title: Acute physical dependence: time course and relation to human plasma morphine concentrations.
abstract: OBJECTIVE
  To characterize the postmorphine time course of precipitated withdrawal responses in comparison with the time course of opioid agonist effects and of plasma morphine concentrations.
  
  
  BACKGROUND
  The study provides a more detailed and comprehensive assessment of the postagonist time course of acute dependence effects in humans than previously available.
  
  
  METHODS
  Opioid agonist effects, morphine plasma levels, and withdrawal effects precipitated by naloxone (10 mg/70 kg, administered 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, administered intramuscularly) in 10 nondependent opioid-experienced subjects.
  
  
  RESULTS
  The intensity of subjectively reported precipitated withdrawal effects was greatest when testing was conducted at 6 hours after morphine administration, whereas peak intensity of agonist effects (pupil constriction and subjective ratings) and highest plasma morphine concentrations (57.3 ng/ml) were observed at the shortest test interval (1 hour) after morphine. Offset time course of naloxone-precipitated effects differed across specific measures, with hot and cold feelings elevated for the longest time after morphine (36 hrs), but significant effects were generally apparent for up to 24 hours after morphine pretreatment. Agonist effects lasted through only 12 hours; trace amounts of morphine 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 duration after morphine administration than do other agonist effects. This suggests that neuronal adaptations underlying physical dependence develop and decay gradually over time during a single episode of receptor occupancy. The presence of detectable morphine in plasma is consistent with a competitive displacement mechanism of precipitated effects, although noncompetitive actions of morphine or its metabolites are not ruled out.
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Md, USA.
authors.forename: H L
authors.initials: HL
authors.lastname: June
authors.forename: M L
authors.initials: ML
authors.lastname: Stitzer
authors.forename: E
authors.initials: E
authors.lastname: Cone
mesh_terms: D000208:Acute Disease; D000328:Adult; D000704:Analysis of Variance; D006801:Humans; D007273:Injections, Intramuscular; D008297:Male; D009020:Morphine / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood*; D009021:Morphine Dependence / Q000097:blood* / Q000503:physiopathology; D009270:Naloxone / Q000008:administration & dosage; D013375:Substance Withdrawal Syndrome / Q000097:blood* / Q000503:physiopathology; D013997:Time Factors
chemical_list: D009270:Naloxone; D009020:Morphine