Prehospital Emergency Care
`
`ISSN: 1090-3127 (Print) 1545-0066 (Online) Journal homepage: https://www.tandfonline.com/loi/ipec20
`
`Evidence-Based Guidelines for EMS Administration
`of Naloxone
`
`Kenneth Williams, Eddy S. Lang, Ashish R. Panchal, James J. Gasper, Peter
`Taillac, John Gouda, John W. Lyng, Jeffrey M. Goodloe & Mary Hedges
`
`To cite this article: Kenneth Williams, Eddy S. Lang, Ashish R. Panchal, James J. Gasper,
`Peter Taillac, John Gouda, John W. Lyng, Jeffrey M. Goodloe & Mary Hedges (2019): Evidence-
`Based Guidelines for EMS Administration of Naloxone, Prehospital Emergency Care, DOI:
`10.1080/10903127.2019.1597955
`To link to this article: https://doi.org/10.1080/10903127.2019.1597955
`
`© 2019 The Author(s). Published with
`license by Taylor & Francis Group, LLC
`
`Accepted author version posted online: 29
`Mar 2019.
`Published online: 17 Apr 2019.
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`EVIDENCE-BASED GUIDELINES FOR EMS ADMINISTRATION OF NALOXONE
`Kenneth Williams, MD, Eddy S. Lang, MDCM, CCFP (EM), Ashish R. Panchal, PhD, MD,
`James J. Gasper, PharmD, BCPP, Peter Taillac, MD, John Gouda, MB BCH BAO,
`John W. Lyng, MD, NRP, Jeffrey M. Goodloe, MD, Mary Hedges, MPA
`
`ABSTRACT
`
`The opioid crisis is a growing concern for Americans, and
`it has become the leading cause of injury-related death in
`the United States. An adjunct to respiratory support that
`can reduce this high mortality rate is the administration
`of naloxone by Emergency Medical Services (EMS) practi-
`tioners for patients with suspected opioid overdose.
`However, clear evidence-based guidelines to direct EMS
`use of naloxone for opioid overdose have not been devel-
`oped. Leveraging the recent Agency for Healthcare
`Research and Quality (AHRQ) systematic review on the
`EMS administration of naloxone for opioid poisonings,
`federal partners determined the need for a clinical practice
`guideline for EMS practitioners faced with suspected opi-
`oid poisoning. Project
`funding was provided by the
`National Highway Traffic Safety Administration, Office of
`EMS, (NHTSA OEMS), and the Health Resources and
`Services Administration, Maternal and Child Health
`Bureau’s EMS for Children Program (EMSC). The objec-
`tives of this project were to develop and disseminate an
`
`evidence-based guideline and model protocol for adminis-
`tration of naloxone by EMS practitioners to persons with
`suspected opioid overdose. We have four recommenda-
`tions relating to route of administration, all conditional,
`and all supported by low or very low certainty of evi-
`dence. We recommend the intravenous route of adminis-
`tration to facilitate titration of dose, and disfavor the
`intramuscular route due to difficulty with titration, slower
`time to clinical effect, and potential exposure to needles.
`We equally recommend the intranasal and intravenous
`routes of administration, while noting there are variables
`which will determine which route is best for each patient.
