{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T12:41:49Z","timestamp":1793277709751,"version":"4.5.0"},"reference-count":32,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2024,4,27]],"date-time":"2024-04-27T00:00:00Z","timestamp":1714176000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2024,4,27]],"date-time":"2024-04-27T00:00:00Z","timestamp":1714176000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Trials"],"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n                <jats:title>Background<\/jats:title>\n                <jats:p>The fragility index is a statistical measure of the robustness or \u201cstability\u201d of a statistically significant result. It has been adapted to assess the robustness of statistically significant outcomes from randomized controlled trials. By hypothetically switching some non-responders to responders, for instance, this metric measures how many individuals would need to have responded for a statistically significant finding to become non-statistically significant. The purpose of this study is to assess the fragility index of randomized controlled trials evaluating opioid substitution and antagonist therapies for opioid use disorder. This will provide an indication as to the robustness of trials in the field and the confidence that should be placed in the trials\u2019 outcomes, potentially identifying ways to improve clinical research in the field. This is especially important as opioid use disorder has become a global epidemic, and the incidence of opioid related fatalities have climbed 500% in the past two decades.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>Six databases were searched from inception to September 25, 2021, for randomized controlled trials evaluating opioid substitution and antagonist therapies for opioid use disorder, and meeting the necessary requirements for fragility index calculation. Specifically, we included all parallel arm or two-by-two factorial design RCTs that assessed the effectiveness of any opioid substitution and antagonist therapies using a binary primary outcome and reported a statistically significant result. The fragility index of each study was calculated using methods described by Walsh and colleagues. The risk of bias of included studies was assessed using the Revised Cochrane Risk of Bias tool for randomized trials.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>Ten studies with a median sample size of 82.5 (interquartile range (IQR) 58, 179, range 52\u2013226) were eligible for inclusion. Overall risk of bias was deemed to be low in seven studies, have some concerns in two studies, and be high in one study. The median fragility index was 7.5 (IQR 4, 12, range 1\u201326).<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>Our results suggest that approximately eight participants are needed to overturn the conclusions of the majority of trials in opioid use disorder. Future work should focus on maximizing transparency in reporting of study results, by reporting confidence intervals, fragility indexes, and emphasizing the clinical relevance of findings.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Trial registration<\/jats:title>\n                <jats:p>PROSPERO CRD42013006507. Registered on November 25, 2013.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s13063-024-08104-x","type":"journal-article","created":{"date-parts":[[2024,4,27]],"date-time":"2024-04-27T07:02:29Z","timestamp":1714201349000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Assessing fragility of statistically significant findings from randomized controlled trials assessing pharmacological therapies for opioid use disorders: a systematic review"],"prefix":"10.1186","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0994-1109","authenticated-orcid":false,"given":"Leen","family":"Naji","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brittany","family":"Dennis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Myanca","family":"Rodrigues","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monica","family":"Bawor","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alannah","family":"Hillmer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caroul","family":"Chawar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eve","family":"Deck","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew","family":"Worster","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James","family":"Paul","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lehana","family":"Thabane","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zainab","family":"Samaan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,4,27]]},"reference":[{"key":"8104_CR1","unstructured":"Products - Vital Statistics Rapid Release - Provisional Drug Overdose Data. https:\/\/www.cdc.gov\/nchs\/nvss\/vsrr\/drug-overdose-data.htm. Accessed April 26, 2020."