Opioids diminish the placebo antidepressant response: Observational post hoc findings from a randomized controlled ketamine trial.

The endogenous opioid system may influence the placebo antidepressant response. A post hoc analysis of a randomized, placebo-controlled trial of intravenous ketamine in depressed patients undergoing routine surgery tested whether baseline opioid use affected antidepressant responses. The analysis found that baseline opioid use significantly reduced post-treatment depression severity in patients who received placebo, but not in those who received ketamine. This reduction was independent of baseline depression severity, pain intensity, and ethnicity. The findings, based on a small sample, require confirmation by prospective controlled studies. Opioid use at baseline attenuated the placebo antidepressant response independently of pain, while the antidepressant response was preserved in opioid users who received ketamine.

Study at a glance

Abstract

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. The analysis showed that baseline opioid use significantly reduced post-treatment depression severity in patients who received placebo, but not in those who received ketamine. This reduction was independent of baseline depression severity, baseline pain intensity, and ethnicity. Additionally, there was negligible correlation between postoperative pain intensity and depression severity. This post hoc analysis was conducted on a small sample, and 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.