`Where we are unable to make recommendations due to
`evidence limitations (dosing, titration, timing, and trans-
`port) we offer technical remarks. Limitations of our work
`include the introduction of novel synthetic opioids after
`many of the reviewed papers were produced, which may
`affect the dose of naloxone required for effect, high risk of
`bias and imprecision in the reviewed papers, and the
`introduction of new naloxone administration devices since
`many of
`the reviewed papers were published. Future
`
`Received March 17, 2019 from Department of Emergency Medicine, Rhode Island Dept. of Health and National Association of State EMS
`Officials (NASEMSO), Brown University, Providence, Rhode Island (KW); Emergency Medicine Department, Cumming School of Medicine,
`University of Calgary, Alberta Health Services, Calgary, Alberta (ESL); National Registry of EMTs (NREMT) and Department of Emergency
`Medicine, The Ohio State University Wexner Medical Center, Columbus, Ohio (ARP); California Department of Health Care Services,
`Sacramento, California (JJG); University of Utah School of Medicine, Bureau of EMS and Preparedness, Utah Department of Health, Salt Lake
`City, Utah (PT); Emergency Medicine Department, Cumming School of Medicine, University of Calgary, Calgary, Alberta (JG); Office of the
`Medical Directors, North Memorial Health Ambulance & Air Care, Minneapolis, Minnesota (JWL); Department of Emergency Medicine,
`University of Oklahoma School of Community Medicine, Tulsa, Oklahoma (JMG); National Association of State EMS Officials (NASEMSO),
`Falls Church, Virginia (MH). Accepted for publication March 18, 2019.
`
`While this manuscript was reviewed and shaped by many members of the Technical Expert Panel (TEP or Panel), only those meeting the
`criteria for authorship by the International Committee of Medical Journal Editors (ICMJE) have been listed as authors. We wish to acknowledge
`the work of other contributors, including Project Coordinator Zoe Renfro, whose technical editing skills made this document possible, and Mary
`Hedges, Program Manager, whose coordination and organizational skills facilitated the work of the TEP. The members of the TEP, their
`expertise and affiliations, are available in Table 1.
`
`The contents of this report are solely the responsibility of the authors and do not necessarily represent the official views of NHTSA.
`
`This document was produced with support from the US Department of Transportation, National Highway Traffic Safety Administration
`(NHTSA), Office of Emergency Medical Services and the Health Resources and Services Administration, Maternal and Child Health
`Bureau’s EMS for Children Program through cooperative agreement DTNH2217H00031.
`
`James Gasper, Ashish Panchal, John Gouda, Peter Taillac, and Mary Hedges report no conflict of interest. Eddy Lang reports receiving an
`honorarium from NASEMSO for the support he provided this project as a GRADE methodologist. Kenneth A Williams reports receiving
`an honorarium from NASEMSO for his leadership of the project.
`
`Address correspondence to Kenneth Williams, MD, Department of Emergency Medicine, Rhode Island Dept. of Health and National
`Association of State EMS Officials (NASEMSO), Brown University, Providence, RI 02903, E-mail:kwilliamsMD@gmail.com
`ß 2019 The Author(s). Published with license by Taylor & Francis Group, LLC
`
`This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License
`(http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial re-use, distribution, and reproduction in any
`medium, provided the original work is properly cited, and is not altered, transformed, or built upon in any way.
`doi:10.1080/10903127.2019.1597955
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`research should be conducted to evaluate new devices
`and address the introduction of synthetic opioids. Key
`naloxone;
`opioid-related disorders;
`narcotic
`words:
`antagonists; drug overdose; emergency medical services;
`evidence-based emergency medicine
`PREHOSPITAL EMERGENCY CARE 2019;00:000–000
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`BACKGROUND
`
`Impact of the Opioid Crisis
`Rates of opioid overdose (OD) in the United States
`have increased fourfold since 2000, with data for
`2016 indicating that over 42,000 died from opioid
`overdose that year alone (1). In 2016, opioid over-
`dose deaths (2) overtook traffic crashes (3) as the
`leading cause of death by traumatic injury in the
`United States. In recent years, synthetic opioids, pre-
`dominantly illicitly-manufactured fentanyl and its
`analogs, have overtaken prescription opioids and
`heroin as the leading cause of overdose deaths (1).
`In 2017,
`the sharpest
`increase in drug overdose
`fatalities was related to fentanyl and fentanyl ana-
`logs, representing nearly 30,000 overdose deaths (1).
`As many opioid overdose patients are discovered
`by family and close friends (4), the US Surgeon
`General issued an advisory urging more Americans
`to carry naloxone to combat the opioid crisis (5).
