Palmitoylethanolamide in the Treatment of Pain and Its Clinical Application Prospects

Abstract

Palmitoylethanolamide (PEA) has attracted increasing attention from researchers as an endogenous lipid mediator. It exhibits a unique mechanism of action in alleviating pain, controlling inflammation, and providing neuroprotection. It primarily regulates downstream signaling pathways by activating peroxisome proliferator-activated receptor alpha (PPAR-α) to inhibit the activity of nuclear factor kappa B (NF-κB), thereby reducing the production of pro-inflammatory cytokines. Additionally, PEA interacts synergistically with the endogenous cannabinoid system to modulate neurotransmission by enhancing the function of endogenous cannabinoids. The anti-inflammatory effects of PEA are also reflected in the regulation of glial cells and mast cells, effectively reducing local and central inflammation, thus protecting neuronal cells and promoting their regeneration. Clinical studies have shown that the application of PEA in various types of pain demonstrates good safety and tolerability, particularly suited for use in combination with traditional analgesics to enhance efficacy, reduce dependence, and minimize side effects. Despite existing research proving the effectiveness of PEA, challenges remain in its clinical promotion, including dosage form diversity, overall insufficient evidence, and patient individual differences. Therefore, future efforts should focus on strengthening multi-center large sample randomized controlled trials, coupled with biomarker investigations for personalized treatment research, to facilitate the widespread application of PEA in clinical pain management.

Keywords: clinical applications; inflammation; neuroprotection; pain management; palmitoylethanolamide.

Graphical abstract

Figure 1

The relevant mechanisms of pain and their interactions mediated by endocrine-immune-glial cells. (A) The diverse mechanism underlying chronic pain and neuropathic pain, including (a) peripheral sensitization, (b) central sensitization, (c) other contributing factors. (B) Neuroendocrine-immune-glial crosstalk in pain, including (a) inflammation regulation, (b) multi-target approach, (c) pain modulation.

Figure 2

Sources of PEA, synthesis methods, and its analgesic and anti-inflammatory effects. (A) The sources and synthesis methods of PEA. (B) The applications of PEA in pain and inflammation treatments.

Figure 3

The specific regulatory mechanism of PEA on pain relief. PEA can alleviate pain and inflammation, as well as minimizing adverse effects associated with conventional cannabinoids.

Figure 4

The formulation improvement and precision medical application of PEA. (A) The different drug formats of PEA. (B) The methods to delineate the expression variances of PEA receptors and downstream molecules including single cell sequencing technology and real-time molecular imaging technology. (C) The advantages of PEA in clinic.