Acute opioid physical dependence in humans: Effect of varying the morphine-naloxone interval II

Previous studies have demonstrated antagonist-precipitated withdrawal from 45 min to 24 hr after acute opioid administration in nondependent human subjects. The purpose of this study was to examine longer postagonist intervals and to determine the maximum interval between agonist administration and antagonist challenge at which precipitated withdrawal can be observed. During this study 6 nondependent male volunteers who reported using opiates an average of 4 times per week received naloxone challenges (10 mg/70 kg i.m.) at 6, 12, 24, 36, 48, 60 or 72 hr after single i.m. injections of morphine (18 mg/70 kg or 30 mg/70 kg). Each interval was tested independently in random order. Naloxone reliably precipitated withdrawal signs and symptoms at 6 and 12 hr postmorphine. Withdrawal symptoms were greatly diminished in intensity at 24-hr postmorphine and were not elicited at postmorphine intervals longer than 24 hr. Withdrawal precipitation persisted somewhat longer than pupillary constriction because pupils had returned to predrug diameters by 24 hr postmorphic but, generally, there appeared to be correspondence between offset of agonist effects and dissipation of precipitated withdrawal. This study extends observations about the time course of acute physical dependence effects which begin within minutes after acute morphine exposure, dissipate within 36 hr, are associated with the onset and offset of agonist effects and do not require chronic opioid administration.