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Three Part Question

In [Emergency Department (ED) patients presenting with opiate overdose], is [the distribution of Take-Home Naloxone (THN)] effective in [reducing opioid related deaths]?

Clinical Scenario

A 31-year-old woman presents at the Emergency Department by ambulance following a heroin overdose. She requires naloxone for opioid-reversal. She has made a full recovery and is ready for discharge.

Search Strategy

Medline 1966-31/8/21 using PubMed interface.

[Opioid overdose] AND [Take home naloxone] AND [emergency department]

Search Outcome

62 papers were found in Medline of which 53 were irrelevant and a further 1 of insufficient quality. A further 5 relevant papers were found by scanning the references of relevant papers.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Katzman J, et al 2020 United States	395 participants >18 years enrolled at an Addiction and Substance Abuse Opioid Treatment Program, with a positive history of opioid use disorder treated with opioid replacement.	Retrospective cohort study (2b)	To measure the association of take-home naloxone with overdose reversals performed by patients with opioid use disorder within enrolled in an opioid treatment program.	18% of participants performed 14 OD reversals in the community using take home naloxone	• All participants were already receiving opioid replacement • Data collected in outpatient setting rather than the Emergency Department • No comparison with patients not receiving take-home naloxone as this was not deemed ethical
Samuels E, et al 2018 United States	151 participants: ED patients discharged after non-fatal opioid overdose in the six months after implementation of an ED naloxone distribution and recovery coach consultation program	Observational retrospective cohort study (2b)	To measure the effect of THN and recovery coach consultation program on initiation of medication for opioid use disorder, repeat ED visits for opioid overdose, and all-cause mortality.	All-cause mortality was 6.7% (95%CI 2.5, 16.7) for patients receiving usual care after opioid overdose and 3.8 [0.5,23.8] for patients receiving THN. No statistically significant difference.	• Number of participants did not reach desired effect size • Selection bias may have impacted participant treatment group assignment (was determined by provider and patient discretion)
Chen Y, et al 2020 Australia	Using PRISMA guidelines, four databases (Medline; Embase; Scopus; PsycINFO) were searched for peer reviewed articles on ED based interventions to prevent opioid overdose	Systematic review based on observational cohort studies and RCTs (2a)	To examine the feasibility of ED-based delivery of opioid overdose prevention interventions	7/13 studies focused on provision of take-home naloxone and overdose education describing the successful delivery of THN by ED staff and barriers to delivery	• Examined feasibility of providing THN in an ED setting rather than the effectiveness of THN in reducing opioid overdose deaths
Gunn A 2018 United States	Using PRISMA guidelines, six databases were searched for peer-reviewed journals using a combination of ED and naloxone terminology	Systematic review based on observational cohort studies and RCTs (2a)	To review the literature relating to THN and ED, in order to assess whether ED is a potential setting for THN distribution.To review the literature relating to THN and ED, in order to assess whether ED is a potential setting for THN distribution.	Available evidence is limited. ED distribution of THN has the potential for harm reduction, but barriers include burden on workflow and physician resistance.	• Poor follow-up in many studies due to the social and economic factors of patient population • Small sample size- highlights need for future research • Meta-analysis not possible due to heterogeneity of interventions and analysis.
Dwyer et al 2015 United States	359 patients who had received overdose education (n=359) or overdose education plus intranasal THN (N=59) in the Emergency Department	Observational retrospective cohort study (2b)	To evaluate the feasibility of an ED-based overdose prevention program	No significant differences in behaviour in a witnessed overdose between the overdose education (OE) + THN and OE-only groups. In the OE+ THN group, 16% (6/37) reported using their kit to successfully reverse a witnessed overdose	• Only a small percentage of study members were given naloxone as an intervention • Follow up was poor via telephone consultation • Some of the OE group received THN from other sources (other than ED)
Banta-Green C, et al 2019 United States	219 patients abusing opiates were identified by reviewing electronic medical records	Randomised control trial (low quality- <80% follow up) (2b)	Primary outcome to identify time to first opioid overdose-related event resulting in medical attention or death, using competing risks survival analysis	No significant difference in overdose events between intervention (behavioural intervention + THN) and comparison group (sub-hazard ratio: 0.83; 95%CI 0.49-1.40)	• Null findings may be related to poor housing security, drug use, unemployment and acute health care issues. • Limited by sample size and challenge of study recruitment
