Cannabis Use Impact on Pain and Recovery Post-Surgery - The Role of the Endocannabinoid System

About This Grant

Inflammatory pain due to symptomatic osteoarthritis (OA) is one of the leading indications for opioid prescriptions prior to definitive treatment with surgery. The endocannabinoid (eCB) system modulates pain by regulating synaptic transmission and immune reaction/ inflammation peripherally and centrally, as well as interacting with ion channels and receptors. The rapid rise in cannabis legalization has allowed patients to self-medicate resulting in altered states of eCB synthesis and degradation, and receptor activation prior to seeking medical care. The clinical consequences of an altered eCB system due to exogenous cannabinoids are unknown. We propose a comprehensive, systematic and highly integrated multidisciplinary basic and clinical science approach to characterize the a) human eCB system response to chronic pain associated with osteoarthritis, b) acute pain directly post-surgery, as well as c) pain resolution or pain chronification in TKA patients 6-months post-surgery and d) to mechanistically study changes in eCB signaling in preclinical animal models. Our goal is to determine the role of the eCB system in the maintenance and resolution of inflammatory pain using a prospective observational clinical study in a cohort of cannabis users and non-users undergoing TKA to validate existing animal models. We will test the overarching hypothesis that a functional eCB system is necessary for inflammatory pain resolution. Aim 1 will determine the effect of cannabis use and chronic inflammatory pain on the eCB system by comparing cytokine and eCB/lipid signatures associated with pain in patients with chronic OA to healthy subjects without pain to validate animal pain models. Exogenous cannabinoid use will be assessed with self-report and verified by quantitative LC-MS/MS assays. A reverse translational approach will examine identified changes in the patients to mechanistically study effects on eCBs on pain modulation and synaptic plasticity in preclinical models of inflammation and surgical incision. In Aim 2 we will determine effects of acute surgical pain (TKA) on the eCB system in cannabis-users compared to non-users and assess mechanisms in preclinical pain models. Effects of cannabis use on eCB signaling and synaptic plasticity in will be examined in two major pain-processing regions such as dorsal horn (DH) of the spinal cord and periaqueductal gray (PAG). Aim 3 will follow patients for post-surgical pain outcomes and opioid/cannabis use with a validated, innovative dried blood spot-based home monitoring strategy as an objective outcome measure. Pre-clinical studies will assess changes in eCBs/lipids in a TKA/post-incision rodent pain model in the absence and presence of cannabis. The results of these studies will inform whether adaptations in the eCB system induced by cannabis use contribute to hyperalgesia and regression to chronic pain in patients undergoing TKA procedures. We will be able to validate and mechanistically qualify preclinical animal models of persistent inflammation and post-incision pain. Physicians will be better informed on effects of cannabis use on patient outcomes.