More than just availability: Who has access and who administers take-home naloxone in Baltimore, MD.

BACKGROUND: Fatal opioid overdose is a pressing public health concern in the United States. Addressing barriers and augmenting facilitators to take-home naloxone (THN) access and administration could expand program reach in preventing fatal overdoses.
METHODS: THN access (i.e., being prescribed or receiving THN) was assessed in a Baltimore, Maryland-based sample of 577 people who use opioids (PWUO) and had a history of injecting drugs. A sub-analysis examined correlates of THN administration among those with THN access and who witnessed an overdose (N = 345). Logistic generalized estimating equations with robust standard errors were used to identify facilitators and barriers to accessing and using THN.
RESULTS: The majority of PWUO (66%) reported THN access. In the multivariable model, decreased THN access was associated with the fear that a person may become aggressive after being revived with THN (aOR: 0.55, 95% CI: 0.35-0.85), police threaten people at an overdose event (aOR: 0.68, 95% CI: 0.36-1.00), and insufficient overdose training (aOR: 0.43, 95% CI: 0.28-0.68). Enrollment in medication-assisted treatment, personally experiencing an overdose, and graduating from high school were associated with higher access. About half (49%) of PWUO with THN access and who had witnessed an overdose reported having administered THN. THN use was positively associated with "often" or "always" carrying THN (aOR: 3.47, 95% CI: 1.99-6.06), witnessing more overdoses (aOR:5.18, 95% CI: 2.22-12.07), experiencing recent homelessness, and injecting in the past year. THN use was reduced among participants who did not feel that they had sufficient overdose training (aOR: 0.56, 95% CI: 0.32-0.96).
CONCLUSION: THN programs must bolster confidence in administering THN and address barriers to use, such as fear of a THN recipient becoming aggressive. Normative change around carrying THN is an important component in an overdose prevention strategy.

Introduction

Opioids were involved in more than 47,000 deaths in the US in 2017, killing more people than motor vehicle accidents and firearms [1-3]. Recently, the majority of fatal opioid overdose deaths have been attributed to fentanyl, a synthetic opioid [1,4]. The proliferation of fentanyl and its analogs in recent years has increased the risk of overdose fatality due to their heightened potency [5]. Fatal opioid overdose is preventable with the administration of opioid overdose reversal drugs, such as naloxone. Naloxone is a fast-acting μ-opioid receptor antagonist that competitively displaces opioids, reversing the central nervous system depression that occurs during an opioid overdose [6]. The World Health Organization guidelines strongly recommend equipping people who are likely to witness an overdose with naloxone rescue kits (“take-home naloxone”, THN) and providing training in the management of opioid overdose [7]. The efficacy of naloxone in reversing an opioid overdose is largely independent of route of administration, and THN formulations include intramuscular, subcutaneous, and intranasal [7]. There are many THN training programs available, however the core component of all programs is to enable the management of an opioid overdose through effective administration of THN [7]. People who use opioids (PWUO) are especially in need of THN as they are highly likely to witness overdose events [8,9]. Strang and colleagues found that 97% of PWUO report having witnessed an overdose and Ogeil and colleagues found that 21% of prescription overdose deaths were witnessed by another person [10,11].

In efforts to increase access to THN, many municipalities have implemented interventions such as provision of THN at pharmacies and other community-based sites providing services for individuals with substance use disorders [12-14]. For example, in Baltimore City, there has been a standing order policy in place since 2015 which eliminates the need for individual prescriptions for THN [15]. Despite concentrated efforts to increase THN distribution and training, many PWUO have never received THN and overdose response strategies by bystanders are often inconsistent and ineffective [10,16].

Few studies have examined barriers and facilitators of THN access and administration among PWUO [17-19]. Kenney et al. examined correlates of THN use among PWUO using a sample of participants who were enrolled in an inpatient opioid detoxification program [18]. The study found that recent injection drug use, history of overdose, witnessing an overdose in the past year, non-Black race, and detoxification from heroin were associated with THN administration [18]. Perceived negative consequences of administering THN may also reduce access to and use of THN. Among people enrolled in medication-assisted treatment (MAT), Khatiwoda and colleagues found that fear of prosecution by police was cited as a reason for not having access to THN [19]. Further, a recent qualitative study identified that some PWUO report not wanting to use THN for fear of an aggressive response from the overdose victim after administering THN [17]. While THN has minimal side effects, it does induce acute withdrawal symptoms in opioid-dependent individuals [6,20], and precipitated withdrawal can provoke an aggressive reaction in some individuals [20-22].

This fear of police and an aggressive response by the overdose victim after administering THN may prevent accessing and using THN during a witnessed overdose. Additional, yet unexplored barriers to access and use of THN may include insufficient training to effectively administer THN and inconsistencies in carrying THN. Further, access to health services may increase training on THN and facilitate access and use of THN [13]. The primary aim of the current study was to examine facilitators and barriers to THN access among PWUO. The secondary aim was to identify predictors of administering THN among PWUO who had witnessed an overdose and had access to THN.

