Palmitoylethanolamide: “Medical Food” used to treat pain

Palmitoylethanolamide, a Special Food for Medical Purposes, in the Treatment of Chronic Pain: A Pooled Data Meta-analysis | Pain physician | February 2016             

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.  


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.


Double-blind, controlled, and open-label clinical trials were selected consulting the PubMed, Google Scholar, and Cochrane databases, and proceedings of neuroscience meetings.

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 showed that PEA elicits a progressive reduction of pain intensity significantly higher than control.

  • [in experimental group] The magnitude of reductionequals 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.


Noteworthy, serious adverse events related to PEA were not registered and/or reported in any of the studies.


These results confirm that PEA might represent an exciting, new therapeutic strategy to manage chronic and neuropathic pain associated with neuroinflammation.

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I had previously blogged about another medical food being used:
“Medical Food” for Chronic Low Back Pain

Here’s some background information about PEA from Wikipedia:

Palmitoylethanolamide (PEA) is an endogenous fatty acid amide, belonging to the class of nuclear factor agonists.

PEA has been demonstrated to bind to a receptor in the cell-nucleus (a nuclear receptor) and exerts a great variety of biological functions related to chronic pain and inflammation.

The main target is thought to be the peroxisome proliferator-activated receptor alpha (PPAR-α).[2][3]

PEA also has affinity to cannabinoid-like G-coupled receptors GPR55 and GPR119.[4]

PEA cannot strictly be considered a classic endocannabinoid because it lacks affinity for the cannabinoid receptors CB1 and CB2.[5] However, the presence of PEA (and other structurally related N-acylethanolamines) has been known to enhance anandamide activity by a so-called “entourage effect“.[6][7]

Several papers have demonstrated that an imbalance of the endocannabinoid system (ECS) and alterations in the levels of PEA occur in acute and chronic inflammation.[8]

For instance during β-amyloid-induced neuroinflammation the deregulation of cannabinoid receptors and its endogenous ligands accompanies the development and progression of disease.[9]

PEA has been shown to have anti-inflammatory,[3]anti-nociceptive,[10] neuroprotective,[11] and anticonvulsant properties.[12]

Animal models of chronic pain and inflammation

PEA has been tested in a variety of animal models for chronic and neuropathic pain. As cannabinoids, such as THC, have been proven to be effective in neuropathic pain states.[29]

The analgesic and antihyperalgesic effects of PEA in two models of acute and persistent pain seemed to be explained at least partly via the de novo neurosteroid synthesis.[30][31]

PEA inhibits the release of both preformed and newly synthesised mast cell mediators, such as histamine and TNF-alpha.[33]

PEA seems to be produced in human as well as in animals as a biological response and a repair mechanism in chronic inflammation and chronic pain.[36]

PEA’s mechanism on non-neuronal cells

PEA, as an N-acylethanolamine, has physico-chemical properties comparable to anandamide, and while it is not strictly an endocannabinoid, it is often studied in conjunction with anandamide because of their overlapping synthetic and metabolic pathways. N-acylethanolamines like PEA often act as signaling molecules, activating intracellular and membrane-associated receptors to regulate a variety of physiological functions. The signaling lipid PEA is known to activate intracellular, nuclear and membrane-associated receptors and regulate many physiological functions related to the inflammatory cascade and chronic pain states. Endocannabinoid lipids like PEA are widely distributed in nature, in a variety of plant, invertebrate, and mammalian tissues.[41]

Clinical relevance

From a clinical perspective the most important and promising indications for PEA are linked to neuropathic and chronic pain states, such as diabetic neuropathic pain, sciatic pain, CRPS, pelvic pain and entrapment neuropathic painstates.[36][40][48][49][56][57]

In 2012, 20 patients suffering from thalidomide and bortezomib induced neuropathy were reported to have improved nerve functions and less pain after a two months treatment with PEA 600 mg daily.[59] \

30 patients suffering from neuropathic pain, which were refractory to treatment with analgesics, included pregabalin, were responding well in 45 days, with a decrease of painscores > 50% when pregabalin was tapered in again, up to 600 mg/day in combination with PEA, without signs of drug-drug interaction.[60]

PEA is available as capsules (400 mg), tablets (300 and 600 mg) and as cream (0,3% and 1.5%).



If this is as good as it sounds, I’m surprised I haven’t heard of it before. In these times of desperate searching for non-opioid pain relief, why is this not being pursued?

Could this be so neglected because there’s no money to be made?

2 thoughts on “Palmitoylethanolamide: “Medical Food” used to treat pain

  1. Dee199

    Thank you for sharing. We are just now hearing about this supplement. Harvard Medical has recommended it to Pain Management Physicians. We are going to try it.

    Liked by 1 person


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