`The opioid epidemic has widespread impact on the
`population at large, affecting family and friends,
`employers and coworkers, and others who know
`overdose patients. Factors which contribute to the
`crisis include substance use disorders, mental health
`disorders such as depression and bipolar disorder,
`chronic pain, relapse after a period of abstinence
`during drug treatment or incarceration and poly-
`pharmacy (6, 7).
`A drastic burden is placed on society as more
`resources and personnel are allocated to combat this
`epidemic. Between 2012 and 2016, the rate of nalox-
`one administration by EMS increased 75.1%, from
`573.6 to 1004.4 per 100,000 EMS events (8). The
`increased rate of administration of naloxone mirrors
`the overdose mortality rate (8). A retrospective
`study which analyzed data from Northern New
`England revealed that basic life support (BLS) prac-
`titioners were as effective as advanced life support
`(ALS) practitioners in naloxone administration (9).
`The role of first responders has expanded to include
`identification and management of the effects of opi-
`oid toxicity through supportive management as well
`as reversal
`through the administration of nalox-
`one (10).
`
`Management of Opioid Overdose
`For EMS practitioners who suspect an opioid over-
`dose, the first step is to evaluate the extent of the
`patient’s
`respiratory depression. Overdoses
`of
`opioids are associated with both central nervous
`system (CNS) and respiratory depression, making
`the primary risk of death inadequate oxygenation
`and ventilation, which can decompensate to cardiac
`arrest. In many situations,
`it may not be readily
`apparent if a patient is suffering an opioid overdose
`versus respiratory depression due to other etiologies
`or co-ingestions. Due to these concerns, the patient’s
`airway and respiratory mechanics must be assessed
`immediately upon patient contact and supported
`with airway maneuvers and ventilation (e.g., bag-
`valve-mask) as indicated. Even when naloxone is
`clinically indicated, respiratory support should be
`given first or at least contemporaneously. Bag-valve-
`mask ventilation,
`incorporating oropharyngeal or
`nasopharyngeal airways to promote a patent air-
`way, should be used to provide adequate oxygen-
`ation and ventilation until the patient is able to
`breathe adequately without support. In cases where
`the response to naloxone is inadequate, further air-
`way management may be required, such as a supra-
`glottic
`airway
`device
`or
`endotracheal
`tube
`placement (if within applicable scopes of practice).
`In other cases, respiratory support may result in
`recovery as accumulated carbon dioxide is purged,
`and naloxone may not be necessary.
`
`Naloxone. Naloxone is a mu-opioid receptor antagon-
`ist effective at reversing the symptoms of opioid tox-
`icity and associated life-threatening respiratory
`depression. First synthesized in 1961, naloxone was
`approved for use in 1971 as an opioid reversal agent,
`and EMS practitioners began administering naloxone
`shortly thereafter (11). The need for rapid access to
`naloxone in the community has expanded naloxone
`use to include both first responders and laypersons
`in the out of hospital setting (12). Common routes of
`naloxone administration include intravenous (IV),
`intramuscular (IM), subcutaneous (SQ), and intra-
`nasal
`(IN). Two Food and Drug Administration
`(FDA) approved products for layperson use have
`been developed: an autoinjector for IM administra-
`tion and a commercial nasal spray with a bioavail-
`ability of approximately 50% relative to IM (13).
`Naloxone has a rapid onset of action, reaching
`maximal serum concentration within 2 minutes after
`IV administration,
`10 minutes
`after
`IM,
`and
`15–30 minutes after IN (14). Naloxone distributes to
`the central nervous system and equilibrates with the
`plasma within minutes (15). Naloxone is extensively
`metabolized in the liver to inactive metabolites with
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`K. Williams et al. EMS NALOXONE GUIDELINE
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`3
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`a serum half-life of 30–90 minutes (15). Naloxone is
`an extremely safe medication but can precipitate
`opioid withdrawal symptoms including agitation or
`irritability, anxiety, body aches, nausea or vomiting,
`diarrhea, piloerection,
`rhinorrhea, and sweating.