Methods

Study participants

Study participants were recruited in Baltimore, Maryland, for a randomized clinical trial of an intervention to enhance Hepatitis C and HIV prevention and care among people using substances and residing in impoverished neighborhoods. A total of 518 index participants were recruited using street-based outreach, advertisement, and word-of-mouth. Inclusion criteria for the baseline screening visit included being 18 years of age or older and a history of lifetime injection drug use. Index participants were encouraged to recruit network members who were drug using and/or sexual partners. The study sample includes an additional 71 network members recruited by index participants who completed the baseline screening visit. The current analysis was restricted to 577 of 589 participants (98%), 511 index and 66 network members, who completed a baseline screening visit between December 2016 and September 2018 and reported ever using illicit opioids or non-medical prescription opioids. All participants provided written informed consent. Trained study staff administered a face-to-face survey to collect participant demographic and risk factor data. Sensitive risk behavior questions were assessed via audio computer assisted self-interviewing (ACASI). Participants were paid 20 US dollars for completing the survey. Study protocols were approved by Johns Hopkins Bloomberg School of Public Health IRB.

Measures

Outcome: Access to and administration of THN

Our primary outcomes were access to and administration of THN. THN access was assessed by asking participants, “Have you ever been prescribed or received a kit containing Narcan?” Prior to this question, participants were informed that “Narcan/naloxone is a prescription drug that can be administered to reverse an opiate overdose.” THN administration during a witnessed overdose was assessed using the question, “have you ever used Narcan to reverse an opiate overdose?” Use of THN to respond to a witnessed overdose was only examined among the subset of PWUO who reported receiving THN and who witnessed ≥1 overdoses during their lifetime.

Socio-demographics

Socio-demographic variables included measures of age, gender, education, and homelessness. Age was categorized based on quartiles. Gender was analyzed as a dichotomous measure comparing male to female. Education was defined as a binary measure comparing not graduating from high school vs. high school graduation or higher educational attainment. Homelessness was self-reported as experiencing homelessness at any time in the past 6 months.

THN availability

The frequency of carrying THN was assessed through the question, “how often do you carry Narcan with you?” For the analysis, the response categories were dichotomized as “never,” “rarely,” or “sometimes” versus “often” or “always.”

Drug use and overdose characteristics

Injection drug use in the past year was assessed through the question, “When was the last time you injected drugs to get high?” One person did not answer the question and was coded at the median of having injected in the past year. Personal overdose experience was assessed as responding with one or more to the question, “How many times in your life have you overdosed?” The number of overdoses witnessed was categorized into five categories using natural breaks in the distribution (0, 1–2, 3–4, 5–9, or ≥10 overdoses).

Fentanyl perceptions

Perceived prevalence of fentanyl was assessed by the question “What percentage of heroin on the streets of Baltimore do you think contains fentanyl?” Responses were categorized as “more than half” versus “half,” “less than half,” or unsure/not familiar with fentanyl.

Perceived barriers of responding

Three items assessed perceived barriers to assist in the event of an overdose. The first assessed insufficient training to respond to an overdose with the statement, “I am going to need more training before I would feel confident to help someone who has overdosed.” For the analysis, the variable was dichotomized as “strongly agree” or “agree” versus “strongly disagree,” “disagree,” or “neither agree nor disagree.” The second assessed fear of an aggressive response after administration of THN using the statement, “I would be afraid of giving Narcan in case the person becomes aggressive afterward.” We dichotomized responses as “strongly agree” or “agree” versus “strongly disagree,” “disagree,” or “neither agree nor disagree” for the analysis. The third assessed the perceived threat from police with the question, “When the police show up at an overdose, how often do they threaten the people present, including the victim, with drug charges or arrest?” Responses were dichotomized as “never” or “rarely” versus “sometimes,” “often,” or “always.” One participant responded, “don’t know” and was categorized as “never.”

Health services access and engagement

Access to health services was assessed with survey items on receiving MAT and having health insurance. MAT was defined as reporting currently taking buprenorphine, methadone, or naltrexone. Health insurance status was dichotomized as having health insurance versus not having health insurance at the time of the survey.

Location of THN training

Among participants who reported having been trained in THN, training location was assessed through the open-ended question: “If you wanted to get Narcan or a refill where would you go to obtain it?” Responses were assessed for recurring locations and coded as community outreach programs (e.g. syringe service programs and community events), recovery programs, clinics, detention centers, through friends, or other avenues.

Statistical analysis

Differences in the distribution of participant characteristics by the primary (access to THN) and secondary (THN administration) outcomes were accessed with Chi-square tests. Two multivariable models were constructed to identify independent predictors of access to THN and administration of THN. Due to anticipated correlations among some of the variables, backwards stepwise selection was used to refine multivariable models with a threshold p-value of .10. The demographic variables of age, gender, and education were also included in the multivariable models. Logistic generalized estimating equations with robust standard errors accounted for the clustered structure of the data (i.e., that index participants recruited network members). A sensitivity analysis was performed among PWUO who injected drugs in the past year, as they represent a subsample at elevated risk of overdose and in need of THN. Statistical analysis was conducted with STATA version 14 software [23].

