title: Inhibition of CYP2D6-mediated tramadol O-demethylation in methadone but not buprenorphine maintenance patients.
abstract: BACKGROUND
  Management of pain in opioid dependent individuals is problematic due to numerous issues including cross-tolerance to opioids. Hence there is a need to find alternative analgesics to classical opioids and tramadol is potentially one such alternative. Methadone inhibits CYP2D6 in vivo and in vitro. We aimed to investigate the effect of methadone on the pathways of tramadol metabolism: O-demethylation (CYP2D6) to the opioid-active metabolite M1 and N-demethylation (CYP3A4) to M2 in subjects maintained on methadone or buprenorphine as a control.
  
  
  CONCLUSIONS
  Compared with subjects on buprenorphine, methadone reduced the clearance of tramadol to active O-desmethyl-tramadol (M1) but had no effect on N-desmethyltramadol (M2) formation. Similar to other analgesics whose active metabolites are formed by CYP2D6 such as codeine, reduced formation of O-desmethyltramadol (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.
  
  
  OBJECTIVE
  To compare the O- (CYP2D6 mediated) and N- (CYP3A4 mediated) demethylation metabolism of tramadol between methadone and buprenorphine maintained CYP2D6 extensive metabolizer subjects. METHODS Nine methadone and seven buprenorphine maintained subjects received a single 100 mg dose of tramadol hydrochloride. Blood was collected at 4 h and assayed for tramadol, methadone, buprenorphine and norbuprenorphine (where appropriate) and all urine over 4 h was assayed for tramadol and its M1 and M2 metabolites.
  
  
  RESULTS
  The urinary metabolic ratio [median (range)] for O-demethylation (M1) was significantly lower (P= 0.0002, probability score 1.0) in the subjects taking methadone [0.071 (0.012-0.103)] compared with those taking buprenorphine [0.192 (0.108-0.392)], but there was no significant difference (P= 0.21, probability score 0.69) in N-demethylation (M2). The percentage of dose [median (range)] recovered as M1 was significantly lower in subjects taking methadone compared with buprenorphine (0.069 (0.044-0.093) and 0.126 (0.069-0.187), respectively, P= 0.04, probability score 0.19), M2 was significantly higher in subjects taking methadone compared with buprenorphine (0.048 (0.033-0.085) and 0.033 (0.014-0.049), respectively, P= 0.04, probability score 0.81). Tramadol was similar (0.901 (0.635-1.30) and 0.685 (0.347-1.04), respectively, P= 0.35, probability score 0.65).
  
  
  CONCLUSIONS
  Methadone inhibited the CYP2D6-mediated 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.
authors.affiliation: Discipline of Pharmacology, School of Medical Sciences, University of Adelaide, Adelaide, SA 5005, Australia. janet.coller@adelaide.edu.au
authors.forename: Janet K
authors.initials: JK
authors.lastname: Coller
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Michalakas
authors.forename: Heather M
authors.initials: HM
authors.lastname: James
authors.forename: Aaron L
authors.initials: AL
authors.lastname: Farquharson
authors.forename: Joel
authors.initials: J
authors.lastname: Colvill
authors.forename: Jason M
authors.initials: JM
authors.lastname: White
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Somogyi
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000701:Analgesics, Opioid / Q000493:pharmacokinetics* / Q000494:pharmacology; D002047:Buprenorphine / Q000494:pharmacology*; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D004347:Drug Interactions; D005260:Female; D006801:Humans; D008297:Male; D008691:Methadone / Q000494:pharmacology*; D008875:Middle Aged; D058850:Opiate Substitution Treatment; D014147:Tramadol / Q000031:analogs & derivatives / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: D000701:Analgesics, Opioid; D065690:Cytochrome P-450 CYP2D6 Inhibitors; C080580:O-demethyltramadol; D014147:Tramadol; D002047:Buprenorphine; C080579:N-demethyltramadol; D019389:Cytochrome P-450 CYP2D6; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D008691:Methadone