Palmitoylethanolamide, a Special Food for Medical Purposes, in the Treatment of Chronic Pain: A Pooled Data Meta-analysis

Background: A growing body of evidence suggests that neuroinflammation, which is characterizedby infiltration of immune cells, activation of mast cells and glial cells, and production of inflammatorymediators in the peripheral and central nervous systems, has an important role in the induction andmaintenance of chronic pain. These findings support the notion that new therapeutic opportunitiesfor chronic pain might be based on anti-inflammatory and pro-resolving mediators that act onimmune cells, in particular mast cells and glia, to mitigate or abolish neuroinflammation. Amonganti-inflammatory and pro-resolving lipid mediators, palmitoylethanolamide (PEA) has been reportedto down-modulate mast cell activation and to control glial cell behaviors.Objective: The aim of this study was to perform a pooled meta-analysis to evaluate the efficacyand safety of micronized and ultra-micronized palmitoylethanolamide (PEA) on pain intensity inpatients suffering from chronic and/or neuropathic pain.Study Design: Pooled data analysis consisting of double-blind, controlled, and open-labelclinical trials.Methods: Double-blind, controlled, and open-label clinical trials were selected consulting the PubMed,Google Scholar, and Cochrane databases, and proceedings of neuroscience meetings. The termschronic pain, neuropathic pain, and micronized and ultra-micronized PEA were used for the search.Selection criteria included availability of raw data and comparability between tools used to diagnoseand assess pain intensity. Raw data obtained by authors were pooled in one database and analyzed bythe Generalized Linear Mixed Model. The changes in pain over time, measured by comparable tools,were also assessed by linear regression post-hoc analysis and the Kaplan-Meier estimate.Twelve studies were included in the pooled meta-analysis, 3 of which were double-blind trialscomparing active comparators vs placebo, 2 were open-label trials vs standard therapies, and 7were open-label trials without comparators.Results: Results showed that PEA elicits a progressive reduction of pain intensity significantlyhigher than control. The magnitude of reduction equals 1.04 points every 2 weeks with a 35%response variance explained by the linear model. In contrast, in the control group pain, reductionintensity equals 0.20 points every 2 weeks with only 1% of the total variance explained by theregression. The Kaplan-Meier estimator showed a pain score ≤ 3 in 81% of PEA treated patientscompared to only 40.9% in control patients by day 60 of treatment. PEA effects were independentof patient age or gender, and not related to the type of chronic pain.Limitations: Noteworthy, serious adverse events related to PEA were not registered and/orreported in any of the studies.Conclusion: These results confirm that PEA might represent an exciting, new therapeutic strategyto manage chronic and neuropathic pain associated with neuroinflammation.Key words: Chronic pain, neuropathic pain, neuroinflammation, astrocytes, glia, mast cells,microglia, micronized and ultra-micronized palmitoylethanolamide