The Effect of Palmitoylethanolamide on Pain Intensity, Central and Peripheral Sensitization, and Pain Modulation in Healthy Volunteers—A Randomized, Double-Blinded, Placebo-Controlled Crossover Trial

Abstract

Palmitoylethanolamide (PEA) is marketed as a “dietary food for special medical purposes”. Its broad-spectrum analgesic, anti-inflammatory, and neuroprotective effects make PEA an interesting substance in pain management. However, the underlying analgetic mechanisms have not yet been investigated in humans. The aim of our study is to provide a deeper understanding of the involved mechanisms, which is essential for differentiating therapeutic approaches and the establishment of mechanism-based therapeutic approaches. In this randomized, placebo-controlled, double-blinded crossover trial, 14 healthy volunteers were included. PEA (3 × 400 mg per day) or placebo were taken for 4 weeks. Our study investigated the mode of action of PEA using an established pain model, “Repetitive phasic heat application”, which is well-suited to investigate analgesic and anti-hyperalgesic effects in healthy volunteers. Parameters for peripheral and central sensitization as well as for pain modulation were assessed. Repetitive heat pain was significantly decreased, and the cold pain tolerance was significantly prolonged after the PEA treatment. The pressure pain tolerance and the conditioned pain modulation were increased after the PEA treatment. The wind-up ratio and the average distance of allodynia were significantly decreased after the PEA treatment. The heat pain tolerance was significantly higher after the PEA treatment. The present study has demonstrated that PEA has clinically relevant analgesic properties, acting on both peripheral and central mechanisms as well as in pain modulation.

Palmitoylethanolamide in the Treatment of Chronic Pain: A Systematic Review and Meta-Analysis of Double-Blind Randomized Controlled Trials

“…However, recent meta-analyses have provided evidence for the efficacy of PEA in the treatment of inflammation and neuropathic pain [ 14 , 38 ]. Data from healthy volunteers has also shown that PEA is capable of reducing central sensitization and moderating pain modulation [ 12 ], which are desirable features for chronic pain treatments and are consistent with observations from our included studies.…”

“…Recently, our group published the results of a randomized crossover study demonstrating clinically relevant analgesic properties of PEA. We used a model of thermal pain, thus investigating its effects on peripheral and central nociceptive mechanisms and on pain modulation [ 12 ].…”

What Do We Know about Nociplastic Pain?

“…PEA was found to be a mechanism of action that includes mast cells and basophils and has been proven to exhibit a neuroprotective effect in cerebellar granule cells [ 127 ]. However, taking into account the pathophysiology of NcplP and the cannabimimetic actions of PEA, it is likely to be worth investigating whether PEA will elicit analgesia [ 127 , 128 , 129 ]. In addition to that, PEA was shown to suppress inflammation [ 127 , 129 , 130 ].…”

The Dose-Response Relationship between Opioid Agonist Therapy and Alterations in Pain Pathways in Patients with Opioid Use Disorders: A Cross-Sectional Study

“…in the thalamus. This process is called central sensitization [ 4 , 5 ]. Sensitization, on the one hand, is generally understood to be a physiological, adaptive, self-limiting process that aids in the healing of injuries.…”