{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,8]],"date-time":"2026-06-08T08:59:18Z","timestamp":1780909158861,"version":"3.54.1"},"reference-count":104,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2026,6,6]],"date-time":"2026-06-06T00:00:00Z","timestamp":1780704000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Opioids comprise a class of substances characterized by a narrow therapeutic window and significant euphoric effects. Opioid-related mortality remains a critical global health issue, primarily resulting from respiratory depression associated with full \u03bc-opioid receptor agonists. Buprenorphine is distinguished by its pharmacological profile as a partial \u03bc-opioid receptor agonist, exhibiting a ceiling effect on both respiratory depression and euphoria. These characteristics render buprenorphine particularly valuable in opioid replacement therapy for opioid use disorder and in the management of both chronic and acute pain. Current literature indicates that, due to these properties, buprenorphine possesses a superior safety profile compared to other opioids. This narrative review evaluates whether buprenorphine can cause fatal overdose despite its protective ceiling effect and examines cases of buprenorphine-related fatalities. The review synthesizes data from pre-clinical, clinical, pharmacological, and toxicological studies. Current literature supports the consensus that the established ceiling effect on respiratory depression does not fully eliminate the risk of fatal overdose. Polysubstance use, particularly co-ingestion of other central nervous system depressants, significantly increases this risk, and most buprenorphine-related deaths involve such combinations. Additionally, buprenorphine\u2019s safety is reduced in vulnerable populations, including opioid-naive individuals, children, and patients with pre-existing respiratory compromise. While buprenorphine alone presents a substantially lower fatality risk compared to other opioids, the ceiling effect is pharmacodynamic rather than absolute, and toxicity or fatal overdose may still occur. Current data gathered from clinical and pre-clinical studies suggest that buprenorphine is safer than full \u03bc-opioid receptor agonists, but it is not without risk. The ceiling effect\u2019s protective benefits depend on context. Therefore, despite its improved safety profile, buprenorphine should not be regarded as risk-free.<\/jats:p>","DOI":"10.3390\/ph19060903","type":"journal-article","created":{"date-parts":[[2026,6,8]],"date-time":"2026-06-08T07:43:02Z","timestamp":1780904582000},"page":"903","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Can Buprenorphine Be Overdosed? The Ceiling Effect and Its Clinical Implications"],"prefix":"10.3390","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-4798-2167","authenticated-orcid":false,"given":"Rozalia Beata","family":"Kozi\u0144ska","sequence":"first","affiliation":[{"name":"Scientific Society for Psychopharmacology, Department of Forensic Medicine, Wroclaw Medical University, Mikulicza-Radeckiego 4J, 50-345 Wroclaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-1528-6259","authenticated-orcid":false,"given":"Julia","family":"\u015al\u0119zak","sequence":"additional","affiliation":[{"name":"Scientific Society for Psychopharmacology, Department of Forensic Medicine, Wroclaw Medical University, Mikulicza-Radeckiego 4J, 50-345 Wroclaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-5130-2182","authenticated-orcid":false,"given":"Ignacy","family":"Ilski","sequence":"additional","affiliation":[{"name":"Scientific Society for Psychopharmacology, Department of Forensic Medicine, Wroclaw Medical University, Mikulicza-Radeckiego 4J, 50-345 Wroclaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maja","family":"Podsiad\u0142a","sequence":"additional","affiliation":[{"name":"Scientific Society for Psychopharmacology, Department of Forensic Medicine, Wroclaw Medical University, Mikulicza-Radeckiego 4J, 50-345 Wroclaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-2157-103X","authenticated-orcid":false,"given":"Kamil","family":"Biedka","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pathophysiology, Division