Simultaneous measurement and integrated analysis of analgesia and respiration after an intravenous morphine infusion.
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.
Dahan
Albert
A
Department of Anesthesiology, Leiden University Medical Center, The Netherlands. a.dahan@lumc.nl
Romberg
Raymonda
R
Teppema
Luc
L
Sarton
Elise
E
Bijl
Hans
H
Olofsen
Erik
E
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*
D000701:Analgesics, Opioid; D009022:Morphine Derivatives; D002245:Carbon Dioxide; C035349:morphine-6-glucuronide; D009020:Morphine; C018108:morphine-3-glucuronide