Kerensky and Walley Addict Sci Clin Pract (2017) 12:4
`DOI 10.1186/s13722-016-0068-3
`
`Addiction Science &
`Clinical Practice
`
`REVIEW
`Opioid overdose prevention
`and naloxone rescue kits: what we know
`and what we don’t know
`
`Open Access
`
`Todd Kerensky1* and Alexander Y. Walley2
`
`Abstract
`The opioid use and overdose crisis is persistent and dynamic. Opioid overdoses were initially driven in the 1990s and
`2000s by the increasing availability and misuse of prescription opioids. More recently, opioid overdoses are increas-
`ing at alarming rates due to wider use of heroin, which in some places is mixed with fentanyl or fentanyl derivatives.
`Naloxone access for opioid overdose rescue is one of the US Department of Health and Human Services’ three priority
`areas for responding to the opioid crisis. This article summarizes the known benefits of naloxone access and details
`unanswered questions about overdose education and naloxone rescue kits. Hopefully future research will address
`these knowledge gaps, improve the effectiveness of opioid overdose education and naloxone distribution programs,
`and unlock the full promise of naloxone rescue kits.
`Keywords: Naloxone rescue kits, Overdose prevention, Opioid overdose education
`
`Background
`As a leading cause of preventable injury and death, opioid
`overdose is a major contributor to worsening overall sur-
`vival among middle-age white Americans and an increas-
`ing cause of mortality among all racial and age categories
`[1]. Increases in overdose have been driven by prescrip-
`tion opioids in the 1990s and 2000s and non-prescribed
`opioids in the 2000s and 2010s [2, 3]. In several commu-
`nities, fentanyl has been recognized as a major contribu-
`tor to increases in opioid overdose mortality since 2013
`[2, 4, 5] and fentanyl derivatives such as acetyl fentanyl,
`furanyl fentanyl and carfentanil have been detected in
`drug seizures and overdose toxicology. The US Depart-
`ment of Health and Human Services has recognized opi-
`oid related overdose as a major public health concern and
`acknowledged three priority areas to address this crisis:
`opioid prescriber education, community naloxone access,
`and improved access to medications for opioid use dis-
`order [6]. Each of these priority areas holds promise,
`
`*Correspondence: Todd.Kerensky@bmc.org
`1 Instructor of Medicine, Boston University School of Medicine, Boston
`Medical Center, 801 Massachusetts Avenue, Floor 2, Boston, MA 02118,
`USA
`Full list of author information is available at the end of the article
`
`though the strength of evidence for each of these is dif-
`ferent. There is substantial, strong, and reproducible
`evidence in randomized clinical trials and well-designed
`observational studies that medications for treatment
`of opioid use disorder improve mortality, reduce opioid
`use, reduce infectious risks, reduce incarceration, and
`improves birth outcomes [7]. The effectiveness of opioid
`overdose education and community naloxone distribu-
`tion (OEND) in reducing overdose deaths comes from
`a smaller research set which encompasses less rigorous
`study designs including: interrupted time-series analysis,
`pre-post studies, case series, and cross sectional studies
`[8]. There is less evidence that providing education on
`safe opioid prescribing will impact opioid overdoses and
`deaths.
`As access to naloxone has improved, it is clear that
`much is known about community level overdose educa-
`tion and naloxone rescue distribution, but more research
`and knowledge is needed to optimize OEND as a valu-
`able tool to combat the overdose crisis. This article sum-
`marizes what is known and highlights areas of knowledge
`gaps with respect to opioid overdose education and
`naloxone distribution.
`
`© The Author(s) 2017. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License
`(http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium,
`provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license,
`and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/
`publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
`
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`What we know
`Naloxone is a potent opioid antagonist that is avid at the
`mu opioid receptor. It is FDA approved for emergency
`treatment of known or suspected opioid overdose with
`respiratory and/or central nervous system depression.