of Pathophysiology, Wroclaw Medical University, Chalubinskiego 10, 50-368 Wroclaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2558-5191","authenticated-orcid":false,"given":"Emilia","family":"Kr\u00f3lewicz","sequence":"additional","affiliation":[{"name":"Department of Medical Biochemistry, Wroclaw Medical University, 50-368 Wroclaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1002\/wps.21073","article-title":"Substance Use Disorders: A Comprehensive Update of Classification, Epidemiology, Neurobiology, Clinical Aspects, Treatment and Prevention","volume":"22","author":"Volkow","year":"2023","journal-title":"World Psychiatry"},{"key":"ref_2","unstructured":"World Health Organisation (2023). World Drug Report, WHO."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Ju, J., Li, Z., Liu, J., Peng, X., and Gao, F. (2025). Biased Opioid Receptor Agonists: Balancing Analgesic Efficacy and Side-Effect Profiles. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26051862"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"813","DOI":"10.1111\/bph.15580","article-title":"Understanding and Countering Opioid-Induced Respiratory Depression","volume":"180","author":"Bateman","year":"2023","journal-title":"Br. J. Pharmacol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1899","DOI":"10.1152\/jn.00017.2021","article-title":"Neuronal Mechanisms Underlying Opioid-Induced Respiratory Depression: Our Current Understanding","volume":"125","author":"Ramirez","year":"2021","journal-title":"J. Neurophysiol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"e2022134118","DOI":"10.1073\/pnas.2022134118","article-title":"Neural Basis of Opioid-Induced Respiratory Depression and Its Rescue","volume":"118","author":"Liu","year":"2021","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"e638","DOI":"10.1016\/j.jpainsymman.2023.06.022","article-title":"Should Buprenorphine Be Considered a First-Line Opioid for the Treatment of Moderate to Severe Cancer Pain?","volume":"66","author":"Chwistek","year":"2023","journal-title":"J. Pain Symptom Manag."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"112389","DOI":"10.1016\/j.drugalcdep.2024.112389","article-title":"Buprenorphine Treatment and Clinical Outcomes under the Opioid Use Disorder Cascade of Care","volume":"263","author":"Williams","year":"2024","journal-title":"Drug Alcohol Depend."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"811","DOI":"10.1007\/s11916-023-01185-4","article-title":"Buprenorphine for Chronic Pain Management: A Narrative Review","volume":"27","author":"Vu","year":"2023","journal-title":"Curr. Pain Headache Rep."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1159\/000514192","article-title":"Quality of Life in Opioid Replacement Therapy: A Naturalistic Cross-Sectional Comparison of Methadone\/Levomethadone, Buprenorphine, and Diamorphine Patients","volume":"27","author":"Guillery","year":"2021","journal-title":"Eur. Addict. Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"714","DOI":"10.1093\/pm\/pnz356","article-title":"Understanding Buprenorphine for Use in Chronic Pain: Expert Opinion","volume":"21","author":"Webster","year":"2020","journal-title":"Pain Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1247","DOI":"10.1007\/s40122-025-00753-3","article-title":"Expanding Horizons of Buprenorphine: A Comprehensive Narrative Review of Its Pharmacological Properties and Clinical Applications in Chronic Pain","volume":"14","author":"Fornasari","year":"2025","journal-title":"Pain Ther."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Pande, L.J., Arnet, R.E., and Piper, B.J. (2023). An Examination of the Complex Pharmacological Properties of the Non-Selective Opioid Modulator Buprenorphine. Pharmaceuticals, 16.","DOI":"10.3390\/ph16101397"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Infantino, R., Mattia, C., Locarini, P., Pastore, A.L., Maione, S., and Luongo, L. (2021). Buprenorphine: Far Beyond the \u201cCeiling\u201d. Biomolecules, 11.","DOI":"10.3390\/biom11060816"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1001\/archpsyc.1978.01770280111012","article-title":"Human Pharmacology and Abuse Potential of the