title: Simultaneous measurement and integrated analysis of analgesia and respiration after an intravenous morphine infusion.
abstract: BACKGROUND
  To study the influence of morphine on chemical control of breathing relative to the analgesic properties of morphine, the authors quantified morphine-induced analgesia and respiratory depression in a single group of healthy volunteers. Both respiratory and pain measurements were performed over single 24-h time spans.
  
  
  METHODS
  Eight subjects (four men, four women) received a 90-s intravenous morphine infusion; eight others (four men, four women) received a 90-s placebo infusion. At regular time intervals, respiratory variables (breathing at a fixed end-tidal partial pressure of carbon dioxide of 50 mmHg and the isocapnic acute hypoxic response), pain tolerance (derived from a transcutaneous electrical acute pain model), and arterial blood samples were obtained. Data acquisition continued for 24 h. Population pharmacokinetic (sigmoid Emax)-pharmacodynamic models were applied to the respiratory and pain data. The models are characterized by potency parameters, shape parameters (gamma), and blood-effect site equilibration half-lives. All collected data were analyzed simultaneously using the statistical program NONMEM.
  
  
  RESULTS
  Placebo had no systematic effect on analgesic or respiratory variables. Morphine potency parameter and blood-effect site equilibration half-life did not differ significantly among the three measured effect parameters (P > 0.01). The integrated NONMEM analysis yielded a potency parameter of 32 +/- 1.4 nm (typical value +/- SE) and a blood-effect site equilibration half-life of 4.4 +/- 0.3 h. Parameter gamma was 1 for hypercapnic and hypoxic breathing but 2.4 +/- 0.7 for analgesia (P < 0.01).
  
  
  CONCLUSIONS
  Our data indicate that systems involved in morphine-induced analgesia and respiratory depression share important pharmacodynamic characteristics. This suggests similarities in central mu-opioid analgesic and respiratory pathways (e.g., similarities in mu-opioid receptors and G proteins). The clinical implication of this study is that after morphine administration, despite lack of good pain relief, moderate to severe respiratory depression remains possible.
authors.affiliation: Department of Anesthesiology, Leiden University Medical Center, The Netherlands. a.dahan@lumc.nl
authors.forename: Albert
authors.initials: A
authors.lastname: Dahan
authors.forename: Raymonda
authors.initials: R
authors.lastname: Romberg
authors.forename: Luc
authors.initials: L
authors.lastname: Teppema
authors.forename: Elise
authors.initials: E
authors.lastname: Sarton
authors.forename: Hans
authors.initials: H
authors.lastname: Bijl
authors.forename: Erik
authors.initials: E
authors.lastname: Olofsen
mesh_terms: D000293:Adolescent; D000328:Adult; D000465:Algorithms; D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D002245:Carbon Dioxide / Q000378:metabolism; D004311:Double-Blind Method; D005260:Female; D006207:Half-Life; D006801:Humans; D000860:Hypoxia / Q000503:physiopathology; D007275:Injections, Intravenous; D008297:Male; D015233:Models, Statistical; D009020:Morphine / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D009022:Morphine Derivatives / Q000097:blood; D010147:Pain Measurement / Q000187:drug effects / Q000379:methods*; D012129:Respiratory Function Tests / Q000379:methods*; D015656:Respiratory Mechanics / Q000187:drug effects*
chemical_list: D000701:Analgesics, Opioid; D009022:Morphine Derivatives; D002245:Carbon Dioxide; C035349:morphine-6-glucuronide; D009020:Morphine; C018108:morphine-3-glucuronide