Stakeholders’ Perceptions of Factors Influencing the Use of Take-Home-Naloxone

Background and Aims: Opioid associated death and overdose is a growing burden in societies all over the world. In recent years, legislative changes have increased access to naloxone in the take-home setting for use by patients with a substance use disorder and bystanders, to prevent opioid overdose deaths. However, few studies have explored the factors influencing the uptake by its multiple stakeholders. The aim of this scoping review was to explore the factors influencing the use of take-home naloxone from the perspectives of different stakeholders. Methods: A scoping review methodology was adopted with a systematic search of databases EMBASE, MEDLINE and PubMed. A variation of the search words “naloxone”, “opioid” and “overdose” were used in each database. The articles were screened according to the predetermined inclusion/exclusion criteria and categorized based on their key perspective or target population. Results: The initial database search yielded a total of 1483 articles. After a series of screening processes, 51 articles were included for analysis. Two key stakeholder perspectives emerged: patients and bystanders (n = 36), and healthcare professionals (n = 15). Within the patient and bystander group, a strong consensus arose that there were positive outcomes from increased access to take-home naloxone and relevant training programs. Despite these positive outcomes, some healthcare professionals were concerned that take-home naloxone would encourage high-risk opioid use. Conclusion: Take-home naloxone is slowly being introduced into community practice, with a sense of enthusiasm from patients and bystanders. There are still a number of barriers that need to be addressed from healthcare professionals’ perspective. Future research should be aimed at emergency care professionals outside of the US, who are most experienced with naloxone and its potential impact on the community.


Introduction
Opioid overdose and misuse is a significant public health burden worldwide and is a common cause of drug-related deaths in Australia [1]. In 2012 in Australia, there was a total number of 564 accidental deaths from opioid overdose [2], almost half that of total road accident associated deaths [3]. The number of opioid-related deaths has been sharply rising with a 21-fold increase observed in the

Materials and Methods
A scoping review methodology, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist, was adopted for this study in order to "describe in more detail the findings and range of research in particular areas of study, thereby providing a mechanism for summarizing and disseminating research findings to policy makers, practitioners and consumers" [27,28].

Search Strategy
The literature was searched and retrieved systematically from three databases: PubMed, EMBASE and MEDLINE on the 30 March 2017, in accordance with PRISMA guidelines. A variation of text words, key words and MeSH terms/subject headings were used: "*naloxone" AND "opioid analgesic" OR "opioid*" OR "opiate*" OR "narcotic*" OR "heroin" AND "intoxicat*" OR "drug overdos*" OR "overdos*". See Table A1 for an example of the search strategies.

Study Selection
The study inclusion criteria included primary research articles published in the last ten years (2007)(2008)(2009)(2010)(2011)(2012)(2013)(2014)(2015)(2016)(2017), because the injectable product for this purpose was introduced recently on the market, in peer reviewed journals focusing on stakeholders' perceptions of factors affecting the uptake of take-home naloxone and its use anywhere around the world. Exclusion criteria were: language (not English) and studies focusing on pharmacologic mechanisms of actions, side effect profiles, dosage forms and naloxone in a non-take-home context, such as its use within a hospital. Articles that were not primary research and were excluded from selection included editorials, conference abstracts, notes, letters to the editor, reviews, case reports and supplements.
In the first phase of screening, duplicates, studies which were not primary research and those that did not meet our inclusion criteria based on the title, were removed. In the second phase of screening, abstracts were reviewed. Studies not in English were also excluded prior to the full text screening phase. Next, full texts were screened to focus on topics which met our inclusion criteria. Lastly, studies not identified by the database searches were sought by hand by searching the grey literature and the bibliographies of publications and were added to the pool of literature where relevant.

Assessment of Study Quality
The quality of included studies was assessed using the Joanna Briggs Institute (JBI) Critical Appraisal Checklists. The JBI Critical Appraisal Checklists utilized were specific to the various methodologies employed within the included studies. Within the checklists, each item was scored 0, 0.5 or 1, with higher scores indicating greater quality. As the checklists for various study methodologies contain between 8 and 13 items, scores were normalized to give a final score out of 100 to allow comparison across study types. Studies scoring above 75 were considered high quality, those scoring between 50-75 were considered medium quality and those scoring below 50 were considered low quality.

