neuropathic pain peacure

Treating neuropathic pain with palmitoylethanolamide (PEA)

Upon hearing the term neuropathic pain, we instinctively think of the neuron and its pathology. However, the pathogenesis of neuropathic pain is more complex, and many new developments in this field are not that straight forward. In the literature a new term emerges: gliopathic pain. The natural substance palmitoylethanolamide can be used as a supplement.


Neuropathic pain is gliopathic

This term indicates that an important pathogenetic aspect of neuropathic pain can be found in the metabolism of the glial cells [1]. Glia and asterocyten are therefore seen as new drug targets, to better explore painkillers [2]. Recent research has stressed that due to the fact that the current analgesics are effective to a limited extent only, targeting neuronal networks exclusively, new treatment strategies that focus on neuron-glia interaction are very promising [3].

The current body of thinking about the pathogenesis of neuropathic pain is based on the research efforts of several major pharmaceutical companies that have in recent years introduced products such as gabapentin, pregabalin and duloxetine. The pathogenetic hypothesis which is the most commonly used has its roots than in the nerve cell itself, with its ion channels and neurotransmitters. However, there has long been a great need for pain medications with novel mechanisms, no interactions with other drugs, and less side effects. The mechanisms of modern painkillers belong only to a few classes and are suboptimal. Approximately 5,100 people annually have serious stomach bleeds and more than ten percent of them die as a result of using some of the most commonly used NSAIDs.


Palmitoylethanolamide: a non-psychotropic cannabinoid analgesic

Palmitoylethanolamide (PEA) is an analgesic with a completely new foundation. This substance is related to Cannabis, but without the psychoactive side effects. It is an endogenous substance which became available in the United States in late 2010 as a supplement and is available in capsules of 400 mg and packs of 30 capsules.

In the sixties and seventies of the last century PEA was available under the name Impulsin, for influenza prophylaxis. That indication was at that time underpinned by three separate clinical trials. But due to lack of precise understanding of its mechanism (it is then believed that the substance worked via the lymphocytes) interest in this particular body amide waned. Since the nineties however there is e renewed interest, and hundreds of pharmacology and a number of clinical studies have been published. All research seems to indicate that we are dealing with a very promising analgesic and anti-inflammatory substance, with very few side effects and no significant interactions.

After the discovery of anandamide and the cannabis receptors in 1992 interest in PEA increased. This molecule by now has been explored for half a century in a variety of animals. The pre-clinical and clinical studies range from influenza prophylaxis, via multiple sclerosis, spinal cord trauma and stroke, inflammation, to neuropathic pain.

In the bar chart below you can see the quantity of articles in which PEA is referred to each year.


Palmitoylethanolamide: physicochemical and pharmacological profile

Palmitoylethanolamide, palmidrol, N-Palmitoylethanolamine, palmitamide, palmitylethanolamine, hydroxyethylpalmitamide and N- (2-hydroxyethyl) hexadecanamide, are all terms that can be found for this amide in the literature. The molecular formula is C18H37NO2, molecular masse 299.49, the melting point is between 55 and 60 degrees Celsius, and the substance is soluble in alcohol and DMSO.

PEA is an endogenously produced fatty amide, which is related to anandamide, our own ‘cannabis’. PEA is a shorter and saturated analog of anandamide, and both belong to the family of N-acylethanolamines or endocannabinoids to which also oleoylethanolamide belongs [4]. These molecules are found in various tissue in humans and animals [5]. The endocannabinoid system is an old phylogenetic system that can be found even in fish and invertebrates like sea cucumbers [6] [7].

The endocannabinoids are synthesized via a number of enzymatic steps from a common phospholipid precursor: N-acetyl-phosphatidylethanolamine (NAPE) [8]. N-acylethanolamine-hydrolyzing acid amidase (NAAA) is the enzyme that degrades PEA and other cannabinoids [9]. Other endocannabinoids are also degraded through fatty-acid amide hydrolase. This degradation, which takes place in all cells where PEA is produced, takes place independent of liver and kidney functions. Although no formal studies have been conducted into metabolism with hepatic and renal conditions, it is not necessary to adjust the dosage.

