Pain inhibition by opioids-new concepts

Abstract

Opioids are the oldest and most potent drugs for the treatment of severe pain but they are burdened by detrimental side effects, such as respiratory depression, addiction potential, sedation, nausea and constipation. Their clinical application is undisputed in the treatment of acute (e.g. perioperative) and cancer pain but their long-term use in chronic pain has met increasing criticism and has contributed to the current "opioid crisis". This article reviews the pharmacological principles and new research strategies aiming at novel opioids with reduced side effects. The basic mechanisms underlying pain and opioid analgesia and other effects of opioids are outlined. To illustrate the clinical situation and medical problems, the plasticity of opioid receptors, intracellular signaling pathways, endogenous and exogenous opioid receptor ligands, central and peripheral sites of analgesic and side effects are discussed. The epidemic of opioid misuse has shown that there is alack of fundamental knowledge about the characteristics and management of chronic pain, that conflicts of interest and validity of models must be more intensively considered in the context of drug development and that novel analgesics with less addictive potential are urgently needed. Currently, the most promising perspectives appear to be augmenting endogenous opioid actions and the selective activation of peripheral opioid receptors.