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Conventional \u00b5 receptor opioids have a narrow therapeutic window in part because of their mechanism of action (MoA): they bind to \u00b5 receptors and non-selectively activate two intracellular signaling pathways, leading to analgesia and to ORAEs. This review explores the clinical potential of \u00b5 receptor ligands with differential signaling. Agents with a \u2018differential signaling\u201d MoA represent an innovative approach that may enhance the therapeutic window. These agents modulate \u00b5 receptor activity to selectively engage downstream signaling pathways associated with analgesia while limiting activity in downstream signaling pathways that lead to ORAEs. Differential signaling may fulfill an unmet need in the management of postoperative pain.<\/jats:p>","DOI":"10.1136\/rapm-2018-000010","type":"journal-article","created":{"date-parts":[[2019,1,14]],"date-time":"2019-01-14T14:04:06Z","timestamp":1547474646000},"page":"32-37","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":10,"title":["Improving the therapeutic window of conventional opioids: novel differential signaling modulators"],"prefix":"10.1136","volume":"44","author":[{"given":"Eugene R","family":"Viscusi","sequence":"first","affiliation":[{"name":"Department of Anesthesiology, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA 19107, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"239","published-online":{"date-parts":[[2019,1,3]]},"reference":[{"key":"2025101112470879000_44.1.32.1","unstructured":"Veterans Health Administration . 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