HHS Public Access
`Author manuscript
`Subst Abus. Author manuscript; available in PMC 2016 April 01.
`
`Published in final edited form as:
`Subst Abus. 2015 ; 36(2): 240–253. doi:10.1080/08897077.2015.1010032.
`
`A Review of Opioid Overdose Prevention and Naloxone
`Prescribing: Implications for Translating Community
`Programming into Clinical Practice
`
`Shane R. Mueller, MSW1, Alexander Y. Walley, MD, MSc2, Susan L. Calcaterra, MD, MPH1,4,
`Jason M. Glanz, PhD5,6, and Ingrid A. Binswanger, MD, MPH, MS1,3,4
`1Division of General Internal Medicine, University of Colorado School of Medicine, Aurora, CO,
`USA
`
`2Clinical Addiction Research and Education Unit, Section of General Internal Medicine,
`Department of Medicine, Boston University School of Medicine, Boston, MA, USA
`
`3Division of Substance Dependence, University of Colorado School of Medicine, Aurora, CO,
`USA
`
`4Denver Health Medical Center, Denver CO, USA
`
`5Institute for Health Research, Kaiser Permanente Colorado, Denver, CO, USA
`
`6Department of Epidemiology, Colorado School of Public Health, Aurora, CO, USA
`
`Abstract
`
`Background—As physicians have increased opioid prescribing, overdose deaths from
`pharmaceutical opioids have substantially increased in the United States. Naloxone hydrochloride
`(naloxone), an opioid antagonist, is the standard of care for treatment of opioid induced respiratory
`depression. Since 1996, community-based programs have offered overdose prevention education
`and distributed naloxone for bystander administration to people who use opioids, particularly
`heroin. There is growing interest in translating overdose education and naloxone distribution
`(OEND) into conventional medical settings for patients who are prescribed pharmaceutical
`opioids. For this review, we summarized and classified existing publications on overdose
`education and naloxone distribution to identify evidence of effectiveness and opportunities for
`translation into conventional medical settings.
`
`Methods—For this review, we searched English language PubMed for articles on naloxone
`based on primary data collection from humans, including feasibility studies, program evaluations,
`
`Correspondence should be addressed to Shane R. Mueller, MSW, 12631 E. 17th Ave. B-180 Aurora, CO 80045, USA.
`Shane.Mueller@ucdenver.edu.
`AUTHOR CONTRIBUTIONS
`SR Mueller, IA Binswanger, and AY Walley conceived of the review. SR Mueller, IA Binswanger, AY Walley and JM Glanz
`formulated the methods for the review. SR Mueller conducted the search of the literature. SR Mueller, IA Binswanger, AY Walley
`and SL Calcaterra reviewed the articles. All authors interpreted the review findings. SR Mueller drafted the manuscript. All authors
`reviewed and provided critical revisions to the manuscript. All authors give final approval for publication.
`The authors declare that they have no conflicts of interest.
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`surveys, qualitative studies and studies comparing the effectiveness of different routes of naloxone
`administration. We also included cost-effectiveness studies.
`
`Results—We identified 41 articles that represented 5 categories: evaluations of OEND
`programs, effects of OEND programs on experiences and attitudes of participants, willingness of
`medical providers to prescribe naloxone, comparisons of different routes of naloxone
`administration, and the cost-effectiveness of naloxone.
`
`Conclusions—Existing research suggests that people who are at risk for overdose and other
`bystanders are willing and able to be trained to prevent overdoses and administer naloxone.
`Counseling patients about the risks of opioid overdose and prescribing naloxone is an emerging
`clinical practice which may reduce fatalities from overdose while enhancing the safe prescribing
`of opioids.
`
`Keywords
`overdose; opioids; prevention; primary care
`
`INTRODUCTION
`Unintentional poisoning represents a significant, growing problem in the United States.1–5
`Drug poisoning fatalities now exceed deaths from motor vehicle crashes.6 In 2010, opioid
`poisonings accounted for over 16,000 deaths.7 Unintentional poisoning from pharmaceutical
`opioids has become an epidemic in the last decade, in part due to increasing opioid analgesic
`availability.8 Overdose education and provision of naloxone is one approach to address this
`epidemic.
