title: Elimination of intravenous oxycodone in the elderly: a pharmacokinetic study in postoperative orthopaedic patients of different age groups.
abstract: OBJECTIVE
  Oxycodone is a widely used opioid analgesic, the global use of which has increased several-fold during the last decade. This study was designed to determine the effect of age on the pharmacokinetics of intravenous oxycodone, with special reference to renal function in elderly patients.
  
  
  METHODS
  We compared the pharmacokinetics of 5 mg of intravenous oxycodone in four groups of 10-11 patients, aged 20-40, 60-70, 70-90 years, undergoing orthopaedic surgery. Plasma concentrations of oxycodone and its noroxycodone, oxymorphone and noroxymorphone metabolites were measured for 24 hours with a liquid chromatography-tandem mass spectrometric method. The cytochrome P450 (CYP) 2D6 genotype of the patients was determined. Glomerular filtration rate (GFR) was estimated on the basis of the age, sex and serum creatinine concentration of the patient.
  
  
  RESULTS
  The pharmacokinetics of oxycodone showed age dependency. In the oldest group, the mean area under the plasma concentration-time curve from time zero to infinity (AUC(∞)) of oxycodone was 80% greater (p < 0.001) and the apparent total body clearance of the drug from plasma (CL) was 34% lower (p < 0.05) than in the youngest group. The mean AUC(∞) of oxycodone was also 30-41% greater in the oldest group than in the age groups of 60-70 and 70-80 years (p < 0.05). Oxycodone plasma concentrations from 8 hours post-dose were >2-fold higher (p < 0.01) in patients aged >80 years than in patients aged 20-40 years. Noroxycodone AUC(∞) was increased in the oldest group compared with patients aged 20-40 and 60-70 years (p < 0.05). There were no significant sex-related differences in any of the pharmacokinetic parameters. Because 37 of the 41 patients were extensive metabolizers through CYP2D6, the effect of the CYP2D6 genotype on oxycodone pharmacokinetics could not be properly assessed. There was a linear correlation between GFR and CL (p < 0.01, coefficient of determination [r(2)] = 0.26), volume of distribution at steady state (p < 0.05, r(2) = 0.19) and AUC(∞) (p < 0.01, r(2) = 0.29) of oxycodone.
  
  
  CONCLUSIONS
  Age is an important factor affecting the pharmacokinetics of oxycodone. Following intravenous administration of oxycodone, patients aged >70 years are expected to have, on average, 40-80% higher exposure to oxycodone than young adult patients. Because oxycodone pharmacokinetics are greatly dependent on the age of the patient, it is important to titrate the analgesic dose individually, particularly in the elderly.
authors.affiliation: Department of Anesthesiology, Intensive Care, Emergency Care and Pain Medicine, University of Turku and Turku University Hospital, Turku, Finland. antti.liukas@tyks.fi
authors.forename: Antti
authors.initials: A
authors.lastname: Liukas
authors.forename: Kristiina
authors.initials: K
authors.lastname: Kuusniemi
authors.forename: Riku
authors.initials: R
authors.lastname: Aantaa
authors.forename: Petri
authors.initials: P
authors.lastname: Virolainen
authors.forename: Mikko
authors.initials: M
authors.lastname: Neuvonen
authors.forename: Pertti J
authors.initials: PJ
authors.lastname: Neuvonen
authors.forename: Klaus T
authors.initials: KT
authors.lastname: Olkkola
mesh_terms: D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D019540:Area Under Curve; D002853:Chromatography, Liquid / Q000379:methods; D003404:Creatinine / Q000097:blood; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics*; D005260:Female; D005838:Genotype; D005919:Glomerular Filtration Rate; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D008875:Middle Aged; D009019:Morphinans / Q000493:pharmacokinetics; D019637:Orthopedic Procedures / Q000009:adverse effects / Q000379:methods; D010098:Oxycodone / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D010111:Oxymorphone / Q000493:pharmacokinetics; D010149:Postoperative Pain / Q000188:drug therapy*; D053719:Tandem Mass Spectrometry / Q000379:methods; D014018:Tissue Distribution; D055815:Young Adult
chemical_list: D000701:Analgesics, Opioid; D009019:Morphinans; C077256:noroxycodone; C526569:noroxymorphone; D010111:Oxymorphone; D003404:Creatinine; D010098:Oxycodone; D019389:Cytochrome P-450 CYP2D6