Results

The mean age of study participants (N = 577) was 47 years (SD: 11). The majority were male (66%), had graduated from high school (61%) reported injecting drugs in the past year (63%), were currently enrolled in MAT (63%) and had health insurance coverage (92%). Homelessness in the past 6 months was reported by 47% of study participants. The majority had witnessed (87%) and personally experienced (66%) an overdose in their lifetime. Fentanyl was perceived to be in more than half the heroin supply by 57% of participants, and 57% reported having insufficient training to respond to an overdose. About one-quarter (26%) feared an aggressive response after giving THN, and 51% perceived that police would threaten people at the scene of an overdose with drug charges or arrest.

Additionally, an analysis of study participants who stated that they had been trained to use THN (n = 338) indicated that participants were primarily trained through community outreach programs (36%), recovery programs (34%), and clinics (27%). The minority of participants reported being trained through detention centers (2%), through friends (1%), or other avenues (1%).

Correlates of access to THN

Two-thirds (66%) of study participants reported access to THN. The bivariate analysis compared PWUO with access to THN to those without access (Table 1; N = 577). In the univariate analysis, access to THN was associated with younger age, completion of high school, recent injection drug use, personal overdose experience, witnessing more overdoses, perception of higher amounts of fentanyl in heroin, and current enrollment in MAT. Perceptions of insufficient training and that a THN recipient would become aggressive was associated with decreased access to THN. In the multivariable model (Table 2), access to THN was positively associated with having completed high school education or above (adjusted odds ratio, aOR: 1.68, 95% CI: 1.13–2.50), personally experiencing an overdose (aOR: 2.68, 95% CI:1.79–4.01), and currently receiving MAT (aOR: 3.87, 95% CI: 2.59–5.78). Reduced THN access was associated with a perception of needing more overdose response training (aOR: 0.43, 95% CI: 0.28–0.68), fearfulness that a person would become aggressive after being revived with THN (aOR: 0.55, 95% CI: 0.35–0.85), and perception that police would threaten people at an overdose with charges or arrest (aOR: 0.68, 95% CI: 0.46–1.00). Age, recent injection drug use, number of witnessed overdoses, and perceptions of fentanyl in the heroin supply did not remain independent predictors of access to THN in the multivariate model.

Table 1

Bivariate correlates of access and administration of take-home naloxone (THN) among people who use opioids in Baltimore, MD, USA.

	THN Access			THN Administration
	No (n = 197)	Yes (n = 380)	P value	No (n = 177)	Yes (n = 168)	P value
Socio-Demographic Characteristics
Age (years)
40–49	47 (23%)	94 (25%)	0.003	50 (28%)	35 (21%)	<0.001
50–55	48 (24%)	97 (25%)		49 (28%)	36 (21%)
56+	61 (31%)	70 (18%)		41 (23%)	24 (14%)
Male	136 (69%)	244 (64%)	0.246	110 (62%)	114 (68%)	0.267
High school/GED+	106 (54%)	248 (65%)	0.007	107 (60%)	115 (68%)	0.121
Homeless (past 6 mos.)	83 (42%)	187 (49%)	0.106	69 (39%)	105 (63%)	<0.001
THN Availability
Carry THN Often/Always	---	---		30 (17%)	77 (46%)	<0.001
Drug Use & Overdose History
Injected (past 12 mos.)	107 (54%)	256 (67%)	0.002	100 (56%)	136 (81%)	<0.001
Ever overdosed	99 (50%)	281 (74%)	<0.001	131 (74%)	131 (78%)	0.389
No. of overdoses witnessed
0	38 (19%)	35 (9%)	0.001	---	---
1 to 2	52 (27%)	78 (20%)		58 (33%)	20 (12%)	<0.001
3 to 4	41 (21%)	94 (25%)		55 (31%)	39 (23%)
5 to 9	28 (14%)	67 (18%)		28 (16%)	39 (23%)
10 +	38 (19%)	106 (28%)		36 (20%)	70 (42%)
Perceptions of Fentanyl
>50% of heroin supply has fentanyl	99 (50%)	228 (60%)	0.025	97 (55%)	112 (67%)	0.024
Perceived Barriers of Responding
Perception of insufficient overdose training	143 (73%)	185 (49%)	<0.001	105 (59%)	58 (35%)	<0.001
Perception that Narcan recipient will become aggressive	74 (38%)	77 (20%)	<0.001	48 (27%)	22 (13%)	0.001
Perception that police will threaten people at overdose scene	109 (55%)	184 (48%)	0.115	82 (46%)	85 (51%)	0.428
Health Services Access and Engagement
Medication-Assisted Treatment	82 (42%)	281 (74%)	<0.001	135 (76%)	120 (71%)	0.306
Currently have health insurance coverage	175 (89%)	354 (93%)	0.074	167 (94%)	154 (92%)	0.327

---variable not included in the model

Table 2

Multivariable model of correlates of access and administration take-home naloxone (THN) among people who use opioids in Baltimore, MD, USA.

