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.