Multi-center, randomized controlled efficacy and comparative-effectiveness study evaluating ketamine, stellate ganglion blocks, combination treatment, and sham treatments for posttraumatic stress disorder and traumatic brain injury-associated headache: a study protocol

BACKGROUND: Posttraumatic stress disorder (PTSD) and traumatic brain injury (TBI) are conditions that share common mechanisms and are highly co-prevalent with each other and chronic pain. This pragmatic study will compare ketamine infusions to stellate ganglion blocks (SGB), their combination, and a placebo-sham-controlled arm. METHODS: A double-blind study conducted at 3 U.S. and Ukrainian sites will be performed. Two hundred ten patients with PTSD and/or TBI-associated headache will be allocated in a 2:2:2:1 ratio to receive SGB/placebo ketamine, ketamine/sham SGB, ketamine/SGB, and placebo/sham. The bivariate co-primary outcome will evaluate change in Headache Impact Test and PTSD Checklist depending on diagnosis, at 4 weeks. Participants who experience a positive binary outcome will remain in the study through 6 months or until their outcome becomes negative. DISCUSSION: Because PTSD and TBI have no discrete pathophysiological mechanisms and are co-prevalent with pain and psychopathology, they are associated with poor outcomes, polypharmacy, and high non-adherence rates, indicating a need for minimally invasive treatments that obviate these barriers. Whereas both therapies have evidence underpinning efficacy, results in clinical trials are conflicting. This study will provide real-world evidence in generalizable populations on the efficacy and comparative-effectiveness of ketamine and SGB, alone and in combination, with the possibility of changing clinical guidelines. CLINICAL TRIAL REGISTRATION: www.clinicaltrials.gov identifier is NCT06608277.