Review of Case Narratives from Fatal Overdoses Associated with Injectable Naltrexone for Opioid Dependence
An extended-release injectable naltrexone suspension (Vivitrol®) was approved in USA in 2010 for the prevention of relapse to opioid dependence. Concerns, raised at the time of approval, about rebound overdose risk following the last dose, have not been adequately studied. We sought to determine the time period of concern for fatal overdose associated with Vivitrol.
We performed a retrospective case review of Vivitrol spontaneous reports (October 2010–March 2016) in the US Food and Drug Administration Adverse Event Reporting System via the Freedom of Information Act. Case narratives were manually reviewed to identify overdose deaths amongst current and former patients, extracting information on the time from discontinuation, followed by causality assessment.
Narratives on 263 deaths and overdose-related outcomes were obtained. One hundred and forty-five death reports were assessed for causality. Among these reports, cause of death was unknown in 46%, while 52 fatal overdoses met the case definition. Of 52 overdoses, time between the last dose and death was known for 28; 22 (84.6%) occurred within 2 months of the last Vivitrol injection [median 46 days (interquartile range 29.5–82)]. The sponsor’s causality assessment in 75% of fatal overdoses repeated verbatim text that placed responsibility on underlying opioid dependence and precluded a link between medication and overdose or ignored rebound risk following treatment discontinuation.
Vivitrol adverse event reports suggest the need to investigate two months following the last medicine injection as a period of particular concern for overdose. A registry study would best quantify risk. Providers should report suspected post-discontinuation overdoses to government authorities.
The authors thank the US Food and Drug Administration employees involved in responding to Freedom of Information Act requests.
Compliance with Ethical Standards
This study was funded by Open Society Foundations.
Conflict of interest
Daniel Wolfe is an employee of Open Society Foundations and Roxanne Saucier is a consultant to Open Society Foundations. Nabarun Dasgupta is a part-time employee of the RADARS System, which had no involvement in this study. The RADARS System is supported by subscriptions from pharmaceutical manufacturers, and governmental and non-governmental agencies for data, research, and reporting services. The RADARS System is the property of the Denver Health and Hospital Authority, a political subdivision of the State of Colorado (USA). Employees are prohibited from financial relationships with any biopharmaceutical company.
All data used in this analysis were publicly available and redacted of identifying information by the US Food and Drug Administration, therefore no external institutional review board approval was needed.
- 1.Krupitsky E, Nunes EV, Ling W, Illeperuma A, Gastfriend DR, Silverman BL. Injectable extended-release naltrexone for opioid dependence: a double-blind, placebo-controlled, multicentre randomised trial. Lancet. 2011;377(9776):1506–13. https://doi.org/10.1016/S0140-6736(11)60358-9.CrossRefPubMedGoogle Scholar
- 2.Krupitsky E, Zvartau E, Blokhina E, Verbitskaya E, Wahlgren V, Tsoy-Podosenin M, et al. Randomized trial of long-acting sustained-release naltrexone implant vs oral naltrexone or placebo for preventing relapse to opioid dependence. Arch Gen Psychiatry. 2012;69(9):973–81. https://doi.org/10.1001/archgenpsychiatry.2012.1a.CrossRefPubMedPubMedCentralGoogle Scholar
- 4.Alkermes I. Medication guide vivitrol. 2013. https://www.fda.gov/downloads/drugs/drugsafety/ucm206669.pdf. Accessed 6 Sep 2016.
