Perioperative Endocannabinoid Profiling by LC–MS in Patients Undergoing Total Knee Arthroplasty

Total knee arthroplasty (TKA) for knee osteoarthritis (OA) has long provided pain relief and functional improvement for many patients. While the endocannabinoid system (ECS), which regulates pain and inflammation through central and peripheral mechanisms, may be affected by acetaminophen, there has been limited data compiled regarding how surgery and perioperative care affect the ECS. To address this gap, a joint study conducted by the University of Colorado Anschutz Medical Campus (Aurora, Colorado) and the Mayo Clinic (Jacksonville, Florida) set out to examine the effect of surgery and acetaminophen on the ECS and determine whether perioperative endocannabinoids were associated with pain resolution after surgery. Cerebrospinal fluid and plasma endocannabinoids were quantified using a validated liquid chromatography-mass spectrometry (LC-MS) assay, and the resulting data was analyzed using linear regression models with sex, age, and body mass index as covariates. A paper based on this research was published in Pain Reports. ⁽¹⁾

OA, the most common form of arthritis in adults (affecting 8% of the world’s population), is the leading cause of chronic pain and long-term disability resulting in costly health expenses. ^(2,3) While TKA is an effective measure for the treatment of end-stage knee OA, providing pain relief and functional improvement for patients choosing that route, approximately 15% to 30% of patients will unfortunately develop chronic postoperative pain, which is defined as pain which lasts for at least 3 months after surgery. ^(4,5)As there is conflicting evidence on patient factors associated with pain perseverance (including body mass index [BMI], diabetes, and dyslipidemia) it remains unknown as to why many patients have persistent pain after TKA. ^(6,7)

For this study, forty adult patients with OA undergoing TKA were enrolled in a prospective observational cohort study and given preoperative cerebrospinal fluid (CSF) and blood samples at three 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. The researchers report that patients undergoing TKA have higher CSF and plasma concentrations of N-acylethanolamines anandamide and its congeners compared with control subjects. In addition, 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. ⁽¹⁾

“Chronic pain, acetaminophen, and surgery are associated with endogenous endocannabinoid levels,” write the authors of the study, ⁽¹⁾ “and may present an opportunity for developing targeted nonopioid perioperative analgesia after TKA.” They recommend further study on the endocannabinoid system to identify patients at risk for postoperative pain and to identify novel approaches to individualizing post-surgery pain management strategies. ⁽¹⁾

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References

1. Clendenen, N.; Clendenen, A.; McClain, R. et al. Endocannabinoids, Perioperative Pain, and Acetaminophen in Patients Undergoing Total Knee Arthroplasty: A Prospective Cohort Study. Pain Rep. 2026, 11 (2), e1369. DOI: DOI: 10.1097/PR9.0000000000001369
2. GBD 2021 Osteoarthritis Collaborators. Global, Regional, and National Burden of Osteoarthritis, 1990-2020 and Projections to 2050: A Systematic Analysis for the Global Burden of Disease Study 2021. Lancet Rheumatol. 2023, 5 (9), e508-e522. DOI: 10.1016/S2665-9913(23)00163-7
3. Minnig, M. C. C.; Golightly, Y. M.; Nelson, A. E. Epidemiology of Osteoarthritis: Literature Update 2022-2023. Curr Opin Rheumatol. 2024, 36 (2), 108-112. DOI: 10.1097/BOR.0000000000000985
4. Zhang, A. R.; Cheng, Q. H.; Yang, Y. Z. et al. Meta-Analysis of Outcomes after Total Knee Arthroplasty in Patients with Rheumatoid Arthritis and Osteoarthritis. Asian J Surg. 2024, 47 (1), 43-54. DOI: 10.1016/j.asjsur.2023.09.015
5. Schug, S. A.; Lavand'homme, P.; Barke, A. et al. The IASP Classification of Chronic Pain for ICD-11: Chronic Postsurgical or Posttraumatic Pain. Pain 2019, 160 (1), 45-52. DOI: 10.1097/j.pain.0000000000001413
6. Lawrence, K. W.; Sobba, W.; Rajahraman, V. et al. Does Body Mass Index Influence Improvement in Patient Reported Outcomes Following Total Knee Arthroplasty? A Retrospective Analysis of 3918 Cases. Knee Surg Relat Res. 2023, 35 (1), 21. DOI: 10.1186/s43019-023-00195-1
7. Meert, L.; Mertens, M. G.; Meeus, M. et al. Identification of Metabolic Factors and Inflammatory Markers Predictive of Outcome after Total Knee Arthroplasty in Patients with Knee Osteoarthritis: A Systematic Review. Int J Environ Res Public Health 2023, 20 (10), 5796. DOI: 10.3390/ijerph20105796