{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,9,16]],"date-time":"2025-09-16T16:25:33Z","timestamp":1758039933940,"version":"3.44.0"},"reference-count":43,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,9,11]],"date-time":"2025-09-11T00:00:00Z","timestamp":1757548800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>Analgesic selection following orthopedic trauma presents unique challenges due to potential drug interactions and physiological stress. The impact of different analgesic regimens - buprenorphine, cannabidiol (CBD), their combination, or vehicle - on survival was investigated in a murine model of tibial fracture.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Eighty male C57BL\/6 mice were randomly assigned to one of four group: (1) Buprenorphine (0.1\u00a0mg\/kg, administered subcutaneously every 12\u00a0h for 3\u00a0days) plus cannabidiol (CBD, 100\u00a0mg\/kg, administered intraperitoneally once daily for 7\u00a0days); (2) CBD only; (3) Buprenorphine + vehicle; or (4) Vehicle only. All animals also received carprofen (20\u00a0mg\/kg, subcutaneously, once daily for 3\u00a0days). Survival was monitored over 7\u00a0days post-injury, and necropsies were performed to identify probable causes of death.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Following an orthopedic trauma, mice that received buprenorphine plus CBD exhibited significantly lower survival than those that received either treatment alone or vehicle only (p = 0.0049 and p = 0.02, respectively). No differences were noted between the other groups. Necropsy revealed gastrointestinal complications in most fatalities, while two deaths were linked to acute respiratory arrest post-injection.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>These findings suggest that while buprenorphine and CBD are individually well-tolerated, their co-administration may increase the risk of adverse outcomes in murine orthopedic trauma models. Combining cannabinoids and opioids in translational research requires caution and emphasizes the need for mechanistic evaluation in preclinical models.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fphar.2025.1683842","type":"journal-article","created":{"date-parts":[[2025,9,11]],"date-time":"2025-09-11T05:26:04Z","timestamp":1757568364000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Buprenorphine and cannabidiol co-administration reduces survival in a mouse model of orthopedic trauma"],"prefix":"10.3389","volume":"16","author":[{"given":"Caroline","family":"Bouchard","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Genevi\u00e8ve","family":"Fr\u00e9geau","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ian","family":"Mass\u00e9","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Louis","family":"De Beaumont","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2025,9,11]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"114793","DOI":"10.1016\/j.bbr.2023.114793","article-title":"Antinociceptive action of cannabidiol on thermal sensitivity and post-operative pain in male and female rats","volume":"459","author":"Arantes","year":"2024","journal-title":"Behav. Brain Res."},{"key":"B2","doi-asserted-by":"publisher","first-page":"1087011","DOI":"10.3389\/fneur.2023.1087011","article-title":"Cannabidiol's neuroprotective properties and potential treatment of traumatic brain injuries","volume":"14","author":"Aychman","year":"2023","journal-title":"Front. Neurol."},{"key":"B3","doi-asserted-by":"publisher","first-page":"237","DOI":"10.2174\/157488611798280924","article-title":"Safety and side effects of cannabidiol, a Cannabis sativa constituent","volume":"6","author":"Bergamaschi","year":"2011","journal-title":"Curr. Drug Saf."