{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,23]],"date-time":"2026-08-23T15:09:35Z","timestamp":1787497775245,"version":"build-2736575974"},"reference-count":25,"publisher":"Public Library of Science (PLoS)","issue":"1","license":[{"start":{"date-parts":[[2022,1,27]],"date-time":"2022-01-27T00:00:00Z","timestamp":1643241600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100011404","name":"Indivior","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100011404","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100011404","name":"Indivior","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100011404","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100011404","name":"Indivior","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100011404","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100011404","name":"Indivior","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100011404","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100011404","name":"Indivior","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100011404","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:sec id=\"sec001\">\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Opioid-induced respiratory depression driven by ligand binding to mu-opioid receptors is a leading cause of opioid-related fatalities. Buprenorphine, a partial agonist, binds with high affinity to mu-opioid receptors but displays partial respiratory depression effects. The authors examined whether sustained buprenorphine plasma concentrations similar to those achieved with some extended-release injections used to treat opioid use disorder could reduce the frequency and magnitude of fentanyl-induced respiratory depression.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec002\">\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      In this two-period crossover, single-centre study, 14 healthy volunteers (single-blind, randomized) and eight opioid-tolerant patients taking daily opioid doses \u226590 mg oral morphine equivalents (open-label) received continuous intravenous buprenorphine or placebo for 360 minutes, targeting buprenorphine plasma concentrations of 0.2 or 0.5 ng\/mL in healthy volunteers and 1.0, 2.0 or 5.0 ng\/mL in opioid-tolerant patients. Upon reaching target concentrations, participants received up to four escalating intravenous doses of fentanyl. The primary endpoint was change in isohypercapnic minute ventilation (V\n                      <jats:sub>E<\/jats:sub>\n                      ). Additionally, occurrence of apnea was recorded.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec003\">\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Fentanyl-induced changes in V\n                      <jats:sub>E<\/jats:sub>\n                      were smaller at higher buprenorphine plasma concentrations. In healthy volunteers, at target buprenorphine concentration of 0.5 ng\/mL, the first and second fentanyl boluses reduced V\n                      <jats:sub>E<\/jats:sub>\n                      by [LSmean (95% CI)] 26% (13\u201340%) and 47% (37\u201359%) compared to 51% (38\u201364%) and 79% (69\u201389%) during placebo infusion (\n                      <jats:italic>p<\/jats:italic>\n                      = 0.001 and &lt; .001, respectively). Discontinuations for apnea limited treatment comparisons beyond the second fentanyl injection. In opioid-tolerant patients, fentanyl reduced V\n                      <jats:sub>E<\/jats:sub>\n                      up to 49% (21\u201376%) during buprenorphine infusion (all concentration groups combined) versus up to 100% (68\u2013132%) during placebo infusion (\n                      <jats:italic>p<\/jats:italic>\n                      = 0.006). In opioid-tolerant patients, the risk of experiencing apnea requiring verbal stimulation following fentanyl boluses was lower with buprenorphine than with placebo (odds ratio: 0.07; 95% CI: 0.0 to 0.3;\n                      <jats:italic>p<\/jats:italic>\n                      = 0.001).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec004\">\n                    <jats:title>Interpretation<\/jats:title>\n                    <jats:p>Results from this proof-of-principle study provide the first clinical evidence that high sustained plasma concentrations of buprenorphine may protect against respiratory depression induced by potent opioids like fentanyl.