Analgesic Buprenorphine: A Potential Agent for Treating Narcotic Addiction","volume":"35","author":"Jasinski","year":"1978","journal-title":"Arch. Gen. Psychiatry"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1111\/j.1749-6632.2011.06352.x","article-title":"The History of the Development of Buprenorphine as an Addiction Therapeutic","volume":"1248","author":"Campbell","year":"2012","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"37517","DOI":"10.52965\/001c.37517","article-title":"Buprenorphine and Its Formulations: A Comprehensive Review","volume":"10","author":"Poliwoda","year":"2022","journal-title":"Health Psychol. Res."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Blazes, C.K., and Morrow, J.D. (2020). Reconsidering the Usefulness of Adding Naloxone to Buprenorphine. Front. Psychiatry, 11.","DOI":"10.3389\/fpsyt.2020.549272"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"310","DOI":"10.1213\/ANE.0000000000003368","article-title":"Lack of Evidence for Ceiling Effect for Buprenorphine Analgesia in Humans","volume":"127","author":"Richardson","year":"2018","journal-title":"Anesth. Analg."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"592","DOI":"10.1007\/s12663-022-01841-z","article-title":"Role Safety Profile of Buprenorphine Due to Ceiling Effect in the Era of Abuse Impediment Formulations","volume":"24","author":"Bhagat","year":"2025","journal-title":"J. Maxillofac. Oral Surg."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1016\/j.jsat.2019.07.002","article-title":"Effects of Ascending Buprenorphine Doses on Measures of Experimental Pain: A Pilot Study","volume":"104","author":"Nielsen","year":"2019","journal-title":"J. Subst. Abus. Treat."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1007\/s40265-024-02128-y","article-title":"Buprenorphine Pharmacodynamics: A Bridge to Understanding Buprenorphine Clinical Benefits","volume":"85","author":"Davis","year":"2025","journal-title":"Drugs"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2063","DOI":"10.1007\/s00213-022-06125-5","article-title":"Treatment of Opioid Overdose: Current Approaches and Recent Advances","volume":"239","author":"Britch","year":"2022","journal-title":"Psychopharmacology"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"100131","DOI":"10.1016\/j.dadr.2023.100131","article-title":"Buprenorphine Involvement in Opioid Overdose Deaths: A Retrospective Analysis of Postmortem Toxicology in Marion County, Indiana, 2015\u20132021","volume":"6","author":"Atkins","year":"2023","journal-title":"Drug Alcohol Depend. Rep."},{"key":"ref_25","unstructured":"Kumar, R., Viswanath, O., and Saadabadi, A. (2026). Buprenorphine. StatPearls, StatPearls Publishing."},{"key":"ref_26","first-page":"10","article-title":"Opioid Overdose Deaths with Buprenorphine Detected in Postmortem Toxicology: A Retrospective Analysis","volume":"17","author":"Wightman","year":"2021","journal-title":"J. Med. Toxicol. Off. J. Am. Coll. Med. Toxicol."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Moss, L.M., Algera, M.H., Dobbins, R., Gray, F., Strafford, S., Heath, A., van Velzen, M., Heuberger, J.A.A.C., Niesters, M., and Olofsen, E. (2022). Effect of Sustained High Buprenorphine Plasma Concentrations on Fentanyl-Induced Respiratory Depression: A Placebo-Controlled Crossover Study in Healthy Volunteers and Opioid-Tolerant Patients. PLoS ONE, 17.","DOI":"10.1371\/journal.pone.0256752"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"e2211634","DOI":"10.1001\/jamanetworkopen.2022.11634","article-title":"Analysis of Stimulant Prescriptions and Drug-Related Poisoning Risk Among Persons Receiving Buprenorphine Treatment for Opioid Use Disorder","volume":"5","author":"Mintz","year":"2022","journal-title":"JAMA Netw. Open"},{"key":"ref_29","unstructured":"Regina, A.C., Goyal, A., and Mechanic, O.J. (2026). Opioid Toxicity. StatPearls, StatPearls Publishing."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1385","DOI":"10.1021\/acschemneuro.0c00100","article-title":"Classics in Chemical Neuroscience: Buprenorphine","volume":"11","author":"Kyzer","year":"2020","journal-title":"ACS Chem. Neurosci."