Safety and analgesic efficacy of marine lipid precursors of specialized pro-resolving mediators in adults with chronic temporomandibular pain. - The inflammation-resolving, analgesic, and anxiolytic properties of lipid derivatives of marine omega-3 (n-3) fatty acids offer a novel therapeutic approach for painful temporomandibular disorder (TMD). We used ultra- high performance liquid chromatography (UHPLC) tandem mass spectrometry methods to quantify fatty acids and their lipid derivatives in 605 adults. We reported that low levels of n-3 fatty acids were associated with greater odds of chronic TMD pain, hyperalgesia, psychological distress, sleep disturbance, and greater pain intensity. While promising, these observational study findings lack the rigor of a randomized controlled trial. Design: This phase 2b, proof-of-concept, triple-masked, randomized, placebo-controlled, parallel-group clinical trial will evaluate the safety and analgesic efficacy of a marine oil supplement in adults with chronic TMD myalgia and/or arthralgia. The intervention is a dietary supplement of active fractionated n-3 marine lipid concentrate standardized to 18-HEPE, 14-HDHA and 17-HDHA, which are precursors to specialized proresolving mediators (SPMs) that regulate multiple pain-related biochemical pathways. The primary endpoint is postbaseline change in pain intensity recorded on a 0-100 numeric rating scale. The sample size of 100 provides 80% power to detect a “moderately important” decrease of 34% in pain intensity in the intervention group compared to a “minimally important” decrease of 11% in the placebo group. UG3 planning phase: We will obtain regulatory approvals and develop study documents and data systems needed to implement the trail, optimize recruitment with CTSA resources, and refine UHPLC tandem mass spectrometry analysis for targeted profiling of 67 bioactive oxylipins and SPMs in erythrocytes and plasma. UH3 implementation phase: UH3 Aim 1 will quantify safety by comparing the rate of adverse events between study arms. UH3 Aim 2 will compute change in pain intensity in each treatment arm and estimate efficacy using two approaches in intention-to-treat analyses: (i) a linear mixed model will estimate treatment-group difference in mean post-baseline change in pain intensity; and (ii) a log binomial model will estimate treatment- group difference in the proportion of subjects whose mean pain intensity reduces by at least 30%. UH3 Aim 3 will evaluate reductions in hyperalgesia, psychosocial distress, sleep disturbance, and biochemical changes. We anticipate that the intervention will increase concentrations of proresolving, antinociceptive and anxiolytic oxylipins, and decrease omega-6 derivatives, and that these changes will correlate with changes in the clinical endpoints. UH4 Aim 4 will use causal mediation methods to determine if a therapeutic effect (or non-effect) is due to change (or lack of change) in nociception, psychological distress, sleep disturbance, or headache. Impact: Ten million U.S. adults have chronic TMD pain. This clinical trial may lead to a novel therapeutic approach for chronic TMD pain that resolves inflammation and reduces pain, sleep disturbance and psychological distress while overcoming the efficacy and tolerability limitations of current therapies.
