Comparative Effectiveness Review
`Number 193
`
`Management of
`Suspected Opioid
`Overdose with
`Naloxone by
`Emergency Medical
`Services Personnel
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`
`
`
` Comparative Effectiveness Review
`
`
` Number 193
`
`
`
`
`
` Management of Suspected Opioid Overdose With
`
` Naloxone by Emergency Medical Services Personnel
`
`
`
`
`Prepared for:
`
`Agency for Healthcare Research and Quality
`
`U.S. Department of Health and Human Services
`
`
`5600 Fishers Lane
`
`Rockville, MD 20857
`
`www.ahrq.gov
`
`
`Contract No. 290-2015-00009-I
`
`
`Prepared by:
`
`Pacific Northwest Evidence-based Practice Center
`
`Portland, OR
`
`
`Investigators:
`
`Roger Chou, M.D.
`
`P. Todd Korthuis, M.D., M.P.H.
`
`
`Dennis McCarty, Ph.D.
`
`
`Phillip Coffin, M.D., M.I.A.
`
`
`Jessica Griffin, M.S.
`
`
`Cynthia Davis-O’Reilly, B.S.
`
`
`Sara Grusing, B.A.
`
`
`Mohamud Daya, M.D., M.S.
`
`
`
`
`
`AHRQ Publication No. 17(18)-EHC025-EF
`
`
`November 2017
`
`
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` Key Messages
`
`
` Purpose of Review
`
` To determine optimal doses, routes of administration, and dosing strategies of naloxone for
` suspected opioid overdose in out-of-hospital settings, and whether transport to a hospital
`
`
`
`
` following successful opioid overdose reversal with naloxone is necessary.
`
` Key Messages
`
`
` • Higher concentration intranasal naloxone may be similarly effective and safe compared
`
`
` with intramuscular naloxone, but the available studies did not evaluate formulations
`
`
` approved by the Food and Drug Administration.
`• While field administration of naloxone is generally effective in reversing opioid
`
`
`
`overdose, there is not strong evidence concerning differences in effectiveness between
`
`doses or routes of administration.
`
`
`• More research is needed to determine optimal doses of naloxone, appropriate timing of
`
`
`
`
`repeat dosing, and whether it is necessary to dose patients to full consciousness.
`
`
`• More research is needed to determine whether transporting patients to a hospital after
`
`
`
` successful reversal of overdose is necessary.
`
`
`
`
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` This report is based on research conducted by the Pacific Northwest Evidence-based Practice
`
`
`
`
` Center under contract to the Agency for Healthcare Research and Quality (AHRQ), Rockville,
` MD (Contract No. 290-2015-00009-I). The findings and conclusions in this document are those
`
`
`
` of the authors, who are responsible for its contents; the findings and conclusions do not
`
` necessarily represent the views of AHRQ. Therefore, no statement in this report should be
`
`
`construed as an official position of AHRQ or of the U.S. Department of Health and Human
`Services.
`
`
`
`
`
`
`
`None of the investigators have any affiliations or financial involvement that conflicts with
`
`the material presented in this report.
`
`The information in this report is intended to help health care decisionmakers—patients and
`clinicians, health system leaders, and policymakers, among others—make well-informed
`decisions and thereby improve the quality of health care services. This report is not intended to
`
`be a substitute for the application of clinical judgment. Anyone who makes decisions concerning
`
`
`the provision of clinical care should consider this report in the same way as any medical
`
`reference and in conjunction with all other pertinent information, i.e., in the context of available
`resources and circumstances presented by individual patients.
`
`
`
`This report is made available to the public under the terms of a licensing agreement between the
`
`author and the Agency for Healthcare Research and Quality. This report may be used and
`reprinted without permission except those copyrighted materials that are clearly noted in the
`
`
`report. Further reproduction of those copyrighted materials is prohibited without the express
`permission of copyright holders.
`
`
`
`AHRQ or U.S. Department of Health and Human Services endorsement of any derivative
`
`
`products that may be developed from this report, such as clinical practice guidelines, other
`
`quality enhancement tools, or reimbursement or coverage policies, may not be stated or implied.