`More severe reactions are extremely rare but may
`include acute respiratory distress syndrome (ARDS),
`hypertensive emergency, ventricular tachycardia and
`fibrillation, and sudden death (16). Dosing of nal-
`oxone is based on the goal of restoring adequate
`respiratory function while minimizing the risk of opi-
`oid withdrawal symptoms, which is best accom-
`plished with dose titration and careful monitoring
`when conditions permit.
`
`Presence of Other Substances and Opioids. An appar-
`ently inadequate response to initial dosing of nalox-
`one could be the result of co-ingestants, such as
`ethanol or benzodiazepines. Additionally,
`some
`extremely powerful fentanyl analogs, such as carfen-
`tanil or acetyl fentanyl, as well as the opioid partial
`agonist buprenorphine, may require larger than
`usual or
`repeat doses of naloxone to achieve
`adequate respiratory function and are increasingly
`involved in opioid overdoses.
`
`Occupational Exposure. The potential
`for occupa-
`tional exposure to fentanyl and its analogs has cre-
`ated distinct concern among public safety and EMS
`practitioners. Therefore, it is important that practi-
`tioners utilize appropriate practices and personal
`protective equipment (PPE) when potentially in the
`presence of opioids in a form that could pose tox-
`icity. In responding to most suspected opioid over-
`doses, standard PPE medical gloves are sufficient
`protection. Credible resources exist to advise public
`safety and EMS professionals and include the
`American College of Medical Toxicology’s Statement
`on Fentanyl Exposure (17).
`
`PROJECT OBJECTIVES
`
`The objectives of this project were to develop and
`disseminate an evidence-based guideline and model
`protocol
`for
`administration
`of
`naloxone
`by
`Emergency Medical Services (EMS) practitioners to
`persons with suspected opioid overdose. Also
`included in the objectives were the development of
`training materials for EMS practitioners in imple-
`menting the guideline, the creation of performance
`measures by which adherence to the clinical practice
`guideline and its impact could be assessed, and the
`development of a manuscript for publication in a
`peer-reviewed
`scientific
`journal.
`This
`paper
`
`describes the process by which the evidence-based
`guideline was developed.
`
`METHODS
`
`The Institute of Medicine report on trustworthy clin-
`ical practice guidelines has made clear that
`the
`development of
`recommendations
`intended to
`improve care are to be based on a systematic review
`of
`the scientific literature (18). While systematic
`reviews are the optimal means of evaluating and
`synthesizing the existing scientific evidence to
`inform clinical questions, this information alone is
`insufficient. This clinical practice guideline was
`developed as a follow-up to the Agency for
`Healthcare Research and Quality (AHRQ) system-
`atic review on the prehospital administration of
`naloxone for opioid poisonings that occur in the
`field (10). This evidence was given in-depth consid-
`eration by a panel of
`relevant stakeholders to
`develop concise recommendations based on GRADE
`methodology.
`the National EMS Advisory
`In August 2016,
`Council (NEMSAC) recommended that the National
`Highway Traffic Safety Administration develop an
`evidence-based guideline regarding administration
`of naloxone by EMS clinicians. The advisory was
`approved and published after the September 2016
`National EMS Advisory Council meeting (19). The
`current project was developed in the fall of 2017 by
`the Medical Directors Council of
`the National
`Association of State EMS Officials (NASEMSO) in
`collaboration with the National Association of EMS
`Physicians (NAEMSP) and the EMS Committee of
`the American College of Emergency Physicians
`(ACEP). A Technical Expert Panel (TEP or Panel)
`was assembled, which included experienced EMS
`field practitioners, EMS physician medical directors,
`experts in addiction medicine, pain medicine, toxi-
`cology/pharmacology, and GRADE methodologies,
`as well as a patient advocate (see Table 1: Members
`of Expert Panel). Funding was provided by the
`National Highway Traffic Safety Administration,
`Office of EMS, and the Health Resources and
`Services Administration, Maternal and Child Health
`Bureau’s EMS for Children Program.
