title: Pharmacokinetic-pharmacodynamic modeling of morphine and oxycodone concentrations and analgesic effect in a multimodal experimental pain model.
abstract: Analgesia from most opioids is mediated by mu receptors located mainly in the central nervous system. Previous studies have shown a different pharmacological profile of oxycodone in respect to visceral analgesia. This study investigated if morphine and oxycodone have different pharmacokinetic/pharmacodynamic profiles, in particular with respect to delay between opioid blood concentration and analgesia. Twenty-four healthy subjects had oral morphine (30 mg), oxycodone (15 mg), or placebo. Mechanical, thermal, and electrical pain tests were performed in the skin and viscera. Blood samples and pain measurements were taken at baseline and after 15, 30, 60, 90, and 120 minutes. Pharmacokinetic/pharmacodynamic profiles were modeled using a 2-stage, nonlinear, mixed-effects approach with an effect compartment to represent the concentration-analgesia delay. Morphine kinetics was best described by a 2-compartment model, whereas oxycodone kinetics was best described with a 1-compartment model. Generally the analgesic effects of morphine were best related to plasma concentration by introducing a delay via an effect compartment. However, for oxycodone, this was only the case for analgesia in the somatic pain measures, whereas the plasma concentration correlated better to the course of the analgesia with no delay in the visceral pain measures. Oxycodone and morphine showed different pharmacodynamic/pharmacokinetic relationships for the visceral analgesia, whereas relationships were alike for somatic analgesia.
authors.affiliation: Center for Visceral Biomechanics and Pain, Department of Gastroenterology, University Hospital Aalborg, Hobrovej 18-22, 9000 Aalborg, Denmark. cst@smi.auc.dk
authors.forename: Camilla
authors.initials: C
authors.lastname: Staahl
authors.forename: Richard
authors.initials: R
authors.lastname: Upton
authors.forename: David J R
authors.initials: DJ
authors.lastname: Foster
authors.forename: Lona Louring
authors.initials: LL
authors.lastname: Christrup
authors.forename: Kim
authors.initials: K
authors.lastname: Kristensen
authors.forename: Steen Honoré
authors.initials: SH
authors.lastname: Hansen
authors.forename: Lars
authors.initials: L
authors.lastname: Arendt-Nielsen
authors.forename: Asbjørn Mohr
authors.initials: AM
authors.lastname: Drewes
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000465:Algorithms; D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D019540:Area Under Curve; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004558:Electric Stimulation / Q000009:adverse effects; D005260:Female; D006358:Hot Temperature / Q000009:adverse effects; D006801:Humans; D007263:Infusions, Parenteral; D008297:Male; D008954:Models, Biological; D009020:Morphine / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D010098:Oxycodone / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D010146:Pain / Q000188:drug therapy* / Q000209:etiology; D010147:Pain Measurement / Q000187:drug effects; D017288:Pain Threshold / Q000187:drug effects; D010812:Physical Stimulation / Q000009:adverse effects / Q000379:methods
chemical_list: D000701:Analgesics, Opioid; D009020:Morphine; D010098:Oxycodone