`
`
`
`This report may periodically be assessed for the currency of conclusions. If an assessment is
`
`done, the resulting surveillance report describing the methodology and findings will be found on
`the Effective Health Care Program Web site at www.effectivehealthcare.ahrq.gov. Search on the
`
`title of the report.
`
`
`Persons using assistive technology may not be able to fully access information in this report. For
`
`
`assistance contact EffectiveHealthCare@ahrq.hhs.gov.
`
`Suggested citation: Chou R, Korthuis PT, McCarty D, Coffin P, Griffin J, Davis-O’Reilly C,
`
`
`Grusing S, Daya M. Management of Suspected Opioid Overdose With Naloxone by Emergency
`
`
`Medical Services Personnel. Comparative Effectiveness Review No. 193. (Prepared by the
`
`Pacific Northwest Evidence-based Practice Center under Contract No. 290-2015-00009-I.)
`AHRQ Publication No. 17(18)-EHC025-EF. Rockville, MD: Agency for Healthcare Research
`
`
`and Quality; November 2017. www.effectivehealthcare.ahrq.gov/reports/final.cfm.
`
`DOI: https://doi.org/10.23970/AHRQEPCCER193.
`
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` Preface
`
`
` The Agency for Healthcare Research and Quality (AHRQ), through its Evidence-based Practice
`Centers (EPCs), sponsors the development of evidence reports and technology assessments to
`assist public- and private-sector organizations in their efforts to improve the quality of health
`care in the United States. The National Highway Traffic Safety Administration (NHTSA)
`
`
`
`requested and provided funding for this report.
`
`
`
`
`
`The reports and assessments provide organizations with comprehensive, evidence-based
`information on common medical conditions and new health care technologies and strategies.
`
`
` They also identify research gaps in the selected scientific area, identify methodological and
`scientific weaknesses, suggest research needs, and move the field forward through an unbiased,
`evidence-based assessment of the available literature. The EPCs systematically review the
`
`
`relevant scientific literature on topics assigned to them by AHRQ and conduct additional
`
`analyses when appropriate prior to developing their reports and assessments.
`
`To bring the broadest range of experts into the development of evidence reports and health
`
`technology assessments, AHRQ encourages the EPCs to form partnerships and enter into
`
`collaborations with other medical and research organizations. The EPCs work with these partner
`
`
`organizations to ensure that the evidence reports and technology assessments they produce will
`
`become building blocks for health care quality improvement projects throughout the Nation. The
`
`
`
`reports undergo peer review and public comment prior to their release as a final report.
`
`
`AHRQ expects that the EPC evidence reports and technology assessments, when appropriate,
`
`will inform individual health plans, providers, and purchasers as well as the health care system as
`
`a whole by providing important information to help improve health care quality.
`
` If you have comments on this evidence report, they may be sent by mail to the Task Order
`
`
`
`
`
`
`
`
`
` Officers (TOOs) named below at: Agency for Healthcare Research and Quality, 5600 Fishers
` Lane, Rockville, MD 20857, or by email to epc@ahrq.hhs.gov.
`
`
`
`
`
`
`
`Gopal Khanna, M.B.A.
`
`Director
`
`Agency for Healthcare Research and Quality
`
`Arlene S. Bierman, M.D., M.S.
`
`Director
`
`Center for Evidence and Practice
`Improvement
`
` Agency for Healthcare Research and Quality
`
`
`
`Stephanie Chang, M.D., M.P.H.
`Director
`
`Evidence-based Practice Center Program
`
`Center for Evidence and Practice Improvement
`
`
`
`Agency for Healthcare Research and Quality
`
`
`David Niebuhr, M.D., M.P.H., M.Sc.
`Task Order Officer
`
`Center for Evidence and Practice
`
`
`Improvement
`
`Agency for Healthcare Research and Quality
`
`
`Laura Pincock, Pharm.D., M.P.H.