	THN Access(N = 577)		THN Administration(n = 345)
	aOR (95% CI)	P value	aOR (95% CI)	P value
Socio-Demographic Characteristics
Age (ref: 21-39years)
40–49	0.86 (0.48–1.55)	0.612	0.55 (0.28–1.07)	0.080
50–55	1.00 (0.55–1.81)	0.992	0.75 (0.36–1.54)	0.429
56+	0.70 (0.38–1.29)	0.258	0.66 (0.31–1.40)	0.276
Male	0.78 (0.50–1.19)	0.249	0.96 (0.55–1.70)	0.901
High school/GED+	1.68 (1.13–2.50)	0.010	1.37 (0.80–2.36)	0.254
Homeless	---	---	1.82 (1.08–3.07)	0.024
THN Availability
Carry THN Often/Always	---	---	3.47 (1.99–6.06)	< .001
Drug Use & Overdose History
Injected in past 12mo	---	---	2.61 (1.43–4.76)	0.002
Ever overdosed	2.68 (1.79–4.01)	<0.001	0.61 (0.33–1.12)	0.110
No. of overdoses witnessed(ref: 1–2)
3–4	---	---	2.02 (0.98–4.16)	0.057
5–9	---	---	5.18 (2.22–12.07)	< .001
10+	---	---	5.73 (2.79–11.75)	< .001
Perceived Barriers of Responding
Perception of insufficient overdose training	0.43 (0.28–0.68)	<0.001	0.56 (0.32–0.96)	0.034
Perception that Narcan recipient will become aggressive	0.55 (0.35–0.85)	0.007	0.54 (0.28–1.04)	0.064
Perception that police will threaten people at overdose scene	0.68 (0.46–1.00)	0.052	---	---
Health Services Access and Engagement
Medication-Assisted Treatment	3.87 (2.59–5.78)	<0.001	---	---

---variable not included in the model

A sensitivity analysis among the subset of participants who reported injecting drugs in the past year (n = 363) was highly consistent with findings among all participants (results not shown). However, education was no longer a significant predictor of access to THN.

Correlates of THN administration

Of the 380 participants with access to THN, 345 reported witnessing an overdose and were included in an examination of correlates of using THN. About half of these participants (49%) reported ever administering THN. Bivariate analyses (Table 1) found that THN use was higher among people who had witnessed an overdose, were younger, more frequently carried THN, experienced homelessness, recently injected drugs, witnessed more overdoses, and believed there was more fentanyl in the heroin supply. Perceptions of insufficient overdose training and that THN recipient would become aggressive were associated with not administering THN. In the multivariable model (Table 2), THN availability (i.e. often/always carrying THN) (aOR: 3.47, 95% CI: 1.99–6.06) and homelessness (aOR:1.82, 95% CI:1.08–3.07) were associated with higher odds of using THN. Both injecting in the past year (aOR:2.61, 95% CI:1.43–4.76) and witnessing more overdoses were positively associated with administering THN. Witnessing 5–9 overdoses was associated with 5.18-fold higher odds of administering THN compared to witnessing one or two (aOR:5.18, 95% CI:2.22–12.07). Administration of THN was reduced among those who felt neutral or agreed about needing further overdose training (aOR: 0.56, 95% CI:0.32–0.96). Fear that a THN recipient would become aggressive was marginally associated with reduced odds of administering THN (aOR: 0.54, 95% CI:0.28–1.04). Perceived prevalence of fentanyl was not found to be independently associated with THN administration.

A sensitivity analysis of participants who injected drugs in the past year, had access to THN, and witnessed an overdose (n = 236) yielded comparable results (results not shown) with the exception of a few differences. Perception of a high prevalence of fentanyl in heroin was associated with higher odds of administering THN (aOR: 2.33, 95% CI:1.23–4.42). Further, THN use was significantly reduced among those who reported fear that a person would be aggressive after administration of THN (aOR: 0.37, 95% CI:0.17–0.82). Additionally, among participants who injected drugs, homelessness, and perceptions of insufficient overdose response training were no longer statistically significantly associated with administering THN.

Discussion

Among a community-based sample of PWUO in Baltimore, we identified several correlates of having access to THN and using it to respond to a witnessed overdose. We found that personally experiencing an overdose and current enrollment in MAT were facilitators of accessing THN. THN access was reduced among PWUO who perceived that they had insufficient overdose response training, feared that a person would become aggressive after an overdose, and felt that police would threaten them with arrest or charges at an overdose scene. Consistently carrying THN and witnessing more overdoses were linked to use of THN. THN administration was lower among PWUO who perceived that they were insufficiently trained to respond to an overdose and feared that a THN recipient would become aggressive.