Data Extraction and Analysis
The following data were extracted and collated from the articles predominantly by one of the researchers (TH): country of study, data collection method, sample size, brief method and intervention details, main outcomes and funding source. The studies were then organized based on the sample population or perspectives. Studies were further analysed based on their study design, major findings and themes. Themes were then discussed and clarified (by TH, JP and BC) until a consensus was reached.

Results
The search strategy generated 428 articles from MEDLINE, 474 from EMBASE and 581 from PubMed, yielding 1483 in total. After removal of duplicates, 978 were screened and through various phases of elimination 51 studies were included for analysis as shown in Figure 1. The mean study quality score was 76 (standard deviation ± 17) indicating most were of medium to high quality. Studies were categorized into two groups pertaining to the perspective that each was based on. Thirty-six studies were found relating to the perspectives of patients likely to receive naloxone, and bystanders, who were members of the public who did not have an opioid addiction themselves, but were mostly friends and family of people who were at risk of opioid overdose. Of these, 64% were high quality, 25% medium quality and 11% low quality studies.
Fifteen studies were found exploring healthcare professionals' perspectives, including various medical professionals, staff from prisons, needle exchange facilities and homeless shelter programs. In total, thirty-eight studies were conducted in the United States, seven in the United Kingdom, four in Canada, one in Norway and one in Australia. Of these, 60% were high quality and 40% were medium quality.

Patients' and Bystanders' Perspectives
The most prominent finding (24/36) within the patients' and bystanders' perspectives category was the positive outcomes resulting from access and training to take-home naloxone in terms of knowledge, confidence and rate of opioid reversals . Four studies identified several facilitators including: the fact that naloxone is a life-saving measure; that it has the ability to empower people and potentially decrease drug use and that training was novel and interesting [53][54][55][56]. Some barriers identified included: the delivery of information from healthcare professionals as "professionally led health promotion initiatives appeared to lack credibility amongst the target population", that administration can be challenging due to the potential need to titrate doses and the use of a needle in all routes of use other than intranasal administration. There was also fear of the unpleasant withdrawal symptoms that naloxone almost immediately precipitates, colloquially known as "dopesickness". Furthermore, there was apprehension toward calling emergency services due to the fear of police interaction and the potential for incarceration [53][54][55][56].

Healthcare Professionals' Perspectives
Identification and recognition of key facilitators and barriers to increasing naloxone access were the predominant themes of this category (11/15), unlike the patient and bystander results [65][66][67][68][69][70][71][72][73][74][75]. Seven of these studies were in the form of discussion groups and interviews, and the remaining four were surveys. Some of the facilitating aspects recognised were interventions that were "real-world" driven, provided education and training, had available resources and current involvement or awareness of other harm-reduction programs (such as opioid substitution therapy). Some of the perceived barriers included: financial and other logistical difficulties such as lack of staff and time to appropriately train and educate patients and bystanders, regulations and legalities and lack of education and training. Examples of specific patient-related barriers included concerns regarding offending patients who had not previously experienced an overdose in response to the offer of take-home naloxone as well as a stigma. Stigma is multifaceted, including patients being discriminated against by peers for having this medication, and is related to some healthcare professionals' expressing lowered motivation and interest toward helping people who are using opioids. Two pre-post evaluation studies showed positive outcomes from healthcare professionals receiving additional training for the use of take-home naloxone [76,77].
Two studies were associated with a needle exchange clinic or safe injecting room types of settings [74,77]. Four studies were conducted from a pharmacy perspective, with two of them identifying similar facilitators and barriers as mentioned above [65,67] and two showing mostly positive attitudes of pharmacists toward take-home naloxone but also highlighting a lack in knowledge [71,75]. Emergency care provider opinions were the focus of two studies, one concluding a predominantly negative attitude toward take-home naloxone with the opinion that it would not decrease death rates [73]. The second identified several facilitators and barriers as mentioned above [67].

