Dose Escalation of Naltrexone to Reduce Stress Responses Associated With Opioid Antagonist Induction: A Double-blind Randomized Trial

J Addict Med. 2020 May/Jun;14(3):253-260. doi: 10.1097/ADM.0000000000000560.


Context: To describe the role of opioid antagonist induction in reducing stress response and withdrawal symptoms.

Objective: Complexity of naltrexone induction is limiting broader applicability of opioid antagonist-assisted abstinence. The aim of this clinical trial was to assess the stress response to 2 low-dose naltrexone induction protocols under minimal oral sedation.

Design: Double-blind randomized controlled trial.

Setting: Open setting in-patient unit.

Participants: Adults with opioid use disorder, and at least a year-long history of opioid use.

Intervention protocol: Patients received either a single 12.5 mg naltrexone oral dose (SI group) or escalating dosage regimen starting from 50 μg up to a cumulative dose of 12.5 mg (ED group).

Main outcome measure: Differences in cortisol and adrenocorticotropic hormone (ACTH) concentrations 1 hour after the start of naltrexone induction.

Results: In all, 124 patients were enrolled and 68 remained in the trial at the point of randomization-33 in SI and 35 in ED group. Eight patients were excluded from final analysis. Plasma cortisol and ACTH concentrations were significantly higher in SI group; mean difference between groups 313 nmol/L (95% confidence interval [CI] 182-444, P < 0.001) and 36.9 pg/mL (95% CI 12.3-61.4, P = 0.004), respectively.

Secondary outcomes: SI patients experienced significant increases in plasma cortisol and ACTH concentrations, and withdrawal scores. In ED group these measures remained at or below baseline throughout the 24-hour period from start of naltrexone induction.

Conclusions: Contrary to a single 12.5-mg dose, the escalating naltrexone dosing regimen produced no significant increase in stress response and withdrawal scores during antagonist induction.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenocorticotropic Hormone / blood
  • Adult
  • Double-Blind Method
  • Female
  • Humans
  • Hydrocortisone / blood
  • Male
  • Naltrexone / administration & dosage*
  • Naltrexone / therapeutic use*
  • Narcotic Antagonists / administration & dosage
  • Narcotic Antagonists / therapeutic use*
  • Opioid-Related Disorders / drug therapy*
  • Opioid-Related Disorders / psychology*
  • Substance Withdrawal Syndrome / drug therapy*
  • Substance Withdrawal Syndrome / psychology*


  • Narcotic Antagonists
  • Naltrexone
  • Adrenocorticotropic Hormone
  • Hydrocortisone