To the best of our knowledge, this is the first study to examine correlates of access to and administration of THN by PWUO in a large community-based sample. In contrast to Kenney et al. who found that people with personal overdose experience within an addiction treatment-based sample were more likely to have administered THN, personal overdose experience in this study was associated with access to THN but not with THN administration [18]. Corroborating the findings of Kenney and colleagues, our results suggest that recent injection drug use is strongly associated with administering THN [18].

The current study also identified that access to THN was significantly higher among people receiving MAT. This likely reflects engagement with the health care system as a facilitator for accessing THN. These data highlight the need to develop strategies to extend THN distribution to PWUO who are not engaged with substance use treatment services. Possible strategies could include training PWUO as peer mentors to distribute THN and provide overdose response training to their social networks. Detention facilities and social services accessed by PWUO are other key potential THN distribution points. Although drug treatment was associated with access, it was not associated with the use of THN. This lack of association may be a function of some drug treatment programs providing THN, but individuals in treatment may be less likely to witness an overdose and/or because they receive insufficient training to respond. Syringe service programs, drug treatment, and peer outreach could additionally serve as opportunities to diffuse information about the high proportion of fentanyl in heroin and associated elevated risk of overdose [24,25].

While engagement with services that provide THN influence the ability to access THN, individual factors may influence participants desire to access THN. A quarter of study participants expressed concern about overdose victims becoming aggressive after being revived with THN, which was associated with lower access to and administration of THN. An aggressive response post-revival may be the result of an overdose victim going into withdrawal or being disoriented [22,26]. The principles of trauma-informed care suggest that responders should supportively and clearly provide information about the status of the situation to the overdose victim after they have been revived [27]. THN training programs and outreach workers should provide training in de-escalation techniques and discuss the development of safety plans to further mitigate fears about responding to overdose [28]. Training programs can also emphasize the positive aspects of administering THN and reward individuals in the community who administer THN and hence save community members lives. Additionally, agitation post revival may be influenced by mode of THN administration. A randomized trial of intranasal versus intramuscular naloxone found that patients who received intramuscular naloxone exhibited higher rates of agitation (13%) compared to the intranasal naloxone group (2%) [29]. These findings may be due to the increased effectiveness of naloxone administered intramuscularly [6]. Pharmacological research is needed to determine dosing for opioid antidote medications to effectively respond to potent, fast-acting synthetic opioids while mitigating the risk of antidote-induced withdrawal [30].

The association between perceptions of police behaviors and receiving THN is important to note. In our analysis, we found perceived police threat was associated with lower access to THN among PWUO and among participants who injected drugs in the past year. Despite the passing of the Good Samaritan Law in Maryland, which protects anyone seeking medical assistance for an overdose victim from arrest and prosecution, half of PWUO perceived that police would threaten people at an overdose occurrence with charges or arrest. These data suggest that attempts to use criminal justice approaches at overdose event scenes may unintentionally lead to reduced effectiveness of programs aimed at increasing access to and use of THN for fatal overdose prevention. Police threats at an overdose event may be particularly deleterious for people who inject drugs as they may be carrying drug-related paraphernalia. However, people who inject drugs are at high risk for overdose and are likely to witness overdose events, highlighting that they are key to engage in overdose prevention initiatives by removing barriers such as fear of police threat [31].

Carrying THN was one of the strongest correlates of THN administration identified in our study. This finding suggests the value of a clear message that encourages PWUO to always carry THN. Further research should explore ways to facilitate carrying THN, such as the provision of carrying cases for THN kits. Additionally, potential barriers to carrying THN, such as drug use stigma, warrant further study [19].

Our results also highlighted a need to improve THN trainings. Half of the participants who had access to THN and who witnessed an overdose agreed or strongly agreed with the statement that they needed more training to respond to an overdose event. These findings suggest a need for trainings that focus on increasing confidence to administer THN. Additionally, booster trainings and use of diverse education strategies may be necessary to reinforce skills beyond those provided during a single training session [32].

Study findings should be interpreted in the context of a few limitations. The cross-sectional study design limits our ability to determine temporality. Thus, the association of perceived need for overdose training and receiving THN could reflect that those with access were more likely to be trained or that those who felt that they did not have sufficient training did not seek THN. Third, this study was restricted to PWUO with a history of injecting drugs. Study findings may not be generalizable to PWUO who do not inject drugs. Generalizability may also be influenced by the older age of the study population which may not be representative of findings among younger PWUO. A final limitation is our study’s definition of access to THN. Participants may have received a prescription but not have obtained THN, or they may have received THN previously but no longer have it. Future research should examine structural and individual-level factors associated with obtaining THN, among those with a prescription for THN. Additionally, an examination of how PWUO maintain a consistent supply of THN after use/loss merits further research.

