Authors: Schutz L et al
Anesthesia & Analgesia. September 09, 2025. doi:10.1213/ANE.0000000000007741
This prospective study investigated whether intraoperative levels of the endocannabinoid 2-arachidonoylglycerol (2-AG) are associated with acute postoperative pain after total knee arthroplasty (TKA). Ninety patients were enrolled, and 2-AG levels were measured in synovial fluid (SF) and cerebrospinal fluid (CSF).
Higher SF 2-AG correlated with increased postoperative pain both at rest (r = 0.26, p = 0.0157) and during ambulation (r = 0.39, p = 0.0005). CSF 2-AG also correlated with pain at rest (r = 0.33, p = 0.0017) but not with ambulation. Stratified analyses revealed that these associations were stronger in women compared to men, suggesting a sex-specific effect.
Ex vivo work demonstrated that monoacylglycerol lipase (MAGL), the enzyme that hydrolyzes 2-AG, is coexpressed with COX-2 in synovial tissue. Inhibition of MAGL elevated 2-AG while reducing prostaglandin E2 (PGE2), linking endocannabinoid breakdown to pro-inflammatory prostaglandin production.
These findings suggest that elevated 2-AG tone may predispose patients to greater pain after TKA and position MAGL as a therapeutic target to reduce postoperative pain by limiting PGE2 synthesis.
What You Should Know
• Elevated intraoperative 2-AG levels predict greater postoperative pain after TKA, particularly in women.
• CSF 2-AG correlates with pain at rest, while SF 2-AG correlates with both rest and ambulation pain.
• MAGL links 2-AG metabolism to PGE2 production, highlighting a potential drug target.
• Inhibiting MAGL reduced PGE2 in synovial tissue, supporting mechanistic plausibility.
• Endocannabinoid tone may represent a biomarker for personalized pain management strategies.
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