Explaining differential effects of medication for opioid use disorder using a novel approach incorporating mediating variables

Addiction. 2021 Aug;116(8):2094-2103. doi: 10.1111/add.15377. Epub 2021 Jan 22.


Background and aims: A recent study found that homeless individuals with opioid use disorder (OUD) had a lower risk of relapse on extended-release naltrexone (XR-NTX) versus buprenorphine-naloxone (BUP-NX), whereas non-homeless individuals had a lower risk of relapse on BUP-NX. This secondary study examined differences in mediation pathways to medication effect between homeless and non-homeless participants.

Design: Secondary analysis of an open-label randomized controlled, 24-week comparative effectiveness trial, 2014-17.

Setting: Eight community addiction treatment programs in the United States.

Participants: English-speaking adults with DSM-5 OUD, recruited during inpatient admission (n = 570).

Intervention(s): Randomization to monthly injection of XR-NTX or daily sublingual BUP-NX.

Measurements(s): Mediation analysis estimated the direct effect of XR-NTX versus BUP-NX on relapse and indirect effect through mediators of medication adherence, use of illicit opioids, depressive symptoms and pain, separately by homeless status.

Findings: For the homeless subgroup, the protective indirect path contributed a 3.4 percentage point reduced risk of relapse [95% confidence interval (CI) = -12.0, 5.3] comparing XR-NTX to BUP-NX (explaining 21% of the total effect). For the non-homeless subgroup, the indirect path contributed a 9.4 percentage point increased risk of relapse (95% CI = 3.1, 15.7) comparing XR-NTX to BUP-NX (explaining 57% of the total effect).

Conclusions: A novel approach to mediation analysis shows that much of the difference in medication effectiveness (extended-release naltrexone versus buprenorphine-naloxone) on opioid relapse among non-homeless adults with opioid use disorder appears to be explained by mediators of adherence, illicit opioid use, depressive symptoms and pain.

Keywords: Buprenorphine; depression; homelessness; mediation analysis; naltrexone; opioid use disorder; pain.

Publication types

  • Randomized Controlled Trial

MeSH terms

  • Adult
  • Delayed-Action Preparations / therapeutic use
  • Humans
  • Injections, Intramuscular
  • Mediation Analysis*
  • Naltrexone / therapeutic use
  • Narcotic Antagonists / therapeutic use
  • Opioid-Related Disorders* / drug therapy
  • United States


  • Delayed-Action Preparations
  • Narcotic Antagonists
  • Naltrexone