomain pain intensity ) is the primary focus, whereas other domains are much less considered. 30 , 50 As a result, outcomes chosen to assess treatment response are often difficult to compare across trials. The outcomes often fail to encompass important aspects related to chronic pain, and their significance might be of less relevance to caregivers and patients themselves. For a study to be beneficial and transferable to clinical practice, it is essential to identify the domains (and based on the domains, the corresponding patient-reported outcome measures [PROMs]) that are the most relevant (for all stakeholders, including the patients), the most suitable (based on psychometric properties and comprehensiveness), and the most feasible. However, this is often lacking in pain research, particularly in endometriosis-related studies, despite its multiple and complex symptoms. 149 , 235 The definition and implementation of a minimum standard set of domains and PROMs to be assessed in clinical studies on endometriosis, a Core Outcome Set (COS), could address these problems. 223 Previous work focusing on outcome measures used in surgical trials (plus or minus adjunctive medical therapies) 106 has recommended a COS on this basis. 66 However, the recommended COS focusses on fertility-related outcomes and much less on pain domains, particularly those recommended by IMMPACT for chronic pain trials. 67 The main objective of this review was the investigation of domains and PROMs assessed in clinical trials evaluating the efficacy of nonsurgical pain-related interventions in patients with endometriosis. This work aimed to lay the groundwork for a more targeted assessment of pain-related outcomes in endometriosis-related pain trials and clinical practice by developing a COS of domains (followed by corresponding PROMs) specific to endometriosis.

Supplemental digital content associated with this article can be found online at http://links.lww.com/PAIN/C69 .

This project has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under Grant Agreement No [777500]. This joint undertaking receives support from the European Union's Horizon 2020 research and innovation program and EFPIA (www.imi.europa.eu; www.imi-paincare.eu ). DCR, EM, and KS have no conflicts of interest. EPZ received financial support from Grunenthal for research activities and advisory/lecture fees from Grünenthal, Novartis, and Medtronic. In addition, she receives scientific support from the German Research Foundation (DFG), the Federal Ministry of Education and Research (BMBF), the Federal Joint Committee (G-BA), and the Innovative Medicines Initiative 2 Joint Undertaking under Grant Agreement No 777500. This Joint Undertaking receives support from the European Union's Horizon 2020 research and innovation programme and EFPIA. All money went to the institutions (UM/UKM) EPZ is working for. EPZ is council member of the International Association for the Study of Pain (IASP), executive board member of the German Pain Society, executive board member of the Acute Pain SIG of the IASP, member of the research committee of the European Society of Anaesthesiology and Intensive Care (ESAIC) and member of the ESRA-prospect group ( https://esraeurope.org/pain-management/ ). EPZ is Debuty Editor in Chief for the European Journal of Anaesthesiology and the European Journal of Anaesthesiology and Intensive Care, and section editor of the European Journal of Pain. KV has received, to her institution, research funding from Bayer Healthcare and honoraria for consultancy for Bayer Healthcare, AbbVie, Eli Lilly, and Reckitts. JS has received travel support from Alnylam Pharmaceuticals Inc. and Pfizer, consultant fees from Pfizer Pharma GmbH and speaker fees from Grünenthal GmbH and Alnylam Germany GmbH outside the submitted work. RB has received grants/research support from EU Projects: “Europain” (115007), DOLORisk (633491), IMI Paincare (777500), German Federal Ministry of Education and Research (BMBF): Verbundprojekt: Frühdetektion von Schmerzchronifizierung (NoChro) (13 GW0338C), German Research Network on Neuropathic Pain (01EM0903), Pfizer Pharma GmbH, Sanofi Genzyme GmbH, Grünenthal GmbH, Mundipharma Research GmbH und Co. KG., Alnylam Pharmaceuticals Inc., Zambon GmbH, Bayer AG, Sanofi Aventis GmbH; speaker fees from Pfizer Pharma GmbH, Sanofi Genzyme GmbH, Grünenthal GmbH, Mundipharma, Lilly GmbH, Desitin Arzneimittel GmbH, Teva GmbH, Bayer AG, MSD GmbH, Seqirus Australia Pty. Ltd, Novartis Pharma GmbH, TAD Pharma GmbH, Grünenthal SA Portugal, Grünen-thal Pharma AG Schweiz, Grünenthal B.V. Niederlande, Evapharma, Takeda Pharmaceuticals International AG Schweiz, Ology Medical Education Netherlands, Ever Pharma GmbH, Amicus Therapeutics GmbH, Novo Nordisk Pharma GmbH, Chiesi GmbH, Stada Mena DWC LLC Dubai, Hexal AG, Viatris and consultant fees from Pfizer Pharma GmbH, Sanofi Genzyme GmbH, Grünenthal GmbH, Lilly, Novartis Pharma GmbH, Bristol-Myers Squibb, Biogenidec, AstraZeneca GmbH, Daiichi Sankyo, Glenmark Pharmaceuticals S.A., Seqirus Australia Pty. Ltd, Teva Pharmaceuticals Europe Niederlande, Teva GmbH, Genentech, Mundipharma International Ltd. United Kingdom, Galapagos NV, Kyowa Kirin GmbH, Vertex Pharmaceuticals Inc., Biotest AG, Celgene GmbH, Desitin Arzneimittel GmbH, Regeneron Pharmaceuticals Inc. USA, Theranexus DSV CEA Frankreich, Abbott Products Operations AG Schweiz, Bayer AG, Grünenthal Pharma AG Schweiz, Akcea Therapeutics Germany GmbH, Asahi Kasei Pharma Corporation, AbbVie Deutschland GmbH & Co. KG, Air Liquide Sante International Frankreich, Alnylam Germany GmbH, Lateral Pharma Pty Ltd, Hexal AG, Angelini, Janssen, SIMR Biotech Pty Ltd Australien, Confo Therapeutics N. V. Belgium, Merz Pharmaceuticals GmbH, Neumentum Inc., F. Hoffmann-La Roche Ltd. Switzerland, AlgoTherapeutix SAS France, Nanobiotix SA France, AmacaThera Inc. Canada outside the submitted work. DB has received honoraria for consulting activities from Grunenthal, Bayer, and Air Liquide.