`
`Naloxone is a short-acting opioid antagonist used by medical practitioners to reverse opioid
`overdose since 1971. In the United States, it is approved by the Food and Drug
`Administration (FDA) for prescription use.9 Naloxone antagonizes opioid effects by
`displacing opioid agonists from opioid receptors in the central nervous system, reversing
`respiratory depression. Naloxone can be administered intranasally (IN), intramuscularly
`(IM), intravenously (IV), or subcutaneously and is effective against all opioid agonists,
`including morphine, heroin, oxycodone, and methadone. To reverse long-acting opioids, the
`dose may need to be repeated. The major adverse effect of naloxone in opioid-dependent
`patients is precipitated opioid withdrawal. This effect results from the rapid displacement of
`opioid agonist from the opioid receptor, the same mechanism by which naloxone also
`reverses respiratory depression. Naloxone has no psychoactive properties, is not a scheduled
`drug, and has no abuse potential.10
`
`Community-based and public health organizations have developed overdose education and
`naloxone distribution (OEND) programs to prevent opioid overdose fatalities among people
`who use heroin, and, more recently, among people who use pharmaceutical opioids. In a
`survey of OEND programs completed in 2010,188 programs located in 15 states and the
`District of Colombia provided take-home naloxone to people who used opioids.11 From
`1996 to 2010, these programs had trained and distributed naloxone to over 50,000 persons
`and received reports of over 10,000 overdose reversals.11 Prevention strategies employed by
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`these OEND programs may be applicable to the prevention of pharmaceutical opioid
`overdose deaths in primary care and specialty medical practices.
`
`Provision of naloxone as a part of a strategy to address opioid overdose has been endorsed
`by several US Federal agencies.12 In 2013, the Substance Abuse and Mental Health Services
`Administration released the Opioid Overdose Prevention Toolkit to provide communities
`and local governments information to develop policies to prevent opioid related deaths.13
`Scotland and Wales recently developed national naloxone distribution programs.14 In early
`2014, Norway began offering naloxone for the first time in intranasal form.15 Other
`countries to allow for the distribution of naloxone include Sweden,16 England,17
`Germany,18 Italy,19 Canada,20 and Australia.21
`
`Conventional medical settings, such as primary care, pain clinics, emergency departments,
`and addiction treatment centers are potential venues for overdose education and naloxone
`prescription. These sites provide opioid prescriptions or medications and patients may
`present to these sites with complications from opioid use. Our aim was to review and
`classify existing publications on OEND and naloxone in community-based settings. We
`sought to identify evidence of effectiveness and opportunities for translation of these
`practices into conventional medical settings.
`
`METHODS
`
`Search Strategy and Article Selection
`
`One author searched English language PubMed for peer-reviewed, original research articles
`through May 2014 using the following Medical Subject Heading (MeSH) terms: naloxone,
`drug overdose. This search yielded 254 articles. Two authors reviewed the abstracts of the
`254 articles and excluded 221 articles because they were non-human studies, studies that did
`not focus on pre hospital-based administration of naloxone, efficacy studies in controlled
`settings, commentaries and perspectives, medical news articles, and policy or legal reviews.
`Based on the aim of our review to inform OEND programming in conventional medical
`settings, we included original peer-reviewed articles that involved primary data collection
`from patients or medical providers about OEND programs, including feasibility studies and
`program evaluations (if they included data collected from participants), surveys and
`qualitative studies of attitudes towards take-home naloxone, and studies comparing the
`effectiveness of different routes of naloxone administration in pre- and non-hospital settings.
`We also included cost-effectiveness studies. We also consulted national content experts and
`3 of the authors searched the reference lists of the included articles, producing 7 additional
`articles which met inclusion criteria. A final consensus was reached by these 3 authors on
`the 41 articles included in this review. For reporting purposes, we then classified the articles
`into 5 major topic areas. A PRISMA diagram (Figure 1) summarizes articles that were
`included in our initial search and were excluded based on our article selection criteria.22
`
`Article Abstraction
`
`Two of the authors reviewed each article and recorded the location, the number of
`participants, the population, the study design, the questions addressed by the article, and a
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`summary of key findings. Given the early stage of research in this area and the
`heterogeneous methods and outcomes employed, we chose not to apply systematic methods,
`such as meta-analysis, to summarize outcomes.
