The Magnitude of Acute Tolerance to Morphine Analgesia: Concentration-Dependent or Time-Dependent?

We evaluated the relationship of either the infusion time or the plasma morphine concentrations on the magnitude of acute tolerance to morphine analgesia. Male New Zealand White rabbits were randomly allocated to one of four groups. Group 1 received an IV bolus of morphine 40 mg followed by an infusion at 20 mg/h for 8 h. Group 2 received a 20-mg morphine bolus followed by an infusion at 10 mg/h. Group 3 received a 10-mg morphine bolus followed by an infusion at 5 mg/h. Group 4 received a saline bolus and infusion. Analgesia was determined by the paw-pressure test, and the plasma concentrations of morphine were measured by high-performance liquid chromatography. We found that the plasma concentrations of morphine were maintained at a steady-state between 2 and 8 h after the morphine administration. However, from 2 to 8 h after the morphine infusion, the longer the infusion time was, the less the analgesic effect remained. Furthermore, the magnitude of acute tolerance was significantly correlated to the duration of morphine infusion (r = 0.93;P < 0.01) but not the different steady-state plasma morphine concentrations. We conclude that the magnitude of morphine tolerance is significantly correlated to the duration of infusion but not the different steady-state plasma morphine concentrations.