Roger Chou, MD; P. Todd Korthuis, MD, MPH; Dennis McCarty, PhD; Phillip O. Coffin, MD, MIA; Jessica C. Griffin, MS; Cynthia Davis-O'Reilly, BS; Sara Grusing, BA; Mohamud Daya, MD, MS
Disclaimer: This article is based on research conducted by the Pacific Northwest Evidence-based Practice Center under contract with the AHRQ (contract no. HHSA290-2015-00009-I). The findings and conclusions are those of the authors, who are responsible for its contents; the findings and conclusions do not necessarily represent the views of the AHRQ. No statement in this report should be construed as an official position of the AHRQ or the U.S. Department of Health and Human Services.
Financial Support: By the AHRQ (contract no. HHSA290-2015-00009-I).
Disclosures: Dr. Chou reports a grant from the Agency for Healthcare Research and Quality during the conduct of the study. Dr. Korthuis reports grants from the Agency for Healthcare Research and Quality and the National Institute on Drug Abuse during the conduct of the study. Dr. McCarty reports a task order from the Agency for Healthcare Research and Quality during the conduct of the study, a cooperative agreement with the National Institute on Drug Abuse outside the submitted work, and grants from the National Institute of Mental Health and the National Institute on Drug Abuse outside the submitted work. Dr. Coffin reports that he has directed National Institutes of Health–funded studies that received study medications donated by Alkermes (extended-release naltrexone [2014 to 2015]) and Gilead Sciences (ledipasvir–sofosbuvir [2016 to 2017]). Dr. Daya reports a grant from the Agency for Healthcare Research and Quality during the conduct of the study. Authors not named here have disclosed no conflicts of interest. Disclosures can also be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M17-2224.
Editors' Disclosures: Christine Laine, MD, MPH, Editor in Chief, reports that she has no financial relationships or interests to disclose. Darren B. Taichman, MD, PhD, Executive Deputy Editor, reports that he has no financial relationships or interests to disclose. Cynthia D. Mulrow, MD, MSc, Senior Deputy Editor, reports that she has no relationships or interests to disclose. Deborah Cotton, MD, MPH, Deputy Editor, reports that she has no financial relationships or interest to disclose. Jaya K. Rao, MD, MHS, Deputy Editor, reports that she has stock holdings/options in Eli Lilly and Pfizer. Sankey V. Williams, MD, Deputy Editor, reports that he has no financial relationships or interests to disclose. Catharine B. Stack, PhD, MS, Deputy Editor for Statistics, reports that she has stock holdings in Pfizer and Johnson & Johnson.
Reproducible Research Statement:Study protocol: Available on PROSPERO (CRD42016053891) and at https://effectivehealthcare.ahrq.gov/topics/emt-naloxon/research-protocol. Statistical code: Not applicable. Data set: Available from the Systematic Review Data Repository (https://srdr.ahrq.gov) or from Dr. Chou (e-mail, email@example.com).
Requests for Single Reprints: Roger Chou, MD, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Mail Code BICC, Portland, OR 97239; e-mail, firstname.lastname@example.org.
Current Author Addresses: Drs. Chou, Korthuis, McCarty, and Daya; Ms. Griffin; Ms. Davis-O'Reilly; and Ms. Grusing: Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Mail Code BICC, Portland, OR 97239.
Dr. Coffin: San Francisco Department of Public Health, 25 Van Ness Avenue, Suite 500, San Francisco, CA 94102.
Author Contributions: Conception and design: R. Chou, P.T. Korthuis, D. McCarty, P.O. Coffin, M. Daya.
Analysis and interpretation of the data: R. Chou, P.T. Korthuis, D. McCarty, P.O. Coffin, J.C. Griffin, M. Daya.
Drafting of the article: R. Chou, P.O. Coffin, J.C. Griffin, S. Grusing, M. Daya.
Critical revision of the article for important intellectual content: R. Chou, P.T. Korthuis, D. McCarty, P.O. Coffin, J.C. Griffin, M. Daya.
Final approval of the article: R. Chou, P.T. Korthuis, D. McCarty, P.O. Coffin, J.C. Griffin, C. Davis-O'Reilly, S. Grusing, M. Daya.
