Temporal effects of Palmitoylethanolamide (PEA) in modulating knee osteoarthritis symptoms: A randomized, double-blind, placebo-controlled trial

Background Osteoarthritis involves cartilage degradation, driven by elevated matrix metalloproteinases and inflammatory signalling, while available therapies offer only symptomatic relief. Palmitoylethanolamide (PEA), an endogenous fatty acid amide with anti-inflammatory and analgesic activity, modulates inflammation and downregulates chondrocyte metalloproteinase. This study evaluates dose-dependent nociceptive effect of PEA supplementation in individuals with knee pain. Methods In this randomized placebo-controlled trial, adults with symptomatic mild to moderate knee osteoarthritis received low-dose, high-dose Palmitoylethanolamide or placebo for 12 weeks. The primary endpoint was change in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) total score at Week 12. Secondary outcomes included WOMAC subscales, PROMIS-29 scores, and OMERACT-OARSI responder analysis. Results Baseline WOMAC scores were comparable across the groups. At Week 4, the placebo group exhibited greater improvement; however, in next 8 weeks, greater reductions in the scores were observed with PEA-LD (−16.05) and PEA-HD (−15.43) versus placebo (−11.76), although not statistically significant (p > 0.05). WOMAC scores decreased significantly from baseline in all groups (p < 0.001). Post-hoc analysis demonstrated a higher responder rate with PEA-HD versus placebo at Week 12 (p = 0.034). PEA was well tolerated without major safety concerns. Conclusion PEA supplementation showed a pattern of pain relief and improved functional outcomes by Week 12, despite an early placebo response. Although, primary outcome was not statistically significant, subgroup analysis supports the analgesic potential in individuals with higher baseline pain scores. PEA was well tolerated and may represent a safe joint adjunct in osteoarthritis.