Plasma and interstitial levels of endocannabinoids and N-acylethanolamines in patients with chronic widespread pain and fibromyalgia: a systematic review and meta-analysis

The endocannabinoid system (ECS) is an essential endogenous signaling system that may be involved in the pathophysiology of chronic widespread pain (CWP) and fibromyalgia syndrome (FMS). Further research is required to understand the role of ECS in the development and maintenance of CWP and FMS. We provided the first systematic review and meta-analysis exploring the clinical relevance of ECS alterations in patients with CWP and FMS by comparing plasma and interstitial levels of endocannabinoids and N-acylethanolamines in patients and healthy controls. A systematic search was conducted to identify studies that measured plasma and/or interstitial levels of endocannabinoids and N-acylethanolamines in patients with CWP or FMS and healthy controls. A total of 8 studies were included for qualitative review, and 7 studies were included for meta-analysis. The findings identified increased plasma levels of oleoylethanolamide and stearoylethanolamide in patients with FMS compared with those in controls (P = 0.005 and P < 0.0001, respectively) and increased plasma levels of palmitoylethanolamide and interstitial levels of stearoylethanolamide in patients with CWP compared with those in controls (P = 0.05 and P = 0.001, respectively). There were no significant differences in other ECS parameters. Most studies did not account for variables that may influence ECS function, including cannabis use, concomitant medication, comorbidities, physical activity, stress levels, circadian rhythm, sleep quality, and dietary factors, suggesting that future studies should explore the correlation between these variables and endocannabinoid activity. We highlight the importance of investigating endocannabinoid activity in CWP and FMS because it will underpin future translational research in the area.