},{"key":"B4","doi-asserted-by":"publisher","first-page":"364","DOI":"10.3390\/diagnostics13030364","article-title":"The role of physical exercise and rehabilitative implications in the process of nerve repair in peripheral neuropathies: a systematic review","volume":"13","author":"Chiaramonte","year":"2023","journal-title":"Diagn. (Basel)"},{"key":"B5","doi-asserted-by":"publisher","first-page":"87","DOI":"10.1016\/j.ejphar.2004.11.052","article-title":"Broad analgesic profile of buprenorphine in rodent models of acute and chronic pain","volume":"507","author":"Christoph","year":"2005","journal-title":"Eur. J. Pharmacol."},{"key":"B6","doi-asserted-by":"publisher","first-page":"515","DOI":"10.2147\/TCRM.S79409","article-title":"The unsolved case of bone-impairing analgesics: the endocrine effects of opioids on bone metabolism","volume":"11","author":"Coluzzi","year":"2015","journal-title":"Ther. Clin. Risk Manag."},{"key":"B7","doi-asserted-by":"publisher","first-page":"6682","DOI":"10.3390\/ijms25126682","article-title":"Effects of cannabinoids on intestinal motility, barrier permeability, and therapeutic potential in gastrointestinal diseases","volume":"25","author":"Crowley","year":"2024","journal-title":"Int. J. Mol. Sci."},{"key":"B8","doi-asserted-by":"publisher","first-page":"1027","DOI":"10.1097\/ALN.0000000000002184","article-title":"Averting opioid-induced respiratory depression without affecting analgesia","volume":"128","author":"Dahan","year":"2018","journal-title":"Anesthesiology"},{"key":"B9","doi-asserted-by":"publisher","first-page":"11286","DOI":"10.1038\/s41598-022-15134-5","article-title":"Effects of chronic cannabidiol in a mouse model of naturally occurring neuroinflammation, neurodegeneration, and spontaneous seizures","volume":"12","author":"Dearborn","year":"2022","journal-title":"Sci. Rep."},{"key":"B10","doi-asserted-by":"publisher","first-page":"699","DOI":"10.1056\/NEJMc1708349","article-title":"Trial of cannabidiol for drug-resistant seizures in the Dravet syndrome","volume":"377","author":"Devinsky","year":"2017","journal-title":"N. Engl. J. Med."},{"key":"B11","doi-asserted-by":"publisher","first-page":"1888","DOI":"10.1056\/NEJMoa1714631","article-title":"Effect of cannabidiol on drop seizures in the lennox-gastaut syndrome","volume":"378","author":"Devinsky","year":"","journal-title":"N. Engl. J. Med."},{"key":"B12","doi-asserted-by":"publisher","first-page":"e1204","DOI":"10.1212\/WNL.0000000000005254","article-title":"Randomized, dose-ranging safety trial of cannabidiol in Dravet syndrome","volume":"90","author":"Devinsky","year":"","journal-title":"Neurology"},{"key":"B13","doi-asserted-by":"publisher","first-page":"208","DOI":"10.3389\/fnagi.2017.00208","article-title":"Microglial activation in traumatic brain injury","volume":"9","author":"Donat","year":"2017","journal-title":"Front. Aging Neurosci."},{"key":"B14","doi-asserted-by":"publisher","first-page":"e2009","DOI":"10.1089\/neu.2023.0539","article-title":"Cannabidiol alleviates neurological deficits after traumatic brain injury by improving intracranial lymphatic drainage","volume":"41","author":"Dong","year":"2024","journal-title":"J. Neurotrauma"},{"key":"B15","doi-asserted-by":"publisher","first-page":"283","DOI":"10.1089\/can.2022.0011","article-title":"Cannabidiol impairs brain mitochondrial metabolism and neuronal integrity","volume":"8","author":"Drummond-Main","year":"2023","journal-title":"Cannabis Cannabinoid Res."},{"key":"B16","doi-asserted-by":"publisher","first-page":"178","DOI":"10.1097\/01.rhu.0000128851.12010.46","article-title":"Risk of upper gastrointestinal injury and events in patients treated with cyclooxygenase (COX)-1\/COX-2 nonsteroidal antiinflammatory drugs (NSAIDs), COX-2 selective NSAIDs, and gastroprotective cotherapy: an appraisal of the literature","volume":"10","author":"Dubois","year":"2004","journal-title":"J. Clin. Rheumatol."