`
`RESULTS
`
`We identified 41 articles that met our inclusion criteria (Table 1). After reviewing articles
`that met inclusion criteria, we categorized the articles into 5 topical categories. Nineteen
`articles evaluated overdose prevention programs. These studies were largely observational in
`nature and included evaluations of programming. They also included 4 prospective cohort
`studies which followed participants over time.18, 23–25 The next set of articles (n=11)
`evaluated the effects of OEND programs on the experiences and attitudes of participants.
`These included qualitative (n=4) and survey (n=7) studies. Four articles described
`willingness of medical providers to prescribe naloxone. Five studies compared routes of
`naloxone administration in pre-hospital settings. In this category were 4 prospective studies,
`of which 2 were observed cohorts and 2 were randomized trials. Finally, two studies
`evaluated the cost-effectiveness of naloxone. The following results summarize our findings.
`
`Evaluation of Overdose Education and Naloxone Distribution Programs
`
`Community based organizations and a number of state public health departments began
`conducting and sponsoring OEND programs in 1996.11 OEND programs typically make
`naloxone directly available to people who use opioids, outside of a medical setting, and
`include training on opioid overdose prevention, recognition, and response. The overdose
`response training includes seeking help from the emergency medical system, rescue
`breathing, administering naloxone, and staying with the victim until recovery or help arrives.
`
`The articles representing program evaluations of OEND programs in Table 1 suggests that
`mortality from overdose can be prevented by providing overdose education and naloxone to
`a variety of participants, including people who used needle exchange programs and injected
`heroin,18, 23, 26–36 people using pharmaceutical opioids,37, 38 people who use opioids in
`treatment,24, 25 and the family and friends of people who use drugs.39, 40 These studies
`demonstrated that OEND trainings improved participants’ knowledge of opioid overdoses
`and equipped them to administer naloxone safely and effectively when witnessing an
`overdose. One study suggested that participants reduced their frequency of injecting drugs
`and were more likely to enter treatment six months after naloxone training compared to
`baseline.35 In Chicago, overdose deaths were reduced after the introduction of the OEND
`program.33 An analysis that compared communities in Massachusetts with no OEND
`implementation to those with low implementation (1–100 people trained per 100,000
`population) and high implementation (greater than 100 people trained per 100,000
`population), demonstrated 27% and 46% reductions in opioid overdose mortality rates,
`respectively, after adjusting for community level demographic and substance use factors.40
`
`Effects of OEND Programs on Experiences and Attitudes of Participants
`
`A number of articles support the feasibility of OEND programs. One concern that may
`inhibit naloxone prescribing is that potential bystanders or witnesses may not wish to
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`intervene in response to an overdose. Several studies confirm that witnesses are willing to
`take action to revive victims.19, 41–44 One study of people who use heroin showed that
`nearly every participant was willing to administer naloxone and perform rescue breathing if
`they had been trained.45 The majority of participants from a needle exchange program who
`used heroin (92 percent) in an Australian study also reported a willingness to participate in
`an OEND program. Other studies assessed the willingness of participants to have naloxone
`used on them in an overdose event, with most participants responding that they would want
`naloxone to be administered to them in an overdose.46
`
`Because naloxone must be administered by a bystander, concerns that lay bystanders cannot
`accurately identify an opioid overdose and properly administer naloxone have been raised.47
`Several studies suggest that bystanders, including people who use opioids, are capable of
`recognizing an opioid overdose and administering naloxone.48, 49 In addition to targeting
`people who use opioids, some OEND programs focus on educating family members and/or
`bystanders who may witness an opioid overdose.50 An evaluation of six OEND programs
`concluded that trained participants were more likely to recognize overdose scenarios and
`identify when naloxone administration was indicated compared to those who had not
`received training.49 Trained respondents scored similarly to medical experts in accurately
`recognizing overdose scenarios and identifying instances when naloxone was indicated.49 In
`a prospective study of overdose training and naloxone provision in 239 people who use
`opioids, participants had significant improvements in their knowledge of the risk factors for
