Overview of Palmitoylethanolamide (PEA) for Chronic Pain

Palmitoylethanolamide (PEA) is a natural compound found in small amounts in egg, milk, peanut, and soy [1]. PEA is also naturally-produced by the human body [1].

“PEA was identified in the 1950s as a therapeutic principle with potent anti-inflammatory properties. Since 1975, its analgesic properties have been noted and explored in a variety of chronic pain states. Since 2008, PEA has been available as a nutraceutical under the brand names Normast® and PeaPure®. A literature search on PEA meanwhile has yielded over 350 papers, all referenced in PubMed, describing the physiologic properties of this endogenous modulator and its pharmacologic and therapeutic profile.” [2]

Many studies have shown beneficial effects on health for patients taking PEA supplements. In addition to chronic pain, the effect of PEA on a number of other ailments has been studied.

“Palmitoylethanolamide (PEA) is naturally occurring and has been available as a nonprescription medical food supplement in Europe since 2008. PEA has been tested in thousands of human subjects without any noted significant side effects.” [4]

To date, the most successful treatment studies have focused on reducing severe chronic pain.

2012 article in Pain Medicine

A 2012 study published in the journal Pain Medicine concluded: “In this study, PEA was effective and safe in the management of chronic pain in different pathological conditions.” [3] The study was “conducted on 610 patients who were unable to effectively control chronic pain with standard therapies.” [3] Of those 610 patients, 515 complained of poor pain control with standard medications, and another 95 had stopped using standard pain medications due to side effects. They all had a pain score — on the Numeric Rating Scale (NRS) — of greater than or equal to 4 [scale of 0 to 10]. These patients had a range of different diseases or injuries causing their pain.

“PEA (600 mg) was administered twice daily for 3 weeks followed by single daily dosing for 4 weeks.” [3] A typical dosage of PEA is 1200 mg/day, taken as 400 mg three times a day or 600 mg twice a day. Unlike prescription pain relievers, reduction of pain using PEA takes weeks to establish. However, many strong painkillers are less effective, the longer they are taken, whereas PEA increases in effectiveness over the course of time. Maximum effectiveness for PEA is typically reached after 3 to 7 weeks of daily use. Most of the patients in this study continued to take their prescribed pain medications, even though those medications did not reduce pain sufficiently. Some of the patients only took PEA, having given up on standard pain medications. About 7.5% of the 610 patients who began this study, dropped out and stopped using PEA. [3, table 2].

How effective was PEA in this study? “PEA treatment markedly decreased the mean score pain intensity evaluated in all patients who completed the study.” [3] The average pain score at the start of the study was 6.5 (plus or minus 1.4), implying that about half the patients had moderate pain (NRS 4-6) and half had severe pain (NRS 7-10). At the end of the 7-week study, the average pain score was reduced to 2.5 (plus or minus 1.3). An NRS of 2.5 is mild pain, and a value of 2.5 plus 1.3 (3.8) is just below the moderate pain level (4-6). Results were highly statistically significant (P = 0.0001).

2012 article in Journal of Pain Research

A 2012 “case series” in the Journal of Pain Research examined the use of PEA in the treatment of pain caused by neurological disorders. [5] Seven cases were examined in this study.

Patient 1 was “a 61-year-old Caucasian male suffering from metastatic prostate cancer…. His pain score was 7/10 on the numeric rating scale (NRS), with periods of peak pain of 9.” After treatment with PEA at 1200 mg/day for three weeks, his average pain score was reduced to 1-2 (NRS). [5]

Patient 2 was “a 62-year-old Caucasian male diagnosed with failed back surgery syndrome and a history of several surgical interventions for painful hernia” who scored 7 on the NRS pain scale. After treatment with PEA at 1200 mg/day for three weeks, his average pain score was reduced to 4 (NRS). [5]

Patient 3 was “a 54-year-old Caucasian man who had suffered for the past 7 years from type II diabetes … hypertension, hypercholesterolemia, and stomach complaints…. Treatment with PEA 600-mg tablets twice daily and R-alpha-lipoic acid … was started, and pain dropped to NRS score 3.” [5]

Patients 4, 5, and 6 also had successful reduction in pain using PEA. [5] Patient 7 did not respond to the use of PEA to treat her chronic pain. PEA does not work in all cases of chronic pain, but it has been effective across a wide range of different medical disorders that cause severe chronic pain.

2011 article in CNS & Neurological Disorders

A 2011 study in the journal CNS & Neurological Disorders involved 20 patients afflicted with a type of cancer called multiple myeloma. Their chemotherapy treatments caused severe neurological pain. Each patient was treated with 600 mg of PEA per day. After two months on the treatment, “pain and all neurophysiological measures … significantly improved (P < 0.05).” [6] Note that the dosage in this study is half of the more common dosage of 1200 mg/day.

