title: Fentanyl utility function: a risk-benefit composite of pain relief and breathing responses.
abstract: BACKGROUND
  Integrating opioid risk and benefit into a single function may give a useful single measure of the opioid's positive and negative effects. An explorative study on the effects of fentanyl on antinociception and respiratory depression was performed to construct fentanyl risk-benefit (utility) functions.
  
  
  METHODS
  Twelve volunteers received a 3.5-μg/kg fentanyl intravenous injection on 2 separate study days. On one occasion, ventilation at a clamped increased carbon dioxide concentration was measured and on another the pain tolerance to electrical stimulation. In both sessions, arterial plasma samples were obtained. The data were analyzed with a population pharmacokinetic-pharmacodynamic model. A simulation study was performed, using the model parameter estimates and their variances, in which simulated subjects received 3.5 μg/kg of fentanyl. The resultant distributions were used to calculate the utility functions, defined as the probability of at least 50% analgesia (an increase in pain tolerance by ≥50%) minus the probability of at least 50% respiratory depression (a reduction in ventilation by ≥50%). Utility functions were constructed in concentration and time domains.
  
  
  RESULTS
  Fentanyl produced significant respiratory depression and analgesia. The pharmacokinetic and pharmacodynamic models adequately described the data. The constructed utility functions were negative at effect-site concentrations of greater than 0.5 ng/ml in the first 90 min after the 3.5 μg/kg bolus infusion.
  
  
  CONCLUSIONS
  Utility functions based on fentanyl's experimental effects on respiration and pain relief were successfully constructed. These functions are useful in multiple effect comparisons among experimental drugs. Further studies are required to assess whether this risk-benefit analysis is valuable in clinical practice.
authors.affiliation: Department of Anesthesiology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Merel
authors.initials: M
authors.lastname: Boom
authors.forename: Erik
authors.initials: E
authors.lastname: Olofsen
authors.forename: Meike
authors.initials: M
authors.lastname: Neukirchen
authors.forename: René
authors.initials: R
authors.lastname: Fussen
authors.forename: Justin
authors.initials: J
authors.lastname: Hay
authors.forename: Geert Jan
authors.initials: GJ
authors.lastname: Groeneveld
authors.forename: Leon
authors.initials: L
authors.lastname: Aarts
authors.forename: Elise
authors.initials: E
authors.lastname: Sarton
authors.forename: Albert
authors.initials: A
authors.lastname: Dahan
mesh_terms: D000328:Adult; D000701:Analgesics, Opioid / Q000494:pharmacology*; D003198:Computer Simulation; D005283:Fentanyl / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D010146:Pain / Q000188:drug therapy*; D012119:Respiration / Q000187:drug effects*
chemical_list: D000701:Analgesics, Opioid; D005283:Fentanyl