`overdose, characteristics of an overdose, and the appropriate actions to reverse a potentially
`fatal overdose.24 In Massachusetts, where a state sponsored OEND program has been in
`existence since 2007, methadone maintenance and medically supervised withdrawal
`(inpatient detoxification) patients have been successfully trained in overdose prevention,
`equipped with naloxone rescue kits, and rescued people in the community.37 One study
`investigated the ability of participants to accurately share information about overdose
`prevention and naloxone administration with their peers and family, finding that they were
`able to successfully diffuse information from the program to others.51
`
`Naloxone may be particularly beneficial in populations that may avoid or delay calling for
`emergency services (e.g. 911) when they witness an overdose due to fear of arrest for heroin
`or opioid analgesic possession, a pre-existing warrant, or because they are afraid of
`jeopardizing their housing.45, 52 While overdose education typically includes instruction on
`calling emergency services, trained bystanders may feel more capable to handle an overdose
`without help from paramedics or medical personnel. A survey of prospective OEND trainees
`in Baltimore reported that fewer subjects would call for help after naloxone training.53
`These concerns may be reduced through legislation and collaboration with law enforcement
`to shield bystanders from legal consequences when calling 911 or administering naloxone.35
`
`Medical Providers Willingness to Prescribe Naloxone
`
`Prescribers in general medical practice have limited experience regarding naloxone for take-
`home use and potential misconceptions about naloxone. In one study of 571 physicians
`conducted from 2002 to 2003, 23% of those surveyed were aware of the option of
`prescribing take-home naloxone as an intervention to prevent the development of overdose
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`symptoms in people who use injection drugs.54 Most physicians (54%) indicated that they
`would never consider prescribing naloxone to a patient who injected drugs, suggesting that
`providers may either be uncomfortable or lack knowledge about providing care for these
`patients.54 This data was collected before pharmaceutical opioid overdose rates rapidly
`increased and community programs were well known, and did not assess physicians’
`willingness to prescribe naloxone to patients receiving prescription opioids. In another study
`conducted from 2001 to 2003, one-third of 363 nurse practitioners, physicians, and
`physician assistants surveyed said they would consider prescribing naloxone.55 In a recent
`investigation of medical provider attitudes towards prescribing naloxone, providers
`expressed concerns that naloxone may condone riskier drug use.56
`
`Studies Comparing Routes of Naloxone Administration in Pre-Hospital Settings
`
`The intranasal route of administration is not currently FDA approved, but its safety,
`convenience, and effectiveness (compared with IM naloxone) has been reported in
`controlled trials in pre-hospital settings.57–62 IN naloxone is available for off-label use and
`is the local standard of care in many emergency departments.62 In a study of people who
`used heroin, researchers reported a preference for IN naloxone administration over naloxone
`administered by needle injection due to its ease of use, reduced risk of blood-borne viruses,
`and less pain and risk from needle injection.41
`
`In a study of adverse events after IM and IV naloxone treatment, by paramedics, the most
`common adverse events in 1,192 overdose episodes were withdrawal-related, including
`gastrointestinal discomfort, physical aggressiveness, tachycardia, shivering, sweating,
`tremors, confusion, and restlessness.63 Overall, only 0.3% of patients were hospitalized for
`adverse events related to the administration of naloxone. Another study of 155 participants
`administered IM (n=71) or IN (n=84) naloxone involved no major adverse events.59 Other
`studies have shown that while there is a longer mean response time and an additional dose of
`naloxone required when using IN naloxone, there were no additional adverse outcomes
`associated with its use.59, 64, 65
`
`Cost Effectiveness
`
`Two studies, one in the US and one in Russia, estimated the cost-effectiveness of
`distributing naloxone to people who use heroin and concluded that naloxone distribution is
`cost-effective.66, 67
`
`DISCUSSION
`
`Existing research suggests that training people who are at risk for overdose and their peers is
`a feasible and effective way to prevent mortality from overdose. The articles included in this
`review indicate that people are willing to be trained about the risk factors for an overdose
`and are capable of responding appropriately when witnessing an overdose. Both IM and IN
`naloxone have been shown to be effective at reversing an overdose in pre-hospital settings
`without considerable risks of adverse outcomes.
