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

Acute opioid physical dependence refers to the withdrawal symptoms precipiated by an opioid antagonist administered after a single dose or short-term infusion of an opioid agonist. This phenomenon is particularly interesting given that the abstinence syndrome has generally been thought to develop only after chronic exposure to opioid agonists. The purpose of this study was to determine the minimum time after agonist administration when antagonist-precipitated withdrawal could be observed. Naloxone (10 mg/80 kg) was administered i.m. either 0, 15, 45 or 90 min after single i.m. injections of morphine (18 mg/70 kg) in five nondependent male opiate users. Physiological and subjective report measures revealed no effect of morphine or naloxone at the 0 and 15 min morphine-naloxone interval conditions; however, before the naloxone challenge 45 and 90 min postmorphine, agonist effects (e.g., miosis, respiratory depression and good drug effect subjective ratings) were clearly evident. Naloxone reversed these effects to premorphine levels and simultaneously precipitated subjective symptoms and observer rated signs of opiate withdrawal. Thus, this study showed that antagonist-precipiated withdrawal in humans was first observed 45 min after agonist administration. Further, the onset of naloxone-precipiated withdrawal effects closely paralleled the onset of morphine agonist effects. The results of this study suggest that adaptational changes underlying the development of physical dependence begin within minutes after acute exposure to an opiate.