Chronic & acute pain? Try palmitoylethanolamide!

During an international medical congress on October 28th 2011, a number of professors presented a breakthrough in the treatment of chronic pain. Only a small number of patients has benefited from the painkillers that have been available so far. This changed thanks to the introduction of the pain relieving, anti-inflammatory bodily substance palmitoylethanolamide (P.E.A. Cure).

This special substance has an entirely new working mechanism, which supports the body’s own biological mechanism. This mechanism is similar to the working of opioids, but without the negative side effects. It is remarkable how this substance, contrary to all other known painkillers, penetrates the cell nucleus and influences the nucleus receptor. Whereas the currently known painkillers always block a function of the body, palmitoylethanolamide promotes the body’s own natural ability to recover.

In a study the substance showed to work better than the best painkillers in this area. Not only did the pain decrease significantly, function and quality of life also improved measurably. The patients also tolerated the substance well, without any problematic side effects.

It also became clear during this congress that palmitoylethanolamide can have a pain relieving effect on a number of other chronic pain complaints, like severe diabetes pains, MS, chronic inflammation in the pelvis, and carpal tunnel syndrome.


Pain causes a waterfall of misery in the body

Pain causes a waterfall of misery in the body. All sorts of substances are created that flare up pain and maintain inflammation. Most scientists keep looking for inhibitors for those substances. This works temporarily, but the effect is neutralized immediately by other substances.

It’s quite naïve to think you can win the war by inhibiting one or several substances, just like you can’t win a war by simply removing the weapons during a battle. Everyone will just continue to fight with their fists!

However, our body has developed build-in mechanisms to create peace. This happens with bodily substances that bring activated belligerent cells back to a peaceful state. In biological language this is called changing the activated phenol type of the cells to the constructive phenotype.

Two types of cells form the foundation of all the misery, pain and inflammation, the mast cells and glia cells. Exactly these two cells can be brought back from an activated state to a peaceful state with the bodily substance palmitoylethanolamide.

You win a war by bringing in a peacekeeper. The bodily molecule palmitoylethanolamide is this peacekeeper and the substance is pretty convincing. The substance is created by the body in case of pain and inflammation, however not in high enough levels. Because this substance brings belligerent cells back on the path to peace. An additional special advantage is that these cells will then also join the renewal process.

Professors Cruccu and Costa were able to prove that palmitoylethanolamide decreased pain and inflammation in both humans and animals. They were also able to show that the constructive phase was reinitiated after treatment with PEA. There were even signs of nerve recovery after nerve damage in both humans and animals.

With palmitoylethanolamide (P.E.A. Cure) we have the first causal pain treatment in our hands!

During this congress, for the first time in the world, a number of professors all presented prove that lead to the insight that this bodily substance is an extraordinary break through in the treatment of chronic pain, because of its unique working mechanism. The substance is also tolerated well, with virtually no side effects.

More and more attention is being given to the big importance of the body-based anti-inflammatory palmitoylethanolamide, a substance that has been used to treat many thousands of people in the world who suffer from chronic pains and inflammations.


1. Palmitylethanolamide is a body-own anti-inflammatory
2. The body produces palmitoylethanolamide to obstruct or slow down chronic & acute pain
3. Chronic inflammations tend to grow worse when the body produces a lack of palmitoylethanolamide
4. The inflammation reduces or disappears when palmitoylethanolamide is added

It slowly becomes clear that this substance plays a significant role in our body and prevents the inflammation and pain to grow worse. Or, as many researchers recently had formulated it: impairment of endocannabinoid and palmitoylethanolamide levels might contribute to the development of chronic inflammatory processes such as granuloma.


Body-based molecule against inflammation & pain

In their article ‘Levels of endocannabinoids and palmitoylethanolamide and their pharmacological manipulation in chronic granulomatous inflammation in rats’, the Filippi’s and their colleagues describe the body-based molecules which regulate inflammations. Those are the body-based substances such as anandamide (who function through the cannabis receptor) and palmitoylethanolamide, which function through other receptors:

The endocannabinoids anandamide and 2-arachidonoylglycerol, and the anandamide-congener, palmitoylethanolamide, are all substrates for the enzyme fatty acid amide hydrolase, and are endowed with anti-inflammatory actions exerted via cannabinoid receptors or, in the case of palmitoylethanolamide, also via other targets.

The demolition and biosynthesis of these body-based regulating molecules is comparable:

“Palmitoylethanolamide and anandamide also share a similar biosynthetic pathway, both compounds being produced from the corresponding N-acyl-phosphatidylethanolamines (NAPE) through, among others, the catalytic action of NAPE-specific phospholipase D (NAPE-PLD)”

The authors stress the exquisite differentiated function of palmitoylethanolamide through different body processes:

“PEA was suggested to exert anti-inflammatory and analgesic actions via several molecular mechanisms, including direct activation of peroxisome proliferator-activated receptor-α (PPAR-α), or indirect activation of cannabinoid receptors and transient receptor potential vanilloid type-1 (TRPV1) channels following potentiation of AEA activity at these targets. More recently, PEA2 was suggested to exert potent anti-hyperalgesic actions in an animal model of neuropathic pain via possible indirect activation not only of CB1 and TRPV1 receptors but also of PPAR-γ, thus underlying the complexity of the molecular mechanism of action of this compound”.


Chronic pain, acute pain and inflammations in the body arise due lack of palmitoylethanolamide

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 and pain.

For example, during β-amyloid-induced neuroinflammation the deregulation of cannabinoid receptors and its endogenous ligands accompanies the development and progression of disease.

This is also shown from another research, the reason why Alzheimer-researchers are currently fairly looking into palmitoylethanolamide.

