Review ArticlesPeripherally acting opioid analgesics and peripherally-induced analgesiaMartínez, Vicentea,,b; Abalo, Raquelc,,d,,eAuthor Information aDepartment of Cell Biology, Physiology and Immunology; Neuroscience Institute; Universitat Autònoma de Barcelona, Barcelona bCentro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid cÁrea de Farmacología y Nutrición, Departamento de Ciencias Básicas de la Salud, Universidad Rey Juan Carlos (URJC), Alcorcón dUnidad Asociada I+D+i del Instituto de Química Médica (IQM), Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain eHigh Performance Research Group in Physiopathology and Pharmacology of the Digestive System NeuGut-URJC, Madrid, Spain Received 2 January 2020 Accepted as revised 14 February 2020 Correspondence to Raquel Abalo, PhD, Área de Farmacología y Nutrición, Departamento de Ciencias Básicas de la Salud, Universidad Rey Juan Carlos (URJC), 28922 Alcorcón, Spain, E-mail: email@example.com Behavioural Pharmacology: April 2020 - Volume 31 - Issue 2&3 - p 136-158 doi: 10.1097/FBP.0000000000000558 Buy Metrics Abstract The management of pain, particularly chronic pain, is still an area of medical need. In this context, opioids remain a gold standard for the treatment of pain. However, significant side effects, mainly of central origin, limit their clinical use. Here, we review recent progress to improve the therapeutic and safety profiles of opioids for pain management. Characterization of peripheral opioid-mediated pain mechanisms have been a key component of this process. Several studies identified peripheral µ, δ, and κ opioid receptors (MOR, DOR, and KOR, respectively) and nociceptin/orphanin FQ (NOP) receptors as significant players of opioid-mediated antinociception, able to achieve clinically significant effects independently of any central action. Following this, particularly from a medicinal chemistry point of view, main efforts have been directed towards the peripheralization of opioid receptor agonists with the objective of optimizing receptor activity and minimizing central exposure and the associated undesired effects. These activities have allowed the characterization of a great variety of compounds and investigational drugs that show low central nervous system (CNS) penetration (and therefore a reduced side effect profile) yet maintaining the desired opioid-related peripheral antinociceptive activity. These include highly hydrophilic/amphiphilic and massive molecules unable to easily cross lipid membranes, substrates of glycoprotein P (a extrusion pump that avoids CNS penetration), nanocarriers that release the analgesic agent at the site of inflammation and pain, and pH-sensitive opioid agonists that selectively activate at those sites (and represent a new pharmacodynamic paradigm). Hopefully, patients with pain will benefit soon from the incorporation of these new entities. Copyright © 2020 YEAR Wolters Kluwer Health, Inc. All rights reserved.