Pharmacokinetics and pharmacodynamics of subcutaneous morphine pellets in the rat
The pharmacokinetics and drug release characteristics of a standard, widely available s.c. morphine pellet were examined in the rat, together with antinociceptive (tailflick) effects and physical dependence. Over a 72-hr implant period one, two or three 75-mg morphine pellets released 12.5, 22.6 and 27.6 mg of morphine, respectively. Mean plasma morphine concentration after two morphine pellets reached a peak at 4 to 6 hr, then declined to a mean apparent steady-state level of 210 ng/ml at 36 hr that was maintained until the pellets were removed at 72 hr. The antinociceptive action of two morphine pellets peaked at 4 to 6 hr and had returned to predrug base-line values by 36 hr. After pellet removal, the plasma elimination kinetics of morphine were biexponential with a terminal T1/2 of 8.3 hr. The plasma morphine concentration declined 85% before the onset of significant weight loss could be measured. Peak abstinence weight loss was dose-related and was significantly correlated with both plasma morphine levels just before withdrawal and total dose of morphine absorbed over the 72-hr implant. These studies indicate that the release of morphine from s.c. implanted pellets in the rat is characterized by an initially higher rate of release (dose dumping effect) over the first 24 hr followed by a very constant release from 36 to 72 hr after implantation. The pharmacodynamic consequences of these dosage characteristics are the rapid development of tolerance and maintenance of physical dependence during the period of the implant.