Palmitoylethanolamide (PEA), also called palmitoylethanolamine or N-2 hydroxyethyl palmitamide), belongs to the family of N-acylethanolamines (NAEs), naturally occuring, biologically active lipids that act on cannabinoid receptor (CR2) and interact with inflammatory cells in the nervous system.
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.
Conditions with Evidence of Benefit with PEA
-Arthritis – osteoarthritis & rheumatoid arthritis
Peripheral neuropathies – diabetic neuropathy & chemotherapy-induced peripheral neuropathy
-Carpal tunnel syndrome
-Opioid Tolerance and Hyperalgesia (An increased sensitivity to feeling pain and an extreme response to pain. Hyperalgesia may occur when there is damage to the nerves or chemical changes to the nerve pathways involved in sensing pain.)
-Low back pain – herniated disc disease, failed back surgery syndrome.
-Neuropathic pain – related to stroke & multiple sclerosis
-Inflammatory Bowel Disease
-Chronic pelvic pain
-Shingles pain (post herpetic neuralgia - Post-herpetic neuralgia is a lasting pain in the areas of your skin where you had shingles. Around one in five people with shingles will get post-herpetic neuralgia. People age 50 and over are particularly at risk. Many people with post-herpetic neuralgia make a full recovery within a year.)
-Vaginal pain (vulvadynia)
-Post-operative dental surgery pain
-Traumatic Brain Injury/Chronic Traumatic Encephalopathy
How does PEA work with 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 behaviours. What is particularly exciting about PEA is that it is a naturally occurring 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, including micronized (m.PEA) and ultra-micronized PEA ( u.m.PEA), commercially available forms of PEA structured to improve absorption and activity of PEA. Twelve studies met high standards of research criteria and included 1,188 patients who were treated for chronic pain with m.PEA or u.m.PEA for periods of 21 to 60 days with daily doses ranging from 300 to 1200 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 reseach on PEA has focused on neuropathic (nerve) pain where significan 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 infammatory pain conditions as wel as visceral pain syndromes including endometriosis, interstitial systitis and inflammatory bowel disease.
PEA also appears to possess effectivenes 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.
PEA does not dissolve well in water and as such the rate at which it dissolves in the stomach and intestine is often the rate-limiting step for oral absorption and bioavailability. The rate at which PEA dissolves is influenced by, among other factors, it’s particle size and therefore it is usually micronized or ultra-micronized. (manufactured in very small particle size) in order for it to dissolve more rapidly. Micronization and ultramicronization processes yield different crystalline structures with higher energy content and smaller particle size which result in better diffusion and distribution of these molecules.
Dosing of PEA
PEA is generally advised to be between 300-600 mg twice a day, or up to 1200 mg/day. Duration of treatment has not been studied, although most research has looked at up to 3-6 months of treatment. While no safety concerns are recognized for longer term use, it may be advisable to take treatment breaks after 3- 6 months treatment duration.
PEA and Specific Pain Conditions
Fibromyalgia (FM) A 2015 study evaluated FM patients for a total duration of 3 months in which the patients currently treated with duloxetine (Cymbalta) plus pregabalin (Lyrica) were provided supplementary PEA (PEA-um tablets 600mg twice a day in the first month, and PEA-m tablets 300 mg twice a day in the next 2 months). The addition of PEA was noted to significantly reduce pain scores in the FM patients.
Muscular Cramps Although the pathophysiology of muscular cramps remains poorly understood, PEA might play a role in stabilizing overactive muscles that give rise to night cramps. While PEA has not been studied extensively, a recent article published in 2016 reports three cases of patients with severe, persistent muscle cramps that responded with complete resolution of the cramps within 2-4 weeks, with PEA dosed at 400mg 2-3x/day.
Arthritis A growing body of evidence now points to inflammation, locally and more systemically, as a promoter of damage to joints and bones, as well as joint-related functional problems. The disease process underlying joint diseases is currently believed to involve communication between cartilage and the subchondral bone beneath the cartilage in the joint—and a loss of balance between these two structures. Dysregulation of the mast cells in these structures is associated with damage to these structures (cartilage, bone, synovia, matrix, nerve end- ings, and blood vessels). This process includes neuroinflammation which in turn contributes to the chronic pain associated with arthritis.