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"675","DOI":"10.1517\/17425255.2013.783567","article-title":"Metabolic and Toxicological Considerations of the Opioid Replacement Therapy and Analgesic Drugs: Methadone and Buprenorphine","volume":"9","author":"Moody","year":"2013","journal-title":"Expert Opin. Drug Metab. Toxicol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1007\/s40122-019-00143-6","article-title":"A Narrative Pharmacological Review of Buprenorphine: A Unique Opioid for the Treatment of Chronic Pain","volume":"9","author":"Gudin","year":"2020","journal-title":"Pain Ther."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"668","DOI":"10.1111\/bph.12796","article-title":"BU08073 a Buprenorphine Analogue with Partial Agonist Activity at \u03bc-Receptors in Vitro but Long-Lasting Opioid Antagonist Activity in Vivo in Mice","volume":"172","author":"Khroyan","year":"2015","journal-title":"Br. J. Pharmacol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1007\/s00425-014-2056-8","article-title":"Benzylisoquinoline Alkaloid Biosynthesis in Opium Poppy","volume":"240","author":"Beaudoin","year":"2014","journal-title":"Planta"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1002\/jcph.1923","article-title":"Clinical Pharmacology, Toxicity, and Abuse Potential of Opioids","volume":"61","author":"Vearrier","year":"2021","journal-title":"J. Clin. Pharmacol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1007\/s11864-021-00910-8","article-title":"Treating Chronic Pain with Buprenorphine-The Practical Guide","volume":"22","author":"Case","year":"2021","journal-title":"Curr. Treat. Options Oncol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"27241","DOI":"10.52965\/001c.27241","article-title":"Buprenorphine for Chronic Pain: A Safer Alternative to Traditional Opioids","volume":"9","author":"Dalal","year":"2021","journal-title":"Health Psychol. Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"3691","DOI":"10.1093\/pm\/pnaa089","article-title":"Is Buprenorphine Effective for Chronic Pain? A Systematic Review and Meta-Analysis","volume":"21","author":"Lazaridou","year":"2020","journal-title":"Pain Med."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Lee, Y.K., Gold, M.S., Blum, K., Thanos, P.K., Hanna, C., and Fuehrlein, B.S. (2023). Opioid Use Disorder: Current Trends and Potential Treatments. Front. Public Health, 11.","DOI":"10.3389\/fpubh.2023.1274719"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"358","DOI":"10.1016\/j.clinthera.2015.12.016","article-title":"Evaluation of the Pharmacokinetics of Single- and Multiple-Dose Buprenorphine Buccal Film in Healthy Volunteers","volume":"38","author":"Bai","year":"2016","journal-title":"Clin. Ther."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1460","DOI":"10.1111\/j.1360-0443.2011.03424.x","article-title":"The Pharmacodynamic and Pharmacokinetic Profile of Intranasal Crushed Buprenorphine and Buprenorphine\/Naloxone Tablets in Opioid Abusers","volume":"106","author":"Middleton","year":"2011","journal-title":"Addiction"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1211","DOI":"10.1007\/s40265-018-0953-z","article-title":"Treating Chronic Pain: An Overview of Clinical Studies Centered on the Buprenorphine Option","volume":"78","author":"Davis","year":"2018","journal-title":"Drugs"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1186\/s13321-018-0324-5","article-title":"BioTransformer: A Comprehensive Computational Tool for Small Molecule Metabolism Prediction and Metabolite Identification","volume":"11","author":"Fiamoncini","year":"2019","journal-title":"J. Cheminform."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Jain, L., Meeks, T.W., and Blazes, C.K. (2024). Reconsidering the Usefulness of Long-Term High-Dose Buprenorphine. Front. Psychiatry, 15.","DOI":"10.3389\/fpsyt.2024.1401676"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1097\/ADM.0000000000000457","article-title":"Buprenorphine Pharmacology Review: Update on Transmucosal and Long-Acting Formulations","volume":"13","author":"Coe","year":"2019","journal-title":"J. Addict. Med."