`Task Order Officer
`
`Center for Evidence and Practice
`
`Improvement
`
`Agency for Healthcare Research and Quality
`
`
`
`
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` Acknowledgments
`
`
`
` The authors gratefully acknowledge the following individuals for their contributions to this
` project: Elaine Graham, M.L.S.; Tracy Dana, M.L.S.; Leah Williams, BS; and Hyon Hildebrant,
`
`
`B.A.
`Key Informants
`
`
` Key Informants were not involved in the development of this report.
`
` Technical Expert Panel
`In designing the study questions and methodology at the outset of this report, the EPC consulted
`
`
`
`several technical and content experts. Broad expertise and perspectives were sought. Divergent
`
`and conflicting opinions are common and perceived as healthy scientific discourse that results in
`a thoughtful, relevant systematic review. Therefore, in the end, study questions, design,
`
`
`methodologic approaches, and/or conclusions do not necessarily represent the views of
`
`
`individual technical and content experts.
`
`
`
`
`Technical Experts must disclose any financial conflicts of interest greater than $10,000 and any
`
`
`other relevant business or professional conflicts of interest. Because of their unique clinical or
`
`
`content expertise, individuals with potential conflicts may be retained. The TOO and the EPC
`
`work to balance, manage, or mitigate any potential conflicts of interest identified.
`
`
`The list of Technical Experts who provided input to this report follows:
`
`
`
`Caleb Banta-Green, Ph.D., M.P.H., M.S.W.
`University of Washington
`
`Seattle, WA
`
`
`Michael Dailey,* M.D., FACEP, FAEMS
`
`
`Albany Medical College
`
`Albany, NY
`
`
`Corey Davis,* J.D., M.S.P.H., EMT-B
`
`Network for Public Health Law
`
`Los Angeles, CA
`
`
`
`James J. Gasper,* Pharm.D., BCPP
`
`California Department of Healthcare Services
`
`Sacramento, CA
`
`Christopher Jones, Pharm.D., Ph.D.
`
`U.S. Department of Health and Human Services
`
`Washington, DC
`
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`Scott Russell,* R.N., B.S.N., EMT-P
`
`Metrohealth
`
`Cleveland, OH
`
`
`Karl Sporer, M.D.
`
`
`University of California, San Francisco
`
`San Francisco, CA
`
`
`Sharon Stancliff,* M.D.
`
`
`Harlem East Life Plan
`
`
`New York, NY
`
`Gregory Terman,* M.D., Ph.D.
`University of Washington
`
`Seattle, WA
`
`
`
`U.S. Food and Drug Administration*
`
`Center for Drug Evaluation and Research
`
`Office of New Drugs
`
`Division of Analgesia, Anesthesia, and Addiction Products
`
`Silver Spring, MD
`
`Alexander Walley, M.D., M.Sc.
`
`Boston University
`
`Boston, MA
`
`
`*Provided input on Draft Report.
`
` Peer Reviewers
` Prior to publication of the final evidence report, EPCs sought input from independent Peer
`
`
`
`
` reviewers without financial conflicts of interest. However, the conclusions and synthesis of the
`
` scientific literature presented in this report do not necessarily represent the views of individual
`
`
`
` reviewers.
`
`Peer Reviewers must disclose any financial conflicts of interest greater than $10,000 and any
`
`
`
`other relevant business or professional conflicts of interest. Because of their unique clinical or
`
`
`content expertise, individuals with potential nonfinancial conflicts may be retained. The TOO
`
`
`and the EPC work to balance, manage, or mitigate any potential nonfinancial conflicts of interest
`
`identified.
`
`
`The list of Peer Reviewers follows:
`
`
`Steven Aks, D.O., FACMT, FACEP
`
`Toxicon Consortium,
`
`Cook County Health and Hospitals System
`
`
`
`Chicago, IL
`
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` Jeffrey Bratberg, Pharm.D.
`
`
` University of Rhode Island
`
` Kingston, RI
`
`Christian Martin-Gill, M.D., M.P.H.
`
`University of Pittsburgh
`
`Pittsburgh, PA
`
`Jennifer Plumb, M.D., M.P.H.
