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. 2024 Jul 2;165(11):2419–2444. doi: 10.1097/j.pain.0000000000003290

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

Daniela Constanze Rosenberger a, Emilia Mennicken a, Iris Schmieg a, Terkia Medkour b, Marie Pechard b, Juliane Sachau c, Fabian Fuchtmann a, Judy Birch d, Kathrin Schnabel a, Katy Vincent e, Ralf Baron c, Didier Bouhassira b, Esther Miriam Pogatzki-Zahn a,*
PMCID: PMC11474936  PMID: 38968394

Supplemental Digital Content is Available in the Text.

Keywords: Chronic pelvic pain, PROMs, Systematic literature research, Endometriosis, Core outcome set

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.

1. Introduction

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.

2. Methods

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).

2.1. Inclusion and exclusion criteria

The inclusion and exclusion criteria were defined following the PICOS criteria (P, population; I, intervention; C, comparison; O, outcome; S, study design137). 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.

Table 1.

Inclusion and exclusion criteria.

Category Inclusion Exclusion
Formal Article written in English, German, or French
Abstract and full text available
Completed study (peer-reviewed)
Foreign language (other than English, German, and French)
No abstract or full text available
Ongoing study
Duplicate
Population (P) Chronic pelvic pain of ≥3 mo duration, related to endometriosis (including disease duration with painful symptoms ≥3 mo)
No. of patients ≥20
Age ≥18 y
Not chronic pain (<3 mo duration)
Diseases other than endometriosis
Children, animals
Intervention (I) Topic or systemic drugs, or nonpharmacological treatment
Treatment duration ≥2 wk or follow-up ≥2 wk in case of drugs with long-term efficacy
Treatment duration <2 wk
No pain management
Comparison (C) Not applicable No limitations
Outcome (O) Patient-reported outcome measures (PROMs) used Proxy-/clinician-reported outcomes, objective measures
Pain not assessed
Study design (S) Randomized-controlled trial Observational study/retrospective analysis
Original article Review article

mo, months; wk, weeks; y, years

2.2. Search strategy

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”).

2.3. Screening of studies

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.

2.4. Data collection

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 area222) 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 disposition67 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 pain 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 guidelines95,113 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

2.5. Data analysis

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).

3. Results

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.

Figure 1.

Figure 1.

PRISMA Flowchart of included studies.

3.1. Descriptive analysis of study characteristics

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).

3.2. Quality-dependent analysis

All included studies were graded according to the risk of bias GRADE criteria95,113 (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).

3.3. Analysis of domains and patient-reported outcome measures

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.

Table 2.

IMMPACT—Core DOMAINs (Pain, Emotional Functioning, Physical Functioning, Satisfaction, and Adverse events) and subdomains assesses by each study included in this SLR

