title: Oxycodone is associated with dose-dependent QTc prolongation in patients and low-affinity inhibiting of hERG activity in vitro.
abstract: BACKGROUND
  During recent years some opioids have been associated with prolonged QT and torsade de pointes (TdP). In vitro testing has shown that most opioids can block the cardiac potassium channels. This indicates that QT prolongation and TdP could be a more general problem associated with the use of these drugs.
  
  
  CONCLUSIONS
  This study is the first to show that oxycodone dose is associated with QT prolongation and in vitro blockade of hERG channels expressed in HEK293. Neither morphine nor tramadol doses are associated with the QT interval length.
  
  
  OBJECTIVE
  During recent years some opioids have been associated with prolonged QT interval and torsade de pointes (TdP). In vitro patch clamp testing has shown that most opioids can block human ether-a-go-go related gene (hERG) channels that are known to underlie cardiac repolarizing I(Kr) current. This indicates that QT prolongation and TdP could be a more general problem associated with the use of these drugs. The aims of this study were to evaluate the association between different opioids and the QTc among patients and measure hERG activity under influence by opioids in vitro.
  
  
  METHODS
  One hundred chronic nonmalignant pain patients treated with methadone, oxycodone, morphine or tramadol were recruited in a cross-sectional study. The QTc was estimated from a 12-lead ECG. To examine hERG activity in the presence of oxycodone, electrophysiological testing was conducted using Xenopus laevis oocytes and HEK293 cells expressing hERG channels.
  
  
  RESULTS
  There were no differences in gender distribution or age between the treatment groups. The known association between methadone dose and QTc was confirmed (R(2) = 0.09; P = 0.02). Higher oxycodone dose was also associated with longer QTc (R(2) = 0.21; P = 0.02). A 100 mg higher oxycodone dose was associated with a 10 ms(1/2) (95% CI 2-19) longer QTc. Neither morphine nor tramadol dose was associated with the QTc. Electrophysiological testing revealed low-affinity inhibition of the potassium current through hERG channels expressed in HEK293 cells (IC(50) = 171 microM oxycodone).
  
  
  CONCLUSIONS
  Among patients treated with methadone or oxycodone, higher doses were associated with longer QTc. Oxycodone is capable of inhibiting hERG channels in vitro.
authors.affiliation: Department of Cardiology, Copenhagen University Hospital Hvidovre, Kettegård Allé 30, Hvidovre, Denmark. sfanoe@dadlnet.dk
authors.forename: Søren
authors.initials: S
authors.lastname: Fanoe
authors.forename: Gorm Boje
authors.initials: GB
authors.lastname: Jensen
authors.forename: Per
authors.initials: P
authors.lastname: Sjøgren
authors.forename: Mads P G
authors.initials: MP
authors.lastname: Korsgaard
authors.forename: Morten
authors.initials: M
authors.lastname: Grunnet
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000701:Analgesics, Opioid / Q000494:pharmacology* / Q000627:therapeutic use; D003430:Cross-Sectional Studies; D003718:Denmark; D064420:Drug-Related Side Effects and Adverse Reactions; D000072237:ERG1 Potassium Channel; D004562:Electrocardiography / Q000187:drug effects; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors*; D005260:Female; D006329:Heart Conduction System / Q000187:drug effects*; D006801:Humans; D008133:Long QT Syndrome / Q000139:chemically induced*; D008297:Male; D008875:Middle Aged; D010146:Pain / Q000188:drug therapy; D018408:Patch-Clamp Techniques; D016171:Torsades de Pointes / Q000139:chemically induced; D055815:Young Adult
chemical_list: D000701:Analgesics, Opioid; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human