},{"key":"8104_CR2","doi-asserted-by":"publisher","unstructured":"Spencer MR, Mini\u00f1o AM, Warner M. Drug overdose deaths in the United States, 2001\u20132021. NCHS Data Brief, no 457. Hyattsville, MD: National Center for Health Statistics. 2022. https:\/\/doi.org\/10.15620\/cdc:122556.","DOI":"10.15620\/cdc:122556"},{"key":"8104_CR3","doi-asserted-by":"publisher","unstructured":"Mattick RP, Breen C, Kimber J, Davoli M. Methadone maintenance therapy versus no opioid replacement therapy for opioid dependence. Cochrane Database Syst Rev. 2009;(3).\u00a0https:\/\/doi.org\/10.1002\/14651858.CD002209.PUB2\/FULL.","DOI":"10.1002\/14651858.CD002209.PUB2\/FULL"},{"issue":"3","key":"8104_CR4","doi-asserted-by":"publisher","first-page":"501","DOI":"10.1111\/J.1360-0443.2011.03676.X","volume":"107","author":"D Hedrich","year":"2012","unstructured":"Hedrich D, Alves P, Farrell M, St\u00f6ver H, M\u00f8ller L, Mayet S. The effectiveness of opioid maintenance treatment in prison settings: a systematic review. Addiction. 2012;107(3):501\u201317. https:\/\/doi.org\/10.1111\/J.1360-0443.2011.03676.X.","journal-title":"Addiction."},{"issue":"1","key":"8104_CR5","doi-asserted-by":"publisher","first-page":"105","DOI":"10.1186\/2046-4053-3-105","volume":"3","author":"BB Dennis","year":"2014","unstructured":"Dennis BB, Naji L, Bawor M, et al. The effectiveness of opioid substitution treatments for patients with opioid dependence: a systematic review and multiple treatment comparison protocol. Syst Rev. 2014;3(1):105. https:\/\/doi.org\/10.1186\/2046-4053-3-105.","journal-title":"Syst Rev."},{"key":"8104_CR6","doi-asserted-by":"publisher","unstructured":"Dennis BB, Sanger N, Bawor M, et al. A call for consensus in defining efficacy in clinical trials for opioid addiction: combined results from a systematic review and qualitative study in patients receiving pharmacological assisted therapy for opioid use disorder. Trials. 2020;21(1). https:\/\/doi.org\/10.1186\/s13063-019-3995-y.","DOI":"10.1186\/s13063-019-3995-y"},{"key":"8104_CR7","unstructured":"British Columbia Centre on Substance Use. (2017). A Guideline for the Clinical Management of Opioid Use Disorder. http:\/\/www.bccsu.ca\/care-guidance-publications\/. Accessed December 4, 2020."},{"key":"8104_CR8","doi-asserted-by":"crossref","unstructured":"Kampman\u00a0 K, Jarvis M. American Society of Addiction Medicine (ASAM) national practice guideline for the use of medications in the treatment of addiction involving opioid use.\u00a0J Addict Med. 2015;9(5):358\u2013367.","DOI":"10.1097\/ADM.0000000000000166"},{"key":"8104_CR9","unstructured":"Srivastava A, Wyman J, Fcfp MD, Mph D. Methadone treatment for people who use fentanyl: recommendations. 2021. www.metaphi.ca. Accessed November 14, 2023."},{"issue":"1","key":"8104_CR10","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/s13063-015-0942-4","volume":"16","author":"BB Dennis","year":"2015","unstructured":"Dennis BB, Roshanov PS, Naji L, et al. Opioid substitution and antagonist therapy trials exclude the common addiction patient: a systematic review and analysis of eligibility criteria. Trials. 2015;16(1):1. https:\/\/doi.org\/10.1186\/s13063-015-0942-4.","journal-title":"Trials."},{"issue":"2","key":"8104_CR11","doi-asserted-by":"publisher","first-page":"201","DOI":"10.1016\/0895-4356(90)90186-S","volume":"43","author":"AR Feinstein","year":"1990","unstructured":"Feinstein AR. The unit fragility index: an additional appraisal of \u201cstatistical significance\u201d for a contrast of two proportions. J Clin Epidemiol. 1990;43(2):201\u20139. https:\/\/doi.org\/10.1016\/0895-4356(90)90186-S.","journal-title":"J Clin Epidemiol."},{"issue":"6","key":"8104_CR12","doi-asserted-by":"publisher","first-page":"622","DOI":"10.1016\/j.jclinepi.2013.10.019","volume":"67","author":"M Walsh","year":"2014","unstructured":"Walsh M, Srinathan SK, McAuley DF, et al. The statistical significance of randomized controlled trial results is frequently fragile: a case for a fragility index. J Clin Epidemiol. 2014;67(6):622\u20138. https:\/\/doi.org\/10.1016\/j.jclinepi.2013.10.019.","journal-title":"J Clin Epidemiol."},{"key":"8104_CR13","doi-asserted-by":"publisher","unstructured":"Holek M, Bdair F, Khan M, et al. Fragility of clinical trials across research fields: a synthesis of methodological reviews. Contemp Clin Trials. 