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1371\/journal.pone.0256752","type":"journal-article","created":{"date-parts":[[2022,1,27]],"date-time":"2022-01-27T13:33:57Z","timestamp":1643290437000},"page":"e0256752","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":47,"title":["Effect of sustained high buprenorphine plasma concentrations on fentanyl-induced respiratory depression: A placebo-controlled crossover study in healthy volunteers and opioid-tolerant patients"],"prefix":"10.1371","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6182-0553","authenticated-orcid":true,"given":"Laurence M.","family":"Moss","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marijke Hyke","family":"Algera","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6069-4425","authenticated-orcid":true,"given":"Robert","family":"Dobbins","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frank","family":"Gray","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephanie","family":"Strafford","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amy","family":"Heath","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monique","family":"van Velzen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7202-5088","authenticated-orcid":true,"given":"Jules A. A. C.","family":"Heuberger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marieke","family":"Niesters","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erik","family":"Olofsen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Celine M.","family":"Laffont","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Albert","family":"Dahan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Geert Jan","family":"Groeneveld","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2022,1,27]]},"reference":[{"key":"pone.0256752.ref001","unstructured":"United Nations Office on Drugs and Crime. World Drug Report 2020, (United Nations publication, Sales No. E.20.XI.6)."},{"key":"pone.0256752.ref002","doi-asserted-by":"crossref","first-page":"999","DOI":"10.1016\/j.yrtph.2015.09.014","article-title":"Ranking the harm of non-medically used prescription opioids in the UK","volume":"73","author":"J van Amsterdam","year":"2015","journal-title":"Regul Toxicol Pharmacol"},{"key":"pone.0256752.ref003","doi-asserted-by":"crossref","first-page":"e1917228","DOI":"10.1001\/jamanetworkopen.2019.17228","article-title":"Trends in prescription analgesic use among adults with musculoskeletal conditions in the United States, 1999\u20132016","volume":"2","author":"A Stokes","year":"2019","journal-title":"JAMA Netw Open"},{"key":"pone.0256752.ref004","doi-asserted-by":"crossref","first-page":"1027","DOI":"10.1097\/ALN.0000000000002184","article-title":"Averting opioid-induced respiratory depression without affecting analgesia","volume":"128","author":"A Dahan","year":"2018","journal-title":"Anesthesiology"},{"key":"pone.0256752.ref005","unstructured":"Centers for Disease Control and Prevention. 2019 Annual Surveillance Report of Drug-Related Risks and Outcomes\u2014United States Surveillance Special Report. Centers for Disease Control and Prevention, U.S. Department of Health and Human Services. Published November 1, 2019. https:\/\/www.cdc.gov\/drugoverdose\/pdf\/pubs\/2019-cdc-drug-surveillance-report.pdf. Accessed August 25, 2020."},{"key":"pone.0256752.ref006","doi-asserted-by":"crossref","first-page":"ES177","DOI":"10.36076\/ppj.2012\/15\/ES177","article-title":"Prevention of opioid abuse in chronic non-cancer pain: an algorithmic, evidence based approach","volume":"15","author":"S Atluri","year":"2012","journal-title":"Pain Physician"},{"key":"pone.0256752.ref007","doi-asserted-by":"crossref","first-page":"290","DOI":"10.15585\/mmwr.mm6911a4","article-title":"Drug and Opioid-Involved Overdose Deaths\u2014United States, 2017\u20132018","volume":"69","author":"N Wilson","year":"2020","journal-title":"MMWR Morb Mortal Wkly Rep"},{"key":"pone.0256752.ref008","first-page":"1419","article-title":"Drug and Opioid-Involved Overdose Deaths\u2013United States, 2013\u20132017","volume":"67","author":"L Scholl","year":"2019","journal-title":"MMWR Morb Mortal Wkly Rep"},{"key":"pone.0256752.ref009","doi-asserted-by":"crossref","first-page":"1197","DOI":"10.15585\/mmwr.mm6643e1","volume":"66","author":"JK O\u2019Donnell","year":"2017","journal-title":"July\u2013December 2016. MMWR Morb Mortal Wkly Rep"},{"key":"pone.0256752.ref010","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1016\/j.jsat.2018.10.007","article-title":"Fentanyl exposure among patients seeking opioid treatment","volume":"96","author":"TA Ochalek","year":"2019","journal-title":"J Subst Abuse Treat"},{"key":"pone.0256752.ref011","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1097\/ALN.0b013e3181c38c25","article-title":"Incidence, reversal, and prevention of opioid-induced respiratory depression","volume":"112","author":"A