- 8.Fishman MJ, Winstanley EL, Curran E, Garrett S, Subramaniam G. Treatment of opioid dependence in adolescents and young adults with extended release naltrexone: preliminary case-series and feasibility. Addiction. 2010;105(9):1669–76. https://doi.org/10.1111/j.1360-0443.2010.03015.x.CrossRefPubMedGoogle Scholar
- 12.Binswanger IA, Blatchford PJ, Mueller SR, Stern MF. Mortality after prison release: opioid overdose and other causes of death, risk factors, and time trends from 1999 to 2009. Ann Intern Med. 2013;159(9):592–600. https://doi.org/10.7326/0003-4819-159-9-201311050-00005.CrossRefPubMedPubMedCentralGoogle Scholar
- 13.Lim S, Seligson AL, Parvez FM, Luther CW, Mavinkurve MP, Binswanger IA, et al. Risks of drug-related death, suicide, and homicide during the immediate post-release period among people released from New York City jails, 2001–2005. Am J Epidemiol. 2012;175(6):519–26. https://doi.org/10.1093/aje/kwr327.CrossRefPubMedGoogle Scholar
- 18.Tanum L, Solli KK, Z-e-H Latif, Benth JŠ, Opheim A, Sharma-Haase K, et al. The effectiveness of injectable extended-release naltrexone vs daily buprenorphine-naloxone for opioid dependence. JAMA Psychiatry. 2017;74(12):1197–205. https://doi.org/10.1001/jamapsychiatry.2017.3206.CrossRefPubMedGoogle Scholar
- 20.Lee JD, Nunes EV Jr, Novo P, Bachrach K, Bailey GL, Bhatt S, et al. Comparative effectiveness of extended-release naltrexone versus buprenorphine-naloxone for opioid relapse prevention (X:BOT): a multicentre, open-label, randomised controlled trial. Lancet. 2018;391(10118):309–18. https://doi.org/10.1016/S0140-6736(17)32812-X.CrossRefPubMedGoogle Scholar
- 21.Morgan JR, Schackman BR, Leff JA, Linas BP, Walley AY. Injectable naltrexone, oral naltrexone, and buprenorphine utilization and discontinuation among individuals treated for opioid use disorder in a United States commercially insured population. J Subst Abuse Treat. 2018;85:90–6. https://doi.org/10.1016/j.jsat.2017.07.001.CrossRefPubMedGoogle Scholar
- 23.US Department of Health and Human Services. FDA Adverse Event Reporting System (FAERS): latest quarterly data files. 2016. http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Surveillance/AdverseDrugEffects/ucm082193.htm. Accessed 12 Sep 2016.
- 25.US Food and Drug Administration. Clinical pharmacology and biopharmaceutics review(s): application number 21-897. Silver Spring (MD): US Department of Health and Human Services; 2006. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2006/021897s000_ClinPharmR.pdf. Accessed 5 Sep 2016.
- 27.US Food and Drug Administration. Drug approval package Vivitrol (naltrexone). 2008. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2006/021897_toc_Vivitrol.cfm. Accessed 29 Jan 2018.
- 29.Stejbach M. Vivitrol: a new commercial model responsive to a complex environment. Alkermes analyst and investor event (September 26, 2016). 2016. https://www.scribd.com/document/351102245/Alkermes-2016-Analyst-and-Investor-Event-Presentation. Accessed 15 Feb 2018.
- 30.Goodnough A, Zernike K. Seizing on opioid crisis, a Drug Maker Lobbies Hard for its Product. In: New York Times. 2017. https://www.nytimes.com/2017/06/11/health/vivitrol-drug-opioid-addiction.html. Accessed 8 Feb 2018.
- 31.MacGillis A. The last shot. ProPublica. 2017. https://www.propublica.org/article/vivitrol-opiate-crisis-and-criminal-justice. Accessed 12 Sep 2017.
- 32.Dissell R. Ohio’s spending on opioid addiction treatment drugs Vivitrol and Suboxone spikes, spurs debate on what treatments work. The Plain Dealer (Cleveland, Ohio). 2017. http://www.cleveland.com/metro/index.ssf/2017/04/ohios_spending_on_opioid_addiction_treatment_drugs_like_vivitrol_and_suboxone_spikes_spurs_debate_what_treatments_work.html. Accessed 12 Sep 2017.
- 34.Schwartz J, Wang Y, Keshawarz A, Cormier N, Dykhoff H, McNamara RL, et al. Claims-based and hybrid measures of 30-day mortality following acute ischemic stroke hospitalization incorporating risk adjustment for stroke severity: technical report. Yale New Haven Health Services Corporation/Center for Outcomes Research & Evaluation, New Haven (CT). 2015. http://www.cms.gov/Medicare/Quality-Initiatives-Patient-Assessment-Instruments/MMS/Downloads/Claims-Based-and-Hybrid-Measures-of-30-Day-Mortality-Following-Acute-Ischemic-Stroke-Hospitalization-Incorporating-Risk-Adjustment-for-Stroke-Severity-Technical-Report-.pdf. Accessed 29 Jan 2018.