Effects of Palmitoylethanolamide (PEA) on Nociceptive, Musculoskeletal and Neuropathic Pain: Systematic Review and Meta-Analysis of Clinical Evidence

Damiana Scuteri,^1,2,† Francesca Guida,^3,† Serena Boccella,³ Enza Palazzo,³ Sabatino Maione,^3,4,5 Juan Francisco Rodríguez-Landa,^6,7 Lucia Martínez-Mota,⁸ Paolo Tonin,² Giacinto Bagetta,¹ and Maria Tiziana Corasaniti⁹

¹Pharmacotechnology Documentation and Transfer Unit, Preclinical and Translational Pharmacology, Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende, Italy ²Regional Center for Serious Brain Injuries, S. Anna Institute, 88900 Crotone, Italy ³Department of Experimental Medicine, Pharmacology Division, University of Campania “L. Vanvitelli”, 80138 Naples, Italy ⁴Endocannabinoid Research Group, Institute of Biomolecular Chemistry, CNR, 80078 Pozzuoli, Italy ⁵IRCSS, Neuromed, 86077 Pozzilli, Italy ⁶Laboratorio de Neurofarmacología, Instituto de Neuroetología, Universidad Veracruzana, Xalapa 91190, Mexico ⁷Facultad de Química Farmacéutica Biológica, Universidad Veracruzana, Xalapa 91001, Mexico ⁸Dirección de Investigaciones en Neurociencias, Instituto Nacional de Psiquiatría Ramón de la Fuente Muñiz, Mexico City 03440, Mexico ⁹Department of Health Sciences, University “Magna Graecia” of Catanzaro, 88100 Catanzaro, Italy ^†These authors contributed equally to this work.

Abstract

Some 30–50% of the global population and almost 20% of the European population actually suffer from chronic pain, which presents a tremendous burden to society when this pain turns into a disability and hospitalization. Palmitoylethanolamide (PEA) has been demonstrated to improve pain in preclinical contexts, but an appraisal of clinical evidence is still lacking. The present study aimed at addressing the working hypothesis for the efficacy of PEA for nociceptive musculoskeletal and neuropathic pain in the clinical setting. The systematic search, selection and analysis were performed in agreement with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 recommendations. The primary outcome was pain reduction, as measured by a pain assessment scale. The secondary outcome was improvement in quality of life and/or of parameters of function. The results obtained for a total of 933 patients demonstrate the efficacy of PEA over the control (p < 0.00001), in particular in six studies apart from the two randomized, double-blind clinical trials included. However, the results are downgraded due to the high heterogeneity of the studies (I² = 99%), and the funnel plot suggests publication bias. Efficacy in achieving a reduction in the need for rescue medications and improvement in functioning, neuropathic symptoms and quality of life are reported. Therefore, adequately powered randomized, double-blind clinical trials are needed to deepen the domains of efficacy of add-on therapy with PEA for chronic pain. PROSPERO registration: CRD42022314395.

Keywords: palmitoylethanolamide, PEA, nociceptive pain, neuropathic pain, clinical setting