`
`Some of the issues of implementing OEND programming into wider settings include
`medical providers’ reluctance to prescribe naloxone. Medical providers may be concerned
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`about bystanders ability to accurately recognize an overdose and administer naloxone,47 the
`cost of naloxone to patients,11 and condoning riskier drug use.56 Legal concerns may also be
`part of the reason for low engagement of prescribers in overdose education and naloxone
`prescription.68 In a legal review of naloxone prescribing, Burris et al. concluded that if
`medical providers prescribe naloxone to people who use opioids they are doing so in a way
`that is consistent with state and federal laws regulating drug prescribing and the risks of
`malpractice are very low.69
`
`Between 2001 and 2013, 24 states and the District of Columbia (DC) enacted laws
`promoting the accessibility of naloxone in the community through limiting liability for
`prescribing, possessing, and/or administering naloxone.70 Twenty-one of these states
`enacted laws promoting the prescription of naloxone to third parties, meaning those who are
`not themselves at risk for overdose, but may be in such a person’s social network. In the
`absence of special legislation or standing orders permitting third party prescribing, providing
`naloxone to people who are not themselves at risk of overdose, but who may be friends or
`family of people who use opioids might be outside of the prescriber-patient relationship.69
`
`Concerns about police involvement may prevent individuals with criminal justice
`involvement or using non-prescription opioids from carrying prescribed naloxone with them
`and/or calling emergency services during an overdose.25, 31 Further regulatory or legislative
`action and community education/outreach to inform the public about their protections
`related to calling emergency services or administering naloxone may be necessary.71 States
`increasingly recognize the importance of bystanders’ responding to overdose and are
`providing some immunity from arrest and/or prosecution for drug possession crimes and/or
`liability protection for administering naloxone.69 Twenty-one states and the District of
`Columbia have enacted “Good Samaritan” provisions providing some protection from
`prosecution for people who provide help at the scene of an overdose.70
`
`The potential absence of medical personnel at naloxone reversals has led some to express
`concern that individuals who have been revived from overdose outside of a medical setting
`have less opportunity to enter substance use treatment.72 Advocates for naloxone
`distribution respond that it is an intervention that prevents death and allows for future
`possibility of recovery.73 One study suggested education may promote treatment entry35
`Further work is needed about whether OEND or administration of naloxone increases
`treatment admissions for the individual trained or the person who overdosed.35 Another
`common concern is that people may use larger doses of opioids, believing they can be
`rescued from an overdose but this is unlikely because of the unpleasant effects of naloxone
`on opioid dependent individuals, who rapidly experience symptoms of withdrawal with
`naloxone administration.74
`
`Implications for Medical Practice
`
`In 2012, the American Medical Association and Massachusetts Medical Society issued
`endorsements of OEND programs.75 Recently, OEND programs have expanded access to
`naloxone in many states, but a number of states with high drug overdose death rates remain
`without OEND programs.11 Furthermore, OEND programs were originally established to
`address overdose people who inject heroin, but many others are at risk, including people
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`who take pharmaceutical opioids for pain. Additional risk groups have since been proposed
`as potential targets of overdose education and naloxone distribution (see Table 2).
`
`While not addressed in the studies identified by this review, rising rates of pharmaceutical
`opioid use and overdose require novel prevention approaches to reduce risk. These
`approaches could include co-prescription of naloxone with opioids, insurance
`reimbursement for take-home naloxone, pharmacy dispensing of naloxone without a
`prescription, and over-the-counter naloxone distribution.13 More broadly, these
`interventions could be considered within the context of other opioid safety efforts, such as
`safe disposal of excess opioids,38 prescription drug monitoring programs,76 risk evaluation
`and mitigation strategies (REMS),77 and abuse-deterrent medications.78 New administration
`devices, such as Evzio, an auto-injector device, which was fast-tracked for approval by the
`FDA because of the severity of the opioid overdose epidemic, should be evaluated further
`for its effectiveness in pre-hospital settings and its limitations, such as cost and
`availability. 79
`
`Opioid prescribers have a responsibility to assess the overdose risk in their patients and
`educate them about potential adverse events, including overdose.80 Physicians have an
`opportunity to apply their clinical assessment skills to identify patients as candidates for
`overdose education and naloxone prescription based on known risk factors for overdose. A
`thorough clinical history would include asking patients about a history of prior overdose,
`chronic medical illness (pulmonary, renal or hepatic disease), drug use, incarceration
`history, and use of other sedating medications. Key elements of counseling patients may
`include not taking more milligrams or more frequently than prescribed, self-monitoring of
`functional status while on opioids, and letting others in one’s family or social network know
`about the risks of overdose and what to do in the event of an overdose (e.g. calling 911).
