{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T17:48:35Z","timestamp":1791827315931,"version":"4.3.4"},"reference-count":48,"publisher":"National Academy of Sciences","issue":"16","license":[{"start":{"date-parts":[[2026,4,16]],"date-time":"2026-04-16T00:00:00Z","timestamp":1776297600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2026,4,21]]},"abstract":"<jats:p>Development of potent nonopioid analgesics (NOAs) has attracted great attentions from both academic and industrial worlds, aiming at replacing current opioid drugs in acute and chronic pain management. Among the diverse proposed pathways toward nonopioid analgesia, voltage-gated sodium channel stood out as one of the most promising targets in developing potent NOA. Diverging from the prevailing focus on highly subtype-selective blockers, we report here the access of potent analgesia via the simultaneous inhibition on multianalgesic-related sodium channel subtypes. Originated from AI-driven drug discovery and computer-aided drug design, the hit and lead compounds exhibited efficient inhibitory effect on analgesic-related sodium channel subtypes, robust analgesic effect in various rat models and no opioid-related adverse reactions. Furthermore, the potential of such a multi-subtype sodium channel blocker for perioperative use was validated through a surgical simulation. These findings represent a meaningful leap toward the goal of replacing opioids in perioperative period and provide fresh insights for future NOA development.<\/jats:p>","DOI":"10.1073\/pnas.2528910123","type":"journal-article","created":{"date-parts":[[2026,4,16]],"date-time":"2026-04-16T15:59:39Z","timestamp":1776355179000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":2,"title":["The identification of potent nonopioid analgesics and their potential for perioperative use"],"prefix":"10.1073","volume":"123","author":[{"given":"Chaoyi","family":"Deng","sequence":"first","affiliation":[{"name":"Department of Anesthesiology, West China Hospital, Sichuan University","place":["Chengdu, China"]},{"name":"Laboratory of Anesthesia and Critical Care Medicine, National-Local Joint Engineering Research Centre of Translational Medicine of Anesthesiology, West China Hospital, Sichuan University","place":["Chengdu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Deng","sequence":"additional","affiliation":[{"name":"Laboratory of Anesthesia and Critical Care Medicine, National-Local Joint Engineering Research Centre of Translational Medicine of Anesthesiology, West China Hospital, Sichuan University","place":["Chengdu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xudong","family":"Luo","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, West China Hospital, Sichuan University","place":["Chengdu, China"]},{"name":"Department of Pharmacy, West China Tianfu Hospital, Sichuan University","place":["Chengdu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junyu","family":"Lu","sequence":"additional","affiliation":[{"name":"Laboratory of Anesthesia and Critical Care Medicine, National-Local Joint Engineering Research Centre of Translational Medicine of Anesthesiology, West China Hospital, Sichuan University","place":["Chengdu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-7162-5550","authenticated-orcid":false,"given":"Chenyang","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, West China Hospital, Sichuan University","place":["Chengdu, China"]},{"name":"Laboratory of Anesthesia and Critical Care Medicine, National-Local Joint Engineering Research Centre of Translational Medicine of Anesthesiology, West China Hospital, Sichuan University","place":["Chengdu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peiwen","family":"Gao","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, West China Hospital, Sichuan University","place":["Chengdu, China"]},{"name":"Laboratory of Anesthesia and Critical Care Medicine, National-Local Joint Engineering Research Centre of Translational Medicine of Anesthesiology, West China Hospital, Sichuan University","place":["Chengdu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoyu","family":"Xie","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, West China Hospital, Sichuan University","place":["Chengdu, China"]},{"name":"Laboratory of Anesthesia and Critical Care Medicine, National-Local Joint Engineering Research Centre of Translational Medicine of Anesthesiology, West China Hospital, Sichuan University","place":["Chengdu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bingbing","family":"Xiang","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, West China Hospital, Sichuan University","place":["Chengdu, China"]},{"name":"Laboratory of Anesthesia and Critical Care Medicine, National-Local Joint Engineering Research Centre of Translational Medicine of Anesthesiology, West China Hospital, Sichuan University","place":["Chengdu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sicheng","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, West China Hospital, Sichuan University","place":["Chengdu, China"]},{"name":"Laboratory of Anesthesia and Critical Care Medicine, National-Local Joint Engineering Research Centre of Translational Medicine of Anesthesiology, West China Hospital, Sichuan