Communication between the spinal cord and the joint can cause further neuroinflammatory changes at the spinal level involving the central nervous system and brain. A central sensitization process has also been observed in patients with arthritis, where pain thresholds to pressure and prick stimuli are lower than in healthy subjects, making the person experience pain more easily and severely. This central sensitivity to pain does not correlate with radiological findings, suggesting that central sensitization is the factor that contributes most to arthritis pain.
Unfortunately, current conventional treatment strategies for arthritis are directed only at relieving symptoms and do little to limit progression of the disease process itself.
Recent research has focused on the use of PEA as both an arthritic pain-relieving substance but also as a treatment that may slow the progress of further joint deterioration. In synovial (joint) fluid, PEA is normally present at high levels (1,500 pmol/mL), but these levels are markedly reduced in patients with osteoarthritis or rheumatoid arthritis, suggesting a protective role for PEA in these conditions. In experimental models of joint disease, changes in PEA levels were also found in the spinal cord, supporting the theory of dysregulation in PEA metabolism in joint diseases. This suggests that PEA supplementation may prove beneficial in these situations.
Both membrane and nuclear receptors are important targets for controlling arthritis disease progression. Among membrane receptors, endocannabinoids play a key role in bone maintenance. Both cannabinoid receptors CB1 and CB2 are present in the skeleton. CB1 and CB2 receptor agonists have been shown to have a protective role in joint diseases and PEA indirectly acts on the CB2 receptor suggesting potential benefit in arthritis. Agonists at the nuclear receptor PPARc reduce the synthesis of inflammatory agents to prevent breakdown of cartilage and PEA also acts on PPARc receptors.
To summarize, PEA offers benefit for arthritis both in regards to reducing the development and maintenance of chronic pain but also to help limit the progress of joint destruction associated with arthritis.
Post-Operative Pain Recent studies have indicated that nearly half of all surgical patients still have inadequate pain relief. Multiple mechanisms are involved in postoperative pain including neuroinflammation and mast cell activation. Previous studies have shown that incisions can cause mast cell degranulation resulting in the release of many chemicals that promote the development of acute and chronic pain. Studies suggest that reducing neuroinflammation and stabilizing mast cells reduce post-operative pain.
One study looking at post-operative pain after surgical extraction of impacted lower third molars did show reduction of pain with PEA. While specific studies for post-operative pain are lacking, when one evaluates the mechanisms postulated for the evolution of acute to chronic pain, especially in spinal surgery, the use of PEA as a glial cell inhibitor to reduce the development of pathologic neuroinflammation makes sense. Along with other glial cell inhibitors including resveratrol and low dose naltrexone, PEA may offer a role as a safe supplement to be taken in the post-operative period to reduce the evolution of chronic pain at little risk of side effects or harm.
A Closer Look at the Mechanisms of Action of PEA ( for those really interested)
The proposed mechanisms of action of PEA have largely focused on it’s effects upon mast cells and glial cells. However, PEA activity also involves CB2-like cannabinoid receptors, ATP-sensitive K+-channels, TRP channels, and NFkB, although the best evidence is for an action of PEA upon the nuclear receptor peroxisome proliferator-activated receptor α (PPARα). These are not the only actions of PEA: it can also interact as an agonist with GPR119, an orphan receptor involved in glucagon-like peptide-1 secretion, which may affect endocannabinoid signalling by acting as a competing substrate for the endocannabinoid homologue anandamide (N-arachidonoylethanolamine).
Mast Cells Mast cells are immune cells mostly located within tissues at the boundary of the external environment, in close proximity to blood vessels and nerve endings and found also within the endoneurial compartment (lining) of peripheral nerves.
Mast cells can modify sensory transmission via a wide spectrum of mediators, including biogenic amines such as histamine and serotonin, cytokines (interleukin-1b (IL-1b) and tumour necrosis factor-a (TNF-a) in particular), enzymes, lipid metabolites, ATP, neuropeptides, nerve growth factor (NGF), and heparin—most of which can interact with sensory nerve terminals. Sensory neurons, in turn, by releasing neuropeptides may provoke mast cell activation/ degranulation.
Mast cell-nerve terminal activity results in nociceptor sensitization, reduced pain threshold at the site of inflammation and, ultimately, dysfunctional pain signalling and hyperalgesia and when it persists, increased responsiveness of nociceptors can also sensitize spinal cord neurons, leading to central sensitization.