`Naloxone can be administered intravenously (IV), intra-
`muscularly (IM), subcutaneously (SC), and intranasally
`(IN). Naloxone has no effect in people who are not taking
`opioids. OEND programs educate laypersons to recog-
`nize opioid overdose and instruct them how to adminis-
`ter naloxone to reverse respiratory depression. Access to
`OEND to potential overdose bystanders through com-
`munity programs has expanded to 30 states since the late
`1990s [9, 10]. Most OEND programs also provide educa-
`tion about overdose prevention by instructing potential
`rescuers to recognize known risk factors for overdose
`such as: mixing opioids with other sedatives, changes
`in drug potency or purity, using high doses of prescrip-
`tion opioids, and using opioids alone. Empowering peo-
`ple who use opioids to engage overdose prevention by
`recognizing and addressing modifiable risk factors is an
`important feature of OEND programs. A randomized
`controlled trial has shown motivational interviewing
`focused on overdose risk reduction to be superior to
`usual care in reducing self-reported opioid overdose
`risk behaviors in patients presenting to the emergency
`department with non-medical use of prescription opioids
`[11]. This is promising evidence that non-judgmental,
`goal directed interviewing can reduce risky behaviors in
`patients using opioids non-medically. Future studies will
`be needed to evaluate outcomes in other at risk groups
`for opioid overdose as well as whether including nalox-
`one education and distribution may amplify reductions
`in risk taking behaviors.
`Equipped with the education and training provided
`by OEND programs, naloxone can be administered by
`bystanders, whether that bystander is a person who also
`uses opioids, a friend, family member, acquaintance or
`first responder, such as police or firefighter personnel
`[12]. In some communities, people who use opioids and
`their social networks can obtain training and naloxone
`rescue kits at many different venues including needle-
`syringe access programs, inpatient and outpatient addic-
`tion treatment programs [9], primary care [13], and
`support group meetings [14]. It is important to recognize
`periods of abstinence resulting in loss of opioid tolerance,
`such as post-incarceration [15, 16] or after completing
`varying types of addiction treatment [17], as a high-risk
`time for an overdose event if relapse occurs. Therefore,
`providing OEND to opioid users and their social net-
`works while they are engaged in addiction treatment,
`general health care, or the criminal justice system is criti-
`cally important [18].
`
`The legal framework in most states has shifted to pro-
`mote access to naloxone kits by allowing health pro-
`fessionals to prescribe naloxone to third-party family
`members as well as making naloxone available without
`a prescription at retail pharmacies via a standing, often
`state-wide, prescription [19]. While community based
`naloxone programs remain the most common driver for
`naloxone distribution [9], naloxone prescriptions dis-
`pensed at US retail pharmacies have risen steeply since
`2013 [20]. Retail pharmacy distribution is a promising
`way to improve access to naloxone, especially in rural
`areas which may be underserved by community OEND
`programs.
`A mortality benefit from OEND is supported by observa-
`tional evidence including an interrupted time series study
`that showed Massachusetts communities with OEND had
`reduced opioid overdose death rates compared to commu-
`nities that did not have OEND [21] and a pre-post study
`in Scotland showed a reduction in overdose death rates
`among people released from prison [22]. A modeling study
`has demonstrated OEND to be cost effective for people
`who use heroin [23]. A trial published in 2016 found that
`co-prescribing naloxone rescue kits to patients treated
`with opioids for chronic pain in primary care resulted in
`reduced opioid-related emergency department visits [13].
`This evidence in the context of an opioid overdose crisis
`is compelling for improving access to OEND; however,
`important questions remain unanswered.
`
`What we don’t know
`Who should receive opioid overdose education
`and naloxone rescue kits?
`Existing evidence has focused primarily on training
`and delivering naloxone kits to people who use heroin
`(PWUH) via community based programs. This approach
`has proved fruitful, likely because PWUH are apt to use
`with others and/or be a bystander for another’s overdose.
