Naloxone reversal of morphine- and morphine-6-glucuronide-induced respiratory depression in healthy volunteers: a mechanism-based pharmacokinetic-pharmacodynamic modeling study.
BACKGROUND
Opioid-induced respiratory depression is antagonized effectively by the competitive opioid receptor antagonist naloxone. However, to fully understand the complex opioid agonist-antagonist interaction, the effects of various naloxone doses on morphine and morphine-6-glucuronide (M6G)-induced respiratory depression were studied in healthy volunteers.


METHODS
Twenty-four subjects received 0.15 mg/kg morphine intravenously at t = 0 followed by placebo, 200 or 400 microg naloxone at t = 30 min. Thirty-two subjects received 0.3 mg/kg M6G intravenously at t = 0 followed by placebo, 25, 100, or 400 microg naloxone at t = 55 min. There were a total of 8 subjects per treatment group. Respiration was measured on a breath-to-breath basis at constant end-tidal Pco2. A mechanism-based pharmacokinetic-pharmacodynamic model consisting of a part describing biophase equilibration and a part describing receptor association-dissociation kinetics was used to analyze the data.


RESULTS
Naloxone reversal of M6G-induced respiratory depression developed more slowly than reversal of the respiratory effect of morphine. A simulation study revealed that this was related to the slower receptor association-dissociation kinetics of M6G (koff M6G = 0.0327 +/- 0.00455 min versus morphine 0.138 +/- 0.0148 min; values are typical +/-SE). Duration of naloxone reversal was longer for M6G. This was related to the three- to fourfold greater potency of naloxone as an antagonist against M6G compared with morphine. Increasing the naloxone dose had no effect on the speed of reversal, but it did extend reversal duration.


CONCLUSIONS
Naloxone reversal of the opioid effect is dependent on the receptor association-dissociation kinetics of the opioid that needs reversal with respect to the rate of reversal. The pharmacodynamics of naloxone determines reversal magnitude and duration.
Olofsen
Erik
E
Department of Anesthesiology, Leiden University Medical Center, Leiden, The Netherlands.
van Dorp
Eveline
E
Teppema
Luc
L
Aarts
Leon
L
Smith
Terry W
TW
Dahan
Albert
A
Sarton
Elise
E
D000293:Adolescent; D000328:Adult; D005260:Female; D006801:Humans; D008297:Male; D008954:Models, Biological; D009020:Morphine / Q000009:adverse effects / Q000493:pharmacokinetics*; D009022:Morphine Derivatives / Q000009:adverse effects / Q000493:pharmacokinetics*; D009270:Naloxone / Q000493:pharmacokinetics* / Q000627:therapeutic use; D012131:Respiratory Insufficiency / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism*; D016037:Single-Blind Method; D055815:Young Adult
D009022:Morphine Derivatives; D009270:Naloxone; C035349:morphine-6-glucuronide; D009020:Morphine