The current study suggests that THN distribution programs in Baltimore have reached many individuals with a history of opioid and injection drug use, with just under half of those with access having administered THN. However, the rates of fatal overdose in Baltimore, and in many other cities, continue to rise [33-35]. Hence, there is a need for more aggressive distribution of THN beyond drug treatment settings. THN trainings should seek to increase confidence to administer THN as well as ensure responders’ safety and comfort in responding. In addition, there is a need to change norms to encourage PWUO always to carry THN as well as how police interact with overdose victims and witnesses.

This is the supporting dataset.

Narcan_Data_PlosOne_6.13.19.

(XLSX)

Click here for additional data file.

8 Aug 2019

PONE-D-19-16811

More than just access: Who obtains and who administers take-home naloxone in Baltimore, MD

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Reviewer #1: The authors of this manuscript utilized data from a randomized clinical trial conducted in Baltimore, MD to investigate factors associated with obtaining and utilizing naloxone to reverse opioid overdose. This topic is of critical importance since take-home naloxone prevents fatal opioid overdoses if administered in a timely manner. There is strong evidence indicating that the most effective means of reversing opioid overdose with naloxone is to make it available to people who use drugs and are most likely to witness overdose. The authors clearly define their study aims and propose public health interventions to address their findings. Several fairly minor clarifying questions are listed below to improve this strong manuscript.

1) A stated implication of these findings is the need for more aggressive distribution of THN beyond drug treatment settings. Understanding where people access THN in this community is an important priority, particularly for people not engaged in care, and may give insight into how to expand access. Did the study assess where THN was accessed to add to these findings?

2) On a related note, I continued to consider the definition of and use of the term THN “access” throughout the manuscript. As the title itself suggests, it’s “More than just access: it is who obtains…” This distinction between lack of access (i.e., due to structural barriers or lack of opportunity to access it) vs. not obtaining THN despite access are two different outcomes and could be differentiated more clearly throughout the manuscript. The factors associated with decreased THN “access” – the fear that a person may become aggressive, fear of police threats, and insufficient overdose training – all reflect factors that would be associated with a lower likelihood of obtaining THN rather than factors that would affect likelihood of access. The authors state the limitations of their assessment of access (i.e., “have you ever been prescribed or received a kit containing Narcan?”) and while it may not be possible to distinguish between access to THN vs. obtaining THN given how it was assessed, I would still suggest re-considering the use of the term access for clarity.

3) The study focuses on a population of people who use opioids and have a history of injecting drugs. An additional limitation that should be noted is the specification of having injected drugs and findings possibly not being generalizable to PWUO who do not inject. This could be particularly relevant to those people who use prescription opioids who as the authors note in the introduction are less likely to have someone present during an overdose.

Minor:

1) Though I feel like it is implied that the authors are referring to intranasal naloxone throughout the paper, it would be helpful to explicitly state this in the introduction. In the context of the question of participants feeling that they have insufficient training, it would also be helpful for the reader to have a brief explanation of what naloxone training entails.

2) Though this may not need to be specifically described as a limitation, as a reader I’m curious why so few network members were recruited by index participants in the clinical trial. Is there any reason to think that those people who responded to outreach and advertisement to participate in the study may not be representative of PWUO in Baltimore City?

3) Please provide justification for dichotomizing responses to the three questions related to perceived barriers to assist in the event of an overdose.

4) P. 14 – “our results suggest that recent injection drug use and having witnessed an overdose are strongly associated with administering THN” – please clarify this statement, as all individuals included in the analyses predicting administration of THN were required to have witnessed an overdose.

Reviewer #2: This is a concise, well written description of access to and use of THN naloxone among over 500 at risk individuals in Baltimore, MD. The authors find important correlates and make appropriate recommendations. It would have been interesting to see if there were any associations of actually witnessing a fatality from an overdose. The associations might have been even stronger.

The advanced age of the study population may limit generalizability to younger populations and that should be noted.

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Reviewer #1: Yes: Jessica Magidson

Reviewer #2: Yes: Josiah D. Rich, MD, MPH

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17 Sep 2019

We thank the academic editor and reviewers for their thoughtful review of our paper “More than just availability: Who has access and who administers take-home naloxone in Baltimore, MD.” We appreciate the suggestions and comments provided by reviewers and have responded to each point raised below.

EDITOR COMMENTS:

Thank you for submitting this manuscript to PlOS One for consideration. We have now received two reviewer reports - both reviewers are enthusiastic about the manuscript and the relevance of the topic for the special issue. While noting that the manuscript is well-written, they do provide some recommendations for how to strengthen the manuscript even further while acknowledging a few additional limitations (see below). I look forward to receiving a revised manuscript that addresses these requests for minor revisions.

Thank you for your review of the manuscript. As noted in the sections below, we have incorporated the suggestions of the reviewers.