`Thus, PWUH may be receptive to OEND intervention
`because they understand via their own experience the
`risks associated with opioid use and may be more likely
`to be present at an overdose event. It is not known if tar-
`geting OEND to friends, family members, acquaintances
`of opioid users, or the public could reduce mortality
`beyond the benefits of targeting OEND to PWUH.
`Prescribers and pharmacists need guidance on who
`should receive naloxone rescue kits. One approach is to
`develop an overdose risk tool to help deliver OEND to
`people at risk for overdose. However, OEND should tar-
`get people most likely to witness another’s overdose, in
`addition to focusing on individuals who are at risk them-
`selves. Therefore, providing OEND to the social networks
`of those identified to be high risk for overdose might be
`especially efficient. Importantly, the social networks of
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`people who use opioids may not be interacting with com-
`munity based OEND programs or health care personnel
`may not be identifying them as potential beneficiaries of
`OEND.
`
`Should all patients receiving opioid therapy be offered
`naloxone co‑prescribing?
`Center for Disease Control and Prevention opioid pre-
`scribing guidelines released in 2016 recommend consid-
`ering naloxone and overdose prevention education for
`patients and household members of patients prescribed
`opioids with a history of overdose, history of substance use
`disorder, higher opioid dosages (≥50 MME/day), or con-
`current benzodiazepine use [24]. A study of co-prescribing
`naloxone as a universal precaution to patients on chronic
`opioid therapy for non-cancer related pain demonstrated
`reduced opioid-related emergency department visits after
`substantial, but not universal, uptake by prescribers and
`patients at a group of community health centers [13].
`The patients who actually received naloxone rescue kits
`in this study were more likely to be those on higher doses
`of opioids and with previous opioid-related emergency
`department visits. How best to work with patients, their
`household members, prescribers, and pharmacies to get
`naloxone kits to a broader group of people exposed to opi-
`oids and at risk for overdose warrants further intervention
`development and implementation studies.
`
`Does OEND alter opioid prescribing practices?
`The few studies that have examined how OEND may
`impact prescribing practices are mixed, and point to
`a nuanced relationship between offering naloxone to
`patients treated with prescription opioids. A qualitative
`study found that prescribers were conflicted about co-
`prescribing an opioid and an opioid antagonist [25]. Some
`providers interviewed for this study questioned whether
`opioids were contraindicated if naloxone co-prescribing
`was being considered. Whereas, some felt that the process
`of OEND alone might improve conversations about the
`risks of opioids. Providers felt that discussing and address-
`ing overdose risk with OEND might reduce patients’ risk
`taking behaviors [25]. The previously mentioned study of
`co-prescribing as an intervention for patients on long-
`term opioids for chronic pain found reduced opioid-
`related emergency department visits, but prescribing
`naloxone had no net effect on the prescribed opioid dose
`[13]. A better understanding of how OEND and prescrib-
`ing affect one another will require further study.
`
`How should the perception of risk compensation be
`addressed?
`Some opioid prescribers [25] and policymakers [26] are
`concerned about “risk compensation,” meaning that
`
`having a naloxone rescue kit may increase risky opioid
`use. Well-designed observational studies have shown
`reductions in community level opioid overdose death
`rates where OEND has been implemented [21, 22], and
`reduced opioid-related emergency department visits
`among chronic pain patients who were co-prescribed
`naloxone rescue kits [13]. Thus, if there is any substan-
`tial increase in risky behavior due to risk compensation,
`it is outweighed by the important benefits of OEND. The
`concern about risk compensation is similar to other key
`public health interventions, such as seat belts to pre-
`vent motor vehicle deaths, vaccination and condoms
`to prevent sexually transmitted infections, and needle-
`syringe programs to prevent infectious disease trans-
`mission. Studies that have looked for risk compensation
`from naloxone access among people who use heroin,
`have found no clear evidence of it [27, 28]. This is likely
`because people who use opioids are very averse to nalox-
`one induced opioid withdrawal, and opioid overdose
`education may reduce incremental risky behaviors. How-
`ever, the perception of risk compensation is an important
`barrier to wider implementation of OEND. Therefore,
`implementation studies that address the perception of
`risk compensation among prescribers and minimize
`any increases in overdose risk behaviors resulting from
`OEND are warranted.