Discussion
This review has explored the literature available in regard to factors influencing the use of take-home naloxone from the perspectives of patients/bystanders and healthcare professionals. From the perspectives of patients and bystanders, the findings in the literature depicted positive responses from the increased access to take-home naloxone . A sense of empowerment increase in confidence and ability to recognize overdose symptoms were just some of the encouraging conclusions that these studies made. In conjunction with these findings, it was clear that naloxone administrations were successful in reducing opioid-related overdose deaths, which is ultimately the goal of all harm minimization interventions [30,[32][33][34][35]38,39,[41][42][43][44][45][46][47][48]50,52].
In 1985, the Australian Government adopted harm minimization as a national framework in an attempt to address the range of drug and alcohol issues in society [78]. Whilst it is clear that take-home naloxone has support from its potential users in the community as a harm minimization project, healthcare professionals have expressed concerns about its uptake, as it was perceived to encourage high-risk opioid use [66,[68][69][70][72][73][74][75]. Similar concerns were, and still are, expressed in regard to needle exchange and distribution programs [79]. Needle exchange programs have been implemented in Australia since the mid-1980s under the harm minimization framework mentioned above [79]. Although there has been no evidence that take-home naloxone or syringe exchange programs increased drug use, this stigma still remains [80][81][82]. In fact, studies have shown that naloxone has the potential to decrease drug use, as having access to naloxone motivated and empowered patients to be more health conscious [33,45].
To highlight the stigma associated with naloxone, a comparison can be drawn with adrenaline for anaphylaxis. Both naloxone and adrenaline are patient administered rescue medications that save lives; however, the introduction of adrenaline induced no resistance from the community compared to other harm minimization programs such as syringe exchange or methadone [83]. A systematic review around healthcare professionals' perspectives showed that they expressed "lowered regard, less motivation and feelings of dissatisfaction" toward patients with substance use disorders, consolidating this notion of stigma [84]. As mentioned, naloxone is just as much a life-saving medication as adrenaline, and a healthcare professional's decision to withhold it from patients based on this stigma is a violation of all principles of professional ethics in healthcare [85,86]. Codes of ethics state that, despite a conscientious objection to the supply or prescribing of a medical product, healthcare professionals have an obligation to place the best interests of the patient above all else and, at the very least, maintain continuity of care to all patients [85,86].
It is also known that illicit use of opioid medication, prescription or not, is not the only cause of opioid overdose [87]. Chronic pain patients are also at risk of opioid overdoses due to pharmacokinetic changes with age or confusion about dosing or instructions of use [88]. Despite this, current studies are strongly focused on injecting drug users and patients involved with needle exchange programs, homeless shelters and similar facilities. This disproportionate focus may be due to the fact that talking to non-illicit opioid users about take-home naloxone was identified as a barrier by many healthcare professionals' due to the fear of offending them [67,68]. A way to mitigate this risk would be to educate healthcare professionals on how to identify "high risk" chronic opioid using patients for the potential of opioid overdose and provide all of these patients with take-home naloxone [89,90].
Many healthcare professionals also emphasized the lack of education and training on take-home naloxone in this review [67][68][69][70][71][72][73]75]. Although codes of ethics in healthcare also state that healthcare professionals are bound by an obligation to be life-long learners, it is clear that patients are being adversely affected by healthcare professionals' lack of knowledge [85,86]. Two studies showed that training lasting around an hour was sufficient to increase the knowledge of homeless shelter staff and other healthcare providers [76,77]. All healthcare professionals who prescribe opioids or care for patients at risk of opioid overdose should be provided with training on take-home naloxone.
Barriers identified in this review have all been encountered previously by other harm prevention strategies such as the methadone substitution therapy. Methadone programs were introduced in Australia in the 1970s and over time have slowly overcome barriers associated with training, education and stigma, similar to those identified by the professionals' perspectives category in this review [91,92]. A systematic review about stigma among healthcare professionals towards patients with substance use disorder stressed the importance of training of healthcare professionals "in order to extend the knowledge, skills and self-efficacy of professionals working with patients with substance use disorders" [84]. Alongside this training, two factors were identified by McArther 1999 that assisted methadone in gaining traction in communities and overcoming these barriers including the high demand for it from drug users themselves, and the eventual realization that it played a role in reducing crime rates and reducing HIV/AIDs transmission [92]. This last point indicates that with time, naloxone could gain community awareness, proving its worth and benefits in a take-home setting, as was the case for methadone. In fact, an article in 2007 by Beletsky et al. supported this notion and concluded that physicians with more experience and awareness of patients with substance use disorders were more inclined to respond positively to take-home naloxone prescriptions [93].
Emergency care providers were highlighted in this review as they hold expertise in opioid-related overdoses and take-home naloxone has the potential to impact the nature of their interactions with overdosing patients [67,73]. However, emergency providers were found to hold negative views towards patients with substance use disorders, with one study showing that more than half viewed take-home naloxone training as an ineffective strategy to reduce opioid-related deaths [73]. Addressing emergency providers' concerns and obtaining their support is crucial for successful uptake of take-home naloxone. In addition to the large number of patients that present to the emergency department (ED) that are at risk of an opioid overdose, evidence also shows that patients are likely to stay on the medications prescribed for them in hospital [94]. With this trend in mind, it is imperative that emergency physicians are the focus point for further education about take-home naloxone, in order to increase the dissemination of this life-saving medication into the community. Once the initial uptake has been established, it is assumed that other healthcare providers such as general practitioners and pharmacists are likely to follow this pattern of distribution.
The perspective of the pharmacist was also explored in this review [66,68,72,76]. As take-home naloxone no longer requires a prescription in many countries, pharmacists are becoming increasingly involved in its distribution. Pharmacists are arguably the most accessible healthcare professionals and may be the first point of contact patients have with the healthcare system [72]. Two studies communicated policy regulations as a large barrier to take-home naloxone from a pharmacist's perspective. Regulatory issues are particularly prevalent in the US, where legislation differs between states, causing confusion for all parties involved, in relation to the varying degrees of access to take-home naloxone [95,96]. Furthermore, although pharmacists were found to express positive attitudes towards harm-reduction services, very few stocked naloxone and the majority lacked confidence in their ability to educate patients on naloxone use [72]. Another study noted that pharmacists were supportive of take-home naloxone, but were unaware of the high prevalence of opioid overdose [76]. This limited cognizance regarding take-home naloxone and the opioid burden in general is reflected in the lack of uptake of this medicine in the community. The paucity of information surrounding the role of pharmacists and emergency care professionals, two key stakeholders in the future of take-home naloxone, is an area necessitating further research.
Limitations: The current findings need to be considered in light of several limitations. The review was limited to articles in English; however, there was only one study identified that was not in English, thus it is unlikely that this restriction greatly impacted the results [96]. Second, the majority of the studies included were from the US, limiting the applicability or generalizability of these results to a worldwide setting. Third, only three databases were used for the systematic search strategy; however, this included two of the largest, most comprehensive databases in this area of research. Future researchers could conduct a similar search in databases such as Cumulative Index to Nursing and Allied Health Literature (CINAHL) and International Pharmaceutical Abstracts (IPAs), in order to gain additional literature from a broader range of medical professions. Despite this, we believe that this search was sufficient to support our findings and that all key themes and perspectives were identified.