REVIEWERS COMMENTS:

Reviewer #1: The authors of this manuscript utilized data from a randomized clinical trial conducted in Baltimore, MD to investigate factors associated with obtaining and utilizing naloxone to reverse opioid overdose. This topic is of critical importance since take-home naloxone prevents fatal opioid overdoses if administered in a timely manner. There is strong evidence indicating that the most effective means of reversing opioid overdose with naloxone is to make it available to people who use drugs and are most likely to witness overdose. The authors clearly define their study aims and propose public health interventions to address their findings. Several fairly minor clarifying questions are listed below to improve this strong manuscript.

1) A stated implication of these findings is the need for more aggressive distribution of THN beyond drug treatment settings. Understanding where people access THN in this community is an important priority, particularly for people not engaged in care, and may give insight into how to expand access. Did the study assess where THN was accessed to add to these findings?

We agree that understanding where people access take-home naloxone (THN) provides an important addition to this paper. The study assessed where participants received training to use Narcan, among those who stated that they had been trained to use Narcan (n=338). Study data found that participants were primarily trained through community outreach programs (36%), recovery programs (34%), and clinics (27%). The minority of participants reported being trained through detention centers (2%), through friends (1%), or other avenues (1%). These study findings are now incorporated into the results section.

2) On a related note, I continued to consider the definition of and use of the term THN “access” throughout the manuscript. As the title itself suggests, it’s “More than just access: it is who obtains…” This distinction between lack of access (i.e., due to structural barriers or lack of opportunity to access it) vs. not obtaining THN despite access are two different outcomes and could be differentiated more clearly throughout the manuscript. The factors associated with decreased THN “access” – the fear that a person may become aggressive, fear of police threats, and insufficient overdose training – all reflect factors that would be associated with a lower likelihood of obtaining THN rather than factors that would affect likelihood of access. The authors state the limitations of their assessment of access (i.e., “have you ever been prescribed or received a kit containing Narcan?”) and while it may not be possible to distinguish between access to THN vs. obtaining THN given how it was assessed, I would still suggest re-considering the use of the term access for clarity.

In this paper we have defined access to THN as having received a kit of THN and/or a prescription for THN. While there is no standard definition of access, this definition is aligned with the WHO and NIDA definitions of access (NIDA, 2018, WHO, 2014). We agree with the reviewers’ comments that there is a difference between obtaining THN versus having a prescription for THN. We have therefore revised the manuscript in several ways. First, we amended the title (“More than just availability: Who has access and who administers take-home naloxone in Baltimore, MD”), which removed the word “obtain” to clarify that we did not only examine naloxone possession. Second, we delineate that structural factors affect one’s ability to access THN and individual-level factors may affect one’s desire to access THN in the discussion. We also added a recommendation that future research focus on PWUO who have a prescription for THN and examine factors that influence obtaining THN. As well as suggest that future research examine how people who use opioids maintain a consistent supply after use/loss.

NIDA. (2018, June 8). Medications to Treat Opioid Use Disorder. Retrieved from https://www.drugabuse.gov/publications/research-reports/medications-to-treat-opioid-use-disorder on 2019, September 1

World Health Organization (WHO). Substance use: Community management of opioid overdose. 2014.

3) The study focuses on a population of people who use opioids and have a history of injecting drugs. An additional limitation that should be noted is the specification of having injected drugs and findings possibly not being generalizable to PWUO who do not inject. This could be particularly relevant to those people who use prescription opioids who as the authors note in the introduction are less likely to have someone present during an overdose.

We now include the limitation that study findings may not be generalizable to PWUO who do not inject drugs.

Minor:

1) Though I feel like it is implied that the authors are referring to intranasal naloxone throughout the paper, it would be helpful to explicitly state this in the introduction. In the context of the question of participants feeling that they have insufficient training, it would also be helpful for the reader to have a brief explanation of what naloxone training entails.

We have included a description of available formulations of THN and mentioned that the core component of all programs is to enable the effective administration of THN in the management of an opioid overdose in the introduction. In general, intranasal naloxone appears to be more frequently available but due to price injectable naloxone is still distributed.

2) Though this may not need to be specifically described as a limitation, as a reader I’m curious why so few network members were recruited by index participants in the clinical trial. Is there any reason to think that those people who responded to outreach and advertisement to participate in the study may not be representative of PWUO in Baltimore City?

The clinical trial did not require index participants to recruit a network member in hopes of boosting enrollment among those not wanting to enroll a network. The low number of network members may also be due to low remuneration for recruiting network members and the requirement that the network members have certain attributes. Network enrollment criteria included being 18 or older and did one of the following: 1) had sex with the index in the past 6 months; 2) injected drugs in the past 6 months; or 3) used drugs with client in the past 6 months. Though it is difficult to predict how networks differed from index participants or whether the PWUO in this study represented Baltimore City PWUO more generally, our recruitment at shelters may under-represent middle class PWUO or those who do not keep a primary residence in the city, but rather go between Baltimore city and county lines, which has become more common practice in the current opioid crisis.