`
`How should naloxone be administered and at what dose?
`Naloxone formulations and delivery systems
`There are now four different formulations of naloxone
`that are used in naloxone rescue kits: (1) injectable nalox-
`one that is drawn up out of a vial with a needle into a
`syringe with a dose concentration of 0.4 mg/1 ml, (2) an
`auto injector with audio prompts that administers a
`0.4 mg intramuscular dose via a retractable needle, (3) a
`single-step nasal spray that administers a dose concentra-
`tion of 4 mg/0.1 mL into one nostril, and (4) a multi-step
`nasal spray assembled by combining a pre-filled luer lock
`syringe with a nasal atomizer, that administers a dose
`concentration of 2 mg/2 ml, where 1 ml is administered
`to each nostril.1 OEND programs have favored syringe
`and vial intramuscular naloxone and multi-step nasal
`naloxone because of lower cost and early availability.
`Naloxone kits, regardless of formulation, generally
`include two doses, so that if the first dose does not result
`in spontaneous respirations, then a second dose may be
`administered.
`Intranasal delivery has several potential benefits. First,
`no injection is required which facilitates layperson use
`
`1 Nasal naloxone delivered via syringe and nasal atomizer as 2 mg/2 ml is
`not FDA approved.
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`because there is no fear nor risk of needle stick injury.
`Furthermore, the administration of a nasal spray requires
`less training than the administration of an injection, and
`the nose is typically readily accessible for administration.
`The new FDA-approved single-step nasal device does
`not require assembly providing a potential time saving
`advantage over the multi-step device. In 2016, informa-
`tion about how the single-step device is used in actual
`overdose events in people with opioid tolerance is lack-
`ing. Little is known about how active nasal naloxone is
`at opioid receptors in real world circumstances and how
`reproducible this method of delivery is.
`The IM auto-injector also has benefits. The product was
`designed such that a layperson could easily and quickly
`administer naloxone via a one-piece device that instructs
`rescuers step-by-step, in real time through the process of
`delivering intramuscular naloxone. In addition to provid-
`ing audible instruction, the device protects the needle
`via a plastic housing, thereby reducing unintended nee-
`dle exposure. The cost of the auto-injector has been high
`and insurance coverage variable. Both cost and variable
`insurance coverage are important barriers to naloxone
`access. More information about real-life use of naloxone
`is needed to understand if this technology improves the
`correct and timely delivery of naloxone.
`Some providers and health care systems may favor
`prescribing the single-step nasal device or the IM auto-
`injector because these devices are designed and FDA
`approved for bystander administration. OEND programs
`have favored the multi-step nasal device or intramuscu-
`lar naloxone because the FDA approved devices are more
`expensive. It remains to be seen how the new, higher
`cost, FDA approved devices alter access to naloxone and
`potentially health outcomes.
`
`Dosing
`The most common and clinically important adverse
`effect of naloxone is precipitated opioid withdrawal.