PEA plays a regulatory role in several biological processes, from food intake to inflammation. It is synthesized in biological tissue in reaction to inflammation and chronic pain. There are at least four different mechanisms at play when pain and inflammation occur, which we will describe below. We will discuss experimental data from animal studies associated with these indications.


Impact on the cannabis receptor

Initially, in the 80s, it was thought that PEA worked through the cannabis receptors. That was because PEA and anandamide have many structural similarities, and anandamide activates both cannabis receptors CB1 and CB2. Whether part of the biological effect of PEA indeed takes place via these receptors is still not entirely clear, but it seems unlikely. Experiments have been done where the effects of PEA was cancelled out after treatment with a CB2 antagonist.

The relationship between PEA and the endogenous cannabinoid anandamide became known in the nineties of the last century [10]. In particular the CB2 receptor which acts on white blood cells shed light on the relationship between the inhibition of inflammation by PEA, although it turned out later that there were other reasons for it. PEA and anandamide are classic autocoids. That seems a somewhat outdated term, but the definition remains topical: locally produced tissue hormones. NO and prostaglandins are autocoids too. Autacoid Local Inflammation Antagonism (ALIA) was therefore introduced as a term and ‘ALIAmides ‘ as a collective term for inflammatory agents such as PEA and anandamide [11]. Their anti-inflammatory effect has been demonstrated in many experimental models. For example, the synthetic cannabinoid agonist nabilone and indomethacin were compared to PEA in an inflammation model in which in a rat an acute inflammatory pain and swelling were introduced by means of the injection of carrageenan in the hind leg. All three drugs were able to significantly reduce the inflammation and pain. The administration of a selective CB2 antagonist prior to nabilone and PEA cancelled out the effect [12].


The impact on the vanilloid receptor TRPV1 and the entourage effect

About anandamide it is known that it binds with the vanilloid receptor (TRPV1), an important receptor for pain perception. Anandamide can reduce the activation of TRPV1 [13]. Palmitoylethanolamide (PEA) is able to enhance the effect of anandamide on the TRPV1 receptor [14]. This effect is described as the ‘entourage’ effect, because PEA stimulates another molecule in its operation, without itself binding to the receptor in question. The entourage effect is probably caused by the competitive affinity of PEA and anandamide to the intracellular enzymes that break down these amides [15].

The entourage effect is also reflected by the reduction in blood pressure by anandamide. It was found that when PEA was added to a low dose of anandamide, and no blood pressure-lowering effect had occurred yet, a marked decrease in blood pressure was observed [16]. This is true for different vascular beds [17].


Effect on COX-2 and iNOS

In a model of inflammation, PEA was compared with indomethacin in terms of the influence on cyclo-oxygenase (COX)-activity, on the neurotransmitter nitric oxide (NO) and on the production of radicals. PEA was found to inhibit the inflammation and measurably reduce the edema dependent on the dosage. This effect could not be neutralized by a receptor antagonist of the CB2 receptor. The inflammation increased COX activity, as well as the concentrations of a number of nitrogen radicals, and both PEA and indomethacin lowered those values [18]. In addition, PEA neutralizes the expression of cyclooxygenase-2 (COX-2) and nitric oxide synthase (iNOS) in a model for sciatic nerve compression. Also, the expression of the nuclear receptor PPAR-alpha was inhibited (see below) [19].

The injection of NSAIDs in a rat also shows the reduction of the anandamide degradation enzyme, FAAH, and with anandamide it has additional painkilling effects. In addition, this intervention leads to an increase of the local concentration of PEA [20]. Since FAAH also degrades PEA, obviously when this enzyme is inhibited more PEA is present in the tissue.

The analgesic effect of PEA does not only work via the mechanisms described above, but also through the nuclear receptor PARR-alpha. That is probably the most important mechanism.


PEA affects the nuclear receptor PPAR-alpha

The mechanism by which PEA has anti-inflammatory and analgesic effects has long remained unknown, because the CB2 receptor for many years seemed an obvious explanation. PEA, however, has a much more important target, a nuclear receptor. This nuclear receptor most likely also plays an important role in the glial tissue that is activated when neuropathic pain occurs [21] [22].