Dahan","year":"2010","journal-title":"Anesthesiology"},{"key":"pone.0256752.ref012","doi-asserted-by":"crossref","first-page":"e168","DOI":"10.1016\/j.bja.2018.12.023","article-title":"Opioid-induced respiratory depression in humans: a review of pharmacokinetic-pharmacodynamic modelling of reversal","volume":"122","author":"MH Algera","year":"2019","journal-title":"Br J Anaesth"},{"key":"pone.0256752.ref013","doi-asserted-by":"crossref","first-page":"5994","DOI":"10.2174\/138161212803582469","article-title":"Non-analgesic effects of opioids: opioid-induced respiratory depression","volume":"18","author":"M Boom","year":"2012","journal-title":"Curr Pharm Des"},{"key":"pone.0256752.ref014","doi-asserted-by":"crossref","first-page":"961","DOI":"10.1046\/j.1360-0443.1999.9479612.x","article-title":"Mechanisms of fatal opioid overdose","volume":"94","author":"JM White","year":"1999","journal-title":"Addiction"},{"key":"pone.0256752.ref015","doi-asserted-by":"crossref","first-page":"1253","DOI":"10.1056\/NEJMra1507771","article-title":"Opioid abuse in chronic pain\u2014misconceptions and mitigation strategies","volume":"374","author":"ND Volkow","year":"2016","journal-title":"N Engl J Med"},{"key":"pone.0256752.ref016","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1056\/NEJMra1604339","article-title":"Treatment of Opioid-Use Disorders","volume":"375","author":"MA Schuckit","year":"2016","journal-title":"N Engl J Med"},{"key":"pone.0256752.ref017","doi-asserted-by":"crossref","first-page":"79","DOI":"10.2165\/00139709-200625020-00002","article-title":"Does high-dose buprenorphine cause respiratory depression?: possible mechanisms and therapeutic consequences","volume":"25","author":"B Megarbane","year":"2006","journal-title":"Toxicol Rev"},{"key":"pone.0256752.ref018","first-page":"859","article-title":"Buprenorphine\u2014an attractive opioid with underutilized potential in treatment of chronic pain","volume":"8","author":"IK Khanna","year":"2015","journal-title":"J Pain Res"},{"key":"pone.0256752.ref019","doi-asserted-by":"crossref","first-page":"627","DOI":"10.1093\/bja\/ael051","article-title":"Buprenorphine induces ceiling in respiratory depression but not in analgesia","volume":"96","author":"A Dahan","year":"2006","journal-title":"Br J Anaesth"},{"key":"pone.0256752.ref020","doi-asserted-by":"crossref","first-page":"825","DOI":"10.1093\/bja\/aei145","article-title":"Comparison of the respiratory effects of intravenous buprenorphine and fentanyl in humans and rats","volume":"94","author":"A Dahan","year":"2005","journal-title":"Br J Anaesth"},{"key":"pone.0256752.ref021","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1038\/sj.clpt.6100025","article-title":"Mechanism-based PK\/PD modeling of the respiratory depressant effect of buprenorphine and fentanyl in healthy volunteers","volume":"81","author":"A Yassen","year":"2007","journal-title":"Clin Pharmacol Ther"},{"key":"pone.0256752.ref022","doi-asserted-by":"crossref","DOI":"10.1176\/appi.books.9780890425596","volume-title":"Diagnostic and statistical manual of mental disorders","author":"American Psychiatric Association","year":"2013","edition":"5"},{"key":"pone.0256752.ref023","volume-title":"CDC compilation of benzodiazepines, muscle relaxants, stimulants, zolpidem, and opioid analgesics with oral morphine milligram equivalent conversion factors, 2018 version","author":"National Center for Injury Prevention and Control","year":"2018"},{"key":"pone.0256752.ref024","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1016\/j.biopsych.2006.04.043","article-title":"Buprenorphine duration of action: mu-opioid receptor availability and pharmacokinetic and behavioral indices","volume":"61","author":"M Greenwald","year":"2007","journal-title":"Biol Psychiatry"},{"key":"pone.0256752.ref025","doi-asserted-by":"crossref","first-page":"778","DOI":"10.1016\/S0140-6736(18)32259-1","article-title":"Efficacy and safety of a monthly buprenorphine depot injection for opioid use disorder: a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial","volume":"393","author":"BR Haight","year":"2019","journal-title":"Lancet"}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0256752","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,24]],"date-time":"2023-01-24T18:58:08Z","timestamp":1674586688000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0256752"}},"subtitle":[],"editor":[{"given":"Bernard","family":"Le Foll","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2022,1,27]]},"references-count":25,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2022,1,27]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0256752","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,1,27]]}}}