Palmitoylethanolamide, a Special Food for
Medical Purposes, in the Treatment of Chronic
Pain: A Pooled Data Meta-analysis
Authors: Varrassi Giustino 
Published: February 2021

Background: A growing body of evidence suggests that neuroinflammation, which is characterized
by infiltration of immune cells, activation of mast cells and glial cells, and production of inflammatory
mediators in the peripheral and central nervous systems, has an important role in the induction and
maintenance of chronic pain. These findings support the notion that new therapeutic opportunities
for chronic pain might be based on anti-inflammatory and pro-resolving mediators that act on
immune cells, in particular mast cells and glia, to mitigate or abolish neuroinflammation. Among
anti-inflammatory and pro-resolving lipid mediators, palmitoylethanolamide (PEA) has been reported
to 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 efficacy
and safety of micronized and ultra-micronized palmitoylethanolamide (PEA) on pain intensity in
patients suffering from chronic and/or neuropathic pain.
Study Design: Pooled data analysis consisting of double-blind, controlled, and open-label
clinical 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 terms
chronic 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 diagnose
and assess pain intensity. Raw data obtained by authors were pooled in one database and analyzed by
the 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 trials
comparing active comparators vs placebo, 2 were open-label trials vs standard therapies, and 7
were open-label trials without comparators.
Results: Results showed that PEA elicits a progressive reduction of pain intensity significantly
higher 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, reduction
intensity equals 0.20 points every 2 weeks with only 1% of the total variance explained by the
regression. The Kaplan-Meier estimator showed a pain score ≤ 3 in 81% of PEA treated patients
compared to only 40.9% in control patients by day 60 of treatment. PEA effects were independent
of 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/or
reported in any of the studies.
Conclusion: These results confirm that PEA might represent an exciting, new therapeutic strategy
to 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