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It represents a relevant social-health issue worldwide, and it is considered a significant source of human suffering and disability, strongly affecting patients\u2019 quality of life. Despite several pharmacological strategies to guarantee an adequate pain management have been proposed over the years, opioids still represent one of the primary choices for treating moderate-to-severe pain in both cancer and non-cancer patients. However, chronic use of opioids often leads to numerous side effects, including respiratory depression, constipation, analgesic tolerance, and opioid-induced hyperalgesia (OIH), which can strongly limit their use. Given the fundamental role of opioid system in pain relief, this review provides a general overview about the main actors (endogenous opioid peptides and receptors) involved in its modulation. Furthermore, this review explores the action and the limitations of conventional clinically used opioids and describes the efficacy and safety profile of some promising analgesic compounds. A deeper understanding of the molecular mechanisms behind both analgesic effects and adverse events could advance knowledge in this field, thus improving chronic pain treatment.<\/jats:p>","DOI":"10.1186\/s44158-024-00201-2","type":"journal-article","created":{"date-parts":[[2024,10,11]],"date-time":"2024-10-11T02:01:39Z","timestamp":1728612099000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["Opioid system and related ligands: from the past to future perspectives"],"prefix":"10.1186","volume":"4","author":[{"given":"Laura","family":"Rullo","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Camilla","family":"Morosini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio","family":"Lacorte","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco","family":"Cristani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Flaminia","family":"Coluzzi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sanzio","family":"Candeletti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrizia","family":"Romualdi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,10,11]]},"reference":[{"issue":"1","key":"201_CR1","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1097\/j.pain.0000000000001384","volume":"160","author":"RD Treede","year":"2019","unstructured":"Treede RD, Rief W, Barke A, Aziz Q, Bennett MI, Benoliel R, Cohen M, Evers S, Finnerup NB, First MB, Giamberardino MA, Kaasa S, Korwisi B, Kosek E, Lavand\u2019homme P, Nicholas M, Perrot S, Scholz J, Schug S, Smith BH, Svensson P, Vlaeyen JWS, Wang SJ (2019) Chronic pain as a symptom or a disease: the IASP Classification of Chronic Pain for the International Classification of Diseases (ICD-11). 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