},{"key":"B17","doi-asserted-by":"publisher","first-page":"1694","DOI":"10.3390\/molecules24091694","article-title":"Hepatotoxicity of a cannabidiol-rich cannabis extract in the mouse model","volume":"24","author":"Ewing","year":"2019","journal-title":"Molecules"},{"key":"B18","doi-asserted-by":"publisher","first-page":"113844","DOI":"10.1016\/j.expneurol.2021.113844","article-title":"Cannabidiol reduces lesion volume and restores vestibulomotor and cognitive function following moderately severe traumatic brain injury","volume":"346","author":"Friedman","year":"2021","journal-title":"Exp. Neurol."},{"key":"B19","first-page":"8","article-title":"The magnitude and duration of the analgesic effect of morphine, butorphanol, and buprenorphine in rats and mice","volume":"39","author":"Gades","year":"2000","journal-title":"Contemp. Top. Lab. Anim. Sci."},{"key":"B20","doi-asserted-by":"publisher","first-page":"385","DOI":"10.2147\/JPR.S342627","article-title":"Pain management strategies after orthopaedic trauma: a mixed-methods study with a view to optimizing practices","volume":"15","author":"Grzelak","year":"2022","journal-title":"J. Pain Res."},{"key":"B21","doi-asserted-by":"publisher","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":"B22","doi-asserted-by":"publisher","first-page":"535","DOI":"10.30802\/AALAS-CM-19-000013","article-title":"Influence of pain and analgesia on orthopedic and wound-healing models in rats and mice","volume":"69","author":"Huss","year":"2019","journal-title":"Comp. Med."},{"key":"B23","doi-asserted-by":"publisher","first-page":"238","DOI":"10.1016\/j.neuropharm.2017.12.032","article-title":"Progress in understanding mechanisms of opioid-induced gastrointestinal adverse effects and respiratory depression","volume":"131","author":"Imam","year":"2018","journal-title":"Neuropharmacology"},{"key":"B24","doi-asserted-by":"publisher","first-page":"11229","DOI":"10.1073\/pnas.1711351114","article-title":"Cannabidiol attenuates seizures and social deficits in a mouse model of Dravet syndrome","volume":"114","author":"Kaplan","year":"2017","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"B25","doi-asserted-by":"publisher","first-page":"1560","DOI":"10.1002\/jbmr.4902","article-title":"Cannabidiol and cannabigerol, nonpsychotropic cannabinoids, as analgesics that effectively manage bone fracture pain and promote healing in mice","volume":"38","author":"Khajuria","year":"2023","journal-title":"J. Bone Min. Res."},{"key":"B26","doi-asserted-by":"publisher","first-page":"859","DOI":"10.2147\/JPR.S85951","article-title":"Buprenorphine - an attractive opioid with underutilized potential in treatment of chronic pain","volume":"8","author":"Khanna","year":"2015","journal-title":"J. Pain Res."},{"key":"B27","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1186\/s40798-020-00251-0","article-title":"Cannabidiol and sports performance: a narrative review of relevant evidence and recommendations for future research","volume":"6","author":"Mccartney","year":"2020","journal-title":"Sports Med. Open"},{"key":"B28","doi-asserted-by":"publisher","first-page":"e386","DOI":"10.1016\/S1473-3099(23)00503-0","article-title":"The global burden of fracture-related infection: can we do better?","volume":"24","author":"Metsemakers","year":"2024","journal-title":"Lancet Infect. Dis."},{"key":"B29","doi-asserted-by":"publisher","first-page":"1888","DOI":"10.1111\/bcp.14038","article-title":"A systematic review of cannabidiol dosing in clinical populations","volume":"85","author":"Millar","year":"2019","journal-title":"Br. J. Clin. Pharmacol."},{"key":"B30","doi-asserted-by":"publisher","first-page":"8870","DOI":"10.3390\/ijms21228870","article-title":"Cannabidiol for pain treatment: focus on pharmacology and mechanism of action","volume":"21","author":"Mlost","year":"2020","journal-title":"Int. J. Mol. Sci."},{"key":"B31","doi-asserted-by":"publisher","first-page":"439","DOI":"10.1111\/bcpt.13710","article-title":"A narrative review of molecular mechanism and therapeutic effect of cannabidiol (CBD)","volume":"130","author":"Peng","year":"2022","journal-title":"Basic Clin. Pharmacol. Toxicol."