`The project scope of work focused on translating
`the systematic review published by the Agency for
`Healthcare Research and Quality (AHRQ)
`in
`November 2017 into an evidence-based guideline
`and model protocol for administration of naloxone
`by EMS practitioners to persons suspected of an
`opioid overdose (10). This was done through review
`of
`the
`Population
`Intervention
`Comparison
`Outcome
`(PICO)
`questions
`addressed in the
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`Name
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`PREHOSPITAL EMERGENCY CARE 䊏/䊏 2019 VOLUME 0 / NUMBER 0
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`TABLE 1. Members of Technical Expert Panel
`
`Area(s) of Expertise
`
`Institution
`
`James Gasper, PharmD, BCPP
`
`Pharmacology
`
`Jeffrey Goodloe, MD
`Co-Investigator (ACEP)
`
`EMS Medical Direction
`Emergency Medicine
`
`Richard Hale
`Vicki L. Hildreth, BA, EMT-B
`
`Eddy Lang, MDCM, CCFP (EM)
`
`John W. Lyng, MD, EMT-P
`Co-Investigator (NAEMSP)
`
`Anne Montera, RN, BSN
`Ashish R. Panchal, MD, PhD
`
`Tim Seplaki, NRP
`Sharon Stancliff, MD
`Nate Sullivan, EMT-P
`Peter Taillac, MD
`
`Debbie Vass, RN, EMT-P
`
`Kenneth A Williams, MD
`Principal Investigator (NASEMSO)
`
`Performance Measure Development
`Patient Advocate
`EMS Clinician
`Pediatrics
`EBG Development
`Emergency Medicine
`GRADE Methodology
`EMS Medical Direction
`Emergency Medicine
`
`Patient Advocate
`Emergency Medicine
`EMS Medical Direction
`Research
`
`EMS Clinician
`Addiction Medicine
`EMS Clinician
`EMS Medical Direction
`Prehospital Guidelines Consortium
`EBG Development
`Performance Measure Development
`EMS Administration
`Clinician
`Performance Measure Development
`EMS Medical Direction
`Emergency Medicine
`
`Pharmacy Benefits Division, California
`Department of Health Care Services
`American College of Emergency Physicians
`(ACEP)
`Emergency Medical Services System for
`Metropolitan Oklahoma City & Tulsa
`Oklahoma Center for Prehospital &
`Disaster Medicine
`ESO Solutions
`WV Department of Health &
`Human Resources
`
`Emergency Medicine Department, Cumming
`School of Medicine, University of Calgary,
`Alberta Health Services
`North Memorial Health Ambulance & Air
`Care (Minneapolis, MN)
`National Association of EMS
`Physicians (NAEMSP)
`Caring Anne Consulting, LLC
`National Registry of EMTs (NREMT)
`Department of Emergency Medicine, The
`Ohio State University Wexner
`Medical Center
`NJ Department of Health, Office of EMS
`Harm Reduction Coalition
`Cherokee County Fire & Emergency Services
`Bureau of EMS and Preparedness, Utah
`Department of Health
`
`Sunstar Paramedics
`Paramedics Plus
`
`Brown Department of Emergency Medicine
`Rhode Island Dept. of Health
`National Association of State EMS
`Officials (NASEMSO)
`
`Staff and Federal Partner Support: Mary Hedges, Project Manager; Zoe Renfro, Project Coordinator; Dia Gainor, NASEMSO Executive Director; Dave Bryson, NHTSA
`
`Office of EMS; Jeremy Kinsman , NHTSA Office of EMS; Cathy Gotschall, NHTSA Office of EMS
` New members added in April 2018. Most members were added in November 2017.
`
`systematic review and the evidence identified by
`the searches. The PICO questions addressed by the
`AHRQ systematic review are listed in Table 2.
