Morphine in postoperative patients: pharmacokinetics and pharmacodynamics of metabolites.
BACKGROUND
There is great variability in the need for morphine in the postoperative period. We performed a pharmacokinetic-pharmacodynamic study considering the potential effect of the two main metabolites of morphine.


METHODS
Fifty patients with moderate to severe pain received morphine as an IV titration, followed by IM administration postoperatively. The plasma concentration of morphine, morphine-6-glucuronide (M-6-G), morphine-3-glucuronide (M-3-G), and pain intensity were measured at frequent intervals. Pharmacokinetic and pharmacodynamic fitting was performed with the software NONMEM.


RESULTS
The pharmacokinetics were largely predictable. M-6-G and M-3-G clearances were markedly decreased in patients with renal failure. The pharmacodynamics was less predictable, with an important interindividual variability. M-6-G was 7.8 times more potent than morphine, but the average time to peak concentration in the effect compartment after a bolus injection of morphine was 4.25 h for M-6-G, when compared to 0.33 h for morphine. M-3-G showed mild inhibition of the analgesic properties of morphine and of M-6-G. The time to M-3-G peak concentration in the effect compartment after a bolus injection of morphine was 10 h.


CONCLUSIONS
M-6-G is a potent opioid agonist and M-3-G a mild opioid antagonist. Both are poorly excreted in patients with renal failure. However, the metabolism of morphine was rapid when compared to the transfer of metabolites through the blood-brain barrier, which appears to be the limiting process. Because poor analgesia due to M-3-G's effect may occur in some patients after 1 or 2 days, a switch to other molecules should be considered.
Mazoit
Jean Xavier
JX
Univ Paris-Sud, Laboratoire d'Anesthésie UPRES 3540, Faculté de Médecine, Le Kremlin Bicêtre, France. jean-xavier.mazoit@u-psud.fr
Butscher
Karin
K
Samii
Kamran
K
D000328:Adult; D000368:Aged; D005260:Female; D006801:Humans; D008297:Male; D053858:Metabolic Networks and Pathways / Q000187:drug effects / Q000502:physiology; D008875:Middle Aged; D009020:Morphine / Q000378:metabolism* / Q000494:pharmacology* / Q000627:therapeutic use; D009022:Morphine Derivatives / Q000378:metabolism; D010149:Postoperative Pain / Q000188:drug therapy / Q000378:metabolism; D011184:Postoperative Period
D009022:Morphine Derivatives; C035349:morphine-6-glucuronide; D009020:Morphine; C018108:morphine-3-glucuronide