Palmitoylethanolamide (PEA) for chronic pain

It supposedly reduces chronic pain by acting on mast and glia cells and reducing neuroinflammation. It was listed as one of the first line treatments for neuropathic pain on an Italian website. Most studies seem to be of low quality. One study showed objective evidence of nerve healing. I wasn't able to muster the energy to properly assess the evidence base myself.
 
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Glia and microglia in particular elaborate pro-inflammatory molecules that play key roles in central nervous system (CNS) disorders from neuropathic pain and epilepsy to neurodegenerative diseases. Microglia respond also to pro-inflammatory signals released from other non-neuronal cells, mainly those of immune origin such as mast cells. The latter are found in most tissues, are CNS resident, and traverse the blood–spinal cord and blood–brain barriers when barrier compromise results from CNS pathology. Growing evidence of mast cell–glia communication opens new perspectives for the development of therapies targeting neuroinflammation by differentially modulating activation of non-neuronal cells that normally control neuronal sensitization – both peripherally and centrally. Mast cells and glia possess endogenous homeostatic mechanisms/molecules that can be up-regulated as a result of tissue damage or stimulation of inflammatory responses. Such molecules include the N-acylethanolamine family. One such member, N-palmitoylethanolamine is proposed to have a key role in maintenance of cellular homeostasis in the face of external stressors provoking, for example, inflammation. N-Palmitoylethanolamine has proven efficacious in mast-cell-mediated experimental models of acute and neurogenic inflammation. This review will provide an overview of recent progress relating to the pathobiology of neuroinflammation, the role of microglia, neuroimmune interactions involving mast cells and the possibility that mast cell–microglia cross-talk contributes to the exacerbation of acute symptoms of chronic neurodegenerative disease and accelerates disease progression, as well as promoting pain transmission pathways. We will conclude by considering the therapeutic potential of treating systemic inflammation or blockade of signalling pathways from the periphery to the brain in such settings.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3930370/
 
I tried PEA again yesterday afternoon & got good relief from severe myalgia.

Nothing else was helping. No relief from Paracetamol, Hydrocortisol, Hemp Oil, Curcumin, Magnesium orotate. Cannot tolerate NSAIDs (get gastric ulceration).
Was considering going to a pain clinic.
 
This was mentioned in a talk by Jesper Mehlsen at the IIMEC 2024 conference. (Starts around 7:29)



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As you mentioned, there are not that many registered medications so we have to look at dietary supplements. And one of the ways that I started out with was when patient mentioned something, I would study it. If a patient, for example, says I can't live without PEA, which is what I'm going to show you, then I have to study and see what's the background literature on this and is it something I would think would work for my patients. And then I would start patients on that and then accumulate a lot of knowledge on that. I think we have about over 1000 patients in the clinic and for this, PEA, we have I think about 6-700 on it. If we look back at what had happened to these patients that would be a good way to look at it.

So with PEA again you know explain what is the biology or the what what is the chemistry, it's an endocannabinol. So we actually do produce cannabis in our bodies. We have two cannabis receptors. CB1 which is the funny one I mean that that's the one that you like to have on. And then there's a CB2 receptor which works on inflammation and that's where PEA has its effect. And PEA is primarily accumulated in the hypothalamus, so it has an effect on hormones and the autonomic nervous system.

And we have, I think, very good results from what we're doing. It has been shown to decrease release of pro-inflammatory cytokines. It stimulates the CB1 receptor, and this receptor is very abundant on microglia cells, and that's probably why it has a good effect on neuroinflammation. We looked into the possible side effects and in rats this is the usual daily dose in rats you can give them up to 1,000 milligram per kilogram, so this is far from where the side effects may arise so this is a safe compound to use.
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Palmitoylethanolamide (PEA) is generally considered safe and can be classified as a feed material. However, there is not enough information to know if it is safe to use for long periods of time.

It seems that this is something that can be sold without license or proof of efficacy because it is a 'food'.

The Mehlsen presentation indicates that there are no useful data on benefit which almost certainly means it does not work other than as a placebo. If it did someone would have done some trials and patented a dosing regimen.

In other words there isn't a dose, because it doesn't have any dose-response.
 
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