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"500","DOI":"10.1111\/j.2042-7158.1981.tb13848.x","article-title":"The Systemic Bioavailability of Buprenorphine by Various Routes of Administration","volume":"33","author":"Brewster","year":"1981","journal-title":"J. Pharm. Pharmacol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1097\/ADM.0000000000001189","article-title":"Evidence on Buprenorphine Dose Limits: A Review","volume":"17","author":"Grande","year":"2023","journal-title":"J. Addict. Med."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"e2117128","DOI":"10.1001\/jamanetworkopen.2021.17128","article-title":"High-Dose Buprenorphine Induction in the Emergency Department for Treatment of Opioid Use Disorder","volume":"4","author":"Herring","year":"2021","journal-title":"JAMA Netw. Open"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"675","DOI":"10.1016\/j.amjms.2022.06.025","article-title":"A Review of the Safety of Buprenorphine in Special Populations","volume":"364","author":"Brandt","year":"2022","journal-title":"Am. J. Med. Sci."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1213\/ANE.0000000000006467","article-title":"Analgesic Effect of Buprenorphine for Chronic Noncancer Pain: A Systematic Review and Meta-Analysis of Randomized Controlled Trials","volume":"137","author":"Wong","year":"2023","journal-title":"Anesth. Analg."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1016\/j.bja.2021.12.001","article-title":"Buprenorphine: A Treatment and Cause of Opioid-Induced Respiratory Depression","volume":"128","author":"Dahan","year":"2022","journal-title":"Br. J. Anaesth."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1064","DOI":"10.1002\/cpdd.934","article-title":"Evaluation of Drug-Drug Interaction Liability for Buprenorphine Extended-Release Monthly Injection Administered by Subcutaneous Route","volume":"10","author":"Kharidia","year":"2021","journal-title":"Clin. Pharmacol. Drug Dev."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"847","DOI":"10.1007\/s00406-019-01091-0","article-title":"Buprenorphine-Cannabis Interaction in Patients Undergoing Opioid Maintenance Therapy","volume":"271","author":"Vierke","year":"2021","journal-title":"Eur. Arch. Psychiatry Clin. Neurosci."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1120","DOI":"10.1002\/cpt.2717","article-title":"Identifying Clinically Relevant Drug-Drug Interactions with Methadone and Buprenorphine: A Translational Approach to Signal Detection","volume":"112","author":"Miano","year":"2022","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1007\/s11904-010-0048-2","article-title":"Methadone, Buprenorphine, and Street Drug Interactions with Antiretroviral Medications","volume":"7","author":"Gruber","year":"2010","journal-title":"Curr. HIV\/AIDS Rep."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1111\/j.1521-0391.2009.00005.x","article-title":"Drug Interactions of Clinical Importance among the Opioids, Methadone and Buprenorphine, and Other Frequently Prescribed Medications: A Review","volume":"19","author":"Sullivan","year":"2010","journal-title":"Am. J. Addict."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1186\/s40981-022-00535-2","article-title":"Postoperative Respiratory Depression in Patients on Sublingual Buprenorphine: A Retrospective Cohort Study for Comparison between Postoperative Continuation and Discontinuation of Buprenorphine","volume":"8","author":"Komatsu","year":"2022","journal-title":"JA Clin. Rep."},{"key":"ref_58","first-page":"21","article-title":"Transmucosal Buprenorphine in the Treatment of Dyspnea: Case Series and Review of the Literature","volume":"2","author":"Bullis","year":"2021","journal-title":"Palliat. Med. Rep."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1016\/j.annemergmed.2022.07.006","article-title":"Impact of Administering Buprenorphine to Overdose Survivors Using Emergency Medical Services","volume":"81","author":"Carroll","year":"2023","journal-title":"Ann. Emerg. Med."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1016\/j.neubiorev.2021.11.019","article-title":"Alcohol-Medication Interactions: A Systematic Review and Meta-Analysis of Placebo-Controlled Trials","volume":"132","author":"Traccis","year":"2022","journal-title":"Neurosci. Biobehav. Rev."