title: Case report: quantification of methadone-induced respiratory depression using toxicokinetic/toxicodynamic relationships.
abstract: BACKGROUND
  Methadone, the most widely delivered maintenance therapy for heroin addicts, may be responsible for life-threatening poisonings with respiratory depression. The toxicokinetics and the toxicokinetic/toxicodynamic (TK/TD) relationships of methadone enantiomers have been poorly investigated in acute poisonings. The aim of this study was to describe the relationships between methadone-related respiratory effects and their corresponding concentrations.
  
  
  METHODS
  We report a 44-year-old methadone-maintained patient who ingested a 240-mg dose of methadone. He was found comatose with pinpoint pupils and respiratory depression. He was successfully treated with intravenous naloxone infusion over the course of 31 hours at a rate adapted to maintain normal consciousness and respiratory rate. We performed a TK/TD analysis of the naloxone infusion rate needed to maintain his respiratory rate at more than 12 breaths per minute (as toxicodynamics parameter) versus plasma R,S- and R-methadone concentrations (as toxicokinetics parameter), determined using an enantioselective high-performance liquid chromatography assay.
  
  
  RESULTS
  Initial plasma R,S-methadone concentration was 1,204 ng/ml. Decrease in plasma R- and S-methadone concentrations was linear and demonstrated a first-order pharmacokinetics (maximal observed concentrations 566 and 637 ng/ml, half-lives 16.1 and 13.2 hours, respectively). TK/TD correlation between naloxone infusion rate and R,S- and R-methadone concentrations fitted well a sigmoidal Emax model (concentration associated with a half-maximum effect [EC50] 334 and 173 ng/ml, Hill coefficient 10.0 and 7.8, respectively). In our chronically treated patient, EC50 values were in the range of previously reported values regarding methadone analgesic effects, suggesting that plasma methadone concentrations to prevent withdrawal are lower than those associated with methadone analgesic effects.
  
  
  CONCLUSIONS
  After the ingestion of a toxic dose of a racemic mixture, plasma R- and S-enantiomer concentrations decreased in parallel. Despite large inter-individual variability in methadone toxicokinetics and toxicodynamics, TK/TD relationships would be helpful for providing quantitative data regarding the respiratory response to methadone in poisonings. However, further confirmatory TK/TD data are needed.
authors.affiliation: INSERM U705, CNRS, UMR 7157, Université Paris 7, Assistance Publique--Hôpitaux de Paris, Hôpital Lariboisière, Réanimation Médicale et Toxicologique, Paris, France. bruno-megarbane@wanadoo.fr
authors.forename: Bruno
authors.initials: B
authors.lastname: Mégarbane
authors.forename: Xavier
authors.initials: X
authors.lastname: Declèves
authors.forename: Vanessa
authors.initials: V
authors.lastname: Bloch
authors.forename: Christophe
authors.initials: C
authors.lastname: Bardin
authors.forename: François
authors.initials: F
authors.lastname: Chast
authors.forename: Frédéric J
authors.initials: FJ
authors.lastname: Baud
mesh_terms: D000328:Adult; D002851:Chromatography, High Pressure Liquid; D016903:Drug Monitoring; D006801:Humans; D007262:Infusions, Intravenous; D007536:Isomerism; D008297:Male; D008691:Methadone / Q000097:blood* / Q000506:poisoning; D009270:Naloxone / Q000008:administration & dosage*; D009292:Narcotic Antagonists / Q000008:administration & dosage*; D009294:Narcotics / Q000097:blood* / Q000506:poisoning; D011041:Poisoning / Q000097:blood / Q000188:drug therapy / Q000503:physiopathology; D012119:Respiration; D012131:Respiratory Insufficiency / Q000097:blood / Q000139:chemically induced / Q000503:physiopathology*
chemical_list: D009292:Narcotic Antagonists; D009294:Narcotics; D009270:Naloxone; D008691:Methadone