`
`University of Utah
`
`
`Salt Lake City, UT
`
`
`Ken Sternig, M.S.-E.H.S., B.S.N., Paramedic
`
`Office of Emergency Management
`
`Milwaukee, WI
`
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`
`
` Management of Suspected Opioid Overdose With
`
` Naloxone by Emergency Medical Services Personnel
` Structured Abstract
`
` Objectives. To compare different routes, doses, and dosing strategies of naloxone administration
`
`
` for suspected opioid overdose by emergency medical services (EMS) personnel in field settings,
`
`
` and to compare effects of transport to a health care facility versus nontransport following
`
`
` successful reversal of opioid overdose with naloxone.
`
`
`
`Methods. Four databases were searched through September 2017. Additional studies were
`
`
`
`
`
`identified from reference lists and technical experts. We included randomized controlled trials
`
`(RCTs) and cohort studies comparing different naloxone routes of administration, doses, or
`
`
`dosing strategies and on effects of transport or nontransport following successful reversal of
`opioid overdose with naloxone. Two investigators independently applied prespecified criteria to
`
`rate study quality. The strength of evidence was determined based on the overall risk of bias,
`consistency, directness, precision, and reporting bias. Main outcomes were mortality, reversal of
`
`
`
` opioid overdose symptoms, time to reversal of symptoms, recurrence of overdose symptoms, and harms.
`
`
`
`
`
` Results. Thirteen studies met inclusion criteria. Three RCTs and four cohort studies compared
`
`
` different routes of administration. Two trials compared intranasal (IN) with intramuscular (IM)
`
`
`
`
` naloxone administration (strength of evidence [SOE] for all outcomes: low). While 2 mg of a
`
`
` higher concentration formulation of IN naloxone (2 mg/1 mL) is similar in efficacy to 2 mg of
`
`
` IM naloxone, 2 mg of a lower concentration formulation of IN naloxone (2 mg/5 mL) is less
`
`
`
`
`
`
` effective than the same dose IM but associated with decreased risk of agitation and/or irritation.
`
`
` The 2 mg/5 mL formulation of IN naloxone studied in this trial is lower than concentrations used
`
` in the United States. In both trials, IN naloxone was associated with increased likelihood of
`
`
`rescue naloxone use.
`Although one RCT and two observational studies evaluated intravenous (IV) versus IN
`
`
`
`naloxone, evidence was insufficient to determine comparative benefits and harms because of
`
`
`methodological limitations and poor applicability to U.S. EMS settings (SOE: insufficient).
`
`
`There was insufficient evidence from two observational studies to compare parenteral routes of
`
`
`
`administration (IM, IV, or subcutaneous).
`
`No study compared outcomes of patients transported versus not transported following
`
`successful reversal of opioid overdose with naloxone. Six studies reported low rates of deaths
`
`
`and serious adverse events (0% to 1.25%) in patients not transported to a hospital after successful
`
`
`naloxone treatment but used an uncontrolled design and had other methodological limitations
`
`(SOE: insufficient).
`
`
`Limitations. Few studies met inclusion criteria, all studies had methodological limitations, and
`
`
`
`no study evaluated naloxone auto-injectors or IN naloxone formulations recently approved by the
`
`
`
`
`U.S. Food and Drug Administration (FDA).
`
`
`
`Conclusions. Low-strength evidence suggested that higher concentration IN naloxone (2 mg/1
`
`
`mL) is similar in efficacy to IM naloxone (2 mg), with no difference in adverse events. Research
`
`
`is needed on the comparative effectiveness of the FDA-approved naloxone auto-injectors (0.4
`mg and 2 mg) and highly concentrated (4 mg/0.1 mL and 2 mg/0.1 mL) IN naloxone
`
`
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`reformulation, different doses, and dosing strategies. Uncontrolled studies suggest that
`
`
` nontransport of patients following successful naloxone reversal of overdose is associated with a
` low rate of serious harms, but patients were probably at low risk for such events, and no study
`
`
` evaluated risk of transport versus nontransport.