Statistical expertise: R. Chou.
Obtaining of funding: R. Chou.
Administrative, technical, or logistic support: R. Chou, J.C. Griffin, C. Davis-O'Reilly, S. Grusing.
Collection and assembly of data: R. Chou, P.T. Korthuis, P.O. Coffin, J.C. Griffin, C. Davis-O'Reilly, S. Grusing, M. Daya.
Naloxone is effective for reversing opioid overdose, but optimal strategies for out-of-hospital use are uncertain.
To synthesize evidence on 1) the effects of naloxone route of administration and dosing for suspected opioid overdose in out-of-hospital settings on mortality, reversal of overdose, and harms, and 2) the need for transport to a health care facility after reversal of overdose with naloxone.
Ovid MEDLINE (1946 through September 2017), PsycINFO, Cochrane Central Register of Controlled Trials, CINAHL, U.S. Food and Drug Administration (FDA) materials, and reference lists.
English-language cohort studies and randomized trials that compared different doses of naloxone, administration routes, or transport versus nontransport after reversal of overdose with naloxone. Main outcomes were mortality, reversal of overdose, recurrence of overdose, and harms.
Dual extraction and quality assessment of individual studies; consensus assessment of overall strength of evidence (SOE).
Of 13 eligible studies, 3 randomized controlled trials and 4 cohort studies compared different administration routes. At the same dose (2 mg), 1 trial found similar efficacy between higher-concentration intranasal naloxone (2 mg/mL) and intramuscular naloxone, and 1 trial found that lower-concentration intranasal naloxone (2 mg/5 mL) was less effective than intramuscular naloxone but was associated with decreased risk for agitation (low SOE). Evidence was insufficient to evaluate other comparisons of route of administration. Six uncontrolled studies reported low rates of death and serious adverse events (0% to 1.25%) in nontransported patients after successful naloxone treatment.
There were few studies, all had methodological limitations, and none evaluated FDA-approved autoinjectors or highly concentrated intranasal formulations.
Higher-concentration intranasal naloxone (2 mg/mL) seems to have efficacy similar to that of intramuscular naloxone for reversal of opioid overdose, with no difference in adverse events. Nontransport after reversal of overdose with naloxone seems to be associated with a low rate of serious harms, but no study evaluated risks of transport versus nontransport.
Agency for Healthcare Research and Quality. (PROSPERO: CRD42016053891)
* Patients with confirmed or suspected opioid overdose who exhibit altered mental status, miosis, or respiratory distress and are treated in out-of-hospital settings by emergency medical services personnel.
† Administration of naloxone hydrochloride via intranasal, intravenous, intramuscular, or subcutaneous injection (including naloxone autoinjector).
‡ Question 1 addresses comparisons involving route of administration and dose. Question 2 addresses comparisons involving dose titration to varying degrees of return of consciousness (intermediate outcome).
Evidence search and selection.
* Other sources include prior reports, reference lists, referrals from experts, and gray literature.
Appendix Table 1. Characteristics and Results of RCTs Comparing Routes of Naloxone Administration
Appendix Table 2. Characteristics and Results of Observational Studies Comparing Routes of Naloxone Administration
Appendix Table 3. Deaths and Serious Adverse Events After Nontransport to Health Care Facility After Successful Reversal of Suspected Opioid Overdose With Naloxone
Appendix Table 4. Risk-of-Bias Ratings of RCTs
Appendix Table 5. Risk-of-Bias Ratings of Observational Studies
Table. Strength of Evidence
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Roger Chou, P. Todd Korthuis, Dennis McCarty, Phillip O. Coffin, Jessica C. Griffin, Cynthia Davis-O'Reilly, et al. Management of Suspected Opioid Overdose With Naloxone in Out-of-Hospital Settings: A Systematic Review. Ann Intern Med. [Epub ahead of print 28 November 2017]:. doi: 10.7326/M17-2224
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Published: Ann Intern Med. 2017.
Emergency Medicine, High Value Care, Hospital Medicine, Tobacco, Alcohol, and Other Substance Abuse.
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