Robert A. Bonakdar, MD FAAFP FACN
Director of Pain Management
Scripps Center for Integrative Medicine
Scripps Center for Integrative Medicine
San Diego, California
Megan Sweeney, MA, MPH
Doctoral Student
Loma Linda University, School of Behavioral Health
Redondo Beach, California
Palmitoylethanolamide (PEA) is an endogenous fatty acid first isolated in the 1950’s as an anti-viral agent. Further research noted analgesic and anti-inflammatory properties which lead to its designation in Europe as a Food for Special Medical Purposes and more recently as a dietary supplement with increased availability outside Europe. PEA’s mechanism of action appears related to several areas:
PEA binds to and activates PPAR-α, a nuclear receptor that regulates genes involved in inflammation.
Effect: Downregulates pro-inflammatory cytokines (e.g., TNF-α, IL-1β), and reduces COX-2 expression and nitric oxide production.
PEA doesn’t bind directly to CB1 or CB2 receptors but enhances endocannabinoid tone by inhibiting degradation of anandamide (AEA).
Effect: Amplifies AEA’s analgesic and anti-inflammatory effects via CB1/CB2.
PEA inhibits mast cell degranulation, reducing release of histamine, TNF-α, and prostaglandins.
Effect: Decreases neuroinflammation and hypersensitivity.
PEA indirectly desensitizes TRPV1 receptors, which are involved in pain perception and neurogenic inflammation.
Effect: Reduced pain signaling and peripheral sensitization.
PEA reduces activation of microglia and astrocytes in the CNS.
Effect: Diminishes chronic neuroinflammation, often involved in neuropathic and amplified pain conditions.
Purpose/Objectives:
The purpose of this review is to summarize the clinical evidence regarding the use of palmitoylethanolamide (PEA) in managing chronic pain conditions including migraine, neuropathic pain, fibromyalgia, and musculoskeletal pain.
We aimed to assess the effectiveness of various PEA formulations and dosing strategies as reported in human clinical trials and prospective studies. The review summarizes key outcomes related to pain reduction and quality of life, providing a summary of key pain states. By doing so, this review seeks to offer clinicians who may not be familiar with PEA an overview of its potential in often refractory pain states as well as where further research is warranted.
Methods: A narrative review methodology was employed. We searched PubMed, Scopus, and Google Scholar for articles published between 2010 and May 2025 using combinations of keywords including “palmitoylethanolamide,” “PEA,” “mechanism” “safety,” “chronic pain,” “migraine,” “neuropathic pain,” “fibromyalgia,” “musculoskeletal pain,” and "joint pain." Only English-language, human clinical studies (randomized trials, prospective cohort studies, and open-label trials) as well as systematic review of the above were included. No age exclusions were applied.
Studies were eligible if they evaluated PEA as a standalone or adjunctive treatment for pain-related outcomes and reported either pain intensity scores, functional improvement, or quality of life metrics. Case reports and animal studies were excluded. Data extracted included study author, year, PEA dosage and formulation (standard, micronized, ultramicronized), type of pain, and main outcomes.
Results:
The efficacy of palmitoylethanolamide across pain types is summarized below:
Migraine: Briskey et al. (2024) and Piccolo et al (2025) reported that standard and ultramicronized PEA (600 mg/day and 1,200 mg in combination with melatonin (0.2 mg), respectively) in migraine was associated with significant improvements in headache frequency, severity and daily functioning. Papetti et al. (2020) found that umPEA at 600 mg/day in pediatric migraine (mean age of 10.3 ± 2.7 years) has similar benefit in reducing frequency and intensity while also reducing medication consumption by 46%.
Neuropathy: Pickering et al (2022), Cocito et al. (2014 and 2024) found 600 mg BID of standard or 300 mg BID of micronized PEA demonstrated on improvement in burning pain, sleep and mood in diabetic and peripheral neuropathy. Davis et al (2024) found that PEA at 400-800mg/day was not effective in chemotherapy-induced peripheral neuropathy (CIPN) beyond placebo while Zaiss et al (2021) found that a combination PEA formula at 1150 mg/day was beneficial in CIPN.
Fibromyalgia: Schweiger et al (2019) found PEA at various doses was effective as an add-on therapy in fibromyalgia. found that 1,200 mg/day of ultramicronized PEA with 0.2 mg melatonin was associated with improvement in pain severity, sleep quality, and physical function. Sarzi-Puttini et al (2023) found that 600 mg of PEA BID with acetyl-L-carnitine was effective as an add-on to pregabalin and duloxetine.
Musculoskeletal Pain: Steele et al (2019), Scaturro et al (2020) and Gatti et al. (2012) found micronized PEA (300-1200 mg/day) in osteoarthritic, low back and musculoskeletal pain was associated with improved pain scores, stiffness, sleep and mobility scores.
Systematic Review: Schievano et al (2024) found that micronized PEA in chronic pain demonstrated a clinically significant pain intensity reduction of 35.1% within the first month, followed by a further 35.4% during the second month, (p < 0.01) of therapy.
Safety: Across all studies, PEA was well tolerated without serious adverse events noted and mild gastrointestinal side effects. Emerging pediatric literature indicates similar safety and efficacy to adult populations. PEA currently does not have adequate safety data for use in pregnancy or lactation.
Conclusions/Implications for future research and/or clinical care:
Palmitoylethanolamide (PEA) demonstrated safety and efficacy in a variety of chronic pain conditions including migraine, neuropathy, fibromyalgia, and musculoskeletal pain. Findings were less consistent with chemotherapy induced peripheral neuropathy (CIPN) which may be related to formulation. These finding should encourage clinicians to considered PEA as a standalone or adjunctive therapy, especially when other therapies have not provided adequate pain control.
PEA’s findings in divergent pain conditions appears related to its unique mechanisms including modulation at the PPAR-α, TRPV1, cannabinoid, mast and glial cell level. These actions appear to contribute to PEA’s anti-inflammatory and anti-nociceptive benefit in clinical trials along with associated functional and quality of life improvements. Additional conclusions include: