title: Stochastic Pharmacokinetic-Pharmacodynamic Analysis of the Effect of Transdermal Buprenorphine on Electroencephalogram and Analgesia.
abstract: BACKGROUND
  The analgesic effect of opioids is often based on subjective one dimensional measurements. Electroencephalography (EEG) offers a possibility to objectively quantify the brain's activity before and after the administration of opioids. The aim of this study was to investigate the pharmacokinetic-pharmacodynamic (PKPD) properties of the buprenorphine transdermal patch on resting EEG and pain tolerance.
  
  
  METHODS
  Twenty-two healthy male subjects (mean age 23.1 ± 3.8 years) were studied. They received a 144-hour buprenorphine (20 μg/h) or placebo transdermal patch in this experimental, randomized, crossover, double-blind study. Skin heat pain tolerance was measured on the arm before the recordings of resting EEG. From the EEG, the ratio of slow and fast oscillations was calculated for further analysis. A population PKPD model with a stochastic differential equation for drug absorption from the patch was used to analyze the PK and PD data simultaneously by use of the statistical analysis package NONMEM.
  
  
  RESULTS
  Buprenorphine increased EEG ratio (P = 0.0006) and skin pain tolerance (P = 0.0008) compared with placebo. The stochastic model adequately characterized the concentration-time and effect-time courses for both the skin heat stimulation and the resting EEG outcomes with variations in the drug's absorption rate during the 144-hour treatment period. As measured by the potency parameter, the EEG effect was 10 ± 3 (median ± SE) times more sensitive to buprenorphine than the skin pain test.
  
  
  CONCLUSIONS
  Using a stochastic PKPD analysis, the effect of a 144-hour buprenorphine patch application on resting EEG and skin pain tolerance was quantified successfully. Both end points were affected by buprenorphine, although the resting EEG was more sensitive to buprenorphine. The stochastic PKPD analysis allowed the computation of a time-dependent variability in drug absorption from patch to blood. The data suggest that the resting EEG is an attractive and objective alternative for assessing opioid effect.
authors.affiliation: From the *Mech-Sense, Department of Gastroenterology, Aalborg University Hospital, Aalborg, Denmark; †Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark; ‡Department of Anesthesiology, Leiden University Medical Center, RC Leiden, The Netherlands; and §Department of Clinical Medicine, Aalborg University, Aalborg, Denmark.
authors.forename: Anne Estrup
authors.initials: AE
authors.lastname: Olesen
authors.forename: Erik
authors.initials: E
authors.lastname: Olofsen
authors.forename: Trine
authors.initials: T
authors.lastname: Andresen
authors.forename: Carina
authors.initials: C
authors.lastname: Graversen
authors.forename: Asbjørn Mohr
authors.initials: AM
authors.lastname: Drewes
authors.forename: Albert
authors.initials: A
authors.lastname: Dahan
mesh_terms: D000328:Adult; D000698:Analgesia / Q000379:methods; D002047:Buprenorphine / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004569:Electroencephalography / Q000187:drug effects* / Q000379:methods; D006801:Humans; D008297:Male; D013269:Stochastic Processes; D057968:Transdermal Patch; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D002047:Buprenorphine