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For people with OUD who use unregulated fentanyl, slow induction onto opioid agonist therapy (OAT) with gradual dose titration is often ineffective or insufficient for reducing withdrawal symptoms and cravings, thereby hampering engagement and retention in treatment. Given the severe risks associated with continued use of the increasingly toxic unregulated drug supply, new and innovative approaches to the management of OUD are urgently needed. We have developed an alternative induction protocol, using a rapid intravenous symptom-inhibiting fentanyl induction (SIFI) to optimize rotation onto oral OAT.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods<\/jats:title>\n            <jats:p>An open-label, single arm, prospective pilot clinical trial is being conducted in an outpatient setting to assess the safety, feasibility, and efficacy of a rapid symptom-inhibiting intravenous fentanyl induction protocol to establish starting doses of methadone or sustained-release oral morphine (SROM) based on individual opioid requirements, as a treatment strategy for individuals with OUD who use unregulated fentanyl. The primary outcome is safety, as defined by occurrence of study drug-related adverse events (including but not limited to opioid toxicity and QT interval prolongation) that require intervention during induction and the first 7\u00a0days on OAT. Secondary objectives are to determine whether the SIFI protocol will result in use of higher-than-standard starting doses of methadone and SROM, and to determine whether implementation of this protocol will be acceptable to participants and will result in reduced withdrawal symptoms, improved retention, and better long-term outcomes on OAT.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Discussion<\/jats:title>\n            <jats:p>This is the first study to rapidly and objectively estimate opioid tolerance and use it to calculate individualized starting doses of oral OAT in an outpatient setting among people who use unregulated fentanyl. We predict that starting methadone or SROM with individually-tailored doses will lead to therapeutic target concentrations being achieved quickly, safely, and with good patient satisfaction. This approach has the potential to more effectively and safely initiate OAT, to minimize opioid withdrawal and cravings, and in turn to decrease unregulated fentanyl use and increase retention on life-saving OAT.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Trial registration<\/jats:title>\n            <jats:p>ClinicalTrials.gov, NCT05905367; date of registration: June 15, 2023; latest update posted July 18, 2024. <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"https:\/\/clinicaltrials.gov\/study\/NCT05905367\" ext-link-type=\"uri\">https:\/\/clinicaltrials.gov\/study\/NCT05905367<\/jats:ext-link>\n            <\/jats:p>\n            <jats:p>\n              <jats:italic>Protocol version<\/jats:italic>: 4.0, April 22, 2024.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1186\/s13722-025-00586-7","type":"journal-article","created":{"date-parts":[[2025,7,29]],"date-time":"2025-07-29T09:46:24Z","timestamp":1753782384000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Rapid intravenous symptom-inhibiting fentanyl induction (SIFI) to optimize rotation onto oral opioid agonist therapy among individuals who use unregulated fentanyl: protocol for an open-label, single arm clinical trial"],"prefix":"10.1186","volume":"20","author":[{"given":"Pouya","family":"Azar","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Martha J.","family":"Ignaszewski","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marianne","family":"Harris","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zoran","family":"Barazanci","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ruth","family":"Davison","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"James S. 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The investigators will inform the UBC\/PHC REB about the progress of the study and any protocol amendments will be submitted for REB approval before implementation. The investigators will notify the REB of any significant protocol deviations, unanticipated problems, or serious adverse events that may occur during the course of the study.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"See Supplementary Materials for the approved informed consent document.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"PA was a consultant on Indivior-led buprenorphine extended-release studies, and has received speaking honoraria for Indivior-funded buprenorphine presentations, both of which are unrelated to this study protocol. MJI has received honoraria from Indivior, unrelated to this study protocol. The other authors declare that they have have no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"58"}}