Glial Cells Glia cells mediate pain processing at the spinal level. Sensitization of central somatosensory neurons is responsible for the development of chronic neuropathic pain. Microglia, macrophages found in the brain, interact with neurons at the site of injury or disease and can be activated through exposure to a number of molecules, including pro-inflammatory signals released from mast cells. A bidirectional cross talk between brain mast cells and microglia has been theorized, contributing to chronic pain states by releasing pro-inflammatory cytokines, chemokines, and proteases.
Astrocytes, the most abundant glial cell type involved in neuroinflammation, also play a major role in pain processing, contributing to neuropathic pain. When activated, astrocytes release of IL-1b, IL-6, TNF-a and prostaglandin E2. Chronic astrocytic activation in nerve injury results in down-regulation of glutamate transporters, ultimately resulting in decreased glutamate uptake and increased excitatory transmission and facilitation of chronic pain.
PEA, Mast Cells and Glial Cells These chronic neuroinflammatory processes that sustain neuropathic pain are opposed by the production of lipid mediators that are able to switch off inflammation. Assuming that chronic inflammation may lower the levels or actions of these molecules, it is believed that administration of such lipid mediators might provide an reverse or suppress neuroinflammation. N-acylethanolamines (NAEs) are a class of naturally occurring lipid mediators composed of a fatty acid and ethanolamine—the so-called fatty acid ethanolamines (FAEs). The principal FAEs include the endocannabinoid N-arachidonoylethanolamine (anandamide), and its congeners N-stearoylethanolamine, N-oleoylethanolamine and N-palmitoylethanolamine (PEA or palmitoylethanolamide).
PEA, produced by microglia and mast cells, down-modulates mast cell activation and controls microglial cell activity. By controlling these cells, PEA acts is disease-modifying rather than symptom-modifying, since it acts on the ‘‘roots of the problem’’, i.e., on the cells involved in the generation and maintenance of pain. In support of this theory, PEA levels have been shown to be altered in brain and spinal cord areas involved in pain when pain is induced.
Other Mechanisms of Action PEA produces indirect receptor-mediated effects within the Endocannabinoid System (ECS), the site of action of endogenous (natural) cannabinoids (or “endocannabinoids”) such as anandamide (AEA), and plant cannabinoids (phytocannabinoids) like CBD and THC, that directly or indirectly activate CB2 and CB1 receptors. PEA inhibits FAAH, the enzyme that breaks down cannabinoids so it indirectly enhances the activation of CB2 and CB1 receptors.
PEA activates peroxisome proliferator activated receptors (PPAR) in cell nuclei of both dorsal root ganglion sensory neurons and glial cells. This receptor is a regulator of gene networks which control pain and inflammation. Stimulation of PPAR-a modulates both the perception and transmission of peripheral pain signaling and spinal amplificatory pain mechanisms—thereby exerting its activity in different types and phases of pain. PEA also potentiates anandamide actions at cannabinoid receptors (CB2 receptors) on cell membranes, while itself having no appreciable affinity for either CB1 or CB2 receptors, making it an indirect CB2 agonist.
PEA belongs to a class of lipid autacoids, the N-acylethanolamides. Autacoids are modulating factors that influence the function of cells and tissues which are locally produced on demand and which subsequently are metabolized in the same cells and/or tissues. As an autacoid, PEA is produced in the body on demand and accumulates locally inflammatory and pain disorders.
In addition to its affinity for the PPAR, PEA has high affinity for a number of other targets including the TRPV1 channel that is involved with neuropathic pain and is the site of action of capsaicin, a topical analgesic derived from red peppers. Certain TRPV1 channel activators have been recently patented for the treatment of muscular cramps. PEA can be synthesized in muscle tissue and one of the mechanisms of action for PEA’s anti-cramp activity might be its agonistic action at the TRPV1 receptor. PEA synthesis in muscle tissue seems be disturbed in fibromyalgia. TRPV1 channels are also targets for the cannabinoids, both natural (AEA- or 2-AG) and marijuana-based (CBD and THC). In addition, PEA is also able to increase cannabinoid-induced TRPV1 activation and desensitization.
PEA thus possesses two pain-relieving therapeutic effects, a reduction of neuroinflammation and a reduction in pain signaling and transmission.