Furthermore it seems very clear that healthy bodies produce more palmitoylethanolamide to reduce inflammations and pains. Among other things, this has been discovered in case of endometriosis, to which strong stomach aches can occur. By women who suffer less from it, researchers found an activation of the receptors in the substances from the same family as palmitoylethanolamide. It appeared to be a so called opregulation:

a specific up-regulation of CB2 receptors expression in biopsies of women with endometritis occurs to self-limit the inflammatory process.

The body tries to heal itself from inflammations by the production of palmitoylethanolamide
This indicates that the body tries to heal itself by causing more anti-inflammatory effects. Meanwhile we also understand that this applies to fibromyalgia too.

Palmitoylethanolamide can also slow down the very dismal chronic inflammations. They are called granulomatous inflammations and look a bit like a cancer-inflammation, by eliminating an inflammation receptor in the cell core and to calm down the inflammation cells.

In the research that has been done to an animal model with a severe granulomatous inflammation, it appeared that the amount of palmitoylethanolamide and other body-based anti-inflammatories have been reduced indeed.

In line with this previously reported evidence, in this study we found a significant decrease of AEA, 2-AG, and PEA amounts in λ-carrageenin-induced granulomatous tissue.

That was partly because the other body-based anti-inflammatory substances were broken down faster at this inflammation:

The breakdown of AEA, 2-AG and PEA involves, among others, the enzyme FAAH, which we found here to be up-regulated in granuloma.

And no more has been created, through which the necessary concentrations of palmitoylethanolamide to master the inflammation, decreased too much.

The researchers in this research model of chronic inflammations, have given extra palmitoylethanolamide, since that was the most suitable and strongest inflammatory:

PEA is a potent anti-inflammatory compound, and appears to be more suitable for direct administration than AEA and 2-AG because it is not subject to enzymatic oxidation (since does not contain a polyunsaturated fatty acid subject to oxidation, as is the case of endocannabinoids). PEA is also more slowly hydrolysed by FAAH than AEA and 2-AG.

That indeed seemed like the lead to the cure of the inflammatory process to multiple terrains: palmitoylethanolamide slowed down the inflammation, reduced inflammatory molecules and reduces the pathological circulation of the inflammation.

The compound dose-dependently inhibited both granuloma inflammation, evaluated as wet weight and TNF-α protein expression, and new vessel formation, evaluated as hemoglobin content and CD31 protein expression, thus confirming its potential therapeutic use in chronic inflammatory diseases, and supporting our hypothesis that decreased PEA levels in λ-carrageenin-induced granuloma formation might have contributed to the development of this pathological condition.

The researchers closed off with stressing the fact that palmitoylethanolamide is a new, innovative treatment method for chronic inflammations. A method with many benefits:

Our results suggest that pharmacologically induced recovery from λ-carrageenin-induced decrease of endogenous endocannabinoid and PEA levels, might lead to novel therapeutic strategies for the treatment of chronic inflammatory diseases, whilst potentially avoiding the psychotropic and potentially immune-suppressive side-effects of direct CB1 and CB2 receptor agonists, respectively.

Palmitoylethanolamide has been named in more articles as a breakthrough in the treatment of chronic pains and inflammations.



[1] Endocannabinoid Research Group, De Filippis D, D’Amico A, Cipriano M, Petrosino S, Orlando P, Di Marzo V, Iuvone T. (2010 Apr). Levels of endocannabinoids and palmitoylethanolamide and their pharmacological manipulation in chronic granulomatous inflammation in rats. (Pharmalogical Research). Epub 2009 Nov 17.

[2] D’Agostino G, Russo R, Avagliano C, Cristiano C, Meli R, Calignano A. (2012 Jun). Palmitoylethanolamide Protects Against the Amyloid-β25-35-Induced Learning and Memory Impairment in Mice, an Experimental Model of Alzheimer Disease. Neuropsychopharmacology. Epub 2012 Mar 14.

[3] Benito C, TolÃn RM, Castillo AI, Ruiz-ValdepeÃas L, Martínez-Orgado JA, FernÃndez-SÃnchez FJ, VÃzquez C, Cravatt BF, Romero J. (2012 Jun). Î²-Amyloid exacerbates inflammation in astrocytes lacking fatty acid amide hydrolase through a mechanism involving PPAR-α, PPAR-γ and TRPV1, but not CB(1) or CB(2) receptors. British Journal of Pharmacology.

[4] Scuderi C, Esposito G, Blasio A, Valenza M, Arietti P, Steardo L Jr, Carnuccio R, De Filippis D, Petrosino S, Iuvone T, Di Marzo V, Steardo L. (2011 Jan 21). Palmitoylethanolamide counteracts reactive astrogliosis induced by beta-amyloid peptide. Journal of Cellular and Molecular Medicine.

[5] Ghafouri N, Ghafouri B, Larsson B, Turkina MV, Karlsson L, Fowler CJ, Gerdle B. (2011). High levels of N-palmitoylethanolamide and N-stearoylethanolamide in microdialysate samples from myalgic trapezius muscle in women. PLoS One. Epub 2011 Nov 18.

[6] De Filippis D, D’Amico A, Iuvone T. (2008) Cannabinomimetic control of mast cell mediator release: new perspective in chronic inflammation. Journal of Neuroendocrinology.

[7] Esposito E, Cuzzocrea S. (2012 Jun 13). Palmitoylethanolamide is a new possible pharmacological treatment for the inflammation associated with trauma. Mini Reviews in Medicinal Chemistry. 

[8] Marini I, Bartolucci ML, Bortolotti F, Gatto MR, Bonetti GA. (2012 Spring). Palmitoylethanolamide versus a nonsteroidal anti-inflammatory drug in the treatment of temporomandibular joint inflammatory pain. Journal of Orofacial Pain.

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