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1186\/s13011-023-00538-x","article-title":"Drug Use Patterns and Factors Related to the Use and Discontinuation of Medications for Opioid Use Disorder in the Age of Fentanyl: Findings from a Mixed-Methods Study of People Who Use Drugs","volume":"18","author":"Hughto","year":"2023","journal-title":"Subst. Abus. Treat. Prev. Policy"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1097\/JCP.0000000000001707","article-title":"A Rare Case of Serotonin Syndrome with Buprenorphine and Other Serotonergic Medications","volume":"43","author":"Biedlingmaier","year":"2023","journal-title":"J. Clin. Psychopharmacol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"97","DOI":"10.21037\/acr-24-40","article-title":"Recognizing Serotonin Syndrome in the Intensive Care Unit: A Case Report of Serotonin Syndrome in a Patient Taking Amitriptyline, Buprenorphine, Pregabalin, and Fentanyl","volume":"8","author":"Orhun","year":"2024","journal-title":"AME Case Rep."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1007\/164_2020_396","article-title":"The Role of Dynorphin and the Kappa Opioid Receptor in Schizophrenia and Major Depressive Disorder: A Translational Approach","volume":"271","author":"Clark","year":"2022","journal-title":"Handb. Exp. Pharmacol."},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"Fakhri, A., Ritvo, A., Casarella, J., and Tang, Y.-L. (2025). Opioid Use Disorder and Concurrent Benzodiazepine Use: Clinical Risks and Management Strategies. J. Addict. Dis., 1\u20138.","DOI":"10.1080\/10550887.2025.2593244"},{"key":"ref_66","unstructured":"Voss, R.M., and Das, J.M. (2026). Mental Status Examination. StatPearls, StatPearls Publishing."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1097\/CNQ.0000000000000262","article-title":"Clinical Opioid Withdrawal Scale (COWS): Implementation and Outcomes","volume":"42","author":"Canamo","year":"2019","journal-title":"Crit. Care Nurs. Q."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"j1550","DOI":"10.1136\/bmj.j1550","article-title":"Mortality Risk during and after Opioid Substitution Treatment: Systematic Review and Meta-Analysis of Cohort Studies","volume":"357","author":"Sordo","year":"2017","journal-title":"BMJ"},{"key":"ref_69","doi-asserted-by":"crossref","unstructured":"(2020). The ASAM National Practice Guideline for the Treatment of Opioid Use Disorder: 2020 Focused Update. J. Addict. Med., 14, 1\u201391.","DOI":"10.1097\/ADM.0000000000000633"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"764","DOI":"10.1111\/fcp.12630","article-title":"Buprenorphine Exposures in Adolescents and Adults: A 10-Year Experience of a French Poison Control Center","volume":"35","author":"Boulamery","year":"2021","journal-title":"Fundam. Clin. Pharmacol."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"209053","DOI":"10.1016\/j.josat.2023.209053","article-title":"Buprenorphine and Opioid Analgesics: Dispensation and Discontinuity among Accidental Overdose Fatalities in the Indianapolis Metropolitan Area, 2016-2021","volume":"150","author":"Victor","year":"2023","journal-title":"J. Subst. Use Addict. Treat."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"81","DOI":"10.2165\/00003495-197917020-00001","article-title":"Buprenorphine: A Review of Its Pharmacological Properties and Therapeutic Efficacy","volume":"17","author":"Heel","year":"1979","journal-title":"Drugs"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"352","DOI":"10.1136\/spcare-2025-005984","article-title":"Buprenorphine in Palliative Care","volume":"16","author":"Davis","year":"2026","journal-title":"BMJ Support. Palliat. Care"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1016\/j.tox.2013.01.013","article-title":"Gender and Strain Contributions to the Variability of Buprenorphine-Related Respiratory Toxicity in Mice","volume":"305","author":"Alhaddad","year":"2013","journal-title":"Toxicology"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1016\/j.taap.2005.08.002","article-title":"Buprenorphine Is Protective against the Depressive Effects of Norbuprenorphine on Ventilation","volume":"212","author":"Marie","year":"2006","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"584","DOI":"10.1016\/j.bja.2021.10.029","article-title":"Mechanisms of Respiratory Depression Induced by the Combination of Buprenorphine and Diazepam in Rats","volume":"128","author":"Vodovar","year":"2022","journal-title":"Br. J. Anaesth."