“…The use of COX-2 inhibitors has previously been suggested for managing chronic pain in SCD, 2 , 8 especially given evidence of elevated COX-2 expression and/or activity in the leukocytes of mice and patients with SCD, 1 , 6 , 9 with Khasabova et al previously reporting on the analgesic efficacy of R -flurbiprofen in mice with SCD. 6 However, observations in the latest study by Khasabova and colleagues indicate that elevation of 2-AG, upstream of COX-2, may be specific to those SCD mice displaying hyperalgesia, 1 meaning that approaches that can decrease DAGLβ-mediated biosynthesis of 2-AG could provide targeted relief for hyperalgesia in SCD, with theoretically fewer side effects than those of COX inhibitors. 10 Furthermore, combined administration of a selective DAGLβ inhibitor together with opioids could potentially lower the dose of opioid required for analgesia of SCD pain.…”