`
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` Contents
`
`
`
` Executive Summary................................................................................................................ ES-1
`
` Introduction................................................................................................................................... 1
`
`
`
`Background ................................................................................................................................ 1
`
`
`Nature and Burden of Opioid Overdose ................................................................................ 1
`
`
`Field Treatment of Suspected Opioid Overdose With Naloxone .......................................... 1
`
`
`Rationale for Review ............................................................................................................. 3
`
`
`
`Scope and Key Questions ...................................................................................................... 3
`
`
`Analytic Framework .............................................................................................................. 5
`
`
`Methods.......................................................................................................................................... 6
`
`
`Topic Refinement and Review Protocol .................................................................................... 6
`
`
`Literature Search Strategy.......................................................................................................... 6
`
`
`Search Strategy ...................................................................................................................... 6
`
`
`Inclusion and Exclusion Criteria ................................................................................................ 7
`
`
`Data Extraction........................................................................................................................... 9
`
`
`
`
`Risk of Bias Assessment of Individual Studies.......................................................................... 9
`
`
`Assessing Research Applicability ............................................................................................ 10
`
`
`
`Data Synthesis and Rating the Body of Evidence.................................................................... 10
`
`
`
`Peer Review and Public Commentary...................................................................................... 11
`
`
`Results .......................................................................................................................................... 12
`
`
`
`Results of Literature Searches.................................................................................................. 12
`
`
`Description of Included Studies ............................................................................................... 13
`
`
`
`Key Question 1: For patients with confirmed or suspected opioid overdose, what are the
`
`
`
`
`
`comparative benefits and harms of out-of-hospital administration of naloxone by EMS
`
`
`personnel using intravenous, intramuscular, subcutaneous, and intranasal routes of
`
`
`administration?..................................................................................................................... 13
`
`
`
`Key Question 1a: For patients with confirmed or suspected opioid overdose who receive
`
`
`
`
`naloxone in the out-of-hospital setting from EMS personnel, what are the comparative
`
`
`benefits and harms of different intravenous, intramuscular, subcutaneous, or intranasal
`
`
`doses of naloxone?............................................................................................................... 18
`
`Key Question 2: For patients with confirmed or suspected opioid overdose in out-of­
`
`
`hospital settings, what are the comparative benefits and harms of titration of naloxone
`
`
`administered by EMS personnel until the patient resumes sufficient spontaneous respiratory
`
`
`effort versus until the patient regains consciousness? ......................................................... 19
`
`Key Question 3: For patients with confirmed or suspected opioid overdose in out-of­
`
`hospital settings treated with multiple doses of naloxone (including patients who do not
`
`
`improve after an initial dose of intranasal naloxone), what are the effects on benefits and
`
`
`harms of differences in timing of repeat dosing?................................................................. 19
`
`Key Question 4: For patients with confirmed or suspected opioid overdose in out-of­
`
`hospital settings who regain sufficient spontaneous respiratory effort and are alert and
`
`
`oriented after naloxone administration by EMS personnel, what are the benefits and harms
`
`
`
`of transporting patients to a health care facility versus nontransport?................................. 20
`
`Discussion..................................................................................................................................... 22
`
`
`Key Findings and Strength of Evidence................................................................................... 22
`
`
`
`Findings in Relationship to What Is Already Known .............................................................. 23
`
`
`Applicability............................................................................................................................. 24
`
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` Implications for Clinical and Policy Decisionmaking ............................................................. 25
`
` Limitations of the Systematic Review Process ........................................................................ 27
`
`
`
`Limitations of the Evidence Base............................................................................................. 28
