{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T08:27:52Z","timestamp":1788251272729,"version":"build-2803163510"},"reference-count":40,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,4,14]],"date-time":"2021-04-14T00:00:00Z","timestamp":1618358400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Med."],"abstract":"<jats:p><jats:bold>Background:<\/jats:bold> Chronic pruritus affects up to 70% of patients with immune-mediated hepatobiliary disorders. Antagonists of the \u03bc-opioid receptor (MOR) and agonists of the \u03ba-opioid receptor (KOR) are used to treat hepatic itch, albeit with limited success. An imbalance between ligands of MOR and KOR receptors has recently been suggested as a potential mechanism of hepatic pruritus. In this study, we therefore investigated systemic levels of important endogenous opioids such as \u03b2-endorphin, dynorphin A, Leu- and Met-enkephalin in plasma of a large cohort of well-characterized patients with immune-mediated cholestatic disorders, including patients with liver cirrhosis, and during effective anti-pruritic therapy.<\/jats:p><jats:p><jats:bold>Methods:<\/jats:bold> Plasma samples and clinical data were prospectively collected from well-characterized patients with primary\/secondary sclerosing cholangitis (PSC\/SSC), primary biliary cholangitis (PBC) and overlap syndromes suffering from pruritus (<jats:italic>n<\/jats:italic> = 29) and age-, gender- and disease-matched controls without pruritus (<jats:italic>n<\/jats:italic> = 27) as well as healthy controls (<jats:italic>n<\/jats:italic> = 20). General laboratory testing for hepatobiliary and renal function was performed. Levels of \u03b2-endorphin, dynorphin A, Leu- and Met-enkephalin were quantified in plasma by ELISA. Intensity of pruritus over the last week was evaluated using a visual analog scale (VAS, 0\u201310).<\/jats:p><jats:p><jats:bold>Results:<\/jats:bold> PBC and PSC patients with or without pruritus did neither differ in disease entity, disease stage, nor in the presence of cirrhosis. While both dynorphin A and \u03b2-endorphin concentrations were lower in pruritic patients compared to those without pruritus and healthy controls, the MOR\/KOR ligand ratio was unaltered. No significant differences were observed for Leu- and Met-enkephalin concentrations. Opioid levels correlated with neither itch intensity nor stage of disease. Cirrhotic patients displayed higher concentrations of MOR agonist Leu-enkephalin and KOR agonist dynorphin A. Endogenous opioid levels remained largely unchanged after successful treatment with the potent anti-pruritic drugs rifampicin and bezafibrate.<\/jats:p><jats:p><jats:bold>Conclusions:<\/jats:bold> Endogenous opioid levels and the MOR\/KOR ligand ratio neither correlate with itch intensity nor differentiate pruritic from non-pruritic patients with immune-mediated liver diseases. Thus, endogenous opioids may modulate signaling pathways involved in hepatic pruritus, but are unlikely to represent the major pruritogens in liver disease.<\/jats:p>","DOI":"10.3389\/fmed.2021.641163","type":"journal-article","created":{"date-parts":[[2021,4,14]],"date-time":"2021-04-14T05:41:01Z","timestamp":1618378861000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":20,"title":["Endogenous Opioid Levels Do Not Correlate With Itch Intensity and Therapeutic Interventions in Hepatic Pruritus"],"prefix":"10.3389","volume":"8","author":[{"given":"Miriam M.","family":"D\u00fcll","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katharina","family":"Wolf","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcel","family":"Vetter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Dietrich","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Markus F.","family":"Neurath","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas E.","family":"Kremer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,4,14]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1485","DOI":"10.1111\/exd.14024","article-title":"What are new treatment concepts in systemic itch?","volume":"28","author":"Kremer","year":"2019","journal-title":"Experimental Dermatol."},{"key":"B2","doi-asserted-by":"publisher","first-page":"1625","DOI":"10.1056\/NEJMcp1208814","article-title":"Clinical practice. 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