Inline graphic
Studies
Inline graphic
Grading: Quality
Pain Inline graphic
Emotional functioning
Physical functioning Inline graphic
Satisfaction
graphic file with name jop-165-2419-i005.jpg
graphic file with name jop-165-2419-i006.jpg graphic file with name jop-165-2419-i007.jpg graphic file with name jop-165-2419-i008.jpg graphic file with name jop-165-2419-i009.jpg graphic file with name jop-165-2419-i010.jpg graphic file with name jop-165-2419-i011.jpg graphic file with name jop-165-2419-i012.jpg
Ref First author year of publication Pain intensity Pain other items Rescue medication General measures
HRQOL
Sleep Daily activity Other aspects Adverse events
103 Healy, D. (ZOLADEX) 1996 Low
70 Elstein, M. (NEET) 1992 Low
1 Abdou, A 2018 High
2 Abokhrais, I 2020 High
3 Acién, P 2003 High
4 Acién, P 2021 High
5 Àcs, N 2015 High
6 Adamson, G 1994 High
8 Agarwal, S 2015 Low
9 Agarwal, S 1997 High
10 Alborzi, S 2007 Low
11 Alborzi, S 2011 Low
12 Alborzi, S 2019 High
13 Alkatout, I 2013 Low
14 Almassinokiani, F 2013 High
15 Amirsalari, S 2021 High
18 Audebert, A 1998 Low
19 Audebert, A 1997 Low
20 Badawy, A 2012 Low
21 Bayoglu Tekin, Y 2011 Low
23 Beissner, F 2018 Low
26 Bergqvist, A 1997 High
25 Bergqvist, A 1998 High
24 Bergqvist, A 2000 Low
27 Bergqvist, A 2001 Low
28 Bianchi, S 1999 Low
35 Bromham, D. (b) 1995 High
34 Bromham, D. (a) 1995 High
36 Burry, K 1989 Low
37 Busacca, M 2001 Low
39 Carpenter, S 1995 Low
40 Carr, B 2014 High
41 Carr, B 2013 High
42 Caruso, S 2022 High
43 Carvalho, N 2018 High
44 Ceccaroni, M 2021 High
47 Cheewadhanaraks, S 2009 High
46 Cheewadhanaraks, S 2012 High
45 Cheewadhanaraks, S 2013 High
48 Chen, Y 2017 High
49 Cheng, M 2005 Low
51 Cirkel, U 1995 Low
53 Cobellis, L 2004 High
52 Cobellis, L 2011 High
55 Cosson, M 2002 Low
57 Crosignani, P 2006 Low
56 Crosignani, P 1996 Low
58 da Mendes Silva, D 2017 High
60 Diamond, M 2014 High
61 Dlugi, A 1990 Low
62 Dmowski, W 1989 Low
64 Donnez, J 2004 Low
65 Donnez, J 2020 High
68 Edelstam, G 2012 Low
69 El Taha, L 2021 High
72 Fedele, L 1989 Low
75 Fedele, L 1989 Low
73 Fedele, L 1993 Low
74 Fedele, L 1999 Low
76 Fernandez, H 2004 High
77 Ferreira, R 2010 High
78 Ferrero, S 2011 Low
79 Flower, A 2011 High
80 Fraser, I 1991 High
81 Freundl, G 1998 Low
83 Gerlinger, C 2010 High
85 Ghahiri, A 2012 Low
88 Giannini, A 2015 High
89 Gomes, M 2007 High
90 Gonçalves, A 2016 High
91 Gong, L 2015 High
92 Granese, R 2015 High
94 Gregoriou. G 1997 Low
96 Guzick, D 2011 High
97 Halbe, H 1995 Low
100 Harada, T 2008 High
99 Harada, T 2009 High
98 Harada, T 2017 High
101 Harada, T 2022 Low
102 Harrison, R 2000 High
104 Henzl, M 1988 High
110 Hornstein, M 1995 High
109 Hornstein, M 1998 High
108 Hornstein, M 1997 Low
112 Howell, R 1995 Low
114 Huang, C 2018 Low
115 Itoh, H 2011 High
118 Kamencic, H 2008 Low
119 Kennedy, S 1990 High
120 Khodaverdi, S 2019 High
121 Kiilholma, P 1995 High
123 Köhler, G 2010 Low
124 Koninckx, P 2008 High
145 Mukhopadhyay, P 2018 Low
125 Lalchandani, S 2005 Low
126 Lang, J 2017 High
127 Leyland, N 2019 High
128 Ling, F 1999 High
129 Loverro, G 2008 Low
130 Low, R 1984 High
132 Mäkäräinen, L 1996 High
134 Margatho, D 2018 High
133 Margatho, D 2020 High
135 Mehdizadeh Kashi, A 2021 High
136 Meissner, K 2016 High
138 Mettler, L 2014 Low
139 Miller, J 2000 High
140 Mira, T 2015 High
141 Mira, T 2020 Low
142 Moghissi, K 1998 High
143 Moreira, M 2022 Low
144 Morgante, G 1999 Low
147 Muzii, L 2000 Low
146 Muzii, L 2011 High
148 Niakan, G 2021 High
150 Nieto, A 1996 Low
152 Odukoya, O 1995 Low
153 Osuga, Y (a) 2021 High
154 Osuga, Y (b) 2021 High
155 Overton, C 1994 High
157 Parazzini, F 1994 Low
156 Parazzini, F 2000 Low
158 Parker, J 2006 Low
159 Petta, C 2005 High
160 Pokrzywinski, R 2020 High
161 Pokrzywinski, R 2020 High
165 Razzi, S 2007 Low
166 Regidor, P 2001 Low
167 Rock, J 1993 Low
169 Roghaei, M 2010 Low
171 Rotondi, M 2002 Low
172 Rubi-Klein, K 2010 High
173 Rukhliada, N 2020 Low
59 Del Salinas- Asensio, M 2022 Low
175 Santanam, N 2013 Low
176 Schlaff, W 2006 Low
177 Schwertner, A 2013 High
178 Seracchioli, R 2010 High
179 Sesti, F 2007 High
182 Shaw, R 1990 High
183 Shaw R 1992 Low
181 Shaw, R 2001 High
184 Shokeir, T 2015 High
186 Soysal, S 2004 High
187 Stratton, P 2008 High
189 Strowitzki, T 2010 High
188 Strowitzki, T 2010 High
190 Strowitzki, T 2012 High
192 Surrey E 1992 Low
191 Surrey, E 2002 High
193 Surrey, E 2019 High
194 Takaesu, Y 2016 Low
195 Takenaka, M 2015 Low
196 Tang, H 2017 Low
197 Tanmahasamut, P 2012 High
198 Tanmahasamut, P 2017 High
199 Taskin, O 1997 High
200 Taylor, H 2017 High
200 Taylor, H 2017 High
201 Teixeira, M 2017 High
202 Telimaa, S 1987 High
203 Telimaa, S 1987 High
205 Thabet, A 2018 Low
208 Trummer, D 2017 High
209 Vercellini, P 1999 Low
212 Vercellini, P 2002 High
211 Vercellini, P 2003 High
216 Vercellini, P 1994 Low
213 Vercellini, P 1996 High
217 Vercellini, P 1996 High
214 Vercellini, P 2005 High
215 Vercellini, P 1993 High
218 Walch, K 2009 High
219 Wheeler, J 1992 Low
220 Wickström, K 2012 High
221 Wickström, K 2013 High
224 Wong, A 2004 High
225 Wong, A 2010 High
226 Xue, H 2016 Low
227 Ylänen, K 2003 High
232 Zhao, S 1999 Low
231 Zhao, R 2013 High
229 Zhao, L 2012 High
230 Zhao, R 2013 Low
233 Zhao, Yi 2021 High
234 Zhu, S 2014 High
236 Zupi, E 2004 Low
38 Carbonell, J 2016 High
122 Kitawaki, J 2008 Low
170 Rolland, R 1990 Low

