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#65 Is PEA a Pain Option?

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 A large number of white capsules on a grey table depicting PEA
PEA (Palmitoylethanolamide) for Pain Relief
Image Source: The-Lore.com on Unsplash

PEA (Palmitoylethanolamide) for Neuropathic Pain

When you are searching for pain relief, it can seem as though Dr. Google is constantly revealing wonder drugs. But what is the evidence? And is the treatment worth the cost in time, money, and potential side effects? To provide some clarity, here is a brief introduction to one such drug – the “natural analgesic” PEA (palmitoylethanolamide) (1).

Eggs, Fever, and PEA

PEA is “natural” in that it is a compound produced in the body and in foods such as soybeans, peanuts, and eggs (1). In fact, eggs provided the basis for some of the first evidence of the effects of PEA. In the 1930’s, researchers in New York found that feeding dried yolks to undernourished children produced antipyretic (fever reducing) effects (2).

These children had rheumatic fever, an inflammatory response to strep infections. This indicated that a component in the egg yolks had anti-inflammatory properties. It was later identified as PEA (3). Now, almost a hundred years later, scientists are still evaluating the anti-inflammatory potential of PEA. It is even in clinical trials to determine its effects on COVID-19 (4). Clearly, PEA has anti-inflammatory properties, but how does this relate to pain?

PEA and Inflammation

Although PEA was first identified as an antipyretic agent, its reputation was later built on work initiated by neuroscientist Rita Levi-Montalcini. In addition to her Nobel Prize winning research involving nerve growth factor, she examined how the overactivation and accumulation of mast cells (MC) (a type of immune cell) contribute to tissue damage and inflammation. Interestingly, her research team discovered that PEA modulates mast cell activation (5).

In response to damage (or stress), PEA can be produced and released locally in the body at the injury site. There it helps restore homeostasis as a “self-healing molecule” (1). PEA is part of a natural defense mechanism against inflammation and pain.

Graphic displaying the PEA keeping the mast cells in check
Mast Cells (MC) accumulate at an injury site. PEA keeps that accumulation in check,
defending against pain and inflammation.
Image Source: CNA/L. Sullivan

The Case of the Pain-Free Scot

This PEA defense mechanism is evident in the case of the “pain free Scot” (6). In 2019, a 66-year-old Scottish woman had a typically painful surgery to remove the small bone at the base of her thumb. What was usual was that she didn’t need any pain relievers afterward. She also had a history of painless injuries (cuts, burns, and fractures) throughout her life. Researchers discovered that she had a mutation in a pseudogene for an enzyme that normally degrades amides like PEA. Since PEA wasn’t being degraded, she had elevated PEA levels in her body (6). It’s possible that this “natural analgesic” was blunting her pain. This case emphasizes the role of amides, such as PEA, in pain relief.

PEA and Neuropathic Pain

The above research suggests that PEA has both anti-inflammatory and analgesic actions. Since inflammation plays a key role in the development of chronic pain, one could predict that PEA would be an effective treatment for neuropathic pain. Current evidence supports this claim. Clinical studies show that PEA reduces various types of pain, including nerve compression pain (sciatica and carpal tunnel syndrome), arthritis pain, and peripheral neuropathy pain (diabetic and chemotherapy-induced) (7,8,9). Additionally, case reports showed that PEA reduced neuropathic pain in patients who were previously treatment-resistant to analgesics (10).

Side Effects

Numerous clinical studies report that PEA is effective in treating pain without serious adverse effects (reviewed in 9). Although minor gastrointestinal issues were reported rarely in neuropathic patients (10). Overall, PEA has shown high tolerability, safety, and efficacy. Some of these effects could be attributed to the cannabimimetic properties of PEA. This means PEA “mimics” the effects of cannabinoids but doesn’t bind cannabinoid receptors. So, PEA may have the advantage of analgesia with fewer side effects (e.g., confusion, sedation, etc.) compared to cannabis-based medicines (11). If PEA can reduce pain without serious adverse effects, it would be a major therapeutic breakthrough for neuropathic pain.

PEA Formulations

With regard to the treatment regimens in these clinical studies, patients generally received oral tablets of PEA at doses ranging from 300 mg to 1200 once or twice per day for 14-120 days. Importantly, these were micronized and ultramicronized (m- and um-) PEA formulations. The process of micronization creates smaller particle sizes, allowing the drug to dissolve more easily for better absorption. Currently, there are few studies with head-to-head comparisons of PEA with current treatments or different PEA formulations. This is important because most of the PEA supplements on the market are not m- or um-PEA and haven’t been clinically approved or tested.

Is PEA a Good Option?

You know what I am going to say – talk to your doctor. While this research seems promising, there are caveats. Other studies have shown that PEA had no significant effect over placebo for chronic pain (12, 13). Also, it is important to read the “Conflicts of Interest” section of some of these reports.

For example, a recent paper ends with this unambiguous statement: “These results suggest the use of PEA in micronized and ultramicronized forms as an innovative therapeutic tool for the treatment of all conditions characterized by the presence of neuroinflammatory processes and chronic painful states,” but it also states that one of the authors is a co-inventor on a patent for Epitech Group Srl (14). And PEA, under the brand name Normast (Epitech Srl), has been on the market in Italy and Spain since 2008. In fact, Epitech is noted in a number of these studies.

While this research seems promising, there are caveats.