University","place":["Chengdu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6035-8253","authenticated-orcid":false,"given":"Xingxing","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Affiliated Hospital of Zunyi Medical University","place":["Zunyi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoxiao","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, West China Hospital, Sichuan University","place":["Chengdu, China"]},{"name":"Laboratory of Anesthesia and Critical Care Medicine, National-Local Joint Engineering Research Centre of Translational Medicine of Anesthesiology, West China Hospital, Sichuan University","place":["Chengdu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3333-1861","authenticated-orcid":false,"given":"Pan","family":"Chang","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, West China Hospital, Sichuan University","place":["Chengdu, China"]},{"name":"Laboratory of Anesthesia and Critical Care Medicine, National-Local Joint Engineering Research Centre of Translational Medicine of Anesthesiology, West China Hospital, Sichuan University","place":["Chengdu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xia","family":"Wu","sequence":"additional","affiliation":[{"name":"Laboratory of Anesthesia and Critical Care Medicine, National-Local Joint Engineering Research Centre of Translational Medicine of Anesthesiology, West China Hospital, Sichuan University","place":["Chengdu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guoyan","family":"Zhao","sequence":"additional","affiliation":[{"name":"Laboratory of Anesthesia and Critical Care Medicine, National-Local Joint Engineering Research Centre of Translational Medicine of Anesthesiology, West China Hospital, Sichuan University","place":["Chengdu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deying","family":"Gong","sequence":"additional","affiliation":[{"name":"Laboratory of Anesthesia and Critical Care Medicine, National-Local Joint Engineering Research Centre of Translational Medicine of Anesthesiology, West China Hospital, Sichuan University","place":["Chengdu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4549-6324","authenticated-orcid":false,"given":"Jing","family":"Wang","sequence":"additional","affiliation":[{"name":"Laboratory of Anesthesia and Critical Care Medicine, National-Local Joint Engineering Research Centre of Translational Medicine of Anesthesiology, West China Hospital, Sichuan University","place":["Chengdu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5005-2285","authenticated-orcid":false,"given":"Cheng","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, West China Hospital, Sichuan University","place":["Chengdu, China"]},{"name":"Laboratory of Anesthesia and Critical Care Medicine, National-Local Joint Engineering Research Centre of Translational Medicine of Anesthesiology, West China Hospital, Sichuan University","place":["Chengdu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, West China Hospital, Sichuan University","place":["Chengdu, China"]},{"name":"Laboratory of Anesthesia and Critical Care Medicine, National-Local Joint Engineering Research Centre of Translational Medicine of Anesthesiology, West China Hospital, Sichuan University","place":["Chengdu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tao","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, West China Hospital, Sichuan University","place":["Chengdu, China"]},{"name":"Laboratory of Anesthesia and Critical Care Medicine, National-Local Joint Engineering Research Centre of Translational Medicine of Anesthesiology, West China Hospital, Sichuan University","place":["Chengdu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fengming","family":"Luo","sequence":"additional","affiliation":[{"name":"Department of Respiratory and Critical Care Medicine, West China Hospital, Sichuan University","place":["Chengdu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2737-8623","authenticated-orcid":false,"given":"Wensheng","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, West China Hospital, Sichuan University","place":["Chengdu, China"]},{"name":"Laboratory of Anesthesia and Critical Care Medicine, National-Local Joint Engineering Research Centre of Translational Medicine of Anesthesiology, West China Hospital, Sichuan University","place":["Chengdu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2026,4,16]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.eclinm.2021.101198"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/S2468-2667(22)00013-5"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bja.2019.06.009"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(19)32229-9"},{"key":"e_1_3_4_5_2","unstructured":"American Society of Anesthesiologists Statement on nonoperating room anesthesia services. (2023). https:\/\/www.asahq.org\/standards-and-practice-parameters\/statement-on-nonoperating-room-anesthesia-service."},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1097\/ACO.0000000000001123"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1097\/ACO.0000000000001542"},{"key":"e_1_3_4_8_2","article-title":"Postoperative pain-related outcomes and perioperative pain management in China: A population-based study","volume":"39","author":"Liu Y.","year":"2023","unstructured":"Y. Liu , Postoperative pain-related outcomes and perioperative pain management in China: A population-based study. Lancet Reg. Health West Pac. 39, 100822 (2023).","journal-title":"Lancet Reg. Health West Pac."