2020;97. doi:https:\/\/doi.org\/10.1016\/j.cct.2020.106151","DOI":"10.1016\/j.cct.2020.106151"},{"key":"8104_CR14","doi-asserted-by":"publisher","unstructured":"Sterne JAC, Savovi\u0107 J, Page MJ, et al. RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ. 2019;366. doi:https:\/\/doi.org\/10.1136\/bmj.l4898","DOI":"10.1136\/bmj.l4898"},{"key":"8104_CR15","unstructured":"Kane SP. Fragility Index Calculator. ClinCalc: https:\/\/clincalc.com\/Stats\/FragilityIndex.aspx. Updated July 19, 2018. Accessed October 17, 2023."},{"key":"8104_CR16","doi-asserted-by":"publisher","first-page":"372","DOI":"10.1136\/bmj.n71","volume":"2021","author":"MJ Page","year":"2020","unstructured":"Page MJ, McKenzie JE, Bossuyt PM, The PRISMA, et al. statement: an updated guideline for reporting systematic reviews. BMJ. 2020;2021:372. https:\/\/doi.org\/10.1136\/bmj.n71.","journal-title":"BMJ."},{"issue":"1","key":"8104_CR17","doi-asserted-by":"publisher","first-page":"97","DOI":"10.1016\/S0376-8716(00)00163-0","volume":"62","author":"S Petitjean","year":"2001","unstructured":"Petitjean S, Stohler R, D\u00e9glon JJ, et al. Double-blind randomized trial of buprenorphine and methadone in opiate dependence. Drug Alcohol Depend. 2001;62(1):97\u2013104. https:\/\/doi.org\/10.1016\/S0376-8716(00)00163-0.","journal-title":"Drug Alcohol Depend."},{"issue":"10","key":"8104_CR18","doi-asserted-by":"publisher","first-page":"1303","DOI":"10.1001\/JAMA.283.10.1303","volume":"283","author":"KL Sees","year":"2000","unstructured":"Sees KL, Delucchi KL, Masson C, et al. Methadone maintenance vs 180-day psychosocially enriched detoxification for treatment of opioid dependence: a randomized controlled trial. JAMA. 2000;283(10):1303\u201310. https:\/\/doi.org\/10.1001\/JAMA.283.10.1303.","journal-title":"JAMA."},{"issue":"9358","key":"8104_CR19","doi-asserted-by":"publisher","first-page":"662","DOI":"10.1016\/S0140-6736(03)12600-1","volume":"361","author":"J Kakko","year":"2003","unstructured":"Kakko J, Dybrandt Svanborg K, Kreek MJ, Heilig M. 1-year retention and social function after buprenorphine-assisted relapse prevention treatment for heroin dependence in Sweden: a randomised, placebo-controlled trial. Lancet (London, England). 2003;361(9358):662\u20138. https:\/\/doi.org\/10.1016\/S0140-6736(03)12600-1.","journal-title":"Lancet (London, England)."},{"issue":"8","key":"8104_CR20","doi-asserted-by":"publisher","first-page":"777","DOI":"10.1056\/NEJMoa0810635","volume":"361","author":"E Oviedo-Joekes","year":"2009","unstructured":"Oviedo-Joekes E, Brissette S, Marsh DC, et al. Diacetylmorphine versus methadone for the treatment of opioid addiction. N Engl J Med. 2009;361(8):777\u201386. https:\/\/doi.org\/10.1056\/NEJMoa0810635.","journal-title":"N Engl J Med."},{"issue":"10","key":"8104_CR21","doi-asserted-by":"publisher","first-page":"1108","DOI":"10.1001\/ARCHGENPSYCHIATRY.2009.130","volume":"66","author":"GK Hulse","year":"2009","unstructured":"Hulse GK, Morris N, Arnold-Reed D, Tait RJ. Improving clinical outcomes in treating heroin dependence: randomized, controlled trial of oral or implant naltrexone. Arch Gen Psychiatry. 2009;66(10):1108\u201315. https:\/\/doi.org\/10.1001\/ARCHGENPSYCHIATRY.2009.130.","journal-title":"Arch Gen Psychiatry."},{"issue":"4","key":"8104_CR22","doi-asserted-by":"publisher","first-page":"285","DOI":"10.1016\/j.jsat.2004.02.002","volume":"26","author":"EM Krupitsky","year":"2004","unstructured":"Krupitsky EM, Zvartau EE, Masalov DV, et al. Naltrexone for heroin dependence treatment in St. Petersburg, Russia. J Subst Abuse Treat. 2004;26(4):285\u201394. https:\/\/doi.org\/10.1016\/j.jsat.2004.02.002.","journal-title":"J Subst Abuse Treat"},{"issue":"5","key":"8104_CR23","doi-asserted-by":"publisher","first-page":"533","DOI":"10.1046\/J.1360-0443.2002.00090.X","volume":"97","author":"AL Krook","year":"2002","unstructured":"Krook AL, Br\u00f8rs O, Dahlberg J, et al. A placebo-controlled study of high dose buprenorphine in opiate dependents waiting for medication-assisted rehabilitation in Oslo. Norway Addiction. 2002;97(5):533\u201342. https:\/\/doi.org\/10.1046\/J.1360-0443.2002.00090.X.","journal-title":"Norway. Addiction."},{"issue":"8","key":"8104_CR24","doi-asserted-by":"publisher","first-page":"877","DOI":"10.1001\/ARCHPSYC.1980.01780210035003","volume":"37","author":"RL Hartnoll","year":"1980","unstructured":"Hartnoll RL, Mitcheson MC, Battersby A, et al. Evaluation of heroin maintenance in controlled trial. Arch Gen Psychiatry. 