Accurate Education - Palmitoylethanolamide (PEA ) - Infectious Diseases

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Palmitoylethanolamide (PEA ) – Infectious Diseases

Palmitoylethanolamide (PEA), an endogenous (manufactured by the body) fatty acid amide, is emerging as a new agent in the treatment of pain and inflammation. As an endogenous agent and one also found in foods such as eggs and milk, no serious side effects or drug–drug interactions been identified. PEA has been used for many decades in the Netherlands and Europe, but since the 1990s interest in the U.S. has surged. It is classified as a “food for medical purposes” in Europe and as a diet supplement in the U.S.

PEA has demonstrated effectiveness for chronic pain of multiple types associated with many painful conditions, especially with neuropathic (nerve) pain, inflammatory pain and visceral pain such as endometriosis and interstitial cystitis.

See: Palmitoylethanolamide (PEA )

PEA may also be effective as a therapy for respiratory infections such as influenza and the common cold. In the age of COVID-19 there may be a role for supplementation with PEA to potentially reduce symptoms and risk for severe outcomes.

For links to PEA supplements currently available, see:

Supplements: Palmitoylethanolamide (PEA)

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Palmitoylethanolamide (PEA) – Infectious Diseases

Palmitoylethanolamide (PEA), also called palmitoylethanolamine or N-2 hydroxyethyl palmitamide), is a naturally occuring, biologically active lipids that act on cannabinoid receptor (CR2) and interacts 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. Investigators noted that the occurrence of rheumatic fever was reduced in children fed egg yolk powder and subsequently PEA was identified in the 1950s as being an active anti-inflammatory agent in chicken egg yolk.

Since 1970, the anti-inflammatory and other immune-modulating properties of PEA have been evaluated in a number of placebo-controlled double-blind clinical trials on influenza and common cold and has demonstrated positive results. PEA has been marketed for clinical use of in Czechoslovakia under the brand name Impulsin. It has also been marketed as a food for special medical purposes in Italy and Spain, under the brand name Normast (Epitech Srl) and as a food-supplement named PeaPure (JP Russell Science Ltd.).

On this page, PEA will be reviewed as an anti-inflammatory agent with potential for treatment for influenza and the common cold. These findings could offer possible alternative treatment options in the COVID-19 pandemic.

Conditions with Evidence of Benefit with PEA

Arthritis – osteoarthritis & rheumatoid athritis
Fibromyalgia
Peripheral neuropathies – diabetic neuropathy & chemotherapy-induced peripheral neuropathy
Carpal tunnel syndrome
Opioid Tolerance and Hyperalgesia
Low back pain – herniated disc disease, failed back surgery syndrome, other
Sciatic pain
Dental pain
Neuropathic pain – related to stroke & multiple sclerosis
Inflammatory Bowel Disease
Chronic pelvic pain
Shingles pain (postherpetic neuralgia)
Vaginal pain (vulvadynia)
Post-operative dental surgery pain
Traumatic Brain Injury/Chronic Traumatic Encephalopathy

How does PEA work with pain?

Neuroinflammation

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 ma
y 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, 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.

See below for more information on mechanisms of action of PEA.

Valditiy of Research

Regarding the strengths/weaknesses of the available studies on PEA, there are several concerns, mainly the small size of most studies. Studies based on smaller numbers of patients lack statistical strength for their conclusions, leaving the conclusions vulnerable to inaccuracy. Large, well-designed studies are lacking for the most part although the recent meta-analysis in 2016 does support the validity of PEA effectiveness.

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 Products

Formulations of PEA

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. As compared to naıve PEA (particle size profile ranging between 100 and 700 lm), micronized and ultramicronized PEA differ in their particles size profile (2–10 lm and 0.8–6 lm at most, respectively). 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.

In addition, a recently released formulation combines PEA with lecithin as a liposomal version of PEA that also allows for a greater absorption rate. Head-to-head comparisons studies of the different formulations of PEA in humans are lacking however, and thus there is no clinical data yet to support the use of one formulation over another.

Commercial Products

PEA is currently marketed as a nutraceutical in humans: PeaCure in the U.S.; (NormastTM, PelvilenTM [Epitech]), PeaPureTM [JP Russel Science Ltd]) in some European countries (e.g. Italy, Spain; it is sold as a food supplement in other countries, such as the Netherlands). It also is a constituent of a cream (Physiogel AITM, Stiefel) marketed for dry skin. PeaCure offers a liposomal liquid product and a micronized capsule product whereas PeaPure offers micronized and ultramicronized products.