`Ideally the dose of naloxone would be large enough to
`successfully reverse respiratory depression, yet small
`enough to avoid opioid withdrawal. It is not well known
`whether the dose of naloxone currently being utilized
`optimally balances the lifesaving properties of naloxone
`with risk of inducing withdrawal. The newer one-step
`nasal spray delivers naloxone at higher concentration
`and larger dose compared to intramuscular delivery
`of 0.4  mg/1  ml naloxone in healthy volunteers. It is
`expected, but not yet proven, that the one-step device
`will result in more successful reversals of respiratory
`depression compared to other delivery devices. How-
`ever, it is also anticipated that naloxone induced with-
`drawal symptoms will be more frequent and possibly
`more severe because a higher dose of naloxone is used
`
`in this device. The trade-off between high doses of
`naloxone to prevent overdoses that fail to reverse with
`naloxone and the increased risk of withdrawal gener-
`ally favors giving higher dose naloxone to help save
`lives. However, we do not yet know if naloxone induced
`withdrawal results in greater risk of repeat opioid use
`and recurrent overdose. In addition, it is reasonable
`to expect that locales with higher potency heroin and/
`or greater use of fentanyl or fentanyl derivatives would
`benefit more from higher dose naloxone. Thus, commu-
`nities with more high potency opioid use may be more
`inclined to adopt higher dose naloxone kits, and accept
`the potential for more frequent and severe opioid with-
`drawal. More information about the frequency of opioid
`overdoses not responding to naloxone as well as a better
`understanding of what happens to patients after receiv-
`ing naloxone, especially those who experience induced
`withdrawal, will help inform decisions regarding nalox-
`one dosing.
`
`What happens after overdose rescue with naloxone
`to keep people safe?
`Due to the neurobehavioral adaptations that occur
`among people who have an opioid use disorder, overdose
`survivors are unlikely to seek and engage wholeheartedly
`in addiction treatment immediately after receiving nalox-
`one. Most survivors will be experiencing precipitated
`withdrawal from naloxone and will be having intense
`cravings to use opioids. Treating a survivor in withdrawal
`with a daily long-acting opioid agonist, like methadone
`or buprenorphine, is the most promising way to work
`towards engaging him or her in treatment and the best
`way to keep him or her safe from using more unsuper-
`vised opioids. Initiation of buprenorphine/naloxone in
`the emergency department (ED) has been evaluated
`in a randomized clinical trial of 329 opioid-dependent
`patients, of which 8.8% presented to the ED with an
`overdose event. This study demonstrated that initia-
`tion of buprenorphine/naloxone treatment in the emer-
`gency department with referral to further care resulted in
`improved engagement in medical care, less self-reported
`opioid use and less utilization of inpatient services at
`30 days compared to referral to outpatient treatment or
`brief intervention [29]. This study is promising evidence,
`in a small number of patients at one academic medical
`center, that immediate initiation of agonist therapy may
`improve outcomes. This study did not report on out-
`comes in the subset of participants who required nalox-
`one. Offering agonist therapy immediately after overdose
`requiring naloxone, whether the person experienced
`naloxone induced withdrawal or not, is an important
`area of future research to improve care after an overdose
`event.
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`Some have called for mandated treatment after an
`overdose, which has unclear efficacy as well as ethical
`and civil rights implications [30]. Other potential inter-
`ventions include survivor-centered harm reduction and
`treatment outreach to people who have overdosed and
`their social networks. The Anchor Recovery Coach Pro-
`gram in Rhode Island provides on-call recovery coaches
`to survivors presenting to the emergency department
`[31]. When the survivor has a disease that involves using
`opioids despite adverse consequences, engaging others in
`the survivor’s social network to promote overdose pre-
`vention strategies and support seeking treatment may
`reduce the likelihood of the next overdose. Programs
`providing care, counseling, and OEND immediately after
`an overdose to survivors and their social networks may
`provide a unique opportunity to reduce repeat opioid
`overdose and encourage engagement in further care, and
`therefore need to be evaluated.
`
`What are the subacute effects of non‑fatal opioid overdose
`and how can they be treated or prevented?
`Complications from non-fatal overdose include but are
`not limited to: aspiration, anoxic brain injury, nerve pal-
`sies, and trauma related injuries. The incidence of these
`complications has not been well described. Addition-
`ally, it is not known how long and in what setting people
`should be monitored after naloxone rescue to reduce the
`risks of overdose complications.
`
`What kind of training should be provided with naloxone
`distribution?
