title: Opioid-volatile anesthetic synergy: a response surface model with remifentanil and sevoflurane as prototypes.
abstract: BACKGROUND
  Combining a hypnotic and an analgesic to produce sedation, analgesia, and surgical immobility required for clinical anesthesia is more common than administration of a volatile anesthetic alone. The aim of this study was to apply response surface methods to characterize the interactions between remifentanil and sevoflurane.
  
  
  METHODS
  Sixteen adult volunteers received a target-controlled infusion of remifentanil (0-15 ng/ml) and inhaled sevoflurane (0-6 vol%) at various target concentration pairs. After reaching pseudo-steady state drug levels, the Observer's Assessment of Alertness/Sedation score and response to a series of randomly applied experimental pain stimuli (pressure algometry, electrical tetany, and thermal stimulation) were observed for each target concentration pair. Response surface pharmacodynamic interaction models were built using the pooled data for sedation and analgesic endpoints. Using computer simulation, the pharmacodynamic interaction models were combined with previously reported pharmacokinetic models to identify the combination of remifentanil and sevoflurane that yielded the fastest recovery (Observer's Assessment of Alertness/Sedation score > or = 4) for anesthetics lasting 30-900 min.
  
  
  RESULTS
  Remifentanil synergistically decreased the amount of sevoflurane necessary to produce sedation and analgesia. Simulations revealed that as the duration of the procedure increased, faster recovery was produced by concentration target pairs containing higher amounts of remifentanil. This trend plateaued at a combination of 0.75 vol% sevoflurane and 6.2 ng/ml remifentanil.
  
  
  CONCLUSIONS
  Response surface analyses demonstrate a synergistic interaction between remifentanil and sevoflurane for sedation and all analgesic endpoints.
authors.affiliation: Department of Bioengineering, University of Utah, Salt Lake City, Utah 84132, USA.
authors.forename: Sandeep C
authors.initials: SC
authors.lastname: Manyam
authors.forename: Dhanesh K
authors.initials: DK
authors.lastname: Gupta
authors.forename: Ken B
authors.initials: KB
authors.lastname: Johnson
authors.forename: Julia L
authors.initials: JL
authors.lastname: White
authors.forename: Nathan L
authors.initials: NL
authors.lastname: Pace
authors.forename: Dwayne R
authors.initials: DR
authors.lastname: Westenskow
authors.forename: Talmage D
authors.initials: TD
authors.lastname: Egan
mesh_terms: D000328:Adult; D000465:Algorithms; D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000493:pharmacokinetics; D018685:Anesthetics, Inhalation / Q000008:administration & dosage / Q000493:pharmacokinetics; D003198:Computer Simulation; D016292:Procedural Sedation; D003627:Data Interpretation, Statistical; D004311:Double-Blind Method; D004357:Drug Synergism; D023381:Endpoint Determination; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008738:Methyl Ethers / Q000008:administration & dosage / Q000493:pharmacokinetics; D015233:Models, Statistical; D010147:Pain Measurement / Q000187:drug effects; D010880:Piperidines / Q000008:administration & dosage / Q000493:pharmacokinetics; D000077208:Remifentanil; D000077149:Sevoflurane
chemical_list: D000701:Analgesics, Opioid; D018685:Anesthetics, Inhalation; D008738:Methyl Ethers; D010880:Piperidines; D000077149:Sevoflurane; D000077208:Remifentanil