This randomised, double-blind, placebo-controlled trial protocol and pilot study (n=42) is testing ketamine 0.5 mg/kg given under propofol sedation for chronic pain with depression, with pain as the main outcome. In six pilot participants, there were no serious adverse events and propofol seemed to help mask treatment allocation, although many still guessed ketamine immediately after sedation.
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.
Ketamine has shown promise for treatment-refractory chronic pain and depression, but a major problem in randomised trials is that its acute dissociative effects can reveal treatment allocation and distort outcomes through expectancy effects. The authors note that earlier ketamine studies have often failed to maintain blinding, even when active placebos were used, leaving uncertainty about how much benefit is genuinely pharmacological versus driven by participants’ expectations. Propofol sedation is presented as a potential way to mask ketamine’s subjective effects, but the extracted text says this had not previously been tested prospectively outside surgical settings. Lii and colleagues therefore set out to describe and evaluate a randomised, double-blind, placebo-controlled protocol in which ketamine or saline would be given under propofol sedation to adults with chronic pain and comorbid depression. The paper reports both the planned powered trial and a six-participant pilot meant to assess feasibility, safety, and whether propofol could preserve the blind. The study is framed as a methodological test that could improve interpretability not only for ketamine research, but potentially for other psychoactive therapeutics as well.
The paper describes a single-centre, randomised, double-blind, placebo-controlled, parallel-group superiority trial conducted at Stanford University Hospital. The powered study was planned to enrol 36 additional participants after a six-person pilot, for a total target sample of 42 adults with chronic pain and comorbid depression. Participants were recruited mainly from Stanford’s Pain Management Centre, with broader community recruitment also described. The pilot followed the same procedures as the main study. Participants were randomised 1:1 to receive a single intravenous infusion of racemic ketamine 0.5 mg/kg or an equivalent volume of normal saline. The infusion lasted 40 minutes and was administered under propofol sedation. Propofol was started by a board-certified anaesthesiologist using a bolus and target-controlled infusion, with dosing adjusted to maintain an electroencephalography-derived Patient State Index of 30-50 and avoid burst suppression. Sedation was maintained for 40 minutes after the infusion to try to mask ketamine’s acute effects. Standard monitoring included oxygen saturation, capnography, electrocardiography, and frequent blood pressure checks. Stable chronic pain and depression treatments could continue, but new analgesics were restricted around the intervention. The primary outcome was change in mean daily pain intensity on a 0-10 Numeric Rating Scale from the 7 days before treatment to the 7 days after treatment. Secondary outcomes included depressive symptoms measured with the 16-item Quick Inventory of Depressive Symptomatology Self-Report and blinding integrity assessed by treatment guesses and certainty ratings. Exploratory measures included expectancy and baseline opioid use. Adverse events were graded using CTCAE criteria, and ketamine side effects were assessed with the Ketamine Side Effects Tool. Follow-up extended through Day 28. Analyses were planned on an intention-to-treat basis, using a two-sample t test for the primary comparison when assumptions were met, with non-parametric sensitivity analyses otherwise. Blinding was to be quantified using Bang’s Blinding Index, and missing data handled with multiple imputation where feasible.
