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.
The placebo antidepressant response was weaker in depressed patients who were already taking opioid medications, independent of their pain levels. In a re-analysis of a randomized trial, patients on chronic opioid therapy who received a placebo showed depression scores 10 points higher on the Montgomery-Åsberg Depression Rating Scale (MADRS) across 1 to 14 days after treatment, indicating less improvement. When measured as percent change, opioid users experienced 38.4% less improvement than non-users. For patients who received ketamine, baseline opioid use did not significantly affect depression scores. Pain intensity did not predict depression outcomes, and the link between depression and pain was negligible. These results come from a small, unregistered post hoc analysis and require confirmation.