`In many communities, laypersons can obtain naloxone
`at different locations which provide varied informa-
`tion about overdose and naloxone. This education dif-
`fers across several potentially important variables which
`could alter the impact of OEND programs. First, the
`material may be conveyed in multiple formats. Com-
`monly utilized techniques include: didactic education,
`hand-out media such as pamphlets, and/or media like
`video that is consumed while at the training session.
`Some programs utilize hands-on training via a demo
`device, while in some locations this may not be avail-
`able. Second, who delivers the content and for how long
`is not standardized. In some places, trained community
`members provide instruction while in more formal medi-
`cal settings, physicians, nurses, or pharmacists may lead
`overdose education and naloxone training. Third, the
`length of OEND training also fluctuates between set-
`tings, trainers, and trainees. Space, trainer time, and
`trainee time may be limited and trainee knowledge and
`cognition may require different training intensity. Further
`study into how best to educate laypersons about overdose
`and naloxone is needed to optimize the effectiveness
`
`and efficiency of OEND. Standardization of the core
`elements of OEND training, yet allowing for some flex-
`ibility of other elements of the training, will help ensure
`the future rescuer achieves a minimum competency and
`comfort level with naloxone. Standardizing and tailoring
`OEND curriculum will need to evolve as more naloxone
`devices with various concentrations, doses, and delivery
`mechanisms become available to wider groups of poten-
`tial rescuers.
`The American Heart Association (AHA), in its most
`recent update in November 2015, incorporated nalox-
`one into its emergency response algorithms [32]. This
`presents a new opportunity for opioid overdose educa-
`tion and naloxone training to occur along with AHA
`emergency response trainings. While OEND can be
`incorporated into AHA trainings, it is not known if more
`advanced resuscitation skills, such as chest compres-
`sions and automatic defibrillator use should be provided
`at existing OEND programs. These additional skills may
`be useful in opioid overdose rescues, however teaching
`these skills may result in additional barriers to naloxone
`access in the community. AHA cardiopulmonary resus-
`citation course includes proficiency testing prior to cer-
`tification and requires a refresher course every 2 years to
`maintain certification. It is not known whether testing
`proficiency or requiring recertification might improve
`overdose related clinical outcomes.
`
`After recognizing an overdose, what is the correct order
`of actions?
`OEND programs and the AHA instruct rescuers to
`call for help, start ventilation or CPR, deliver naloxone,
`remain with the person until help arrives, and place vic-
`tim in the rescue position. OEND programs, naloxone
`package inserts, the World Health Organization and the
`AHA have various recommendations regarding the spe-
`cific order in which these key steps should be performed.
`It is not known if or how the order of these rescue steps
`could alter clinical outcomes. Further study will hopefully
`standardize how we respond to opioid overdose events.
`
`How do local and state laws affect OEND?
`The legal framework in which OEND programs oper-
`ate may have significant implications for how effectively
`naloxone reduces overdose deaths. OEND programs exist
`in different state and local legal environments. Many
`states have attempted to limit civil or criminal liabilities
`for responding to an overdose, as well as administering,
`prescribing or distributing naloxone. These laws differ by
`location but generally encourage wider access to OEND
`and help encourage rescuers to call for emergency ser-
`vices by reducing fears of legal repercussions when first-
`responders, including police, arrive. Currently, we do not
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`know how OEND effects a rescuer’s decision to call for
`emergency help. OEND programs recommend calling for
`emergency services, but rescues are occurring without
`summoning professional help. This may be due to fear of
`legal consequences to either the overdose survivor or the
`rescuer, but other less well known factors may also dis-
`courage calling for help. The implications of layperson
`rescue without the survivor interacting with professional
`help after this event are not known. It would be informa-
`tive to compare effectiveness and distribution of naloxone
`in areas that have different legal protections and evaluate
`how OEND effects professional help seeking after over-
`dose to understand and address potential barriers to
`naloxone use.
