ACUTE PHYSICAL-DEPENDENCE - TIME-COURSE AND RELATION TO HUMAN PLASMA MORPHINE CONCENTRATIONS

Objectives: To characterize the postmorphine time course of precipitat ed withdrawal responses in comparison with the time course of opioid a gonist effects and of plasma morphine concentrations. Background: The study provides a more detailed and comprehensive assessment of the pos tagonist time course of acute dependence effects in humans than previo usly available. Design: Opioid agonist effects, morphine plasma levels , and withdrawal effects precipitated by naloxone (10 mg/70 kg, admini stered intramuscularly) were examined at 1, 3, 6, 12, 18, 24, 30, 36, and 42 hours after a single dose of morphine (18 mg/70 kg, administere d intramuscularly) in 10 nondependent opioid-experienced subjects. Res ults: The intensity of subjectively reported precipitated withdrawal e ffects was greatest when testing was conducted at 6 hours after morphi ne administration, whereas peak intensity of agonist effects (pupil co nstriction and subjective ratings) and highest plasma morphine concent rations (57.3 ng/ml) were observed at the shortest test interval (1 ho ur) after morphine. Offset time course of naloxone-precipitated effect s differed across specific measures, with hot and cold feelings elevat ed for the longest time after morphine (36 hrs), but significant effec ts were generally apparent for up to 24 hours after morphine pretreatm ent. Agonist effects lasted through only 12 hours; trace amounts of mo rphine were detected in plasma for up to 30 hours after administration . Conclusions: Results show that acute physical dependence engendered by a single dose of morphine peaks later and persists over a longer du ration after morphine administration than do other agonist effects. Th is suggests that neuronal adaptations underlying physical dependence d evelop and decay gradually over time during a single episode of recept or occupancy. The presence of detectable morphine in plasma is consist ent with a competitive displacement mechanism of precipitated effects, although noncompetitive actions of morphine or its metabolites are no t ruled out.