Precipitated opioid withdrawal across acute physical dependence induction methods

Pharmacol Biochem Behav. 2004 Feb;77(2):263-8. doi: 10.1016/j.pbb.2003.10.017.


The phenomenon of acute opioid physical dependence (APD) is an established and well-characterized experimental model for studying the clinical phenomenon of physical dependence to opioids in humans. In this paradigm, an opioid withdrawal syndrome is elicited in non-opioid-dependent humans by the parenteral administration of naloxone (NX) following a single large dose of opioid agonist. Although induced by various opioids and NX administration schedules, lacking is a direct comparison of different induction protocols with respect to withdrawal severity. Using a crossover design, we compared withdrawal severity in four healthy male subjects pretreated with morphine (MS; 18 mg/70 kg im), MS (10 mg/70 kg iv) and hydromorphone (HM; 2 mg/70 kg) followed 2 or 6 h later with NX (10 mg/70 kg iv). Dependent measures included both physiological and subjective indicators of withdrawal. All opioid pretreatments reliably induced APD and repeated-measures analysis of variance (ANOVA) showed that both pattern and severity of precipitated withdrawal were similar across conditions. Thus, despite altering the pretreatment opioid and route of administration, all three APD protocols produced similar and reliable withdrawal symptoms in humans.

Publication types

  • Clinical Trial
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adult
  • Cross-Over Studies
  • Dose-Response Relationship, Drug
  • Heart Rate / drug effects
  • Humans
  • Hydromorphone / pharmacology
  • Injections, Intramuscular
  • Injections, Intravenous
  • Male
  • Morphine / administration & dosage
  • Morphine / pharmacology
  • Naloxone / pharmacology*
  • Narcotic Antagonists / pharmacology*
  • Narcotics / administration & dosage
  • Narcotics / pharmacology
  • Pupil / drug effects
  • Respiratory Mechanics / drug effects
  • Substance Withdrawal Syndrome / physiopathology*
  • Substance Withdrawal Syndrome / psychology
  • Substance-Related Disorders / physiopathology*
  • Substance-Related Disorders / psychology


  • Narcotic Antagonists
  • Narcotics
  • Naloxone
  • Morphine
  • Hydromorphone