Norpropoxyphene Explained

Norpropoxyphene is a major metabolite of the opioid analgesic drug dextropropoxyphene,[1] and is responsible for many of the side effects associated with use of this drug, especially the unusual toxicity seen during dextropropoxyphene overdose.[2] [3] [4] It has weaker analgesic effects than dextropropoxyphene itself, but is a relatively potent pro-convulsant and blocker of sodium and potassium channels,[5] particularly in heart tissue,[6] [7] which produces prolonged intracardiac conduction time and can lead to heart failure following even relatively minor overdoses.[8] [9] [10] [11] The toxicity of this metabolite makes dextropropoxyphene up to 10 times more likely to cause death following overdose compared to other similar mild opioid analgesics,[12] and has led to dextropropoxyphene being withdrawn from the market in some countries.[13]

Because norpropoxyphene has a long half-life in the body of up to 36 hours (compared to around 6–12 hours for dextropropoxyphene), it can accumulate in tissues during chronic use of dextropropoxyphene-containing medications, especially in people whose excretion of drugs is slower than normal such as young children, the elderly, and individuals with reduced kidney or liver function, and so side effects including serious adverse events are more common in these groups and use of dextropropoxyphene should be avoided where possible.[14] [15] [16]

Notes and References

  1. Somogyi AA, Menelaou A, Fullston SV . CYP3A4 mediates dextropropoxyphene N-demethylation to nordextropropoxyphene: human in vitro and in vivo studies and lack of CYP2D6 involvement . Xenobiotica; the Fate of Foreign Compounds in Biological Systems . 34 . 10 . 875–87 . October 2004 . 15764408 . 10.1080/00498250400008371 . 7680532 .
  2. Gustafson A, Gustafsson B . Acute poisoning with dextropropoxyphene. Clinical symptoms and plasma concentrations . Acta Medica Scandinavica . 1976 . 200 . 4 . 241–8 . 10.1111/j.0954-6820.1976.tb08226.x . 983792 .
  3. McBay AJ . Propoxyphene and norpropoxyphene concentrations in blood and tissues in cases of fatal overdose . Clinical Chemistry . 22 . 8 . 1319–21 . August 1976 . 10.1093/clinchem/22.8.1319 . 949842 . free .
  4. Nickander RC, Emmerson JL, Hynes MD, Steinberg MI, Sullivan HR . Pharmacologic and toxic effects in animals of dextropropoxyphene and its major metabolite norpropoxyphene: a review . Human Toxicology . 3 Suppl . 13S–36S . August 1984 . 6090306 . 10.1177/096032718400300103 . 1333582 .
  5. Nickander R, Smits SE, Steinberg MI . Propoxyphene and norpropoxyphene: pharmacologic and toxic effects in animals . The Journal of Pharmacology and Experimental Therapeutics . 200 . 1 . 245–53 . January 1977 . 13200 .
  6. Lund-Jacobsen H . Cardio-respiratory toxicity of propoxyphene and norpropoxyphene in conscious rabbits . Acta Pharmacologica et Toxicologica . 42 . 3 . 171–8 . March 1978 . 580345 . 10.1111/j.1600-0773.1978.tb02187.x .
  7. Ulens C, Daenens P, Tytgat J . Norpropoxyphene-induced cardiotoxicity is associated with changes in ion-selectivity and gating of HERG currents . Cardiovascular Research . 44 . 3 . 568–78 . December 1999 . 10690289 . 10.1016/s0008-6363(99)00258-8 . free .
  8. Young RJ . Dextropropoxyphene overdosage. Pharmacological considerations and clinical management . Drugs . 26 . 1 . 70–9 . July 1983 . 6349964 . 10.2165/00003495-198326010-00004 . 46978533 .
  9. Lawson AA, Northridge DB . Dextropropoxyphene overdose. Epidemiology, clinical presentation and management . Medical Toxicology and Adverse Drug Experience . 1987 . 2 . 6 . 430–44 . 3323775 . 10.1007/BF03259877 . 13452948 .
  10. Afshari R, Maxwell S, Dawson A, Bateman DN . ECG abnormalities in co-proxamol (paracetamol/dextropropoxyphene) poisoning . Clinical Toxicology . 2005 . 43 . 4 . 255–9 . 10.1081/CLT-66069 . 16035201 . 36817890 .
  11. Simkin S, Hawton K, Sutton L, Gunnell D, Bennewith O, Kapur N . Co-proxamol and suicide: preventing the continuing toll of overdose deaths . QJM . 98 . 3 . 159–70 . March 2005 . 15728397 . 10.1093/qjmed/hci026 . free .
  12. Afshari R, Good AM, Maxwell SR, Bateman DN . Co-proxamol overdose is associated with a 10-fold excess mortality compared with other paracetamol combination analgesics . British Journal of Clinical Pharmacology . 60 . 4 . 444–7 . October 2005 . 16187978 . 10.1111/j.1365-2125.2005.02468.x . 1884826 .
  13. Sandilands EA, Bateman DN . Co-proxamol withdrawal has reduced suicide from drugs in Scotland . British Journal of Clinical Pharmacology . 66 . 2 . 290–3 . August 2008 . 18489609 . 10.1111/j.1365-2125.2008.03206.x . 2492929 .
  14. Gibson TP, Giacomini KM, Briggs WA, Whitman W, Levy G . Propoxyphene and norpropoxyphene plasma concentrations in the anephric patient . Clinical Pharmacology and Therapeutics . 27 . 5 . 665–70 . May 1980 . 7371364 . 10.1038/clpt.1980.94 . 24099122 .
  15. Inturrisi CE, Colburn WA, Verebey K, Dayton HE, Woody GE, O'Brien CP . Propoxyphene and norpropoxyphene kinetics after single and repeated doses of propoxyphene . Clinical Pharmacology and Therapeutics . 31 . 2 . 157–67 . February 1982 . 7056023 . 10.1038/clpt.1982.25 . 38421623 .
  16. Flanagan RJ, Johnston A, White AS, Crome P . Pharmacokinetics of dextropropoxyphene and nordextropropoxyphene in young and elderly volunteers after single and multiple dextropropoxyphene dosage . British Journal of Clinical Pharmacology . 28 . 4 . 463–9 . October 1989 . 2590604 . 10.1111/j.1365-2125.1989.tb03527.x . 1379997 .

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