Placebo adjunct to methadone for OUD improves treatment retention, sleep quality

Key takeaways:

• Patients assigned to conditioned placebo and methadone had higher 90-day treatment retention rates than those on methadone only.
• Researchers highlighted the approach’s low cost and minimal burden for clinics.

The use of open-label placebo alongside methadone for opioid use disorder was associated with greater 90-day treatment retention rates and better sleep quality compared with the use of methadone alone, a randomized clinical trial found.

“The clinical implications of our intervention have great potential impact, as retention in treatment is a serious challenge for the field of addiction medicine,” Annabelle M. Belcher, PhD, an assistant professor of psychiatry at the University of Maryland School of Medicine, said in a press release. “We’ve demonstrated it’s feasible to administer a placebo in addition to standard-of-care methadone in a community-based opioid treatment setting without adding a significant burden to clinic procedures; the low-cost, low-risk nature of this intervention could provide an appealing strategy to target early methadone treatment adherence.”

Methadone is a first-line treatment for opioid use disorder (OUD), but because of adverse effects of high dosages like constipation or cardiac arrhythmia, “strategies rendering methadone effective at lower dosages are needed,” Belcher and colleagues wrote in JAMA Network Open.

They pointed out that one such strategy is harnessing placebo effects through pharmacologic conditioning, “wherein a medication’s therapeutic effects are conferred to placebos following repeated pairings with the drug.”

To evaluate the effectiveness of this approach, Belcher and colleagues conducted a single site randomized clinical trial between Dec. 5, 2017, and Aug. 2, 2019, where participants were exposed to either pharmacologic conditioned open-label placebo (C-OLP) and methadone or solely methadone as part of treatment as usual (TAU).

The study included 131 participants (mean age, 45 years), 64.1% of whom were men. Following randomization, 77 were assigned to C-OLP while 54 were assigned to TAU.

The researchers did not find any significant differences in the mean methadone dose at 90 days — which was 83.1 mg for the TAU group and 79.4 mg for the C-OLP group — despite hypothesizing mean dosage would be lower for C-LOP.

“We can only speculate as to why there were no significant differences between the groups, but due to its bioavailability, clearance and half-life, methadone dosing is highly individualized,” they wrote. “Furthermore, to avoid the risk of overdose, a patient’s methadone dose is affected by missed days, which can result in dose cuts or the need for reassessment and re-initiation. These influences may have precluded the ability to observe any potential group differences in methadone dose.”

However, methadone retention rates at 3 months for participants on C-OLP (77.9%) were significantly greater than those receiving TAU (61.1%). C-OLP participants also reported better sleep quality, with an estimated mean Pittsburgh Sleep Quality Index score difference of 1.79 points between the two groups.

“Although our results do not speak to mechanism, the beneficial effect of C-OLP on methadone treatment retention could be related to the benefits observed in sleep quality or other not-yet-assessed effects on overall function,” Belcher and colleagues wrote.

While the researchers underlined the strategy’s potential for low burden and financial impacts, “future studies should rigorously evaluate implementation outcomes, however (eg patient and staff acceptability, measures of feasibility), to better inform the practicality of implementing a placebo adjunct to methadone treatment.”

They added that further studies are also needed “to evaluate this intervention’s efficacy on methadone treatment retention.”

References:

• Belcher A, et al. JAMA Netw Open. 2023;doi:10.1001/jamanetworkopen.2023.7099.
• Taking a placebo improves adherence to treatment for opioid use disorder, study finds. https://www.eurekalert.org/news-releases/985725. Published April 12, 2023. Accessed April 14, 2023.