{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T11:25:22Z","timestamp":1785929122013,"version":"3.56.0"},"reference-count":36,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2012,10,9]],"date-time":"2012-10-09T00:00:00Z","timestamp":1349740800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Brit J Clinical Pharma"],"published-print":{"date-parts":[[2012,11]]},"abstract":"<jats:p><jats:bold>WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT<\/jats:bold><\/jats:p><jats:p>\u2022\u2003Management of pain in opioid dependent individuals is problematic due to numerous issues including cross\u2010tolerance to opioids. Hence there is a need to find alternative analgesics to classical opioids and tramadol is potentially one such alternative.<\/jats:p><jats:p>\u2022\u2003Methadone inhibits CYP2D6<jats:italic>in vivo<\/jats:italic>and<jats:italic>in vitro<\/jats:italic>.<\/jats:p><jats:p>\u2022\u2003We aimed to investigate the effect of methadone on the pathways of tramadol metabolism: O\u2010demethylation (CYP2D6) to the opioid\u2010active metabolite M1 and N\u2010demethylation (CYP3A4) to M2 in subjects maintained on methadone or buprenorphine as a control.<\/jats:p><jats:p><jats:bold>WHAT THIS STUDY ADDS<\/jats:bold><\/jats:p><jats:p>\u2022\u2003Compared with subjects on buprenorphine, methadone reduced the clearance of tramadol to active O\u2010desmethyl\u2010tramadol (M1) but had no effect on N\u2010desmethyltramadol (M2) formation.<\/jats:p><jats:p>\u2022\u2003Similar to other analgesics whose active metabolites are formed by CYP2D6 such as codeine, reduced formation of O\u2010desmethyltramadol (M1) is likely to result in reduced analgesia for subjects maintained on methadone. Hence alternative analgesics whose metabolism is independent of CYP2D6 should be utilized in this patient population.<\/jats:p><jats:p><jats:bold>AIMS<\/jats:bold>To compare the O\u2010 (CYP2D6 mediated) and N\u2010 (CYP3A4 mediated) demethylation metabolism of tramadol between methadone and buprenorphine maintained CYP2D6 extensive metabolizer subjects.<\/jats:p><jats:p><jats:bold>METHODS<\/jats:bold>Nine methadone and seven buprenorphine maintained subjects received a single 100\u2003mg dose of tramadol hydrochloride. Blood was collected at 4\u2003h and assayed for tramadol, methadone, buprenorphine and norbuprenorphine (where appropriate) and all urine over 4\u2003h was assayed for tramadol and its M1 and M2 metabolites.<\/jats:p><jats:p><jats:bold>RESULTS<\/jats:bold>The urinary metabolic ratio [median (range)] for O\u2010demethylation (M1) was significantly lower (<jats:italic>P<\/jats:italic>= 0.0002, probability score 1.0) in the subjects taking methadone [0.071 (0.012\u20130.103)] compared with those taking buprenorphine [0.192 (0.108\u20130.392)], but there was no significant difference (<jats:italic>P<\/jats:italic>= 0.21, probability score 0.69) in N\u2010demethylation (M2). The percentage of dose [median (range)] recovered as M1 was significantly lower in subjects taking methadone compared with buprenorphine (0.069 (0.044\u20130.093) and 0.126 (0.069\u20130.187), respectively,<jats:italic>P<\/jats:italic>= 0.04, probability score 0.19), M2 was significantly higher in subjects taking methadone compared with buprenorphine (0.048 (0.033\u20130.085) and 0.033 (0.014\u20130.049), respectively,<jats:italic>P<\/jats:italic>= 0.04, probability score 0.81). Tramadol was similar (0.901 (0.635\u20131.30) and 0.685 (0.347\u20131.04), respectively,<jats:italic>P<\/jats:italic>= 0.35, probability score 0.65).<\/jats:p><jats:p><jats:bold>CONCLUSIONS<\/jats:bold>Methadone inhibited the CYP2D6\u2010mediated metabolism of tramadol to M1. Hence, as the degree of opioid analgesia is largely dependent on M1 formation, methadone maintenance patients may not receive adequate analgesia from oral tramadol.<\/jats:p>","DOI":"10.1111\/j.1365-2125.2012.04256.x","type":"journal-article","created":{"date-parts":[[2012,2,27]],"date-time":"2012-02-27T13:56:52Z","timestamp":1330351012000},"page":"835-841","source":"Crossref","is-referenced-by-count":25,"title":["Inhibition of CYP2D6\u2010mediated tramadol O\u2010demethylation in methadone but not buprenorphine maintenance patients"],"prefix":"10.1111","volume":"74","author":[{"given":"Janet K.","family":"Coller","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer R.","family":"Michalakas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heather M.","family":"James","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aaron L.","family":"Farquharson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joel","family":"Colvill","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jason M.","family":"White","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew A.","family":"Somogyi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2012,10,9]]},"reference":[{"key":"e_1_2_7_2_2","unstructured":"UNODC.2008World drug report. 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