1980;37(8):877\u201384. https:\/\/doi.org\/10.1001\/ARCHPSYC.1980.01780210035003.","journal-title":"Arch Gen Psychiatry."},{"issue":"9","key":"8104_CR25","doi-asserted-by":"publisher","first-page":"1337","DOI":"10.1046\/J.1360-0443.1999.94913376.X","volume":"94","author":"G Fischer","year":"1999","unstructured":"Fischer G, Gombas W, Eder H, et al. Buprenorphine versus methadone maintenance for the treatment of opioid dependence. Addiction. 1999;94(9):1337\u201347. https:\/\/doi.org\/10.1046\/J.1360-0443.1999.94913376.X.","journal-title":"Addiction."},{"issue":"9","key":"8104_CR26","doi-asserted-by":"publisher","first-page":"1185","DOI":"10.2105\/AJPH.81.9.1185","volume":"81","author":"SR Yancovitz","year":"1991","unstructured":"Yancovitz SR, Des Jarlais DC, Peyser NP, et al. A randomized trial of an interim methadone maintenance clinic. Am J Public Health. 1991;81(9):1185\u201391. https:\/\/doi.org\/10.2105\/AJPH.81.9.1185.","journal-title":"Am J Public Health."},{"issue":"1","key":"8104_CR27","doi-asserted-by":"publisher","first-page":"159","DOI":"10.1590\/S1807-59322011000100027","volume":"66","author":"MK Demange","year":"2011","unstructured":"Demange MK, Fregni F. Limits to clinical trials in surgical areas. Clinics (Sao Paulo). 2011;66(1):159\u201361. https:\/\/doi.org\/10.1590\/S1807-59322011000100027.","journal-title":"Clinics (Sao Paulo)."},{"issue":"7","key":"8104_CR28","doi-asserted-by":"publisher","first-page":"1236","DOI":"10.1007\/S11606-019-04928-5","volume":"34","author":"C Wayant","year":"2019","unstructured":"Wayant C, Meyer C, Gupton R, Som M, Baker D, Vassar M. The fragility index in a cohort of HIV\/AIDS randomized controlled trials. J Gen Intern Med. 2019;34(7):1236\u201343. https:\/\/doi.org\/10.1007\/S11606-019-04928-5.","journal-title":"J Gen Intern Med."},{"issue":"7748","key":"8104_CR29","doi-asserted-by":"publisher","first-page":"305","DOI":"10.1038\/D41586-019-00857-9","volume":"567","author":"V Amrhein","year":"2019","unstructured":"Amrhein V, Greenland S, McShane B. Scientists rise up against statistical significance. Nature. 2019;567(7748):305\u20137. https:\/\/doi.org\/10.1038\/D41586-019-00857-9.","journal-title":"Nature."},{"issue":"8","key":"8104_CR30","doi-asserted-by":"publisher","first-page":"e124","DOI":"10.1371\/journal.pmed.0020124","volume":"2","author":"JPA Ioannidis","year":"2005","unstructured":"Ioannidis JPA. Why most published research findings are false. PLoS Med. 2005;2(8):e124. https:\/\/doi.org\/10.1371\/journal.pmed.0020124.","journal-title":"PLoS Med."},{"issue":"12","key":"8104_CR31","doi-asserted-by":"publisher","first-page":"995","DOI":"10.7326\/0003-4819-130-12-199906150-00008","volume":"130","author":"SN Goodman","year":"1999","unstructured":"Goodman SN. Toward evidence-based medical statistics. 1: the p value fallacy. Ann Intern Med. 1999;130(12):995\u20131004. https:\/\/doi.org\/10.7326\/0003-4819-130-12-199906150-00008.","journal-title":"Ann Intern Med"},{"issue":"11","key":"8104_CR32","doi-asserted-by":"publisher","first-page":"2561","DOI":"10.1073\/PNAS.1802324115","volume":"115","author":"DB Allison","year":"2018","unstructured":"Allison DB, Shiffrin RM, Stodden V. Reproducibility of research: issues and proposed remedies. Proc Natl Acad Sci U S A. 2018;115(11):2561\u20132. https:\/\/doi.org\/10.1073\/PNAS.1802324115.","journal-title":"Proc Natl Acad Sci U S A."}],"container-title":["Trials"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13063-024-08104-x.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s13063-024-08104-x\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13063-024-08104-x.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,4,27]],"date-time":"2024-04-27T07:11:48Z","timestamp":1714201908000},"score":1,"resource":{"primary":{"URL":"https:\/\/trialsjournal.biomedcentral.com\/articles\/10.1186\/s13063-024-08104-x"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,4,27]]},"references-count":32,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2024,12]]}},"alternative-id":["8104"],"URL":"https:\/\/doi.org\/10.1186\/s13063-024-08104-x","relation":{},"ISSN":["1745-6215"],"issn-type":[{"value":"1745-6215","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,4,27]]},"assertion":[{"value":"11 December 2022","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"10 April 2024","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"27 April 2024","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Not applicable.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare that they have no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"286"}}