{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T04:57:00Z","timestamp":1788411420136,"version":"build-2803163510"},"reference-count":69,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2025,12,28]],"date-time":"2025-12-28T00:00:00Z","timestamp":1766880000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2025,12,28]],"date-time":"2025-12-28T00:00:00Z","timestamp":1766880000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["European Journal of Pain"],"published-print":{"date-parts":[[2026,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>The opioid system is involved in the regulation of pain as well as stress homeostasis. Stress\u2010induced opioid dysregulation has been proposed as a mechanism for pain development in patients with fibromyalgia (FM) and chronic low back pain (cLBP). However, the evidence to support this hypothesis is conflicting.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We conducted a systematic literature search in MEDLINE, EMBASE, and the Cochrane Library database to investigate whether patients with FM or cLBP exhibit (1) different levels of endogenous opioids or anti\u2010opioids in body fluids or tissue samples, or (2) altered levels of opioid receptor expression or availability compared to pain\u2010free controls.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>We identified 33 studies eligible for inclusion in the review, investigating 863 patients and 636 pain\u2010free controls. Three meta\u2010analyses of beta\u2010endorphin levels in blood and cerebrospinal fluid (CSF) were performed, revealing no significant differences between patients with FM or cLBP and controls. However, the grading of the evidence was very low. Mu\u2010opioid receptor (MOR) dysfunction emerged as a potential feature of FM, with some evidence suggesting reduced MOR binding in the brain and decreased MOR expression in immune cells.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Current evidence does not support altered peripheral endorphin levels in FM or cLBP, while emerging PET findings indicate reduced central MOR availability in FM. These results suggest receptor\u2010level dysregulation rather than peripheral opioid deficits. Limitations mainly arose from low sample sizes and inadequate study methodologies, underscoring the need for well\u2010designed studies with larger sample sizes to clarify the role of endogenous opioid dysfunction in FM and cLBP.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Significance<\/jats:title>\n                    <jats:p>This systematic review highlights emerging evidence of mu\u2010opioid receptor dysfunction in fibromyalgia, despite no consistent differences in beta\u2010endorphin levels. The findings underscore significant methodological limitations in existing studies and point to the need for rigorous, well\u2010powered research to clarify the role of endogenous opioid dysregulation in chronic pain.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/ejp.70192","type":"journal-article","created":{"date-parts":[[2025,12,29]],"date-time":"2025-12-29T05:38:16Z","timestamp":1766986696000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["A Systematic Review With Meta\u2010Analysis of Endogenous Opioid System Biomarkers in Patients With Chronic Axial Pain, Chronic Widespread Pain, and Fibromyalgia"],"prefix":"10.1002","volume":"30","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3106-2461","authenticated-orcid":false,"given":"Karin Due","family":"Bruun","sequence":"first","affiliation":[{"name":"Pain Research Group, Pain Center Odense University Hospital  Odense Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-0046-2025","authenticated-orcid":false,"given":"Maria Charlotte Reiersoel","family":"Moerkeberg","sequence":"additional","affiliation":[{"name":"Pain Research Group, Pain Center Odense University Hospital  Odense Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7924-5312","authenticated-orcid":false,"given":"Julie Roenne","family":"Pedersen","sequence":"additional","affiliation":[{"name":"Pain Research Group, Pain Center Odense University Hospital  Odense Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4247-6053","authenticated-orcid":false,"given":"Daniel","family":"Broholm","sequence":"additional","affiliation":[{"name":"Pain Research Group, Pain Center Odense University Hospital  Odense Denmark"},{"name":"Department of Clinical Research, Faculty of Health Sciences University of Southern Denmark  Odense Denmark"},{"name":"Pain Center Middelfart, Department of Anesthesiology University Hospital of Southern Denmark  Vejle Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7759-5642","authenticated-orcid":false,"given":"Morten Rune","family":"Blichfeldt\u2010Eckhardt","sequence":"additional","affiliation":[{"name":"Pain Center Middelfart, Department of Anesthesiology University Hospital of Southern Denmark  Vejle Denmark"},{"name":"Department of Regional Health Research, Faculty of Health Sciences University of Southern Denmark  Odense Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lotte","family":"Abildgren","sequence":"additional","affiliation":[{"name":"Centre of Research in Patient Communication, Odense University Hospital University of Southern Denmark  Odense Denmark"},{"name":"SimC, Simulation Centre Odense University Hospital  Odense Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,12,28]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1007\/s003930050241"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/0165-1781(83)90005-7"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuropharm.2020.108131"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neubiorev.2014.12.018"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1097\/j.pain.0000000000001270"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2474-5-48"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.3344\/kjp.2016.29.4.249"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/j.1532-2149.2011.00021.x"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1097\/AJP.0000000000000389"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pain.2006.11.013"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13063-021-05776-7"},{"key":"e_1_2_8_13_1","unstructured":"Bruun K. 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