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.