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Multiple randomised clinical trials have shown that the use of naloxone as a peripherally acting mu\u2010opioid receptor antagonist, in combination with oxycodone can prevent or reduce opioid\u2010induced constipation while having equivalent analgesic efficacy to oxycodone alone. However, clinical experience has shown that unexpected events may occur in some patients when unrecognized liver impairment is present. We describe the underlying biological reasons and propose simple, but effective steps to avoid this unusual but potentially serious occurrence. In healthy individuals, naloxone undergoes extensive hepatic first pass metabolism resulting in low systemic bioavailability. However, in patients with hepatic impairment, porto\u2010systemic shunting can increase systemic bioavailability of naloxone, potentially compromising the analgesic efficacy of oral naloxone\u2013oxycodone combinations. This reduced first pass effect can occur in a range of settings that may not always be apparent to the treating clinician, including silent cirrhosis, non\u2010cirrhotic portal hypertension and disruption of liver internal vasculature by metastases. Hepatic function test results correlate poorly with presence and extent of liver disease, and are not indicative of porto\u2010systemic shunting. Presence of hepatic impairment should thus be considered when medication\u2010related outcomes with oxycodone\u2013naloxone combination are not as expected, even if liver function test results are normal.<\/jats:p>","DOI":"10.1111\/ajco.13561","type":"journal-article","created":{"date-parts":[[2021,3,4]],"date-time":"2021-03-04T02:00:43Z","timestamp":1614823243000},"page":"13-18","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Oxycodone\/naloxone prolonged\u2010release tablets in patients with moderate\u2010to\u2010severe, chronic cancer pain: Challenges in the context of hepatic impairment"],"prefix":"10.1111","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0830-4864","authenticated-orcid":false,"given":"Brian H","family":"Le","sequence":"first","affiliation":[{"name":"The Royal Melbourne Hospital Parkville Integrated Palliative Care Service  Victoria Australia"},{"name":"Department of Medicine The University of Melbourne  Victoria Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ghauri","family":"Aggarwal","sequence":"additional","affiliation":[{"name":"Concord Hospital Concord Centre for Palliative Care  New South Wales Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carol","family":"Douglas","sequence":"additional","affiliation":[{"name":"Royal Brisbane and Women's Hospital Health Service  Palliative Care Queensland Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Green","sequence":"additional","affiliation":[{"name":"Department of Medicine The University of Melbourne  Victoria Australia"},{"name":"Sunshine Hospital, Medical Oncology  Victoria Australia"},{"name":"Peter MacCallum Cancer Centre Medical Oncology  Melbourne Victoria Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amanda","family":"Nicoll","sequence":"additional","affiliation":[{"name":"Box Hill Hospital Gastroenterology  Victoria Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sam","family":"Ahmedzai","sequence":"additional","affiliation":[{"name":"The University of Sheffield  Oncology, Western Bank Sheffield UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2021,3,3]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpainsymman.2015.12.340"},{"key":"e_1_2_9_3_1","first-page":"588","article-title":"Cancer pain management: Opioid analgesics, part 2","volume":"8","author":"Wickham RJ","year":"2017","journal-title":"J Adv Pract Oncol"},{"key":"e_1_2_9_4_1","first-page":"CD012592","article-title":"Opioids for cancer pain \u2013 An overview of Cochrane reviews","volume":"7","author":"Wiffen PJ","year":"2017","journal-title":"Cochrane Database Syst Rev"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/ajgsup.2014.4"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1177\/0269216311418869"},{"key":"e_1_2_9_7_1","unstructured":"Product Information TARGIN\u00aemodified release tablets Sydney NSW Australia: Mundipharma Pty Ltd.;2017"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpainsymman.2013.10.013"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpainsymman.2016.10.354"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpainsymman.2013.02.009"},{"key":"e_1_2_9_11_1","unstructured":"CaldwellK PaisR CigoliniM (2018) P04. 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