{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T13:30:08Z","timestamp":1786714208057,"version":"build-2736575974"},"reference-count":53,"publisher":"BMJ","issue":"8","license":[{"start":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T00:00:00Z","timestamp":1786665600000},"content-version":"unspecified","delay-in-days":13,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["BMJ Open"],"accepted":{"date-parts":[[2026,7,30]]},"published-print":{"date-parts":[[2026,8]]},"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Methadone is a long-acting opioid used to treat opioid use disorder, cancer pain and provide perioperative analgesia. Methadone administration has been associated with QTc interval prolongation and consequently an increased risk of ventricular arrhythmias. This mechanism appears to be mediated by HERG channel inhibition, drug\u2013drug interactions and genetic susceptibility. This protocol describes the methodology for a systematic review and meta-analysis aiming to evaluate the association between methadone administration and QTc prolongation and estimate the odds of major cardiac events. Our leading hypothesis is that methadone exerts a dose-dependent and time-dependent effect on QT prolongation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and analysis<\/jats:title>\n                    <jats:p>We will conduct a systematic literature search of randomised controlled trials, prospective and retrospective cohort studies and case\u2013control studies involving adult or paediatric patients receiving oral or intravenous methadone for opioid use disorder, cancer-related pain and surgical pain. Searches will be performed in Ovid MEDLINE, Ovid Embase, Cochrane CENTRAL, Web of Science and ClinicalTrials.gov. The primary outcome will be QTc interval length (in milliseconds). Secondary outcomes will include odds of clinically significant QTc prolongation and major adverse cardiac events. Comparator groups will include baseline pre-methadone QTc measurements and an external control group not exposed to methadone. Random-effects meta-analyses will be conducted, reporting mean differences with 95% CIs. Prespecified subgroup analyses based on methadone dose and duration of exposure will be performed when feasible. Risk of bias will be assessed using the Cochrane Risk of Bias 2 tool for randomised studies and Risk Of Bias In Non-Randomised Studies-of Interventions for non-randomised studies. The certainty of evidence will be evaluated using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Ethics and dissemination<\/jats:title>\n                    <jats:p>Ethical approval is not required. We will include data obtained exclusively from previously published peer-reviewed studies available in reputable databases. The results of this study are intended for dissemination via publication in a peer-reviewed journal.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>PROSPERO registration number<\/jats:title>\n                    <jats:p>CRD420251143441.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/bmjopen-2026-118322","type":"journal-article","created":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T12:40:40Z","timestamp":1786711240000},"page":"e118322","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":0,"title":["Methadone administration and QT interval prolongation: protocol for a systematic review and meta-analysis"],"prefix":"10.1136","volume":"16","author":[{"given":"Eduardo","family":"Nunez-Rodriguez","sequence":"first","affiliation":[{"name":"Department of Anesthesiology, Ochsner Medical Center, New Orleans, Louisiana, USA"},{"name":"Anesthesiology and Surgical Oncology Research Group, Houston, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryan","family":"Wong","sequence":"additional","affiliation":[{"name":"Tilman J Fertitta Family College of Medicine, Houston, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7377-331X","authenticated-orcid":false,"given":"Guido","family":"Mazzinari","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Critical Care, Department of Statistics and Operational Research, Universidad de Valencia, Hospital La Fe, Valencia, Valencian Community, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kate J","family":"Krause","sequence":"additional","affiliation":[{"name":"Research Medical Library, MD Anderson Cancer Center, Houston, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Evan D","family":"Kharasch","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Bermaride LLC, Durham, Duke University, Durham, North Carolina, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3156-1682","authenticated-orcid":false,"given":"Juan P","family":"Cata","sequence":"additional","affiliation":[{"name":"Anesthesiology and Surgical Oncology Research Group, Houston, Texas, USA"},{"name":"Department of Anesthesiology and Perioperative Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2026,8,14]]},"reference":[{"key":"2026081405402878000_16.8.e118322.1","doi-asserted-by":"crossref","first-page":"1153","DOI":"10.1097\/ALN.0b013e318238fec5","article-title":"Perioperative pharmacokinetics of methadone in adolescents","volume":"115","author":"Sharma","year":"2011","journal-title":"Anesthesiology"},{"key":"2026081405402878000_16.8.e118322.2","doi-asserted-by":"publisher","DOI":"10.1001\/jama.194.6.646"},{"key":"2026081405402878000_16.8.e118322.3","doi-asserted-by":"publisher","DOI":"10.1001\/archinte.1966.00290160004002"},{"key":"2026081405402878000_16.8.e118322.4","doi-asserted-by":"publisher","DOI":"10.1097\/ADM.0000000000000668"},{"key":"2026081405402878000_16.8.e118322.5","doi-asserted-by":"crossref","first-page":"112793","DOI":"10.1016\/j.drugalcdep.2025.112793","article-title":"Oral methadone versus sublingual buprenorphine for the treatment of acute opioid withdrawal: a triple-blind, double-dummy, randomized control trial","volume":"274","author":"Shekhawat","year":"2025","journal-title":"Drug Alcohol Depend"},{"key":"2026081405402878000_16.8.e118322.6","doi-asserted-by":"publisher","DOI":"10.1111\/add.13238"},{"key":"2026081405402878000_16.8.e118322.7","doi-asserted-by":"publisher","DOI":"10.7326\/M17-3107"},{"key":"2026081405402878000_16.8.e118322.8","doi-asserted-by":"crossref","unstructured":"Ding H , Song Y , Xin W , et al . 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