title: Opioid challenge evaluation of blockade by extended-release naltrexone in opioid-abusing adults: dose-effects and time-course.
abstract: BACKGROUND
  Oral naltrexone's effectiveness as an opioid antagonist has been limited due to poor patient adherence. A long-acting naltrexone formulation may be beneficial. This study evaluated the effects of extended-release injectable naltrexone (XR-NTX), targeted for a one-month duration of action, in blocking opioid agonist challenge effects in humans.
  
  
  METHODS
  Outpatient non-dependent opioid abusers (N=27) were randomly assigned to a single double-blind IM administration of 75, 150, or 300 mg XR-NTX. To assess the extent of opioid blockade, hydromorphone challenges (0, 3, 4.5, 6 mg IM in ascending order at 1-h intervals [up to 13.5 mg total]) were given at pretreatment baseline and on days 7, 14, 21, 28, 42, and 56. Opioid blockade was assessed via (1) tolerability of the ascending hydromorphone doses; (2) visual analog scale (VAS) ratings of subjective opioid effects and (3) pupil diameter. Effects on the VAS and pupils were assessed via the slope of the time-action function over ascending hydromorphone doses, with zero slope indicating complete blockade.
  
  
  RESULTS
  Blockade of the VAS "any drug effect" response to 3 mg hydromorphone was complete for 14, 21, and 28 days, respectively, for the XR-NTX doses of 75, 150, and 300 mg. Subjective effects were more readily blocked than was pupil constriction. Higher hydromorphone doses produced only modest increases in agonist effects. With the 300 mg XR-NTX dose the slope of VAS responses remained at or near zero for one month even with maximal cumulative hydromorphone dosing.
  
  
  CONCLUSIONS
  These data quantify the month-long opioid blockade underlying XR-NTX's efficacy in opioid dependence treatment.
authors.affiliation: Behavioral Pharmacology Research Unit, Johns Hopkins University School of Medicine, Bayview Campus, Baltimore, MD 21224, USA. bigelow@jhmi.edu
authors.forename: George E
authors.initials: GE
authors.lastname: Bigelow
authors.forename: Kenzie L
authors.initials: KL
authors.lastname: Preston
authors.forename: John
authors.initials: J
authors.lastname: Schmittner
authors.forename: Qunming
authors.initials: Q
authors.lastname: Dong
authors.forename: David R
authors.initials: DR
authors.lastname: Gastfriend
mesh_terms: D000328:Adult; D001794:Blood Pressure / Q000187:drug effects; D003692:Delayed-Action Preparations; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D004091:Hydromorphone / Q000037:antagonists & inhibitors; D008297:Male; D009271:Naltrexone / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D009292:Narcotic Antagonists / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D009294:Narcotics; D009293:Opioid-Related Disorders / Q000188:drug therapy*; D010100:Oxygen / Q000097:blood; D011680:Pupil / Q000187:drug effects; D056152:Respiratory Rate / Q000187:drug effects; D012881:Skin Temperature / Q000187:drug effects; D013997:Time Factors
chemical_list: D003692:Delayed-Action Preparations; D009292:Narcotic Antagonists; D009294:Narcotics; D009271:Naltrexone; D004091:Hydromorphone; D010100:Oxygen
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