Papers cited by this study that are also in Blossom
Mcintyre, R. S., Rosenblat, J. D., Nemeroff, C. B. et al. · American Journal of Psychiatry (2021)
Noppers, I., Niesters, M., Swartjes, M. et al. · European Journal of Pain (2012)
Lii, T. R., Smith, A. E., Flohr, J. R. et al. · Nature Mental Health (2023)
Bahji, A., Vazquez, G. H., Zarate, C. A. · Journal of Affective Disorders (2021)
Berman, R. M., Cappiello, A., Anand, A. et al. · Biological Psychiatry (2000)
Deverett, B., Li, D., Lii, T. R. et al. · JAMA Psychiatry (2026)
Matsingos, A., Wilhelm, M., Noor, L. et al. · Frontiers in Psychiatry (2024)
Nayak, S., Bradley, M. K., Kleykamp, B. A. et al. · Journal of Clinical Psychiatry (2023)
Feder, A., Parides, M. K., Murrough, J. W. · JAMA Psychiatry (2014)
Cubała, W. J., Szarmach, J., Galuszko-Wegielink, M. et al. · Medicine (2021)
Holze, F., Becker, A. M., Kolaczynska, K. E. et al. · Clinical Pharmacology and Therapeutics (2022)
The pilot enrolled 6 participants between November 2024 and May 2025, with 3 randomised to ketamine and 3 to placebo. Screening was relatively inefficient: 54 individuals were pre-screened, 13 were fully screened, and the overall recruitment rate was 11%. The sample was small and heterogeneous in pain type, with all participants reporting moderate-to-severe pain and substantial prior treatment failure. Propofol induction boluses ranged from 1.2 to 1.7 mg/kg, and the median maintenance infusion rate was 129 micrograms/kg/min. Blinding appeared to be only partly compromised. Immediately after sedation, 5/6 participants guessed that they had received ketamine, but at later time points only 2/6 correctly identified their allocation, one from each group. Confidence in guesses varied, and expectation ratings were variable rather than clearly favouring either arm. Pre-treatment expectations for ketamine were moderate to high in both groups, whereas expectations for placebo were lower and more variable. Over time, expectations generally declined in both treatment groups. Pain outcomes did not clearly favour ketamine in this small pilot. Baseline mean pain scores were similar between groups. In the placebo group, all three participants reported reductions in pain, with a mean decrease from 6.1 to 4.6, whereas ketamine participants had mixed responses and minimal group change, from 6.0 to 5.9. Overall mean change across all participants was -0.8. Depression outcomes were also mixed: baseline QIDS-SR-16 scores indicated moderate depression in both groups, and by Day 7 the placebo group had a mean improvement of -4.7 while the ketamine group showed a mean change of +0.3. No severe or life-threatening adverse events occurred during sedation. Five of 6 participants required low-flow oxygen for transient desaturation, and one needed an oral airway to maintain patency. Ketamine recipients reported more new side effects than placebo recipients, with a cumulative median of 23 versus 7 per participant. The most frequent new symptoms were memory or concentration problems, restlessness or agitation, and dissociation. Most side effects were mild, although two severe side effects were recorded in the ketamine group: one participant felt “massively spaced out” post-sedation and another reported transient ear numbness on Day 1; both resolved without intervention.
The authors argue that the protocol addresses a longstanding problem in ketamine and other psychoactive-therapeutic trials: acute drug effects can reveal allocation and bias patient-reported outcomes. They present propofol sedation as a novel blinding strategy intended to reduce expectancy-driven effects and yield more interpretable estimates of ketamine’s true therapeutic action. On the basis of the pilot, they conclude that the approach was feasible and generally safe in carefully selected patients, and that it appeared to reduce the persistence of correct treatment guessing after the immediate post-sedation period. They place these findings in the context of earlier ketamine research, noting that previous trials often struggled to maintain blinding even with active placebos. The authors emphasise that the pilot is far too small to compare efficacy between ketamine and placebo, and that any apparent differences, including instances where placebo seemed better, could easily be due to chance. They discuss several possible interpretations of the powered trial’s future results: if ketamine proves superior under propofol masking, that would support a pharmacological effect; if not, ketamine may offer little beyond placebo, propofol could interfere with ketamine’s action, or propofol itself may have mood- or pain-related effects. They note that propofol was identical across groups, which should balance any nonspecific effects, although it might also reduce the size of ketamine’s detectable advantage. The authors also highlight that the pilot data suggested heterogeneous responses, with minimal pain change for most participants but some depression improvement, particularly in the placebo arm. They interpret this as a reminder that expectancy and participation effects may be substantial in mood outcomes. They say the side-effect profile did not obviously undermine blinding, although ketamine produced more adverse effects. Limitations include the very small pilot sample, the single academic-centre setting, and restricted generalisability to other populations such as pain-only or depression-only patients. They further note that sedation-based masking raises logistical, ethical, and resource concerns, even though no serious adverse events occurred in this pilot. Finally, they suggest the approach may have relevance beyond ketamine, including for agents such as psilocybin and MDMA, where unblinding and expectancy bias are also major methodological challenges.
The authors conclude that the trial is designed to test whether ketamine is superior to placebo when both are given under propofol sedation. They state that the pilot findings support the feasibility and preliminary safety of this masking strategy, and that it may provide a useful model for future trials of psychoactive therapeutics by helping separate pharmacological effects from expectancy-driven improvement.