},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1097\/MS9.0000000000001724"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1007\/s11916-023-01137-y"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2025.04.038"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-025-08618-7"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.abn7065"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1007\/s40265-020-01429-2"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00052.2017"},{"key":"e_1_3_4_16_2","unstructured":"FDA (US Food and Drug Administration) \u201cFDA approves novel non-opioid treatment for moderate to severe acute pain.\u201d News Release January 30. (FDA Silver Spring MD 2025). https:\/\/www.fda.gov\/news-events\/press-announcements\/fda-approves-novel-non-opioid-treatment-moderate-severe-acute-pain."},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2503570122"},{"key":"e_1_3_4_18_2","first-page":"1085","article-title":"1.8 inhibitor for treatment of moderate-to-severe acute pain: Two phase 3 randomized clinical trials","volume":"142","author":"Bertoch T.","year":"2025","unstructured":"T. Bertoch , 1.8 inhibitor for treatment of moderate-to-severe acute pain: Two phase 3 randomized clinical trials. Anesthesiology 142, 1085\u20131099 (2025).","journal-title":"Anesthesiology"},{"key":"e_1_3_4_19_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0404915101"},{"key":"e_1_3_4_20_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(17)30005-4"},{"key":"e_1_3_4_21_2","doi-asserted-by":"publisher","DOI":"10.1097\/j.pain.0000000000001227"},{"key":"e_1_3_4_22_2","doi-asserted-by":"publisher","DOI":"10.1093\/pm\/pnab032"},{"key":"e_1_3_4_23_2","doi-asserted-by":"publisher","DOI":"10.3390\/md10020281"},{"key":"e_1_3_4_24_2","doi-asserted-by":"publisher","DOI":"10.1111\/anae.15270"},{"key":"e_1_3_4_25_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature17976"},{"key":"e_1_3_4_26_2","doi-asserted-by":"publisher","DOI":"10.1113\/JP278148"},{"key":"e_1_3_4_27_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41583-021-00444-w"},{"key":"e_1_3_4_28_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41573-019-0024-5"},{"key":"e_1_3_4_29_2","doi-asserted-by":"publisher","DOI":"10.1021\/ci3001277"},{"key":"e_1_3_4_30_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41587-019-0224-x"},{"key":"e_1_3_4_31_2","doi-asserted-by":"publisher","DOI":"10.1186\/1758-2946-5-26"},{"key":"e_1_3_4_32_2","unstructured":"Daylight Chemical Information Systems Inc. Daylight theory manual (Daylight Version 4.9 2011). https:\/\/www.daylight.com\/dayhtml\/doc\/theory\/. Accessed 28 August 2023."},{"key":"e_1_3_4_33_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-025-59628-y"},{"key":"e_1_3_4_34_2","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.0c02227"},{"key":"e_1_3_4_35_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-38942-3"},{"key":"e_1_3_4_36_2","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jcim.9b00843"},{"key":"e_1_3_4_37_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00232-004-0702-y"},{"key":"e_1_3_4_38_2","unstructured":"European Medicines Agency ICH E10 Choice of control group in clinical trials\u2014Scientific guideline. (2001). https:\/\/www.ema.europa.eu\/en\/ich-e10-choice-control-group-clinical-trials-scientific-guideline. Accessed 1 September 2023."},{"key":"e_1_3_4_39_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.chembiol.2021.01.010"},{"key":"e_1_3_4_40_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41573-022-00472-w"},{"key":"e_1_3_4_41_2","doi-asserted-by":"publisher","DOI":"10.1203\/00006450-200006000-00008"},{"key":"e_1_3_4_42_2","doi-asserted-by":"publisher","DOI":"10.3390\/ijms20061324"},{"key":"e_1_3_4_43_2","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.4c01044"},{"key":"e_1_3_4_44_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0149-7634(05)80090-9"},{"key":"e_1_3_4_45_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.yebeh.2019.02.029"},{"key":"e_1_3_4_46_2","doi-asserted-by":"publisher","DOI":"10.1213\/ANE.0000000000006266"},{"key":"e_1_3_4_47_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejphar.2010.05.038"},{"key":"e_1_3_4_48_2","unstructured":"J. Lu Data from \u201cAnesProject.\u201d Github. https:\/\/github.com\/dumplingdumpling\/AnesProject. Deposited 14 June 2025."}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.2528910123","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,16]],"date-time":"2026-04-16T15:59:48Z","timestamp":1776355188000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/10.1073\/pnas.2528910123"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,16]]},"references-count":48,"journal-issue":{"issue":"16","published-print":{"date-parts":[[2026,4,21]]}},"alternative-id":["10.1073\/pnas.2528910123"],"URL":"https:\/\/doi.org\/10.1073\/pnas.2528910123","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,16]]},"assertion":[{"value":"2025-10-15","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-03-05","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-04-16","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e2528910123"}}