Protocol and pilot results for a double-blind randomized placebo-controlled trial of ketamine under propofol sedation for chronic pain and depression

Ketamine shows promise for treatment-refractory chronic pain and depression, but randomized trials risk unblinding from ketamine’s acute dissociative effects. Propofol sedation may mitigate this, though it has not been prospectively tested as a masking strategy outside of surgical contexts.
This protocol describes a single-center, randomized, double-blind, placebo-controlled, parallel-group superiority trial enrolling 42 adults (including 6 pilot participants) with chronic pain and comorbid depression. Intravenous ketamine (0.5 mg/kg) or placebo (saline) will be administered under propofol sedation spanning the 40-minute infusion and 40 minutes post-infusion. The primary outcome is change in mean daily pain intensity (0–10 Numeric Rating Scale), assuming a detectable difference of 1.5 points. Secondary outcomes include depression severity and blinding measures.
Six pilot participants completed procedures without serious adverse events. While 5/6 guessed ketamine immediately post-sedation, only 2/6 correctly identified allocation at subsequent assessments. Expectancy and confidence ratings varied widely without favoring either treatment.
Propofol-enhanced masking may reduce expectancy bias and improve interpretability for ketamine trials. Pilot results suggest propofol sedation can be used safely and effectively as a blinding tool, offering a framework for studying other psychoactive therapeutics.
www.clinicaltrials.gov identifier is NCT06317636.
What is this article about? Doctors use ketamine to treat depression and chronic pain. But research studies on ketamine face a problem. Ketamine has strong side effects like feeling detached or seeing things that aren’t there. These effects make it easy for patients to guess whether they got ketamine or not. When patients know what they received, their hopes can make results look better than they really are. We tested a new method to fix this. We used a sedative called propofol to put patients to sleep during treatment. This way, they could not tell if they got ketamine or a placebo.
What were the results?
In an early study, we tested this method with six people who had chronic pain and depression. Most of them could not correctly guess which treatment they received. Some people showed improvement in pain and depression. But neither group clearly did better than the other. Ketamine caused more side effects, but they were mostly mild. No one had serious problems from the propofol.
What do the results of the study mean?
These early results show that propofol sedation can make fair and blinded ketamine studies possible. We are now planning a larger study to find out if ketamine truly works better than a placebo for chronic pain and depression. This method could also help test other treatments—like psychedelics—where hiding which treatment patients receive has been a big challenge.