● Domain was assessed.

3.4. Domains

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 2A, 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 2A, Table 2).

Figure 2.

Figure 2.

(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.

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 2A 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%).

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 2B). 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.

Table 3.

Combination of domains assessed within the same studies (n [%]).

Used as PROM
All studies (n = 191) Studies of high/moderate quality (n = 113) Studies of low quality (n = 78)
Combination of 2 domains
 Pain and
  Emotional functioning 12 (6.3) 8 (7.1) 4 (5.1)
  Physical functioning 57 (29.8) 44 (38.9) 13 (16.7)
  Improvement and satisfaction 27 (14.1) 23 (20.4) 4 (5.1)
  Adverse events 147 (77.0) 91 (80.5) 56 (71.8)
 Emotional functioning and
  Physical functioning 12 (6.3) 8 (7.1) 4 (5.1)
  Improvement and satisfaction 1 (0.5) 1 (0.9) 0
  Adverse events 9 (4.7) 7 (6.2) 2 (2.6)
 Physical functioning and
  Improvement and satisfaction 12 (6.3) 10 (8.8) 2 (2.6)
  Adverse events 47 (24.6) 38 (33.6) 9 (11.5)
 Improvement and satisfaction and
  Adverse events 25 (13.1) 21 (18.6) 4 (5.1)
Combinations of 3 domains
 Pain, emotional functioning, and
  Physical functioning 12 (6.3) 8 (7.1) 4 (5.1)
  Improvement and satisfaction 1 (0.5) 1 (0.9) 0
  Adverse events 9 (4.7) 7 (6.2) 2 (2.6)
 Pain, physical functioning, and
  Improvement and satisfaction 12 (6.3) 10 (8.8) 2 (2.6)
  Adverse events 47 (24.6) 38 (33.6) 9 (11.5)
 Pain, improvement and satisfaction, and adverse events 25 (13.1) 21 (18.6) 4 (5.1)
Combination of 4 or more domains
 Pain, emotional functioning, physical functioning, and adverse events 9 (4.7) 7 (6.2) 2 (2.6)
 Pain, physical functioning, improvement and satisfaction, and adverse events 12 (6.3) 10 (8.8) 2 (2.6)
 Pain, emotional functioning, improvement and satisfaction, and adverse events 1 (0.5) 1 (0.9) 0
 Pain, emotional functioning, physical functioning, and improvement and satisfaction 1 (0.5) 1 (0.9) 0
 Pain, emotional functioning, physical functioning, improvement and satisfaction, and adverse events 1 (0.5) 1 (0.9) 0

3.5. Patient-reported outcome measure related to the 5 IMMPACT domains

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.