See: Supplements: PEA (Palmitoylethanolamide)

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. An animal study published in 2017 that looked at PEA in combination with quercetin, a natural antioxidand (see Quercetin) showed that the combination reduced pain and improved joint function, protected cartilage against damage, and reduced levels of inflammatory chemicals in the joint fluid. The magnitude of these benefits was comparable to, or even greater than, those of meloxicam (Mobic), a non-steroidal anti-inflammatory medication similar to ibuprofen.

Traumatic Brain Injury/Chronic Traumatic Encephalopathy (CTE)

Chronic Traumatic Encephalopathy (CTE), is a neurodegenerative disease thought to be associated with a history of repetitive head impacts, such as those sustained through contact sports or military combat. Symptoms of CTE usually manifest years after the head trauma(s). The symptoms of CTE are insidious. They may first manifest as deteriorations in attention, concentration, and memory, as well as disorientation and confusion, and may occasionally be accompanied by dizziness and headaches. Mood conditions may occur such as depression along with irritability, emotional instability, aggressiveness and paranoia. With progression, additional symptoms may develop including a lack of insight and poor judgment which may lead to substance abuse.

PEA’s anti-inflammatory actions involve both neuronal and nonneuronal cells, including microglia and peripheral and central mast cells providing neuroprotective effects including a role in maintaining cellular homeostasis in the face of neuroinflammation, one of the mechanisms involved with the developoment of CTE. Studies in mice show that PEA also protects against amyloid β-peptide-induced learning and memory impairment, another mechanism associated with CTE.

See: Traumatic Brain Injury (TBI)

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.

Pharmacokinetics of PEA

There is very little data available in the open literature concerning the pharmacokinetic properties of PEA. It is not very water soluble, making it slowly absorbed. Different formulations have been made to enhance absorption.

**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 tumor 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 signaling and hyperalgesia and when it persists, increased responsiveness of nociceptors can also sensitize spinal cord neurons, leading to central sensitization.

Mast Cells and Pain Associated with Cold Weather and Weather Change

Mast cells are perhaps the body’s most sensitive sensors for detecting changes in the external environment. They are located along blood vessels and nerves, particularly near the skin’s surface where they have been shown to be responsive to changes in environmental temperature and baroumetric pressure. It has been proposed (by Dr. Ehlenberger) that given their role in nerve pain and their ability to detect and respond to environmental change, mast cells may play a key role in why patients with chronic pain, especially nerve pain, arthritis and fibromyalgia, experience worse pain in cold weather and with changes in weather associated with changes in barometric pressure as occur prior to weather changes. The stabilizing effect PEA has on mast cells suggests that PEA may be an effective treatment for reducing pain sensitivity to cold weather and weather change.

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.

References

Palmitoylethanolamide4Pain.com

PEA – Availability

Palmitoylethanolamide (PEA)

PEA – Overview

PEA – Anxiety and Depression

Effects of palmitoylethanolamide and luteolin in an animal model of anxiety:depression. – PubMed – NCBI

PEA – Colds and Flu

PEA – Pain Conditions/Diagnoses

PEA – Arthritis

PEA – Back Pain

Palmitoylethanolamide in the Treatment of Failed Back Surgery Syndrome – 2017

PEA – Carpal Tunnel and Nerve Comeprssion Syndromes

PEA – CRPS (Chronic Regional Pain Syndrome)

PEA – Endometriosis

PEA – Traumatic Brain Injury (TBI)/Chronic Traumatic Encephalopathy (CTE)

PEA – Pain Types/Mechanisms

PEA – Neurobiology Overviews

PEA – PEA and the Endocannabinoid System

PEA – PEA and the PPAR

PEA – Anti-inflammatory Mechanisms

PEA – Central Sensitivity, Oxidative Stress and Pain

PEA – Opioid Tolerance and Hyperalgesia

PEA – Neuroinflammation, Glial Cells and Mast Cells

PEA – Neuropathic Pain

PEA – Peripheral Neuropathy

PEA – Inflammatory Bowel Disease

PEA – Visceral Pain, Endometriosis

PEA – Trauma

PEA – PEA & Quercetin

A novel composite formulation of palmitoylethanolamide and quercetin decreases inflammation and relieves pain in inflammatory and osteoarthritic pain models – 2017

PEA – Products

PEA – Liposomal Product Formulations

Getting into the brain – liposome-based strategies for effective drug delivery across the blood–brain barrier – 2016

PEA – Micronization Product Formulations

PEA –Safety

PEA –Topical

Emphasis on Education
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