2016 article in Pain Physician

A 2016 meta-study in the journal Pain Physician pooled the data from 12 past studies, including double-blind, controlled, and open-label clinical trials. Results showed a statistically significant reduction in pain scores of approximate 1 point every 2 weeks, with 81% of patients achieving a final pain score of less than or equal to 3 (NRS). [7] The authors of the meta-study stated:

“PEA effects were independent of patient age or gender, and not related to the type of chronic pain…. Noteworthy, serious adverse events related to PEA were not registered and/or reported in any of the studies…. These results confirm that PEA might represent an exciting, new therapeutic strategy to manage chronic and neuropathic pain associated with neuroinflammation.” [7]

Most of these pooled studies used a dosage of 1200 mg/day; two studies used a dosage of 600 mg/day. Most of the studies had dozens of patients in the trials; two studies had over 600 patients each. Pain reduction was found to be progressive [7, fig. 5], with maximum pain reduction achieved by the two month mark. PEA was effective in reducing pain for degenerative diseases, neurological diseases, and some other ailments/injuries. Pain reduction, on average, was reduced from moderate or severe to mild. But PEA does NOT generally offer complete relief from chronic severe pain, only a substantial reduction in pain.

2010 study in Dolor [Pain]

This study was published in Spanish medical journal Dolor [meaning “Pain”]. The study comprised 636 patients, men and women, who had chronic severe neurologic pain from sciatica (compressive type). The study was double-blind, controlled, and randomized. One group of patients received a placebo, another group received 300 mg/day PEA (Normast brand), a third group received 600 mg/day PEA (Normast brand). The placebo group continued to receive standard treatment for this disorder. [8]

The study authors found that “both pain reduction and quality of life are significantly different among the three treatment groups”, with the 300 mg/day dosage significantly better than placebo, and the 600 mg/day dosage significantly better than both of the other groups. Pain relief with PEA is dose-dependent, with more typical doses in studies at 1200 mg/day, rather than the 300 or 600 mg dosage of this study. [8]

Safety and Dosage

Palmitoylethanolamide is approved in Italy, Spain, and Germany as a “special food for medical purposes”. This approval has the effect of permitting the sale, retail purchase, and use of PEA in all EU nations.

“Toxicological data, together with the safety/tolerability profile of micronized and ultramicronized PEA led to authorization by the Italian Ministry of Health for products based on PEA as ‘foods for special medical purposes’ in compliance with European directive 199/21/EC. This classification allows for free circulation of PEA in EU member countries and facilitates its acceptance by Ethics Committees for studies in man. PEA is now available as a ‘special food for medical purposes’ in other European countries (e.g., Spain and Germany), as well.” [9]

The above-cited studies found no significant or severe adverse side effects to the use of PEA at up to 1200 mg/day. In one particular review article, the authors asserted that a dosage as high as 2400 mg/day is safe:

“Although the dose in the studies described above was 600 mg PEA/day, we recommend the double dose (1200 mg/day) based on practice and due to the fact that various clinical trials dosed at a higher dose ranges, and for PEA there are no dose limiting side effects up to 2400 mg/day. Even doses as high as 2400 mg/day have been used in our clinic in hundreds of patients and are free of such side effects.” [10]

However, I could find no other studies or articles recommending a dosage as high as 2400 mg/day. So I suggest that the use of PEA be limited to the usual range of clinically-effective doses: 300 to 1200 mg per day.


[1] Hesselink, et al., “Palmitoylethanolamide: A Natural Body-Own Anti-Inflammatory Agent, Effective and Safe against Influenza and Common Cold”, International Journal of Inflammation. Volume 2013 (2013), Article ID 151028. PDF file

[2] Jan M Keppel Hesselink, “Evolution in pharmacologic thinking around the natural analgesic palmitoylethanolamide: PPAR-alpha agonist and effective nutraceutical”, Journal of Pain Research. 2013:6 625-634. PDF file

[3] Gatti, et al., “Palmitoylethanolamide in the Treatment of Chronic Pain Caused by Different Etiopathogenesis”, Pain Medicine. Volume 13, Issue 9, pages 1121–1130, September 2012. PDF file

[4] Antonucci, et al., “Beneficial Effects of Palmitoylethanolamide on Expressive Language, Cognition, and Behaviors in Autism: A Report of Two Cases”, Case Reports in Psychiatry. Volume 2015 (2015), Article ID 325061, 6 pages. Web page

[5] Hesselink and Hekker, “Therapeutic utility of palmitoylethanolamide in the treatment of neuropathic pain associated with various pathological conditions: a case series”, Journal of Pain Research. 2012:5 437-442. PDF file

[6] Truini, et al., “Palmitoylethanolamide Restores Myelinated-Fibre Function in Patients with Chemotherapy-Induced Painful Neuropathy”, CNS & Neurological Disorders. Volume 10, Number 8, December 2011, pp. 916-920. Web page

[7] Paladini, et al., “Palmitoylethanolamide, a Special Food for Medical Purposes, in the Treatment of Chronic Pain: A Pooled Data Meta-analysis”, Pain Physician. 2016; 19:11-24. Web page

[8] Guida, et al., “La Palmitoiletanolamide (Normast®) en el dolor neuropático crónico por lumbociatalgia de tipo compresivo: Estudio clinic multícéntrico”, Dolor. 2010; 25:35-42.
[“Palmitoylethanolamide (Normast) in chronic neuropathic pain from the compressive type of lumbosciatica: multicenter clinical study”] Abstract online (Spanish)
Google translate used on the study abstract, here.

[9] Paladini, et al., “Chronic Pain in the Elderly: The Case for New Therapeutic Strategies”, Pain Physician. 2015; 18:E863-E876. Web page

[9] Hesselink, et al., “Palmitoylethanolamide, a Natural Retinoprotectant: Its Putative Relevance for the Treatment of Glaucoma and Diabetic Retinopathy”, Journal of Ophthalmology. Volume 2015, Article ID 430596, 9 pages. PDF file

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