`
`
`Research Recommendations..................................................................................................... 28
`
`
`Conclusions.................................................................................................................................. 31
`
`
`References.................................................................................................................................... 32
`
`
`
`Tables
`
`
`Table A. Naloxone: Dose and route of administration ............................................................. ES-4
`
`
`
`Table 1. Naloxone: Dose and route of administration .................................................................... 7
`
`
`Table 2. Characteristics and results of randomized controlled trials comparing routes of naloxone
`
`
`administration ................................................................................................................................16
`
`
`Table 3. Characteristics and results of cohort studies comparing routes of naloxone
`
`
`administration ................................................................................................................................17
`
`
`Table 4. Characteristics and results of uncontrolled studies of patients not transported to hospitals
`
`
`after naloxone administration .......................................................................................................21
`
`
`
`Figures
`
`
`Figure A. Analytic framework...................................................................................................ES-3
`
`
`
`Figure B. Literature flow diagram .............................................................................................ES-7
`
`
`Figure 1. Analytic framework..........................................................................................................5
`
`
`Figure 2. Literature flow diagram..................................................................................................12
`
`
`
`Appendixes
`
`Appendix A. Search Strategies
`
`
`Appendix B. Included Studies List
`
`
`Appendix C. Excluded Studies List
`
`Appendix D. Data Abstraction
`
`Appendix E. Risk of Bias
`
`
`Appendix F. Strength of Evidence
`
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` Executive Summary
`
`
` Background
`
`
`
` Nature and Burden of Opioid Overdose
` Addiction and overdoses associated with prescription and illicit opioids have been
`
` characterized by the U.S. Department of Health and Human Services as a national crisis.1 Since
`
`
`
`2000, the rate of overdose deaths involving opioids has increased four-fold.2,3 Drug overdose
`
`deaths are now the leading cause of injury-related death in the United States.4 Overdoses due to
`
`opioids cause respiratory depression that can progress to cardiac arrest if untreated. In 2015, the
`number of drug overdose deaths involving prescription or illicit opioids exceeded 33,000, the
`
`
`
`highest number on record.3 Of recent concern is whether dosing guidelines are sufficient for
`
`
`
`
`
`
`reversing overdose related to highly potent synthetic opioids (e.g., fentanyl and fentanyl
`
`
`analogues).3,5-9
` Field Treatment of Suspected Opioid Overdose With Naloxone
`
`
` Naloxone can be administered by the intravenous (IV), intramuscular (IM), subcutaneous
`
`(SC), intranasal (IN), endotracheal (ET), nebulized/inhalational, buccal, or sublingual routes.10
`
`
`
`
`The U.S. Food and Drug Administration (FDA) approved a handheld naloxone IM or SC auto-
`injector in 201411 and a new IN formulation and delivery device in 2015;12 both administer a
`
`
`
`
`
` preset dose. With IN administration of highly concentrated naloxone using a preloaded single
`
`
`
` dose device, there is no risk of needle stick injury. Both the auto-injector and IN formulation are
`
`
` designed for ease of administration even by individuals with limited or no health care training.
`
`
`
`
` Off-label administration of IN naloxone in a less concentrated formulation using an improvised
`
`intranasal device is also common. Naloxone has been shown to be effective for reversal of opioid
`overdose across various routes of administration and doses.13,14 Naloxone may precipitate
`
`withdrawal symptoms.15 While uncomfortable, withdrawal symptoms are generally not serious
`
`
`or life-threatening and generally short-lived; the half-life of naloxone is about 30 minutes. Post-
`withdrawal agitation following naloxone administration may put the person administering the
`
`
`
`naloxone at increased risk for injury.16,17
`
`
`
`
`When responding to opioid overdoses, early intervention is critical to prevent death and other
`complications.18 Emergency medical services (EMS) personnel are often involved in
`management of potential opioid overdoses. Management of opioid overdoses by EMS personnel
`
`
`includes airway management and continuous assessment of oxygenation and ventilation, along
`
`with administration of naloxone.19 According to the National EMS Information System database,
`
`
`the number of EMS encounters for suspected opioid overdose has increased,20 with nearly
`
`
`160,000 doses of naloxone administered by EMS personnel in 2014.21 Regulations vary,
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`however, with regard to whether EMS personnel with different levels of training are permitted to
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`administer naloxone. Naloxone administration is not currently within the National EMS Scope of
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`Practice Model for EMTs and EMRs, which was last updated in 2007,22 prior to the introduction
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`of newer naloxone formulations and availability of newer evidence on the benefits of field use of
`naloxone.