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1177\/0271678X231221040","article-title":"Brain PET Imaging Using 11C-Flumazenil and 11C-Buprenorphine Does Not Support the Hypothesis of a Mutual Interaction between Buprenorphine and Benzodiazepines at the Neuroreceptor Level","volume":"44","author":"Auvity","year":"2024","journal-title":"J. Cereb. Blood Flow Metab. Off. J. Int. Soc. Cereb. Blood Flow Metab."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1093\/toxsci\/kfw221","article-title":"Editor\u2019s Highlight: Neurorespiratory Effects of Buprenorphine and Ethanol in Combination: A Mechanistic Study of Drug-Drug Interactions in the Rat","volume":"155","author":"Cohier","year":"2017","journal-title":"Toxicol. Sci. Off. J. Soc. Toxicol."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1111\/fcp.12518","article-title":"Buprenorphine Poisoning in Children: A 10-Year-Experience of Marseille Poison Center","volume":"34","author":"Boulamery","year":"2020","journal-title":"Fundam. Clin. Pharmacol."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1016\/j.annepidem.2019.12.011","article-title":"Epidemiology of Pediatric Buprenorphine and Methadone Exposures Reported to the Poison Centers","volume":"42","author":"Rege","year":"2020","journal-title":"Ann. Epidemiol."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"e782","DOI":"10.1542\/peds.2007-1774","article-title":"Toxicity of Buprenorphine Overdoses in Children","volume":"121","author":"Hayes","year":"2008","journal-title":"Pediatrics"},{"key":"ref_82","unstructured":"Euwema, M.S., and Swanson, T.J. (2026). Deadly Single Dose Agents. StatPearls, StatPearls Publishing."},{"key":"ref_83","unstructured":"Spyres, M., and Makar, G. (2021). The ToxIC NOSE (Novel Opioid and Stimulant Exposure), American College of Medical Toxicology."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"2996","DOI":"10.1111\/bcp.15196","article-title":"An Unusual Case of Buprenorphine Overdose Secondary to Sibling Play: Examining How Medication Delivery Devices Appear to Children","volume":"88","author":"McCartan","year":"2022","journal-title":"Br. J. Clin. Pharmacol."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"212","DOI":"10.1097\/ADM.0000000000001279","article-title":"The Devil\u2019s in the Depot Details: Case of Iatrogenic Opioid Intoxication After Buprenorphine Injection Requiring Surgical Excision","volume":"18","author":"Vais","year":"2024","journal-title":"J. Addict. Med."},{"key":"ref_86","doi-asserted-by":"crossref","unstructured":"Walde, J., Andersson, L., Johnson, B., and H\u00e5kansson, A. (2023). Drug Prescriptions Preceding Opioid-Related Deaths-a Register Study in Forensic Autopsy Patients. PLoS ONE, 18.","DOI":"10.1371\/journal.pone.0285583"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1097\/PHH.0000000000001210","article-title":"Prescription History Before Opioid Overdose Death: PDMP Data and Responsible Prescribing","volume":"27","author":"Shreffler","year":"2021","journal-title":"J. Public Health Manag. Pract."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"2331","DOI":"10.1007\/s00414-024-03273-5","article-title":"Buprenorphine Deaths Confirmed by Toxicology Reveal a Low Proportion of Opioid Agonist Treatment before Death in Finland","volume":"138","author":"Mariottini","year":"2024","journal-title":"Int. J. Leg. Med."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"342","DOI":"10.1097\/ALN.0000000000004622","article-title":"Opioid Overdose: Limitations in Naloxone Reversal of Respiratory Depression and Prevention of Cardiac Arrest","volume":"139","author":"Florian","year":"2023","journal-title":"Anesthesiology"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1111\/acps.13477","article-title":"A Comparison of Mortality Rates for Buprenorphine versus Methadone Treatments for Opioid Use Disorder","volume":"147","author":"Gottlieb","year":"2023","journal-title":"Acta Psychiatr. Scand."