N-Palmitoylethanolamide enhances antinociceptive effect of tramadol in neuropathic rats

The efficacy of opioids in the treatment of chronic pain is limited; however, the adverse effects they produce are considerable. N-palmitoylethanolamide (PEA), a bioactive lipid mediator with structural similarities to endocannabinoids, has exhibited notable anti-inflammatory and analgesic effects in preclinical models. The objective of this study was to investigate the antinociceptive properties, motor coordination (MC), and constipation effects of tramadol and PEA in combination within a neuropathic pain model. The antinociceptive effects of tramadol (TRA) and PEA in various combination ratios were assessed using a CCI model of neuropathic pain in 126 male Wistar rats, divided into 21 groups: vehicles, GBP (1.0-177.78 mg/kg), TRA (1.0-31.62 mg/kg), PEA (0.0316-10 mg/kg), or TRA (1.0-10 mg/kg) with PEA (0.0316-1.0 mg/kg), all compounds were administered orally. The results of the dose-response analyses indicated that PEA was approximately five and eightfold more potent than tramadol in producing anti-hyperalgesic and anti-allodynic effects, respectively. The results of the surface of synergistic interaction (SSI) analysis indicated that the combination of TRA 10 mg/kg + PEA 0.0316 mg/kg exhibited the most pronounced anti-hyperalgesic effects and the most favorable anti-allodynic outcomes among the various combinations. No significant differences in MC or constipation were observed between the vehicle and optimal combination group. The results of this study demonstrate that sub-antinociceptive doses of tramadol, when combined with PEA, significantly enhance the antinociceptive efficacy of tramadol without the induction of typical opioid-associated side effects. These findings propose a novel approach to the treatment of pain.