Table 4.

Frequencies of PROMs that were used in the included studies according to the IMMPACT domains (n [%]).

Used as PROM
All studies (n = 191) Studies of high/moderate quality (n = 113) Studies of low quality (n = 78)
Domain “pain
Pain (all) 188 (98.4) 111 (98.2) 77 (98.7)
  Studies using 1 PROM 129 (67.5) 67 (59.3) 62 (79.5)
  Studies using 2 PROMs 46 (24.1) 33 (29.2) 13 (16.7)
  Studies using 3 PROMs 12 (6.3) 9 (8.0) 3 (3.8)
  Studies using 4 PROMs 2 (1.0) 2 (1.8) 0
Pain intensity 144 (75.4) 99 (87.6) 45 (57.7)
  Studies using 1 PROM 130 (68.1) 88 (77.9) 42 (53.8)
  Studies using 2 PROMs 12 (6.3) 9 (8.0) 3 (3.8)
  Studies using 3 PROMs 2 (1.0) 2 (1.8) 0
 Numerical rating scale (NRS) 18 (9.4) 9 (8.0) 9 (11.5)
 Visual analog scale (VAS) 98 (51.3) 74 (65.5) 24 (30.8)
 Verbal rating scale (VRS) 35 (18.3) 27 (23.9) 8 (10.3)
 Other* 10 (5.2) 1 (0.9) 9 (11.5)
Pain intensity other 67 (35.1) 40 (35.4) 27 (34.6)
  Studies using 1 PROM 57 (29.8) 33 (29.2) 24 (30.8)
  Studies using 2 PROMs 10 (5.2) 7 (6.2) 3 (3.8)
 Biberoglu and Behrman scale 56 (29.3) 34 (30.1) 22 (28.2)
  Incompletely used 25 (13.1) 17 (15.0) 8 (10.3)
  Modified 16 (8.4) 11 (9.7) 5 (6.4)
 Andersch and Milsom score (all modified) 7 (3.7) 4 (3.5) 3 (3.8)
 Other 14 (7.3) 11 (9.7) 3 (3.8)
Pain-specific PROMs, other aspects 3 (1.6) 2 (1.8) 1 (1.3)
  PainDETECT 1 (0.5) 1 (0.9) 0
  McGill questionnaire 2 (1.0) 1 (0.9) 1 (1.3)
  World Health Organization QOL-BREF (“pain and discomfort”) 1 (0.5) 1 (0.9)
  SF-36 (2 items) 1 (0.5) 1 (0.9)
Pain relief (4-point VRS) 3 (1.6) 2 (1.8) 1 (1.3)
Self-constructed scales (pain all) 4 (2.1) 1 (0.9) 4 (5.1)
Others (not further defined) 16 (8.4) 3 (2.7) 13 (16.7)
  Studies using 1 PROM 16 (8.4) 3 (2.7) 13 (16.7)
Rescue medication 68 (35.6) 51 (45.1) 17 (21.8)
  Diary 25 (13.1) 20 (17.7) 5 (6.4)
  Not indicated 35 (18.3) 28 (24.8) 7 (9.0)
  Other* 8 (4.2) 3 (2.7) 5 (6.4)
Domain “emotional functioning
Emotional functioning 13 (6.8) 9 (8.0) 4 (5.1)
  Studies using 1 PROM 4 (2.1) 4 (3.5) 0
  Studies using 2 PROMs 8 (4.2) 4 (3.5) 4 (5.1)
  Studies using 3 PROMs 0 0 0
  Studies using 4 PROMs 1 (0.5) 1 (0.9) 0
 Beck depression inventory (BDI) 2 (1.0) 2 (1.8) 0
 Hospital anxiety and depression scale (HADS) 5 (2.6) 3 (2.7) 2 (2.6)
  1 incompletely used 1 (0.9) 0
 Beck anxiety inventory 1 (0.5) 1 (0.9) 0
 GHQ 12 (shortform) 2 (1.0) 1 (0.9) 1 (1.3)
 Hamilton depression scale 1 (0.5) 1 (0.9) 0
 State trait anxiety inventory 4 (2.1) 3 (2.7) 1 (1.3)
 Pain catastrophizing questionnaire 3 (1.6) 2 (1.8) 1
 Woman health questionnaire (incompletely used, author-indicated) 1 (0.5) 0 1 (1.3)
 Psychological general well-being questionnaire (author-indicated) 1 (0.5) 1 (0.9) 0
 WHO-five 1 (0.5) 1 (0.9) 0
 Perceived stress scale 1 (0.5) 0 1 (1.3)
 Five facets of mindfulness questionnaire 1 (0.5) 0 1 (1.3)
Others: “Diary” 1 (0.5) 1 (0.9) 0
Self-constructed instruments 0 0 0
Domain “physical functioning and generic measures of HRQOL”
Physical functioning 57 (29.8) 44 (38.9) 13 (16.7)
  Studies using 1 PROM 39 (20.4) 33 (29.2) 6 (7.7)
  Studies using 2 PROMs 12 (6.3) 9 (8.0) 3 (3.8)
  Studies using 3 PROMs 3 (1.6) 1 (0.9) 2 (2.6)
  Studies using 4 PROMs 1 (0.5) 0 1 (1.3)
  Studies using 5 PROMs 2 (1.0) 1 (0.9) 1 (1.3)
Generic measures of HRQOL 53 (27.7) 40 (35.4) 13 (16.7)
  Studies using 1 PROM 48 (25.1) 38 (33.6) 10 (12.8)
  Studies using 2 PROMs 5 (2.6) 2 (1.8) 3 (3.8)
 SF-36 22 (11.5) 13 (11.5) 5 (6.4)
