Palmitoylethanolamide (PEA) is an endogenous fatty acid amide, an analog of the endocannabinoid anandamide (AEA), that belongs to the family of N-acylethanolamines (NAE) [1]. NAEs are released from cells in response to noxious stimuli. As all NAEs, also the PEA has a local effect, and its tissue levels are closely regulated through the balance of production and degradation activity. Two intracellular amidases, expressed in the inflammatory cells, have been involved in lipid amide degradation: fatty-acid amide hydrolase (FAAH) and N-acylethanolamine hydrolyzing acid amidase (NAAA) [2].

The effects of the PEA are due to its interaction with several pathways: at first, it reduces, via the peroxisome proliferator-activated receptor alpha (PPARα), the recruitment and activation of mast cells at sites of nerve injury and the release of pro-inflammatory mediators from these cells [3, 4]; secondly, it inhibits the microglia activation and the recruitment of mast cells into spinal cord after peripheral nerve injury, as well as following spinal neuroinflammation or spinal cord injury [5, 6]. In the beginning, PEA was also supposed to be an agonist of the cannabinoid type II receptor (CB2) [7]; subsequently, in their research, Sugiura et al. have demonstrated that PEA has just a very low affinity for this receptor [8], clarifying why CB2 antagonists do not inhibit some of its anti-inflammatory effects [9]. Anyhow, PEA indirectly activates CB2 and the cannabinoid receptor type 1 (CB1) [10], down-modulating fatty acid amide hydrolase (FAAH), the enzyme responsible of the degradation of the anandamide (AEA), a CB1 agonist [11].

Several studies focused on the use of PEA in a multitude of chronic pain conditions. For example, it can have a beneficial effect like adjuvant for the treatment of the low back pain [12] or it was used alone for chronic pain management in critically ill older patients, where the use of traditional analgesics can lead to high risk of adverse effect [13]. Encouraging results have been shown in the treatment of non-surgical radiculopathies with an ultra-micronized formulation of PEA [14] and the combination therapy with alpha-lipoic acid to reduce chronic prostatitis/chronic pelvic pain syndrome [15].