`Following PICO question and evidence review, the
`TEP used the Grading
`of Recommendations
`Assessment, Development and Evaluation (GRADE)
`methodology to summarize the evidence and assess
`the strength of the literature and develop treatment
`recommendations. GRADE is emerging as the most
`widely used system for clinical practice guideline
`development (20). It has been endorsed as an opti-
`mal method for guideline development in the EMS
`environment (21). The advantages of the GRADE
`approach include an outcome-centric analysis of the
`certainty of evidence as well as a transparent and
`explicit means of conveying judgements and recom-
`mendations through evidence profile tables and
`
`tables. GRADE also
`evidence to decision (EtD)
`establishes clear and reproducible approaches to the
`assessment of certainty in evidence, and the direc-
`tion and strength of recommendations.
`
`Evidence Review
`This work leverages the published AHRQ system-
`atic review on the Management of Suspected Opioid
`Overdose with Naloxone by Emergency Medical Services
`Personnel (10). The review synthesized the data from
`inception of databases to September 2017 on four
`key areas: (question 1) route of administration of
`naloxone; (question 2) titration of naloxone dosing
`to specific therapeutic endpoints (e.g. spontaneous
`ventilation); (question 3) timing of repeat dosing of
`naloxone; and (question 4) transportation or non-
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`K. Williams et al. EMS NALOXONE GUIDELINE
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`5
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`Number
`
`PICO Question
`
`TABLE 2. PICO questions in the AHRQ Review (10)
`
`1
`
`For patients with confirmed or suspected opioid overdose, what are the comparative benefits and harms related to
`out-of-hospital administration of naloxone by EMS personnel using intravenous, intramuscular, subcutaneous, and
`intranasal routes of administration?
`For patients with confirmed or suspected opioid overdose who are administered naloxone in the out-of-hospital
`setting by EMS personnel, what are the comparative benefits and harms of different intravenous, intramuscular,
`subcutaneous, or intranasal doses of naloxone?†
`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?
`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?
`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 vs. nontransport?
` To incorporate practitioner safety concerns, the TEP agreed to modify PICO Question 1 as it appeared in the AHRQ review. Question 1 from the AHRQ review is
`
`1a
`
`2
`
`3
`
`4
`
`as follows:
`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?
`†To limit the scope of Question 1a to administration of naloxone by EMS practitioners, the TEP agreed to modify PICO Question 1a as it appeared in the AHRQ review.
`Question 1a from the AHRQ review is as follows:
`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?
`
`transport of patients to a healthcare facility after
`treatment with naloxone. The search strategies and
`the inclusion and exclusion criteria used were previ-
`ously described in detail (10). The systematic review
`identified 1,934 potential
`abstracts
`for articles
`through sources (Figure 1). A total of 202 full text
`articles were identified and reviewed, leading to 13
`included publications (Table 3). Of
`the included
`articles, seven addressed route of administration
`and six addressed transport of patients. There were
`no articles identified addressing dose titration or
`repeat dosing of naloxone.
`
`GRADE Process
`Following review of the identified literature, using
`the GradePro GDT software (22) and concepts for
`evaluation noted in the GRADE manual (23), sum-
`mary of evidence and evidence profile tables were
`generated for each of the interventions for route of
`administration including intranasal (IN) vs.
`intra-
`venous (IV); IV vs. intramuscular (IM); and IV vs.
`subcutaneous (SQ) by the technical expert panel.
`Each article was evaluated for confidence in the esti-
`mate of effect
`(quality)
`following evaluation for
`bias,
`inconsistency,
`indirectness,
`imprecision, and
`possible confounders. These evidence profile tables
`were then used to determine the recommendations
`and their strengths.
`
`RECOMMENDATIONS AND
`TECHNICAL REMARKS
`
`This evidence-based guideline development process
`leveraged the systematic evaluation done by AHRQ
`with the application of GRADE for development of
`summary of evidence and evidence profile tables for
`administration of naloxone by EMS practitioners to
`persons with suspected opioid overdose. Summary
`of evidence and evidence profile tables were only
`able to be generated for key question 1, addressing
`the
`route
`of
`administration
`of
`naloxone.