Bird S, et al 2016 United Kingdom	Data from the National Records of Scotland, including all opioid-related deaths in people who had been either released from prison or discharged from hospital in the 4 weeks previously, comparing 2006-10 with 2011-13.	Observational retrospective cohort study (2b)	The study measured the effectiveness of take-home naloxone in reducing number of opioid-related deaths. Cost effectiveness was assessed by prescription costs against life-years gained per opioid-related death everted.	2006-10 19% of Scotland’s opioid-related deaths had been released from prison or discharged from hospital in 4 weeks prior vs only 14.9% in 2011-13 (p=0.003).	• This study has a main focus on recent inmates and not necessarily applicable to the general population • There is no specification as to whether naloxone kits were distributed in ED or community
Kaucher K, et al 2018 United States	106 patients presenting with opioid overdose were followed up by phone >30 days after initial ED visit	Case series study (4)	Evaluating number of THN kits used, enrolment in opioid-replacement for opioid dependence and return visits to ED for overdose	26% (n = 27) self-reported an opiate overdose, after receiving their THN, which required an ED visit (median = 1 overdose [range 1–4]).	• Inability to compare with patients who did not receive take-home naloxone • Risk of selection bias of patients receiving THN • Focuses on repeat ED visits as outcome rather than opioid-overdose deaths.
Mcdonald R and Strang J 2016 United Kingdom	PubMed, MEDLINE and psych INFO were searched for peer review publications (randomized or observational). No relevant randomized studies available.	Systematic review based on observational cohort studies (2a)	To study the association between THN provision and the number of naloxone administrations, overdose reversals and adverse events.	2249 successful overdose reversals [96.3%; 95%CI=95.5, 97.1], among 2336 THN administrations. This indicates a strong association between THN programmes and overdose survival.	• Review is not specific to the ED environment- review concludes that THN distribution to ‘at-risk users’ should be introduced for community-based prevention • Possible selection bias- 50% of studies relied on spontaneous follow-up with THN programme i.e. participants being asked to report back on naloxone usage when collecting a naloxone refill
Public Health Wales 2020 United Kingdom	Annual report 2019/2020 of drug related mortality in Wales	Outcomes research (2c)	Report measuring prevalence of THN use and number of opioid-related deaths in Wales 2013-20.	THN used in 2855 opioid drug poisoning events since April 2013. Fatal opioid poisoning was reported in 1.3% (n=37) of events where THN was used.	• Report not specific to ED environment • 15% records in 2019/2020 have no recorded outcome of opioid overdoses
Walley AY, Xuan Z, Hackman HH, et al. 2013 United States	Data from the 19 communities within Massachusetts with >4 opioid-related fatal poisonings from each year from 2004-6.	Observational cohort study (2b)	To evaluate impact of overdose education and nasal naloxone distribution on mortality from opiate overdoses in Massachusetts.	OEND programs trained 2912 people who reported 327 rescues. Community-year strata with 1-100 enrolments per 100000 population (adjusted ratio 0.73, 95%CI =0.57-0.91). Significantly reduced adjusted rate ratios compared to communities with no implementation of THN programs	• Community setting rather than ED • True population of opioid users in each community was not known • Opioid overdose fatalities may have been mis-clarified • Overdoses were likely under-reported as description of overdose rescue events were limited to those reported back to the program
Langham S, et al 2018 United Kingdom	Markov model (based on Coffin and Sullivan model) used to evaluate cost-effectiveness of intramuscular naloxone, with the expectation that it reaches 30% of UK heroin users	Analysis based on clinically sensible costs or alternatives with limited reviews of the evidence (2b)	To assess the cost effectiveness of distributing THN kits to adults at risk of opioid overdose, compared to no naloxone distribution	The model predicts that distribution of IM naloxone decreases overdose deaths by 6.6%. This would prevent 2500 deaths in a population of 200000 heroin users with a cost effective QALY of £899.	• Not specific to an ED environment • Only focusing on IM naloxone and not intranasal naloxone • Model uses data based on non-RCT studies.
Papp J, et al 2019 United States	18-89 years with a diagnosis of heroin overdose treated in the ED	Retrospective cohort study (2b)	To measure repeat opioid overdose-elated ED visits, hospitalisation and death at 0-3 months and 3-6 months following opioid overdose	No difference in mortality at 3 or 6 months was detected, p=0.15 and 0.36 respectively	• Number of participants did not reach desired effect size • Overall mortality from heroin overdose increased during study period due to more lethal street-drugs made available • Participants may have obtained naloxone kit outside county in which the study took place