– L. Sullivan

Does this negate the findings? No, but it should be mentioned. And you should be cautious of possible drug interactions, especially when considering unregulated supplements. Again, discuss the options with your doctor. Because even though one clinician states, “Of course, there will always be non-responders to this analgesic endogenous compound, but its safety profile is so benign, that in light of the clinical data one could suggest to always start treatment of pain in chronic pain patients with PEA, given one uses a sufficient dose and the appropriate formulation” (15), this may not be true in all cases (16).

Related CNA Resources

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Food for thought...


  1. Hesselink J. M. (2013). Evolution in pharmacologic thinking around the natural analgesic palmitoylethanolamide: from nonspecific resistance to PPAR-α agonist and effective nutraceutical. Journal of pain research, 6, 625–634. https://doi.org/10.2147/JPR.S48653
  2. Coburn, A. F., & Moore, L. V. (1943). Nutrition as a conditioning factor in the rheumatic state. American Journal of Diseases of Children, 65(5), 744-756. https://jamanetwork.com/journals/jamapediatrics/article-abstract/1179693
  3. Kuehl Jr, F. A., Jacob, T. A., Ganley, O. H., Ormond, R. E., & Meisinger, M. A. P. (1957). The identification of N-(2-hydroxyethyl)-palmitamide as a naturally occurring anti-inflammatory agent. Journal of the American Chemical Society, 79(20), 5577-5578. https://pubs.acs.org/doi/pdf/10.1021/ja01577a066
  4. Clincaltrials.gov. Micronized and Ultramicronized Palmitoylethanolamide in COVID-19 Patients. (ClinicalTrials.gov Identifier: NCT04568876) https://clinicaltrials.gov/ct2/show/NCT04568876
  5. Aloe, L., Leon, A., & Levi-Montalcini, R. (1993). A proposed autacoid mechanism controlling mastocyte behaviour. Agents and actions, 39 Spec No, C145–C147. https://doi.org/10.1007/BF01972748
  6. Habib, A. M., Okorokov, A. L., Hill, M. N., Bras, J. T., Lee, M. C., Li, S., Gossage, S. J., van Drimmelen, M., Morena, M., Houlden, H., Ramirez, J. D., Bennett, D., Srivastava, D., & Cox, J. J. (2019). Microdeletion in a FAAH pseudogene identified in a patient with high anandamide concentrations and pain insensitivity. British journal of anaesthesia, 123(2), e249–e253. https://doi.org/10.1016/j.bja.2019.02.019
  7. Cruccu, G., Stefano, G. D., Marchettini, P., & Truini, A. (2019). Micronized Palmitoylethanolamide: A Post Hoc Analysis of a Controlled Study in Patients with Low Back Pain – Sciatica. CNS & neurological disorders drug targets, 18(6), 491–495. https://doi.org/10.2174/1871527318666190703110036
  8. Keppel Hesselink, J. M., & Kopsky, D. J. (2015). Palmitoylethanolamide, a neutraceutical, in nerve compression syndromes: efficacy and safety in sciatic pain and carpal tunnel syndrome. Journal of pain research, 8, 729–734. https://doi.org/10.2147/JPR.S93106
  9. D’Amico, R., Impellizzeri, D., Cuzzocrea, S., & Di Paola, R. (2020). ALIAmides Update: Palmitoylethanolamide and Its Formulations on Management of Peripheral Neuropathic Pain. International journal of molecular sciences, 21(15), 5330. https://doi.org/10.3390/ijms21155330
  10. Hesselink, J. M., & Hekker, T. A. (2012). Therapeutic utility of palmitoylethanolamide in the treatment of neuropathic pain associated with various pathological conditions: a case series. Journal of pain research, 5, 437–442. https://doi.org/10.2147/JPR.S32143
  11. Vučković, S., Srebro, D., Vujović, K. S., Vučetić, Č., & Prostran, M. (2018). Cannabinoids and Pain: New Insights From Old Molecules. Frontiers in pharmacology, 9, 1259. https://doi.org/10.3389/fphar.2018.01259
  12. Murina, F., Graziottin, A., Felice, R., Radici, G., & Tognocchi, C. (2013). Vestibulodynia: synergy between palmitoylethanolamide + transpolydatin and transcutaneous electrical nerve stimulation. Journal of lower genital tract disease, 17(2), 111–116. https://doi.org/10.1097/LGT.0b013e3182652316
  13. Andresen, S. R., Bing, J., Hansen, R. M., Biering-Sørensen, F., Johannesen, I. L., Hagen, E. M., Rice, A., Nielsen, J. F., Bach, F. W., & Finnerup, N. B. (2016). Ultramicronized palmitoylethanolamide in spinal cord injury neuropathic pain: a randomized, double-blind, placebo-controlled trial. Pain, 157(9), 2097–2103. https://doi.org/10.1097/j.pain.0000000000000623
  14. Cordaro, M., Cuzzocrea, S., & Crupi, R. (2020). An Update of Palmitoylethanolamide and Luteolin Effects in Preclinical and Clinical Studies of Neuroinflammatory Events. Antioxidants (Basel, Switzerland), 9(3), 216. https://doi.org/10.3390/antiox9030216
  15. Keppel Hesselink, J. M. (2018). Chronic Pain and the Use of Palmitoylethanolamide. Austin J Neurol Disord Epilepsy, 5(2), 1042. https://austinpublishinggroup.com/neurological-disorders-epilepsy/download.php?file=fulltext/ajnde-v5-id1042.pdf
  16. https://www.michaelnegraeff.com/blog/2015/7/11/three-things-i-learned-during-a-personal-trial-of-pea
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