Endocannabinoids, perioperative pain, and acetaminophen in patients undergoing total knee arthroplasty: a prospective cohort study
Pain Rep. 2026 Jan 30;11(2):e1369. doi: 10.1097/PR9.0000000000001369. eCollection 2026 Apr.
ABSTRACT
INTRODUCTION: Total knee arthroplasty (TKA) for knee osteoarthritis (OA) provides pain relief and functional improvement for many patients. The endocannabinoid system (ECS) regulates pain and inflammation through central and peripheral mechanisms and may be affected by acetaminophen. There is limited information on how surgery and perioperative care affect the ECS.
OBJECTIVE: We designed this study to examine the effect of surgery and acetaminophen on the ECS and determine whether perioperative endocannabinoids were associated with pain resolution after surgery.
METHODS: Forty adult patients with OA undergoing TKA were enrolled in a prospective observational cohort study and provided preoperative cerebrospinal fluid (CSF) and blood samples at 3 time points (before surgery, after intravenous acetaminophen, and 24 hours postoperative). Defense and Veterans Pain Rating Scale scores at rest and with activity were recorded in the preoperative holding area, in the operating room after intravenous acetaminophen before spinal anesthesia, and 24 to 48 hours postoperatively. Cerebrospinal fluid and plasma endocannabinoids were quantified using a validated liquid chromatography/mass spectrometry assay. We analyzed the data using linear regression models with sex, age, and body mass index as covariates.
RESULTS: Patients undergoing TKA have higher CSF and plasma concentrations of N-acylethanolamines anandamide and its congeners compared with control subjects. Patients with higher pain scores had lower CSF anandamide levels before and after surgery and higher levels of 2-arachidonoylglycerol before surgery but not after.
CONCLUSION: Chronic pain, acetaminophen, and surgery are associated with endogenous endocannabinoid levels and may present an opportunity for developing targeted nonopioid perioperative analgesia after TKA.
PMID:41635474 | PMC:PMC12863799 | DOI:10.1097/PR9.0000000000001369