  2 incompletely used 2 (2.6)
 Short form: SF-12 4 (2.1) 3 (2.7) 1 (1.3)
 Endometriosis health profile questionnaire (EHP-30) 19 (9.9) 14 (12.4) 5 (6.4)
  9 incompletely used 7 (6.2) 2 (2.6)
 Short form: EHP-5 6 (3.1) 5 (4.4) 1 (1.3)
  4 incompletely used 4 (3.5) 0
 Pain disability index (PDI) 1 (0.5) 1 (0.9) 0
 Brief pain inventory 1 (0.5) 1 (0.9) 0
 Nottingham health profile questionnaire 1 (0.5) 0 1 (1.3)
 The duke quality of life scale 1 (0.5) 1 (0.9) 0
 World Health Organization QOL-BREF (short-form) 2 (1.0) 2 (1.8) 0
 VAS 1 (0.5) 1 (0.9) 0
 QoL questionnaire 1 (0.5) 0 1 (1.3)
 Gastrointestinal quality of life index (GQLI) 1 (0.5) 0 1 (1.3)
Self-constructed instruments 1 (0.5) 0 1 (1.3)
Daily activity 8 (4.2) 5 (4.4) 2 (2.6)
 Endometriosis impact diary for productivity 2 (1.0) 0 2 (2.6)
  2 incompletely used 2 (2.6)
 Health related productivity questionnaire 2 (1.0) 2 (1.8) 0
 Work and productivity impairment questionnaire—specific health problem version 2.0 2 (1.0) 1 (0.9) 1 (1.3)
 1-5 scale interference of daily activities 1 (0.5) 1 (0.9) 0
 Diary (difficulty of doing daily activity) 1 (0.5) 1 (0.9) 0
Self-constructed instruments 0 0 0
Sleep 5 (2.6) 3 (2.7) 2 (2.6)
  Studies using 1 PROM 4 (2.1) 2 (1.8) 2 (2.6)
  Studies using 2 PROMs 1 (0.5) 1 (0.9) 0
 Akerstedt and Torsvall (incompletely) 1 (0.5) 0 1 (1.3)
 Pittsburgh sleep quality index (PSQI) 2 (1.0) 1 (0.9) 1 (1.3)
 VASQS 1 (0.5) 1 (0.9) 0
 Diary 1 (0.5) 1 (0.9) 0
 1-5 scale 1 (0.5) 1 (0.9) 0
Self-constructed instruments 0 0 0
Physical functioning other aspects 11 (5.8) 7 (6.2) 4 (5.1)
  Studies using 1PROM 8 (4.2) 6 (5.3) 2 (2.6)
  Studies using 2 PROMs 3 (1.6) 1 (0.9) 2 (2.6)
 Breast cancer prevention trial symptom checklist (modified) 1 (0.5) 0 1 (1.3)
 Index of sexual satisfaction 1 (0.5) 1 (0.9) 0
 Sabbatsberg sexual rating scale 1 (0.5) 1 (0.9) 0
 Sexual activity questionnaire 1 (0.5) 1 (0.9) 0
 Female sexual function index (FSFI) 3 (1.6) 1 (0.9) 2 (2.6)
 Inventory of social support and integration (incompletely used) 1 (0.5) 0 1 (1.3)
 Marburg questionnaire for functional well-being 1 (0.5) 1 (0.9) 0
 Measure your own medical outcomes profile 1 (0.5) 1 (0.9) 0
 Patient-reported outcomes Measurement information system fatigue short form 6a Questionnaire (short form) 1 (0.5) 1 (0.9) 0
 Brief fatigue inventory 1 (0.5) 1 (0.9) 0
 Piper fatigue scale-revised 1 (0.5) 0 1 (1.3)
 Demand control questionnaire 1 (0.5) 0 1 (1.3)
Domain “improvement and satisfaction”
Improvement and satisfaction 27 (14.1) 23 (20.4) 4 (5.1)
  Studies using 1 PROM 26 (13.6) 22 (19.5) 4 (5.1)
  Studies using 2 PROMs 1 (0.5) 1 (0.9) 0
 Patient global impression of change (PGIC) 7 (3.7) 7 (6.2)
 Patient satisfaction 2 (1.0) 2 (2.6)
 Questionnaire 1 incompletely used 1 (1.3)
 5-point Likert scale 3 (1.6) 2 (1.8) 1 (1.3)
Other* 12 (6.3) 11 (9.7) 1 (1.3)
Domain “adverse events”
Adverse events 147 (73.8) 91 (80.5) 56 (71.8)
  Studies using 1 PROM 118 (61.8) 71 (62.8) 47 (60.3)
  Studies using 2 PROMs 29 (15.2) 20 (17.7) 9 (11.5)
 Diary 37 (19.4) 23 (20.4) 14 (17.9)
 Kuppermann index 5 (2.6) 2 (1.8) 3 (3.8)
 Checklist of side effects 3 (1.6) 3 (2.7) 0
 Ferriman and Gallwey Score 2 (1.0) 2 (1.8) 0
 VAS 2 (1.0) 2 (1.8) 0
 Greene scale (modified) 1 (0.5) 1 (0.9) 0
 Memory observation questionnaire 1 (0.5) 0 1 (1.3)
 Global tolerability scale 1 (0.5) 1 (0.9) 0
Other* 26 (13.6) 12 (10.6) 14 (17.9)
Assessed but not indicated how 101 (52.9) 64 (56.6) 33 (42.3)
*

