Opioids Diminish the Placebo Antidepressant Response: A Post Hoc Analysis of a Randomized Controlled Ketamine Trial

The endogenous opioid system is thought to play a role in the placebo antidepressant response. A recent trial comparing the rapid antidepressant effects of ketamine versus placebo in surgical patients, some of whom were on chronic opioid therapy, revealed a substantial placebo effect. This finding provided an opportunity to test the hypothesis that opioid agonist exposure interacts with placebo antidepressant responses.

This post hoc analysis utilized data from a previously reported randomized, anesthesia-blinded, placebo-controlled trial of intravenous ketamine in depressed patients undergoing routine surgery. Mixed-effects models were used to determine whether baseline opioid use influenced antidepressant responses to the trial interventions, as measured by the Montgomery-Åsberg Depression Rating Scale (MADRS) over 1 to 14 days post-treatment.

In the placebo arm, baseline opioid use was associated with a 10-point increase (95% CI: 0.81-19.4) in MADRS scores across all post-treatment time points, indicating worse depression in this subgroup. In an alternative model using percent change in MADRS scores, the difference between opioid users and non-users was 38.4% (95% CI: 8.59-68.2), with opioid users experiencing less improvement. For ketamine-treated participants, baseline opioid use did not significantly impact MADRS scores or the percent change in MADRS scores. Pain intensity was not a significant predictor of MADRS outcomes, and the correlation between post-treatment MADRS scores and pain intensity was negligible (R=0.12).

This analysis was unregistered and conducted on a small sample; the findings need to be confirmed by prospective controlled studies.

Opioid use at baseline attenuated the placebo antidepressant response independently of pain in depressed patients who received the study treatment under general anesthesia for routine surgery. The antidepressant response was preserved in opioid users who received intravenous ketamine.