`
`Would dedicated CME training programs for prescribers
`improve naloxone prescribing and distribution?
`Most clinicians experience with naloxone occurs in a
`hospital or pre-hospital setting where the antidote is
`delivered by nurses or first responders. Relatively little is
`known about prescribers’ knowledge about naloxone for
`community use by lay bystanders. Improving prescriber
`knowledge about community naloxone programs and
`prescribing naloxone via pharmacies may help distribute
`naloxone more broadly, especially in communities that
`do not have access to an OEND program.
`
`What are validated research and clinical measures
`of overdose and overdose risk behaviors?
`We have called for additional research to improve the
`clinical and health system benefits of OEND. High qual-
`ity research relies on well-defined clinical events and
`outcomes as well as validated measures. Fatal opioid
`overdoses are defined typically via cause of death fields
`on death certificates, which are available in all communi-
`ties. However, standardization of what constitutes a fatal
`overdose event is needed to help facilitate research across
`jurisdictions and improve epidemiologic reporting. Addi-
`tionally, there are not validated definitions of non-fatal
`opioid overdose, whether measured by self-report, clini-
`cal, or administrative data. For opioid overdose, the basic
`components are exposure to an opioid that results in
`unresponsiveness and respiratory depression. Definitions
`of overdose which require that help was sought or that
`naloxone was administered likely increase specificity, but
`sacrifice sensitivity. Opioid overdose rescues may occur
`without calling for help and/or administering naloxone.
`If the definition of non-fatal overdoses requires these ele-
`ments, it is likely that some non-fatal opioid overdoses
`would not be classified appropriately, therefore reducing
`sensitivity. On the other hand, a firm definition of non-
`fatal opioid overdose will be needed to exclude other
`
`causes of unresponsiveness and/or respiratory depression
`to improve specificity. Universally accepted definitions of
`both fatal and non-fatal opioid overdose events will be
`needed to help improve OEND research in the future.
`Overdose risk behaviors have been well described.
`Assessing overdose risk and educating patients about it
`are key elements of overdose prevention. We have yet
`to develop a validated, widely applicable overdose risk
`measure that is useful clinically or for research.
`
`Conclusion
`The opioid use and overdose crisis is persistent and
`dynamic, garnering much attention from the public,
`policymakers and public health officials. In an effort
`to curb opioid related overdoses and deaths the federal
`government has prioritized increasing prescriber educa-
`tion, improving access to treatments for opioid use dis-
`order and naloxone. As an antidote to opioid overdoses,
`naloxone has proven to be a valuable tool in combating
`overdose deaths and associated morbidity. Further inves-
`tigation into important knowledge gaps will help unlock
`the potential of naloxone needed to address the pervasive
`opioid overdose crisis.
`
`Abbreviations
`OEND: opioid overdose education and naloxone distribution; PWUH: people
`who use heroin; BLS: basic life support; ACLS: advanced cardiac life support;
`AHA: American Heart Association; IV: intravenous; IM: intramuscular; SC: sub-
`cutaneous; IN: intranasal; ED: Emergency Department.
`
`Authors’ contributions
`TK and AW conceived the aim for the manuscript. TK wrote the first draft of
`the manuscript and revised subsequent drafts. AW edited and revised the
`manuscript. Both authors read and approved the final manuscript draft.
`
`Author details
`1 Instructor of Medicine, Boston University School of Medicine, Boston Medical
`Center, 801 Massachusetts Avenue, Floor 2, Boston, MA 02118, USA. 2 Section
`of General Internal Medicine, Clinical Addiction Research and Education Unit,
`Boston University School of Medicine, Boston Medical Center, 801 Massachu-
`setts Avenue, Floor 2, Boston, MA 02118, USA.
`
`Acknowledgements
`None.
`
`Competing interests
`The authors declare that they have no competing interests.
`
`Received: 12 July 2016 Accepted: 22 December 2016
`
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