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      Clinical applications of palmitoylethanolamide in pain management: protocol for a scoping review

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          Abstract

          Background

          Palmitoylethanolamide (PEA) belong to endocannabinoid family, a group of fatty acid amides. PEA has been proven to have analgesic and anti-inflammatory activity and has been used in several controlled studies focused on the management of chronic pain among adult patients with different underlying clinical conditions.

          Methods/design

          A literature search will be performed using PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials (CENTRAL). The population will be patients who have chronic pain, the intervention will be the administration of PEA alone or in combination with other drugs for the pain management; the comparison will be the standard therapy in accordance with the current guidelines for the treatment of pain. The Outcomes will be the reduction of pain not restricted to specific scales laying out the pain outcome data described in the included studies.

          Discussion

          This scoping review aims to describe the clinical applications of the PEA in chronic pain management and its outcome.

          Scoping review registration

          Open Science Framework https://osf.io/74tmx/.

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          Most cited references12

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          Mast cells express a peripheral cannabinoid receptor with differential sensitivity to anandamide and palmitoylethanolamide.

          A. Leon, L Facci, R. Dal Toso … (1995)
          Article 0 comments Cited 63 times – based on 0 reviews     Review now
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            Palmitoylethanolamide inhibits the expression of fatty acid amide hydrolase and enhances the anti-proliferative effect of anandamide in human breast cancer cells.

            P Orlando, O. Zagoory-Sharon, M Bifulco … (2001)
            Palmitoylethanolamide (PEA) has been shown to act in synergy with anandamide (arachidonoylethanolamide; AEA), an endogenous agonist of cannabinoid receptor type 1 (CB(1)). This synergistic effect was reduced by the CB(2) cannabinoid receptor antagonist SR144528, although PEA does not activate either CB(1) or CB(2) receptors. Here we show that PEA potently enhances the anti-proliferative effects of AEA on human breast cancer cells (HBCCs), in part by inhibiting the expression of fatty acid amide hydrolase (FAAH), the major enzyme catalysing AEA degradation. PEA (1-10 microM) enhanced in a dose-related manner the inhibitory effect of AEA on both basal and nerve growth factor (NGF)-induced HBCC proliferation, without inducing any cytostatic effect by itself. PEA (5 microM) decreased the IC(50) values for AEA inhibitory effects by 3-6-fold. This effect was not blocked by the CB(2) receptor antagonist SR144528, and was not mimicked by a selective agonist of CB(2) receptors. PEA enhanced AEA-evoked inhibition of the expression of NGF Trk receptors, which underlies the anti-proliferative effect of the endocannabinoid on NGF-stimulated MCF-7 cells. The effect of PEA was due in part to inhibition of AEA degradation, since treatment of MCF-7 cells with 5 microM PEA caused a approximately 30-40% down-regulation of FAAH expression and activity. However, PEA also enhanced the cytostatic effect of the cannabinoid receptor agonist HU-210, although less potently than with AEA. PEA did not modify the affinity of ligands for CB(1) or CB(2) receptors, and neither did it alter the CB(1)/CB(2)-mediated inhibitory effect of AEA on adenylate cyclase type V, nor the expression of CB(1) and CB(2) receptors in MCF-7 cells. We suggest that long-term PEA treatment of cells may positively affect the pharmacological activity of AEA, in part by inhibiting FAAH expression.
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              N-palmitoyl-ethanolamine: Biochemistry and new therapeutic opportunities.

              Stefania Petrosino, Teresa Iuvone, Vincenzo Di Marzo (2010)
              Although its presence in mammalian tissues has been known since the 1960s, N-palmitoyl-ethanolamine (PEA) has emerged only recently among other bioactive N-acylethanolamines as an important local pro-homeostatic mediator which, due to its chemical stability, can be also administered exogenously as the active principle of current anti-inflammatory and analgesic preparations (e.g. Normast, Pelvilen). Much progress has been made towards the understanding of the mechanisms regulating both the tissue levels of PEA under physiological and pathological conditions, and its pharmacological actions. Here we review these new developments in PEA biochemistry and pharmacology, and discuss novel potential indications for the therapeutic use of this compound and of synthetic tools that selectively retard its catabolism, such as the inhibitors of the recently cloned N-acylethanolamine-hydrolyzing acid amidase. Copyright 2010 Elsevier Masson SAS. All rights reserved.
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                Author and article information

                Contributors
                Marco Fiore:
                ORCID: http://orcid.org/0000-0001-7263-0229
                marco.fiore@unicampania.it
                Journal
                Journal ID (nlm-ta): Syst Rev
                Journal ID (iso-abbrev): Syst Rev
                Title: Systematic Reviews
                Publisher: BioMed Central (London )
                ISSN (Electronic): 2046-4053
                Publication date (Electronic): 8 January 2019
                Publication date PMC-release: 8 January 2019
                Publication date Collection: 2019
                Volume: 8
                Electronic Location Identifier: 9
                Affiliations
                [1 ]ISNI 0000 0001 2200 8888, GRID grid.9841.4, Department of Women, Child and General and Specialized Surgery, , University of Campania “Luigi Vanvitelli”, ; Piazza L. Miraglia, 2, 80138 Naples, Italy
                [2 ]ISNI 0000 0001 2200 8888, GRID grid.9841.4, Department of Medical, Surgical, Neurological, Metabolic and Aging Sciences, , University of Campania “Luigi Vanvitelli”, ; Piazza L. Miraglia, 2, 80138 Naples, Italy
                Author information
                http://orcid.org/0000-0001-7263-0229
                Article
                Publisher ID: 934
                DOI: 10.1186/s13643-018-0934-z
                PMC ID: 6323836
                PubMed ID: 30621775
                SO-VID: feb888d7-5ed0-4c67-a47c-1a8836cf7283
                Copyright © © The Author(s). 2019
                License:

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                Date received : 20 January 2018
                Date accepted : 26 December 2018
                Categories
                Subject: Protocol
                Custom metadata
                issue-copyright-statement © The Author(s) 2019

                ScienceOpen disciplines: Public health
                Keywords: palmitoylethanolamide,systematic review,pea,pain,pain management,endocannabinoids,ethanolamines,humans,palmitic acids,palmidrol
                Data availability:
                ScienceOpen disciplines: Public health
                Keywords: palmitoylethanolamide, systematic review, pea, pain, pain management, endocannabinoids, ethanolamines, humans, palmitic acids, palmidrol

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