`Unfortunately, due to the paucity of evidence to
`review, we were unable to generate tables for key
`questions 2 (titration of naloxone dosing) and question
`3 (timing of repeat dosing). Although six papers were
`identified for key question 4 (transportation or non-
`transport of patients to a healthcare facility after treat-
`ment), we were unable to generate tables since these
`manuscripts were evaluations of patient refusal of
`transport without comparison groups. Listed in the
`following sections are the recommendations based on
`the summary of evidence and evidence profile tables
`as well as the technical remarks for each key question.
`
`PICO Question 1: Routes of
`Administration
`For patients with confirmed or suspected opioid overdose,
`what are the comparative benefits and harms related to
`out-of-hospital
`administration of naloxone by EMS
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`FIGURE 1. Literature flow diagram from AHRQ systematic review entitled “Management of Suspected Opioid Overdose with Naloxone by
`Emergency Medical Services Personnel.” Figure reprinted with permission from the AHRQ.
`
`personnel using intravenous, intramuscular, subcutane-
`ous, and intranasal routes of administration?
`Recommendation 1: Intranasal (IN) vs. Intramuscular (IM)
`View Evidence to Decision details in Table 4
`Summary:
`
`IN > IM
`
`Evidence Quality: Very Low
` Recommendation Strength: Weak/Conditional
`
`For the comparison of intranasal vs. intramuscular
`naloxone in the setting of suspected opioid overdose,
`the panel is in favor of intranasal over intramuscular
`routes of administration (weak/conditional recom-
`mendation/very low certainty in the evidence).
`
`In making this recommendation the panel’s inter-
`pretation of the evidence was that the comparison
`was to some extent driven by dosing considerations.
`Specifically, very low certainty evidence suggested
`that intranasal naloxone (2 mg) is similar in efficacy
`to intramuscular naloxone (2 mg). The recommenda-
`tion was driven by considerations related to ease of
`administration and practitioner safety, especially in
`relation to agitation and adverse opioid withdrawal
`reactions. There were limited data suggesting that
`agitation may be more likely with IM administration
`relative to IN (24). Needlestick injuries might be of
`particular concern for practitioners who may have
`less experience with intramuscular injections. Non-
`
`Adapt & Opiant Exhibit 2031
`Nalox-1 Pharmaceuticals, LLC v. Adapt Pharma Limited et al.
`IPR2019-00699
`Page 7
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`

`K. Williams et al. EMS NALOXONE GUIDELINE
`
`7
`
`TABLE 3. Articles identified by the AHRQ systematic review (10) in the four key areas
`
`PICO Number and Area
`
`1. Route of Administration
`and 1a. Dose
`
`Number of
`Articles
`Identified
`
`7
`
`2. Dose Titration of Naloxone
`3. Repeat Dosing of Naloxone
`4. Transport/ Non-Transport
`
`0
`0
`6
`
`Literature Identified
`
`Kelly AM, Kerr D, Dietze P, et al. Randomized trial of intranasal versus
`intramuscular naloxone in prehospital treatment for suspected opioid overdose.
`Med J Aust. 2005 Jan 3;182(1):24–7. PMID: 15651944.
`Kerr D, Kelly AM, Dietze P, et al. Randomized controlled trial comparing the
`effectiveness and safety of intranasal and intramuscular naloxone for the
`treatment of suspected heroin overdose. Addiction. 2009 Dec;104(12):2067–74.
`doi: 10.1111/j.13600443.2009.02724.x. PMID: 19922572.
`Sabzghabaee AM, Eizadi-Mood N, Yaraghi A, et al. Naloxone therapy in opioid
`overdose patients: intranasal or intravenous? a randomized clinical trial. Arch
`Med Sci. 2014 May 12;10(2):309–14. doi: 10.5114/aoms.2014.42584. PMID:
`24904666.
`Merlin MA, Saybolt M, Kapitanyan R, et al. Intranasal naloxone delivery is an
`alternative to intravenous naloxone for opioid overdoses. Am J Emerg Med.