PEA is analgesic and anti-inflammatory through this new target in the cell nucleus, the ‘nuclear receptor peroxisome proliferator-activated receptor alpha’ (PPAR-alpha). This receptor owes its name to the fact that certain drugs Activate the production (Proliferation) of peroxisomes (Peroxisome) by binding to this Receptor: PPAR. Peroxisomes are organelles that contain hydrogen peroxide. Hydrogen peroxide breaks down endo- and exotoxins, such as alcohol. Many functions are controlled by these receptors, and the receptors are also known as ‘sensors for stress situations’ [23]. There are four of them, and they were discovered in the early 90’s [24] [25] [26].

PEA activates one of them, the PPAR-alpha receptor, with an EC (50) value of 3.1 +/- 0.4 microM and then PEA is applied topically to the mouse skin, we observe an increase in the expression of PPAR-alpha mRNA. PEA has no apparent biological activity in PPAR-alpha rodents [27]. Other natural PPAR-alpha agonists, such as oleoylethanolamide, and the PPAR-alpha targets of the pharmaceutical industry such as GW7647 and Wy-14643, work in a similar way to PEA [27].

PPAR-alpha modulates inflammatory reactions and PEA uses that mechanism [29] [27]. In a model of allergic dermatitis, PEA also works as a natural anti-inflammatory [31]. The mechanism by which the inflammation is reduced has a number of important aspects. PPAR-stimulation suppresses the production of INF-gamma and IL-17 by CD4 + T-helper cells. It also appears that less lymphocytes move toward the site of the inflammation, through the inhibition of the production of chemokines [32].

Further, stimulation of PPAR-alpha by PEA has a clear analgesic effect [33]. The neuroprotective effect of PEA has already been demonstrated and this mechanism works via PPAR-alpha [34]. The blocking of this receptor turned out to cancel out the neuroprotective effect.

The effects described below on mast cells, lymphocytes and effects described in pain and inflammation models are largely explained by the PARR mechanism.


PEA affects the mast cell

PEA is produced in many different tissues, in neurons and even in the retina, in glia and white blood cells: macrophages, mast cells and basophil cells [35] [36] [10]. It has a modulating effect on all of these inflammatory-related cells. In particular, the mast cell as a target of PEA has been studied extensively. PEA inhibits the degranulation of that cell [38] [39].

Mast cells are found everywhere, for instance also in the central nervous system. Mast cells may secrete a number of substances during a stroke or a cerebral hemorrhage that are neurotoxic, such as tumor necrosis factor-alpha, thereby inducing astroglia to produce neurotoxic concentrations of nitric oxide. PEA reduces the activity of mast cells via the local autocoid mechanism. This way, it counteracts the damage and loss of nerve cells [40]. In ischemic tissues, PEA as biologically useful response. PEA concentrations increase in case of ischemic damage such as in cardiac or cerebral infarction. In the brain, PEA is created in higher dosages by the nerve cells themselves as a response to increased levels of exitatoire neurotransmitters [41].


PEA in animal models for inflammation and pain

Half a century ago PEA was investigated as a booster for the non-specific defense [42]. This resulted in clinical studies conducted in children and adults to find out whether PEA could prevent flu, which indeed seemed to be the case. The substance was introduced as Impulsin [43] [44] [45].

In complex inflammation in animal models, such as multiple sclerosis and traumatic spinal cord injury, PEA can clear reduce the inflammation and improve motor functions [46] [47]. PEA has some obvious beneficial effects, as revealed in the latter model. PEA decreases:

  1. the inflammatory reactions in the spinal cord
  2. the neutrophil cell infiltration
  3. the production of nitrotyrosine
  4. expression of the proinflammatory cytokines
  5. the kappa-B activity
  6. the expression of nitric oxide synthase
  7. the apoptosis

Anandamide and PEA are both synthesized from a common precursor molecule, and work in synergy. In animal models of pain, the analgesic effects of the two molecules are 100 times stronger when they are both present. Gas-chromatographic and mass-spectrometric research has revealed that the concentrations of both molecules produced locally is sufficient to locally stimulate the cannabinoid receptors [48]. PEA in a large number of animal models for inflammatory pain and neuropathic pain has been proven to have a consistent analgesic and anti-inflammatory effect [19] [15] [51] [52] [33] [54] [55] [56].


