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What is Palmitoylethanolamide?

What is palmitoylethanolamide (PEA)?

"Palmitoylethanolamide (PEA) is an endogenous fatty acid amide belonging to the family of the N-acylethanolamines (NAEs) that exerts significant anti-inflammatory, analgesic properties and acts as a neuroprotective mediator (Impellizzeri et al., 2014).

Palmitoylethanolamide (PEA, N‐(2‐hydroxyethyl) hexadecamide, palmidrol; structure shown in Figure 1) belongs to the family of N‐acylethanolamines (NAEs), endogenous biologically active lipids including the endogenous cannabinoid receptor ligand anandamide and the satiety factor oleoylethanolamide.

PEA was identified in the 1950s as being an active anti‐inflammatory agent in chicken egg yolk 1, 2. In mammals, PEA is produced on demand from the lipid bilayer and is ubiquitous, with tissue concentrations in the mid to high pmol/g range being found in rodents 3.

PEA Pain relief

The history of PEA as a natural food ingredient with medicinal properties was first identified in 1943 as part of an epidemiological study focused on childhood rheumatic fever,  which was noted to occur more frequently in those children who ate fewer eggs. Subsequently investigators noted that the occurrence of rheumatic fever was reduced in children fed egg yolk powder. Subsequently PEA was first identified in the 1950s as being an active anti-inflammatory agent in chicken egg yolk.

How does PEA work for pain?

A solid body of evidence growing over the last 5-10 years indicates that chronic pain is largely due to a process called neuroinflammation, a condition characterized by activation of a number of inflammatory cells within the peripheral and central nervous systems. Neuroinflammation is characterized by migration of immune cells into an area of injury which release inflammatory chemical products that lead to activation and maintenance of chronic pain.

These inflammatory cells, mast cells and glial cells, are now targets for development of new medications for treating chronic pain. Evidence indicates that suppression of the activation of these cells may limit or abolish the evolution of acute to chronic pain and may also act to reduce chronic pain.

On the forefront of research into agents that may act on neuroinflammation is palmitoylethanolamide (PEA) which has been reported to reduce mast cell activation and to control glial cell behaviors. What is particularly exciting about PEA is that it is a naturally occuring agent produced by the body that has no reported serious side effects or drug-drug interactions, making it an extraordinarily safe treatment option. Over the last few years, especially in Europe and the Netherlands, more and more clinical research and practical experience have confirmed that PEA is an effective treatment option for chronic pain.

PEA is widely distributed in different body tissues, including the nervous system, and is synthesized on demand following stress, injury and/or pain and accumulates in affected tissues with inflammation. PEA serves to reduce inflammation and pain in different chronic pain conditions.

A systematic review article published in 2016 identified all clinical trials conducted between 2010 and 2014 on PEA.  Twelve studies met high standards of research criteria and included 1,188 patients who were treated for chronic pain with PEA for periods of 21 to 60 days with daily doses ranging from 300 to 1,200 mg. The different pain diagnoses included: degenerative conditions in 1,174 patients (failed back surgery, back disorders, carpal tunnel syndrome etc.); neuropathic in 170 patients (brachial plexus injury, diabetic, post-herpetic neuropathies, stroke); and mixed diagnoses in 82 patients (arthritis, cancer and other miscellaneous painful diagnoses).

The results of the study including only the 1,431 patients with initial pain intensity ≥ 4 (on a 1-10 point scale of pain severity) were considered. The study concluded that on average, there was a significant reduction in pain equal to 1 point every 2 weeks for the 2 month study periods. PEA improved pain in all patients regardless of age or gender, although there was a slightly enhanced benefit in male patients under 65 y/o.

Most of the research on PEA has focused on neuropathic (nerve) pain where significant benefits have been identified. But there is a growing body of research indicating that PEA benefits many types of pain besides neuropathic pain which, incidentally, may also be due to the growing appreciation of the role of neuropathic pain in conditions such as arthritis and other inflammatory pain conditions as well as visceral pain syndromes including endometriosis, interstitial cystitis and inflammatory bowel disease.

PEA also appears to possess effectiveness in syndromes associated with chronic pain including depression and anxiety.

Safety and Effectiveness Over Time

PEA is a natural substance produced by the body and found in various foods. It is not an opioid. It is not addictive. Preliminary studies indicate that PEA does not develop pharmacological tolerance or gradually lose effectiveness over time as occurs with opioids. It has been shown to be safe for patients with no reported serious side effects and it is considered to lack acute or chronic toxicity. It does not interfere with other medication therapies nor does it trigger drug-drug interactions. There are no known contraindications for PEA, and patients with reduced kidney and liver function can be treated with PEA, as its metabolism  is localized and cellular and independent of kidney and liver functions. As with many medications, the safety with long term use over 60 days has not been well studied although thete are reports in the literature of long term use with no problems identified.  

Based on the totality of the evidence reviewed, there is a lack of adverse effects with doses of PEA as high as 1200 mg of microPEA per day. The most common regimen studied was 300 mg twice a day, although a sizeable amount of evidence also supports doses of 1200 mg/day. Adverse side effects have been reported to be absent. In summary, available data from animal and human studies support the safety of PEA in general, and of microPEA specifically, in products intended for human and companion animal consumption.

Conclusions on PEA

Preclinical and clinical studies suggest PEA may potentially be useful in a wide range of therapeutic areas, including eczema, pain and neurodegeneration and at the same time to be essentially devoid of unwanted effects in humans (see e.g. 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 and 20 for examples.

Other publications elucidate the efficacy of PEA as a neuroprotective in central nervous system pathologies (Cordaro et al., 2016; Parrela et al., 2016), as well as in several other diseases and inflammatory states such as irritable bowel syndrome (IBS) (Cremon et al., 2017), endometriosis (Di Paola et al. 2016) and skin inflammation (Cerrato et al., 2010; Vaia et al., 2016).

The clinical studies identified by our search are summarized in Tables 1 and 2. We found 21 clinical studies, of which 16 were clinical trials enrolling a range of 20 to 636 patients and five were case/pilot studies. In the clinical trials, PEA was used for periods ranging from 14 days to 120 days, and the doses ranged from 300 mg to 1200 mg daily.

The administration form of PEA was in most cases oral tablets except some occasional use of sublingual formulations (sachets), and the commonest form of evaluation was the visual analogue scale (VAS), where the patient makes a subjective assessment of her/his pain level on a 10 cm line where the left side represents no pain, and the right side represents the worst imaginable pain 33, 34.

With one exception, all available clinical trials reported significantly reduced pain intensity and an almost complete absence of unwanted effects, the latter confirming early field studies of PEA in healthy individuals 4.

Excerpts from "Palmitoylethanolamide for the treatment of pain: pharmacokinetics, safety and efficacy" Br J Clin Pharmacol. 2016 Oct; 82(4): 932–942.