. 2021 Aug;111(8):e1–e12. doi: 10.2105/AJPH.2021.306306

TABLE 2—

Summary Results of Systematic Reviews Evaluating the Use of Naloxone-Based Interventions for Overdose Rescue

Outcome	No. Unique Studies^a	Main Conclusions and Comments	Level of Evidence^b
Knowledge improvement	4 systematic reviews¹³^,¹⁵^,¹⁶^,²¹ 11 NRSI (n = 19–525) 2 RCT (n = 187–197)	Strong evidence that OEND training produces long-term knowledge improvements regarding overdose recognition, overdose risk factors, overdose response, and naloxone administration. Assessments were primarily test-based. All retrieved research provided positive results.	⋆ ⋆ ⋆
Attitudes toward naloxone	2 systematic reviews¹⁶^,²¹ 6 NRSI (n = 19–525) 2 RCT (n = 187–1598)	Moderate evidence to suggest that educational interventions improve attitudes toward naloxone use among users of opioids. In the general public, factual information and a sympathetic narrative is most effective at producing positive attitudes. Conclusions are primarily based on 2 trials.	⋆ ⋆
Management of overdose	2 systematic reviews¹³^,¹⁶ 14 NRSI (n = 19–1942) 0 RCT	OEND training may improve OEND participant’s ability to respond to overdose; however, it is unclear which educational components are most effective. Results varied considerably across included observational studies.	⋆
Likelihood of naloxone use	1 systematic review¹⁶ 10 NRSI (n = 19–385) 1 RCT (n = 187)	Moderate likelihood that two thirds of OEND participants will administer take-home naloxone in the event of a suspected opioid overdose. Conclusions are based primarily on 7 observational studies with active participant follow-up.	⋆ ⋆
Safety and efficacy	3 systematic reviews¹³^,¹⁵^,¹⁸ 21 NRSI (n = 24–2912) 0 RCT	Strong evidence bystander-administered naloxone is both highly efficacious and safe. Consistent results were found across all retrieved studies in this domain. Ethical limitations (e.g., consent) bar the conduct of RCTs.	⋆ ⋆
Optimal naloxone formulation	1 systematic review¹⁹ 4 NRSI (n = 93–609) 3 RCT (n = 100–182)	At the same dose, high-concentration intranasal naloxone is as effective as intramuscular naloxone, whereas lower-concentration formulations (2 mg/5 mL; > 0.5 mL/nostril) are less efficacious but associated with less risk of agitation. Conclusions are based on 2 medium risk of bias RCTs. Evidence was insufficient to compare other modes of naloxone administration.	⋆ ⋆
Need for hospital transport	1 systematic review¹⁹ 6 NRSI (n = 84–2241) 0 RCT	The need for secondary care (e.g., hospital transport) after successful overdose reversal is inconclusive. Primary studies were at high risk for bias and did not examine linkage to treatment programs for opioid abuse.	?
Overdose-related mortality	4 systematic reviews¹³^,¹⁶^,¹⁸^,²¹ 2 NRSI (n = NR^c to 2912) 0 RCT	Moderate evidence that OEND implementation significantly reduces overdose-related deaths in communities with high participant uptake. Evidence is primarily based on a quasi-experimental interrupted time-series analysis with low risk of bias.	⋆ ⋆
Cost-effectiveness	1 systematic review¹⁸ 2 NRSI (n = NR) 0 RCT	OEND implementation is accessible and cost-effective even under conservative circumstances (e.g., rising naloxone prices; decreased number of observed opioid overdoses). Conclusions are based on consistent results from 2 cost-effectiveness modeling studies simulated in Russia and the United States.	⋆

Note. ⋆ ⋆ ⋆ = strong evidence: high- or moderate-quality systematic reviews demonstrating consistent results from multiple randomized controlled trials; ⋆ ⋆ = moderate evidence: high- or moderate-quality systematic reviews demonstrating consistent evidence from nonintervention studies or less consistent evidence from randomized controlled trials; ⋆ = limited or contradictory evidence: mixed or inconsistent evidence from multiple low- or moderate-quality reviews; ? = limited or inconclusive evidence: inconclusive research evidence at present, but some theoretical support; NR = not relevant; NRSI = nonrandomized studies of interventions; OEND = overdose education and naloxone distribution; RCT = randomized controlled trial.

The primary studies assessing each outcome and overlap between reviews are provided in Appendix D (available as a supplement to the online version of this article at http://www.ajph.org).

Levels of evidence are based on a previously modified version of the Royal College of General Practitioners’ clinical guidelines.¹²

Approximately 3500 vials of naloxone were distributed by Chicago Recovery Alliance’s outreach workers to an unknown number of individuals.