`Prescribers should consider advising patients to secure opioids and other sedating
`medications, such as benzodiazepines, by keeping them locked up in the home to avoid
`diversion and to avoid sharing medications.80
`
`For patients with overdose risk, medical providers should prepare patients with instructions
`to follow in the event of an overdose. Prescribing take-home naloxone could be part of this
`preparation. The prescribing of naloxone should not be seen as a discrete event, but as part
`of an ongoing process that includes patient education, monitoring, and opioid dose
`adjustment.81 Because patients who have been prescribed naloxone are unable to use the
`drug on themselves, their peers and family members must be involved in overdose education
`and management training.73
`
`Barriers to prescribing naloxone may need to be overcome through efforts by physicians,
`pharmacists, policy-makers, patient advocates and health care systems. Pharmacies should
`consider stocking naloxone, intramuscular needles or nasal atomizers, and educational
`materials on administration. Patients may have to pay out-of-pocket for naloxone until
`insurance companies and public payers (e.g. Medicaid) cover naloxone, administration
`devices, and associated counseling/education costs. The Appendix includes several web
`resources produced by a variety of community-based OEND programs, government
`agencies, researchers, and activists which currently aim to educate medical providers about
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`their patients’ risk of opioid overdose and provide information about prescribing naloxone.
`This list is not intended to be all inclusive or exhaustive, but provides a sample of resources
`available for medical providers interested in prescribing naloxone.
`
`Gaps Identified and Further Research Needs
`
`Based on current available evidence, prescribers should consider providing overdose
`education and naloxone in medical practice. Further study of barriers and facilitators to
`OEND in conventional clinical settings with more diverse populations of people at risk for
`overdose is needed. Future research should investigate how to select patients for naloxone
`prescription, how to engage patients and potential bystanders in overdose education and
`management training, the optimal breadth and depth of overdose education, the proper roles
`for different healthcare team members in disseminating OEND, the safety of take-home
`naloxone across a broad range of patient characteristics, and the reach and effectiveness of
`overdose education and naloxone prescription in traditional health care settings. These
`issues are particularly important since OEND programs may not meet the needs of all people
`who use pharmaceutical opioids due to the limited geographic availability of OEND
`programs, stigma against accessing community-based OEND programs, which have
`traditionally served people who use heroin and people who inject drugs, and costs of
`naloxone and related counseling or educational services. Access through traditional medical
`and pharmacy settings may offer some advantages including scale and insurance coverage.
`At the same time, clinical settings may not offer the degree of training or sensitivity to the
`needs of populations at risk demonstrated in dedicated community based programs.
`Additionally, more research should be conducted to understand what may be limiting
`medical providers’ willingness to prescribe naloxone. Finally, more research using empirical
`data is needed to examine the cost-effectiveness of providing naloxone to patients treated
`with pharmaceutical opioids. While overdose education and naloxone distribution may be a
`key component of a public health effort to reduce opioid overdose deaths, our findings
`suggests further research is needed on the role of naloxone in conventional medical practice.
`Medical providers are in an ideal position to prescribe take-home naloxone to reduce
`mortality for opioid overdose amongst their patients.14 Data from observational, health
`services, and randomized controlled trials could further inform physician practice and
`establish a new standard of care, with regards to naloxone prescription to patients receiving
`opioids in medical practice settings.
`
`Acknowledgments
`
`We wish to acknowledge the Harm Reduction Action Center, Lisa Raville, Jane Kennedy, DO, Edward M.
`Gardner, MD, and Steve Koester, PhD for their assistance and thoughtful contributions.
`
`FUNDING
`
`Work on this publication was supported by the National Institute on Drug Abuse of the National Institutes of Health
`under Award Numbers R34DA035952 and R21DA31041. The content is solely the responsibility of the authors and
`does not necessarily represent the official views of the National Institutes of Health.
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