Conclusions
Findings of this study indicated that patients and bystanders who may use take-home naloxone were eager and have positive attitudes towards its use; however, there remain some barriers from a healthcare professional's perspective. In particular, it was found that stigma around drug use negatively affects the implementation/uptake of take-home naloxone, as some healthcare professionals appear to view these patients. Future research should be aimed at exploring how to gain stronger support from emergency care professionals who are experienced with opioid overdoses and the potential impact of take-home naloxone on the community. The obstacles identified in this study, regarding the implementation of take-home naloxone, were not new concepts. With time, allowing for the efficacy of naloxone to be proven, and with an increase in education and training for all parties involved, more patients at risk of opioid overdose should see access to this life-saving medication. In addition, the impact of take-home naloxone should be explored more extensively in settings outside of the US. Acknowledgments: This study was conducted as part of Taylor Holland's Honours degree requirements and only received kind support from the University of Sydney.

Conflicts of Interest:
The authors declare no conflict of interest. 1 and 5 and 8 544 10 limit 9 to human 474 * The asterix in this context is what is known as a "wildcard" and represents any group of characters, including no character. A convenience sample of community support group attendees was surveyed The community group offered naloxone training lasting 20 min. Compared those who received overdose education and naloxone to those who did not.

Appendix A
-Those who received training were more likely to be a parent (91% versus 65%) and have daily contact with opioid user (54% versus 33%) -60% felt encouraged from education at meetings, 72% wanted naloxone in the house -Trainees endorsed "greater sense of security" and "improved confidence" -Of the 27                Contact person of opioid overdose prevention programs (OOPP) were given a survey about their program Initial list from the Ohio Department of Health Survey was emailed or given over the phone -15/20 (83%) of programs experience barriers, which were categorized into: stigma (n = 14), costs (n = 7), staffing (n = 5), legal (n = 4), regulatory (n = 3) and clients (n = 3).
None stated