Clinical trials and casuistry

Never before have so many preclinical studies been available supporting the efficacy of an agent such as palmitoylethanolamide. They have laid the foundations for the design and implementation of a number of clinical trials in chronic pain and diseases involving chronic inflammation.

We discuss briefly the clinical results of PEA with hernia pain, pain associated with carpal tunnel syndrome, pain associated with diabetic neuropathy, pain with temperomandibular dysfunction, post-herpetic pain, pain associated with endometriosis, and pelvic pain.

The largest study with PEA was conducted in patients with severe hernia pain. In a randomized study over 600 patients with a hernia were treated with PEA, or a placebo. The dosage of PEA was 600 mg twice a day, during 3 weeks. The study was carried out in nine hospitals and university centers in Italy. The patients treated with PEA after 3 weeks had significantly more pain relief than patients on the placebo [57].

A second study looked at the effects of PEA in 20 patients with neuropathic pain caused by diabetes, the dosage was 600 mg of PEA per day. Besides pain scores, and neuropathic symptoms, conduction velocities were compared before and after treatment. Both the pain and interfering neuropathic symptoms improved significantly. In addition, the neuro-physiological values had clearly improved, although not significantly [58].

In a third comparative study, pain that occurs in carpal tunnel syndrome was treated with PEA and evaluated after 4 and 8 weeks. After 4 weeks, there were already significant differences, which increased in effect after 8 weeks. The functionality of the hand after treatment with PEA had improved, whereas the hand function had deteriorated after 8 weeks in the control group. The same was true for neurophysiological measurements, such as the amplitude and the speed of the action potentials. All differences were significant for the group treated with PEA [59].

In the syndrome of Costen or temperomandibulair syndrome (TMD), there are problems with the temporomandibular joint and / or the muscles that run along the temporomandibular joint, and chronic pain occurs. In a randomized study, two groups of patients were treated who had quite a lot of pain and had difficulty opening the mouth. Half of them was treated with a conventional analgesic, an NSAID, namely ibuprofen 600 mg three times daily. The other half received a treatment with a total of 900 mg palmitoylethanolamide (PEA). The results were impressive. The treatment with PEA not only resulted in significantly less pain after 2 weeks, but the function of the jaw opening the mouth was better than in the treatment with ibuprofen [60].

In an open study, 8 patients with postherpetic pain in the face received 0.3% PEA lotion. The patients put the lotion on the pain points in the face 2 times daily for 2 to 4 weeks. Five of 8 patients experienced a mean pain decrease of 87.8% [61]. All patients (n = 4) that had pain problems for less than a month reported a marked reduction of pain.

From some case studies it has emerged that PEA also brings relief from endometriosis pain, especially for pain that occurs during sex. Four patients with endometriosis pain benefited from treatment with PEA [62]. The treatment of the endometriosis pain was 90 days of a combination preparation of PEA 400 mg with polydatin 40 mg, 2 times per day. Different types of pain were evaluated: pelvic pain, pain during intercourse, pain with bowel movements, pain when urinating and pain during menstruation. After one month, the pain had partly gone away. Women took fewer painkillers. Furthermore, it appeared on the ultrasound that the endometriosis spots had decreased in size.

Finally, PEA was found in a case description of a 40-year-old man with chronic neuropathic pain in the pelvis to have clearly reduced this pain [63].



PEA is a breakthrough in the field of chronic pain treatment. PEA belongs to the new class of analgesics, endogenous molecules with very few side-effects. There are no interactions reported to date, and no clinically relevant side effects, and the substance is tolerated by the body, even in elderly patients. As the degradation occurs via the FAAH enzyme, and therefore outside of the liver and the kidneys, adjustments in the dosage in patients with kidney and liver disease is not necessary. However, no clinical studies have been done in these areas.

The dose is 1200 mg per day.

PEA is based on an impressive amount of preclinical and clinical studies. Hundreds of thousands of patients have been treated and five positive clinical trials have been conducted, as well as several case studies.

PEA is available in the United States and can be used alongside any medication and painkillers. Plenty is known about the safety and effectiveness of the body’s own painkiller to consider the use of this substance in neuropathic pain syndromes that have proven difficult to treat. Always opt for PEA product of which the purity level is known, and opt for the highest purity by examining the enclosed certificate or labels.




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