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`Although a number of recommendations, guidelines, and protocols are available to inform
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`out-of-hospital management of opioid overdose patients, including naloxone use, guidance varies
`across these documents, and there are uncertainties in a number of areas.23-25 These include the
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` optimal route of administration, the optimal dose for different routes of administration, optimal
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`dosing strategies, and appropriate training levels for EMS personnel who are permitted to
`administer naloxone.
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`The purpose of this systematic review is to synthesize the evidence on naloxone route of
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`administration and dosing for suspected opioid overdose in out-of-hospital settings, and on the
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`need for transport to a hospital following successful opioid overdose reversal with naloxone; the
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`review is intended to inform development of evidence-based guidelines on EMS management of
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`suspected opioid overdose with naloxone and potentially inform an update to the National EMS
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`Scope of Practice Model regarding naloxone use across EMS training levels.
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` Scope and Key Questions
` The report addresses the following Key Questions.
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` Key Question 1: For patients with confirmed or suspected opioid overdose,
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` what are the comparative benefits and harms of out-of-hospital
` administration of naloxone by EMS personnel using intravenous,
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` intramuscular, subcutaneous, and intranasal routes of administration?
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` 1a. For patients with confirmed or suspected opioid overdose who
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` receive naloxone in the out-of-hospital setting from EMS personnel,
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` what are the comparative benefits and harms of different intravenous,
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` intramuscular, subcutaneous, or intranasal doses of naloxone?
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` Key Question 2: For patients with confirmed or suspected opioid overdose
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` in out-of-hospital settings, what are the comparative benefits and harms of
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` titration of naloxone administered by EMS personnel until the patient
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` resumes sufficient spontaneous respiratory effort versus until the patient
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` regains consciousness?
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` Key Question 3: For patients with confirmed or suspected opioid overdose
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` in out-of-hospital settings treated with multiple doses of naloxone (including
` patients who do not improve after an initial dose of intranasal naloxone),
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` what are the effects on benefits and harms of differences in timing of repeat
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` dosing?
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`Key Question 4: For patients with confirmed or suspected opioid overdose
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`in out-of-hospital settings who regain sufficient spontaneous respiratory
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`effort and are alert and oriented after naloxone administration by EMS
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`personnel, what are the benefits and harms of transporting patients to a
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`health care facility versus nontransport?
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`The analytic framework (Figure A) shows the target population, interventions, and health
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` outcomes examined; the Key Questions are numbered and indicated in the framework. We
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` focused on use of IN, IM, and IV naloxone; these are the formulations of naloxone most
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` commonly used for reversal of suspected opioid overdose in the field.
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` Figure A. Analytic framework
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`* P
` atients with confirmed or suspected opioid overdose who exhibit altered mental status, miosis, or respiratory distress and who
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` are treated in the out-of-hospital setting by emergency medical services personnel
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`†Administration of naloxone hydrochloride via the nasal, intravenous, intramuscular, or subcutaneous injection (including the
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`naloxone auto-injector)
`‡ Key Question 1 addresses comparisons involving route of administration and dose; Key Question 2 addresses comparisons
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`involving dose titration to varying degrees of return of consciousness (intermediate outcome)
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` Methods
`The final protocol was posted on the AHRQ Web site on November 30, 2016,
`at: https://www.effectivehealthcare.ahrq.gov/search-for-guides-reviews-and­
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`reports/?pageaction=displayproduct&productid=2360 and registered in PROSPERO
`(CRD42016053891).
` Literature Search Strategy
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` A research librarian conducted searches in Ovid MEDLINE (1946-August Week 2 2016),
` PsycINFO, the Cochrane Central Register of Controlled Trials (CCRCT), and the Cumulative
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`
`
` Index to Nursing and Allied Health Literature (CINAHL). We did not apply search date
`restrictions and updated searches were conducted through September 2017. The Agency for
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`Healthcare Research and Quality (AHRQ) Evidence-based Practice Center (EPC) Scientific
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`Resource Center (SRC) sent email notification to relevant stakeholders about the opportunity to
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`submit Scientific Information Packets (SIPs) via the Effective Health