`2010 Mar;28(3):296–303. doi: 10.1016/j.ajem.2008.12.009. PMID: 20223386.
`Robertson TM, Hendey GW, Stroh G, et al. Intranasal naloxone is a viable
`alternative to intravenous naloxone for prehospital narcotic overdose. Prehosp
`Emerg Care. 2009 Oct-Dec;13(4):512–5. doi: 10.1080/10903120903144866.
`PMID: 19731165.
`Sporer KA, Firestone J, Isaacs SM. Out-of hospital treatment of opioid overdoses
`in an urban setting. Acad Emerg Med. 1996 Jul;3(7):660–7. PMID: 8816181.
`Wanger K, Brough L, Macmillan I, et al. Intravenous vs subcutaneous naloxone
`for out-of-hospital management of presumed opioid overdose. Acad Emerg
`Med. 1998 Apr;5(4):293–9. PMID: 9562190.
`
`Boyd JJ, Kuisma MJ, Alaspaa AO, et al. Recurrent opioid toxicity after pre-
`hospital care of presumed heroin overdose patients. Acta Anaesthesiol Scand.
`2006 Nov;50(10):1266–70. PMID: 17067327.
`Levine M, Sanko S, Eckstein M. Assessing the risk of prehospital administration
`of naloxone with subsequent refusal of care. Prehosp Emerg Care.
`2016;20(5):566–9. PMID: 27018626.
`Rudolph SS, Jehu G, Nielsen SL, et al. Prehospital treatment of opioid overdose
`in Copenhagen–is it safe to discharge on-scene? Resuscitation. 2011
`Nov;82(11):1414–8. doi: 10.1016/j.resuscitation.2011.06.027. PMID: 21745532.
`Vilke GM, Buchanan J, Dunford JV, et al. Are heroin overdose deaths related to
`patient release after prehospital treatment with naloxone? Prehosp Emerg Care.
`1999 JulSep;3(3):183–6. PMID: 10424852.
`Vilke GM, Sloane C, Smith AM, et al. Assessment for deaths in out-of-hospital
`heroin overdose patients treated with naloxone who refuse transport. Acad
`Emerg Med. 2003 Aug;10(8):893–6. PMID: 12896894.
`Wampler DA, Molina DK, McManus J, et al. No deaths associated with patient
`refusal of transport after naloxone-reversed opioid overdose. Prehosp Emerg
`Care. 2011 JulSep;15(3):320–4. doi: 10.3109/10903127.2011.569854.
`PMID: 21612385.
`
`transport was taken into consideration as well, and
`it was felt that intramuscular dosing might carry the
`greatest risk in this regard due to agitation leading
`to transport refusal. Intranasal dosing by EMS prac-
`titioners is titratable if
`lower concentrations are
`used with a syringe and atomizer.
`Research is needed on the comparative effective-
`ness of the FDA-approved naloxone auto-injector
`(2 mg) and highly concentrated (4 mg/0.1 mL and
`2 mg/0.1 mL)
`IN naloxone formulation, different
`doses, and dosing strategies.
`
`Recommendation
`Intravenous (IV)
`View Evidence to Decision details in Table 5
`
`2:
`
`Intranasal
`
`(IN)
`
`vs.
`
`Summary:
`
`IN¼ IV
`
`Evidence Quality: Very Low
` Recommendation Strength: Weak/Conditional
`
`Comparing intranasal and intravenous naloxone, the
`panel
`equally recommends
`the
`intranasal
`and
`
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`8
`
`Summary of findings:
`
`TABLE 4. GRADE Table for Recommendation 1: Intranasal (IN) vs. Intramuscular (IM)
`
`PREHOSPITAL EMERGENCY CARE 䊏/䊏 2019 VOLUME 0 / NUMBER 0
`
`Intranasal naloxone compared to intramuscular naloxone for suspected opioid poisoning
`
`Patient or population: suspected opioid poisoning
`Setting: prehospital
`Intervention: intranasal naloxone
`Comparison: intramuscu