{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,13]],"date-time":"2026-06-13T04:57:24Z","timestamp":1781326644071,"version":"3.54.1"},"reference-count":53,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2026,6,9]],"date-time":"2026-06-09T00:00:00Z","timestamp":1780963200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Background: Chronic pain is a multifactorial condition for which interdisciplinary multimodal rehabilitation is guideline-recommended, yet the biological mechanisms underlying treatment response remain incompletely understood and validated predictive biomarkers have not been established. Objective: This exploratory prospective cohort study examined clinical outcomes and circulating biomarker changes, encompassing the endocannabinoid system (ECS), inflammatory mediators, stress-regulatory markers, and metabolic parameters, in 410 patients with chronic pain of predominantly musculoskeletal etiology undergoing a standardized five-week rehabilitation program. Materials and Methods: Pain intensity and affective pain were assessed at baseline and end of rehabilitation; global performance of treatment (GPT) was additionally recorded. Serum analyses included anandamide (AEA), 2-arachidonoylglycerol (2-AG), IL-6, cortisol, IGF-1, BDNF, and leptin. Biomarker-outcome associations were examined via multiple regression analyses adjusted for demographics and biological and clinical confounders. Results: Statistically significant reductions were observed in pain intensity (\u22120.785 points, NRS; p &lt; 0.001) and affective pain (\u22120.750 points; p &lt; 0.001). IL-6 was associated with pain outcomes across time points. Higher baseline 2-AG independently predicted lower end-of-rehabilitation pain intensity, affective pain, and more favorable GPT. Greater AEA reductions were associated with favorable GPT. Conclusions: Baseline 2-AG emerges as a candidate predictor of treatment response, with lower pre-treatment levels potentially reflecting reduced stress-adaptive capacity, supporting inclusion of ECS markers in future controlled biomarker studies.<\/jats:p>","DOI":"10.3390\/biom16060841","type":"journal-article","created":{"date-parts":[[2026,6,11]],"date-time":"2026-06-11T05:50:58Z","timestamp":1781157058000},"page":"841","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Physiological Adaptations and Serum-Based Biomarker Dynamics During Multimodal Rehabilitation in Chronic Pain: Analysis of a Prospective Cohort Study"],"prefix":"10.3390","volume":"16","author":[{"given":"Meike","family":"Meinzer","sequence":"first","affiliation":[{"name":"Department of Pharmacology, Hannover Medical School, 30625 Hannover, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3279-3386","authenticated-orcid":false,"given":"Markus","family":"Bassler","sequence":"additional","affiliation":[{"name":"Institute for Social Medicine, Rehabilitation Sciencesand Health Services Research (ISRV), Nordhausen University of Applied Sciences, 99734 Nordhausen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Franziska","family":"Kessemeier","sequence":"additional","affiliation":[{"name":"Institute for Quality Assurance in Prevention and Rehabilitation (IQPR), German Sport University Cologne, 50933 Cologne, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Corinna","family":"Webering","sequence":"additional","affiliation":[{"name":"Rehabilitation Center Bad Pyrmont, 31812 Bad Pyrmont, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0145-7507","authenticated-orcid":false,"given":"Detlef","family":"Neumann","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Hannover Medical School, 30625 Hannover, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heike","family":"B\u00e4hre","sequence":"additional","affiliation":[{"name":"Research Core Unit Metabolomics, Hannover Medical School, 30625 Hannover, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ralf","family":"Lichtinghagen","sequence":"additional","affiliation":[{"name":"Institute of Clinical Chemistry and Central Laboratory of Hannover Medical School, 30625 Hannover, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1685-9843","authenticated-orcid":false,"given":"Mathias","family":"Rhein","sequence":"additional","affiliation":[{"name":"Laboratory for Molecular Neuroscience, Department of Psychiatry, Social Psychiatry and Psychotherapy, Hannover Medical School, 30625 Hannover, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johannes","family":"Achenbach","sequence":"additional","affiliation":[{"name":"Department of Anaesthesia and Intensive Care Medicine, Royal Devon University Healthcare NHS-Foundation Trust, Barnstaple EX31 4JB, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6522-1942","authenticated-orcid":false,"given":"Christoph","family":"Gutenbrunner","sequence":"additional","affiliation":[{"name":"Department of Rehabilitation and Sports Medicine, Hannover Medical School, 30625 Hannover, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3502-0023","authenticated-orcid":false,"given":"Matthias","family":"Karst","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Intensive Care Medicine, Pain Clinic, Hannover Medical School, 30625 Hannover, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,9]]},"reference":[{"key":"ref_1","unstructured":"GBD 2021 Diseases and Injuries Collaborators (2024). 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