3) Please provide justification for dichotomizing responses to the three questions related to perceived barriers to assist in the event of an overdose.

The three questions related to perceived barriers to assist at an overdose included perceptions of: insufficient training, that the THN recipient will become aggressive, and that police will threaten people at an overdose scene. These three questions were collected as categorical variables. Based on the distribution and extensive exploratory analyses, we chose to present the dichotomized results in order to enhance interpretability of study findings as the goal of this study was to inform programmatic design. Bivariate sensitivity analyses suggested that dichotomized and categorical study findings were consistent.

4) P. 14 – “our results suggest that recent injection drug use and having witnessed an overdose are strongly associated with administering THN” – please clarify this statement, as all individuals included in the analyses predicting administration of THN were required to have witnessed an overdose.

This statement has been revised to read: “Corroborating the findings of Kenney and colleagues, our results suggest that recent injection drug use is strongly associated with administering THN.”

Reviewer #2:

1) This is a concise, well written description of access to and use of THN naloxone among over 500 at risk individuals in Baltimore, MD. The authors find important correlates and make appropriate recommendations. It would have been interesting to see if there were any associations of actually witnessing a fatality from an overdose. The associations might have been even stronger.

We agree with the reviewer that it would be interesting to assess the association between witnessing an overdose fatality with THN access and use. This data however was not collected in this dataset and therefore cannot be included in the present article.

2) The advanced age of the study population may limit generalizability to younger populations and that should be noted.

We agree and now include older age of study population as a limitation to generalizability within the discussion section.

Again, we appreciate the input of the reviewers and feel that the article has been strengthened due to their contributions. Thank you for your consideration.

Submitted filename: Response to Reviewers.docx

Click here for additional data file.

21 Oct 2019

More than just availability: Who has access and who administers take-home naloxone in Baltimore, MD.

PONE-D-19-16811R1

Dear Dr. Dayton,

We are pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it complies with all outstanding technical requirements.

Within one week, you will receive an e-mail containing information on the amendments required prior to publication. When all required modifications have been addressed, you will receive a formal acceptance letter and your manuscript will proceed to our production department and be scheduled for publication.

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With kind regards,

Bronwyn Myers

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Thank you for submitting this revised manuscript to PlOS One for review. I am pleased to inform you that the reviewers are happy with the changes you have made and this manuscript is now acceptable for publication.

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

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2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

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3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

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4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

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5. Is the manuscript presented in an intelligible fashion and written in standard English?

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Reviewer #1: Yes

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6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: The strengths of this manuscript, as described in the first review, have been enhanced in response to the previous recommendations. I expect that the dissemination of this work will promote further investigation on this important topic in the research community as well as potential changes to current public health practices in response to the authors’ recommendations (e.g. increased or enhanced THN training). Of note, this reviewer appreciates the access provided to the original data. The authors have been response to prior critiques, including the following:

1) Where people access THN: The authors incorporated their data on where participants reported obtaining THN. This information enhances the reader’s understanding of access to THN in the community and where resources might be best targeted in future interventions.

2) “Access” versus “Obtaining”: Though the authors took a different approach than was recommended, this reviewer believes that the choice to focus on the access to THN and distinguish this from obtaining THN substantially strengths the manuscript. The authors added a distinction between structural factors related to access and individual-level factors that may affect a person’s desire to obtain THN. While the data reported in this manuscript do not allow investigation of the factors that influence obtaining THN, the authors identify this as an important target for further research.

3) Focus on PWID: This reviewer feels that the inclusion of a limitation indicating that findings may not be generalizable to PWUD who do not inject drugs is an important addition. Explicit mention of this limitation may prompt further investigation by other researchers into how people who use prescription opioids without injecting access/use THN.

I believe the manuscript is suitable for publication in its current form. Only two minor comments remain that may further strengthen the manuscript:

1) Different formulations of THN: This reviewer appreciates the authors’ description of the different formulations/modes of administration of THN in the introduction. My question remains as to whether mode of administration further impacts use of THN? If the authors agree yet this data is not available, the manuscript could be further strengthened by brief mention of the limitation: lack of THN formulation data that could be associated with participant use of THN and/or perception of insufficient training.

2) Dichotomized participant responses: The authors provide a description of their decision to report participant responses of perceived barriers as dichotomous. Based on their mention of sensitivity analyses, I suggest including this information in the methods section (“Perceived Barriers of Responding,” pg. 7).

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Reviewer #1: Yes: Jessica Magidson, Mary Kleinman

30 Oct 2019

PONE-D-19-16811R1

More than just availability: Who has access and who administers take-home naloxone in Baltimore, MD

Dear Dr. Dayton:

I am pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please notify them about your upcoming paper at this point, to enable them to help maximize its impact. If they will be preparing press materials for this manuscript, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

For any other questions or concerns, please email plosone@plos.org.

Thank you for submitting your work to PLOS ONE.

With kind regards,

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on behalf of

Dr. Bronwyn Myers

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PLOS ONE