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

INTRODUCTION: 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. METHODS: 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. FEASIBILITY RESULTS: 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. DISCUSSION: 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. CLINICAL TRIAL REGISTRATION: www.clinicaltrials.gov identifier is NCT06317636.