Comment(s)

The studies are not of the best quality. The majority of available studies on this topic are retrospective cohort studies rather than randomised control trials, likely due to difficulty in gaining ethical approval. Sample sizes are often too small to produce statistically significant results, largely attributable to poor follow up in a high-risk target population. Estimating overdose mortality relating to THN distribution is further complicated by the following factors. Firstly, the majority of evidence currently available is based on the United States healthcare system and may not be generalizable to the British system. In addition, results may be confounded by a concurrent education programme, which is often delivered at the point of dispensing THN to opiate-users. The kits are also usually used on, or by, an individual other than the receiver of the prescription. If we were to remove ‘ED’ from the search criteria, there is greater evidence available to suggest the benefit of dispensing THN kits within the local community. Thus, a reasonable alternative is for ED staff to liaise with, and signposting to, local drug and housing services, rather than providing THN directly from the emergency department. This encourages ongoing access to support and education for opioid-users in the community after discharge.

Clinical Bottom Line

There is no current statistically significant evidence to demonstrate that take home-naloxone prescribed by the Emergency Department reduces overdose deaths. Instead, a focus on encouraging access to take-home naloxone in the local community may be more beneficial.

References

1. Katzman JG, et al Association of take-home naloxone and opioid overdose reversals performed by patients in an opioid treatment program JAMA Netw Open 2020; 2(2):e200117
2. Samuels EA, et al Peer navigation and take-home naloxone for opioid overdose emergency department patients: Preliminary patient outcomes J Subst Abuse Treat 2018; 94: 29-34
3. Chen Y, et al A systematic review of opioid overdose interventions delivered within emergency departments Drug Alcohol Depend 2020; 213:108009
4. Gunn AH, et al. The emergency department as an opportunity for naloxone distribution West J Emerg Med 19(6)1036-1042
5. Dwyer K, et al Opioid education and nasal naloxone rescue kits in the emergency department West J Emerg Med 2015; 16(3): 381-4
6. Banta-Green CJ, et al Impacts of an opioid overdose prevention intervention delivered subsequent to acute care Inj Prev 2019; 25(3):191-198
7. Bird S, et al Effectiveness of Scotland’s National Naloxone Programme for reducing opioid-related deaths: a before (2006-10) versus after (2011-13) comparison Addiction 2016; 111(5):883-91
8. Kaucher K, et al Emergency department naloxone rescue kits dispensing and patient follow-up Am J Emerg Med 2018; 36(8):1503-1504
9. Mcdonald R and Strang J Are take-home naloxone programmes effective? Systematic review utilizing application of the Bradford Hill criteria Addiction 2016; 111(7):1177-87
10. Public Health Wales Harm Reduction Database Wales: Drug related mortality Substance Misuse programme 2021
11. Walley AY, Xuan Z, Hackman HH, et al Opioid overdose rates and imple- mentation of overdose education and nasal naloxone distribution in Massachusetts: interrupted time series analysis BMJ (Clinical research ed 2013; 346:f174
12. Langham S, et al Cost-Effectiveness of Take-Home Naloxone for the Prevention of Overdose Fatalities among Heroin Users in the United Kingdom Value Health 2018; 21(4):407-415
13. Papp J et al Take-home naloxone rescue kits following heroin overdose in the emergency department to present opioid overdose-related repeat emergency department visits, hospitalisation and death BMC Heath Serv Res 2019; 19(1):957