},{"key":"B32","doi-asserted-by":"publisher","first-page":"7730","DOI":"10.1038\/s41467-024-51884-8","article-title":"Cannabidiol ameliorates mitochondrial disease via PPAR\u03b3 activation in preclinical models","volume":"15","author":"Puighermanal","year":"2024","journal-title":"Nat. Commun."},{"key":"B33","doi-asserted-by":"publisher","first-page":"659","DOI":"10.1096\/fj.07-9574LSF","article-title":"Dose translation from animal to human studies revisited","volume":"22","author":"Reagan-Shaw","year":"2008","journal-title":"FASEB J."},{"key":"B34","doi-asserted-by":"publisher","first-page":"707","DOI":"10.1002\/jor.25791","article-title":"NSAID use in orthopedic surgery: a review of current evidence and clinical practice guidelines","volume":"42","author":"Ryan","year":"2024","journal-title":"J. Orthop. Res."},{"key":"B35","doi-asserted-by":"publisher","first-page":"1609","DOI":"10.3390\/pharmaceutics14081609","article-title":"Cannabidiol reduces Short- and long-term high glutamate release after severe traumatic brain injury and improves functional recovery","volume":"14","author":"Santiago-Castaneda","year":"2022","journal-title":"Pharmaceutics"},{"key":"B36","doi-asserted-by":"publisher","first-page":"287","DOI":"10.1258\/la.2012.012058","article-title":"Optimizing the dosing interval of buprenorphine in a multimodal postoperative analgesic strategy in the rat: minimizing side-effects without affecting weight gain and food intake","volume":"46","author":"Schaap","year":"2012","journal-title":"Lab. Anim."},{"key":"B37","doi-asserted-by":"publisher","first-page":"567","DOI":"10.1007\/s40263-019-00637-z","article-title":"Buprenorphine treatment for opioid use disorder: an overview","volume":"33","author":"Shulman","year":"2019","journal-title":"CNS Drugs"},{"key":"B38","doi-asserted-by":"publisher","first-page":"531939","DOI":"10.3389\/fneur.2020.531939","article-title":"Cannabidiol in the treatment of epilepsy: a focused review of evidence and gaps","volume":"11","author":"Silva","year":"2020","journal-title":"Front. Neurol."},{"key":"B39","doi-asserted-by":"publisher","first-page":"105496","DOI":"10.1016\/j.yrtph.2023.105496","article-title":"Subchronic oral toxicity assessment of a cannabis extract","volume":"144","author":"Tallon","year":"2023","journal-title":"Regul. Toxicol. Pharmacol."},{"key":"B40","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.bbi.2016.03.010","article-title":"The blood-brain barrier in systemic inflammation","volume":"60","author":"Varatharaj","year":"2017","journal-title":"Brain Behav. Immun."},{"key":"B41","doi-asserted-by":"publisher","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":"B42","doi-asserted-by":"publisher","first-page":"e330","DOI":"10.5435\/JAAOS-D-17-00727","article-title":"Effect of NSAIDs on bone healing rates: a meta-analysis","volume":"27","author":"Wheatley","year":"2019","journal-title":"J. Am. Acad. Orthop. Surg."},{"key":"B43","doi-asserted-by":"publisher","first-page":"3824","DOI":"10.1038\/s41598-023-30641-9","article-title":"A buprenorphine depot formulation provides effective sustained post-surgical analgesia for 72 h in mouse femoral fracture models","volume":"13","author":"Wolter","year":"2023","journal-title":"Sci. Rep."}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2025.1683842\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,9,11]],"date-time":"2025-09-11T05:26:05Z","timestamp":1757568365000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2025.1683842\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9,11]]},"references-count":43,"alternative-id":["10.3389\/fphar.2025.1683842"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2025.1683842","relation":{},"ISSN":["1663-9812"],"issn-type":[{"type":"electronic","value":"1663-9812"}],"subject":[],"published":{"date-parts":[[2025,9,11]]},"article-number":"1683842"}}