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1097\/ADM.0000000000001300","article-title":"Higher First 30-Day Dose of Buprenorphine for Opioid Use Disorder Treatment Is Associated with Decreased Mortality","volume":"18","author":"Lei","year":"2024","journal-title":"J. Addict. Med."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1016\/j.ajem.2021.08.071","article-title":"Tele-Buprenorphine for Emergency Department Overdose Visit Follow up and Treatment Initiation","volume":"50","author":"Wightman","year":"2021","journal-title":"Am. J. Emerg. Med."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"e2215287","DOI":"10.1001\/jamanetworkopen.2022.15287","article-title":"Trends and Disparities in Access to Buprenorphine Treatment Following an Opioid-Related Emergency Department Visit Among an Insured Cohort, 2014\u20132020","volume":"5","author":"Stevens","year":"2022","journal-title":"JAMA Netw. Open"},{"key":"ref_94","first-page":"771","article-title":"Post-Overdose Extended-Release Buprenorphine Initiation Facilitated by a Partnership Between Emergency Medical Services and an Outpatient Substance Use Disorder Observation Unit","volume":"45","author":"Taylor","year":"2024","journal-title":"Subst. Use Addict. J."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"e265","DOI":"10.1097\/ADM.0000000000000922","article-title":"Evidence of Buprenorphine-Precipitated Withdrawal in Persons Who Use Fentanyl","volume":"16","author":"Varshneya","year":"2022","journal-title":"J. Addict. Med."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"e2435895","DOI":"10.1001\/jamanetworkopen.2024.35895","article-title":"Buprenorphine-Precipitated Withdrawal Among Hospitalized Patients Using Fentanyl","volume":"7","author":"Thakrar","year":"2024","journal-title":"JAMA Netw. Open"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1111\/add.16646","article-title":"Incidence of Buprenorphine-Precipitated Opioid Withdrawal in Adults with Opioid Use Disorder: A Systematic Review","volume":"120","author":"Gregory","year":"2025","journal-title":"Addiction"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"e2552136","DOI":"10.1001\/jamanetworkopen.2025.52136","article-title":"Barriers to Buprenorphine Initiation in Patients Using Fentanyl","volume":"9","author":"Kawasaki","year":"2026","journal-title":"JAMA Netw. Open"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1186\/s12954-024-00998-9","article-title":"Withdrawal during Outpatient Low Dose Buprenorphine Initiation in People Who Use Fentanyl: A Retrospective Cohort Study","volume":"21","author":"Jones","year":"2024","journal-title":"Harm. Reduct. J."},{"key":"ref_100","doi-asserted-by":"crossref","unstructured":"Papa, A., Salzano, A.M., Di Dato, M.T., Desiderio, V., Buonavolont\u00e0, P., Mango, P., Saracco, E., Tammaro, D., Luongo, L., and Maione, S. (2024). Long-Term Efficacy and Reduced Side-Effects of Buprenorphine in Patients with Moderate and Severe Chronic Pain. Front. Pharmacol., 15.","DOI":"10.3389\/fphar.2024.1454601"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1111\/add.16701","article-title":"Commentary on Gregory et al.: Fear of Precipitated Opioid Withdrawal Should Not Prevent Buprenorphine Initiation","volume":"120","author":"Springer","year":"2025","journal-title":"Addiction"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"695","DOI":"10.1177\/29767342251326339","article-title":"Medications for Opioid Use Disorder: Patients\u2019 Experience, Knowledge, and Preferences in the Era of Illicitly Manufactured Fentanyl","volume":"46","author":"Casey","year":"2025","journal-title":"Subst. Use Addict. J."},{"key":"ref_103","first-page":"74","article-title":"Assessing Opioid Overdose Risk: A Review of Clinical Prediction Models Utilizing Patient-Level Data","volume":"234","author":"Tseregounis","year":"2021","journal-title":"Transl. Res. J. Lab. Clin. Med."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1016\/j.ajem.2024.11.031","article-title":"Initiation of Buprenorphine in the Emergency Department or Emergency Out-of-Hospital Setting: A Mixed-Methods Systematic Review","volume":"88","author":"Armour","year":"2025","journal-title":"Am. J. Emerg. 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