{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T13:37:38Z","timestamp":1790861858927,"version":"4.1.0"},"reference-count":32,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2007,1,15]],"date-time":"2007-01-15T00:00:00Z","timestamp":1168819200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/2.0\/"},{"start":{"date-parts":[[2007,1,15]],"date-time":"2007-01-15T00:00:00Z","timestamp":1168819200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/2.0\/"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Crit Care"],"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n                        <jats:title>Introduction<\/jats:title>\n                        <jats:p>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.<\/jats:p>\n                     <\/jats:sec><jats:sec>\n                        <jats:title>Methods<\/jats:title>\n                        <jats:p>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 <jats:italic>R<\/jats:italic>,<jats:italic>S<\/jats:italic>- and <jats:italic>R<\/jats:italic>-methadone concentrations (as toxicokinetics parameter), determined using an enantioselective high-performance liquid chromatography assay.<\/jats:p>\n                     <\/jats:sec><jats:sec>\n                        <jats:title>Results<\/jats:title>\n                        <jats:p>Initial plasma <jats:italic>R<\/jats:italic>,<jats:italic>S<\/jats:italic>-methadone concentration was 1,204 ng\/ml. Decrease in plasma <jats:italic>R<\/jats:italic>- and <jats:italic>S<\/jats:italic>-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 <jats:italic>R<\/jats:italic>,<jats:italic>S<\/jats:italic>- and <jats:italic>R-<\/jats:italic> methadone concentrations fitted well a sigmoidal <jats:italic>E<\/jats:italic><jats:sub>\n                              <jats:italic>max<\/jats:italic>\n                           <\/jats:sub>model (concentration associated with a half-maximum effect [<jats:italic>EC<\/jats:italic><jats:sub>50<\/jats:sub>] 334 and 173 ng\/ml, Hill coefficient 10.0 and 7.8, respectively). In our chronically treated patient, <jats:italic>EC<\/jats:italic><jats:sub>50<\/jats:sub> 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.<\/jats:p>\n                     <\/jats:sec><jats:sec>\n                        <jats:title>Conclusion<\/jats:title>\n                        <jats:p>After the ingestion of a toxic dose of a racemic mixture, plasma <jats:italic>R<\/jats:italic>- and <jats:italic>S<\/jats:italic>-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.<\/jats:p>\n                     <\/jats:sec>","DOI":"10.1186\/cc5150","type":"journal-article","created":{"date-parts":[[2007,1,16]],"date-time":"2007-01-16T15:44:53Z","timestamp":1168962293000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Case report: quantification of methadone-induced respiratory depression using toxicokinetic\/toxicodynamic relationships"],"prefix":"10.1186","volume":"11","author":[{"given":"Bruno","family":"M\u00e9garbane","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xavier","family":"Decl\u00e8ves","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vanessa","family":"Bloch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christophe","family":"Bardin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fran\u00e7ois","family":"Chast","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fr\u00e9d\u00e9ric J","family":"Baud","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2007,1,15]]},"reference":[{"key":"4670_CR1","doi-asserted-by":"publisher","first-page":"997","DOI":"10.1136\/bmj.309.6960.997","volume":"309","author":"M Farrell","year":"1994","unstructured":"Farrell M, Ward J, Mattick R, Hall W, Stimson GV, des Jarlais D, Gossop M, Strang J: Methadone maintenance treatment in opiate dependence: a review.\n                           BMJ 1994, 309: 997-1001.","journal-title":"BMJ"},{"key":"4670_CR2","first-page":"CD002209","volume-title":"Cochrane Database Syst Rev","author":"RP Mattick","year":"2003","unstructured":"Mattick RP, Breen C, Kimber J, Davoli M: Methadone maintenance therapy versus no opioid replacement therapy for opioid dependence.\n                           Cochrane Database Syst Rev 2003, CD002209."},{"key":"4670_CR3","doi-asserted-by":"publisher","first-page":"277","DOI":"10.1001\/archinte.164.3.277","volume":"164","author":"MJ Krantz","year":"2004","unstructured":"Krantz MJ, Mehler PS: Treating opioid dependence. 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