Modeling of tolerance development and rebound effect during different intravenous administrations of morphine to rats

The development of tolerance and the rebound effect to the antinociceptive effect of morphine were investigated and correlated with morphine pharmacokinetics. Five i.v. regimens, including a bolus dose (35 mumol/kg), 2 constant rate infusions (2.5 and 4.2 mumol/hr) over 4 days, 1 saline bolus dose and 1 glucose infusion were followed for 8 days. Clearance (CL) was estimated as 148 +/- 58 ml/min*kg after the bolus dose and 108 +/- 32 ml/min*kg during infusion (N.S.). Tolerance developed during the first day of morphine infusion and no antinociceptive effect could be measured from the third day. After cessation of the infusions, rebound hyperalgesia, significant for the higher infusion rate (P < .05), was observed. No hyperalgesia was detected after the bolus dose. A pharmacodynamic model with separate effect and tolerance compartments was used to describe the antinociceptive effect over time. The rates of equilibration of drug between the blood and effect compartment and the blood and tolerance compartment, expressed in half-lives, were estimated as 25 +/- 8 min and 26 +/- 6 hr, respectively. It is apparent from these results that an i.v. bolus dose of morphine causes less tolerance than constant rate infusions of morphine. With the presented model it is possible to quantify the rate and extent of tolerance development of morphine.