Effectiveness of Conditioned Open-label Placebo With Methadone in Treatment of Opioid Use Disorder
Authors: Belcher Annabelle M. , Cole Thomas O. , Massey Ebonie , Billing Amy S. , Wagner Michael , Wooten William , Epstein David H. , Hoag Stephen W. , Wickwire Emerson M. , Greenblatt Aaron D. , Colloca Luana , Rotrosen John , Magder Lawrence , Weintraub Eric , Wish Eric D. , Kaptchuk Ted J. 
Published: April 2023

Importance

Methadone treatment is the most effective evidence-based treatment for opioid use disorder (OUD), but challenges related to dosing and premature treatment dropout argue for adjunct interventions to improve outcomes. One potential behavioral intervention with low risk involves harnessing placebo effects.

Objective

To determine the effect of a pharmacologically conditioned open-label placebo (C-OLP) on 90-day methadone dose, retention, drug use, withdrawal, craving, quality of life, and sleep.

Design, Setting, and Participants

This 2-arm, open-label, single-blind randomized clinical trial was conducted between December 5, 2017, and August 2, 2019, in an academically affiliated community opioid treatment program. Analyses were conducted between October 1, 2019, and April 30, 2020. A total of 320 newly enrolled adults seeking treatment for moderate to severe OUD were assessed for study eligibility; 131 met eligibility criteria, provided informed consent, and were randomized to either C-OLP or treatment as usual (TAU) in an unequal-block (3:2) manner. Exclusion criteria were pregnancy, hospital/program transfers, and court-ordered treatment.

Interventions

Participants randomized to C-OLP received pharmacologic conditioning and a placebo pill and methadone, and participants randomized to TAU were given methadone only. Participants met with the study team 5 times: at baseline (treatment intake) and 2, 4, 8, and 12 weeks postbaseline. Interactions were balanced between the 2 groups.

Main Outcomes and Measures

Outcomes included 90-day methadone dose (primary) and treatment retention, drug use, withdrawal, craving, quality of life, and sleep quality (secondary). Analyses were conducted as intention-to-treat.

Results

Of the 131 people enrolled in the study, 54 were randomized to TAU and 77 to C-OLP. Mean (SD) age was 45.9 (11.2) years; most of the participants were Black or African American (83 [63.4%]) and male (84 [64.1%]). No significant group differences were observed in the mean (SD) 90-day methadone dose (83.1 [25.1] mg for group TAU, 79.4 [19.6] mg for group C-OLP; t = 0.621991; P = .43), but the groups differed significantly in their retention rates: 33 (61.1%) for TAU and 60 (77.9%) for C-OLP (χ21 = 4.356; P = .04; number needed to treat for the beneficial outcome of 3-month treatment retention, 6; 95% CI, 4-119). C-OLP participants also reported significantly better sleep quality.

Conclusions and Relevance

In this randomized clinical trial, C-OLP had no effect on the primary outcome of 90-day methadone dose. However, C-OLP participants were significantly more likely to remain in treatment. These findings support the use of C-OLP as a methadone treatment adjunct, but larger trials are needed to further examine the use of C-OLP.

Trial Registration

ClinicalTrials.gov Identifier: NCT02941809