“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%).

3.6. Endometriosis-specific patient-reported outcome measures

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).

3.6.1. Quality-dependent analysis of the use of patient-reported outcome measures

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%).

3.6.2. Characteristics of endometriosis-specific patient-reported outcome measures including the quality of the development process of those most frequently used

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.

4. Discussion

4.1. Domains assessed in clinical trials on chronic pelvic pain related to endometriosis

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

4.2. PROMs assessed in clinical trials on chronic pelvic pain related to endometriosis

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

4.3. Implications for the future

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 pain222), 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 PROM163,204 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

4.4. Strength and limitations

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 reviews31,87,149, 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.

5. Conclusions

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.

Conflict of interest statement

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.

Appendix A. Supplemental digital content

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

Supplementary Material

SUPPLEMENTARY MATERIAL
jop-165-2419-s001.pdf (1.6MB, pdf)

Footnotes

Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (www.painjournalonline.com).

Contributor Information

Daniela Constanze Rosenberger, Email: daniela.rosenberger@ukmuenster.de.

Emilia Mennicken, Email: emilia_mennicken@t-online.de.

Iris Schmieg, Email: iris.schmieg@gmx.de.

Terkia Medkour, Email: terkia.medkour@aphp.fr.

Marie Pechard, Email: marie.pechard@inserm.fr.

Juliane Sachau, Email: juliane.Sachau@uksh.de.

Fabian Fuchtmann, Email: fabian.fuchtmann@ukmuenster.de.

Judy Birch, Email: judy_b@dsl.pipex.com.

Kathrin Schnabel, Email: kathrin.schnabel@ukmuenster.de.

Katy Vincent, Email: katy.vincent@wrh.ox.ac.uk.

Ralf Baron, Email: r.baron@neurologie.uni-kiel.de.

Didier Bouhassira, Email: didier.bouhassira@aphp.fr.

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