Table 1.

Summary of included studies [20–28]

Study	Study details	Effects	ICBR/ICUR/ICER	Cost conversion and inflation ($US, years 2020 values)	Sensitivity analysis	Conclusion	Quality	Limitations
Townsend et al. [20]	Setting: USA Population: Hypothetical individuals with OUD who entered the model at 35 years Intervention: Community distribution of naloxone to community, fire/policy, and EMS Comparator: Eight strategies that encompass all combinations of low and high distribution to laypeople, police and fire, and EMS Model: decision-analytic Time horizon of cost: Lifetime	Intervention reduced overdose deaths	ICUR: $US12,880–15,950/QALY	ICUR: 13,568–16,907/QALY	Considered: - Price of naloxone - Rates of distribution - Percentage of people who intervene in overdose - Hypothetical moral hazard Rate of distribution made the largest impact; did not change conclusion	Naloxone distribution is a good investment and worthwhile, assuming < $US2200 per kit	High	Did not report: - Justification for form of economic evaluation - Quantities of resources
Langham et al. [21]	Setting: UK Population: Adults (≥ 22 years) at risk of heroin overdose Intervention: Community distribution of naloxone for lay administration Comparator: No distribution Model: Markov model with an integrated decision tree Time horizon of cost: Lifetime (default value set to 64 years)	Intervention increased overdoses by 2.7%, reduced overdose deaths by 6.6%, and increased lifetime QALYs by 0.164	ICUR: £899.00/QALY	ICUR: 1312/QALY	Considered: - Price of naloxone - Additional societal costs - Rates of distribution - Witness to overdose No substantive impact; did not change conclusion	Naloxone distribution is worthwhile, assuming a $US20,000 WTP threshold	High	Did not report: - Rationale for comparison intervention - Justification for form of economic evaluation - Quantities of resources - Justification for variables chosen for sensitivity analysis
Cipriano and Zaric [22]	Setting: Toronto, Canada Population: high-school students Intervention: community distribution of naloxone in Toronto District School Board high schools Comparator: other treatment and harm-reduction plans in Toronto (status quo) Model: decision-analytic model Time horizon of cost: Lifetime	Intervention reduced overdose deaths by 40%	ICUR: < CAN$50,000/QALY if 2.7 overdoses/year	ICUR: < 36,525/QALY if 2.7 overdoses/year	Considered: - No. of overdoses per year - Intensity of substance use disorder - Mortality rate Number of overdoses per year had the largest impact	Naloxone distribution is worthwhile, assuming the frequency of overdose is more than 2.7 overdoses per year	High	Did not report: - Details of statistical test - Justification for form of economic evaluation - Rationale for comparison intervention
Uyei et al. [23]	Setting: Connecticut, USA Population: HIV-negative people who inject drugs and were not on PrEP Intervention: Community distribution of naloxone for lay administration Comparator: No additional intervention, naloxone distribution plus linkage to addiction treatment, naloxone distribution plus PrEP, naloxone distribution plus linkage to addiction treatment and PrEP Model: Decision-analytic Markov Time horizon of cost: 20 years	Intervention reduced overdose deaths by 6% but increased HIV deaths	ICUR: $US323/QALY	ICUR: 352/QALY	Considered: - Price of naloxone - Survival rates - Percentage of people who intervene in overdose No substantial impact; did not change conclusion	Naloxone distribution is worthwhile, recommend funding	High	Did not report: - Justification for form of economic evaluation - Quantities of resources
Coffin and Sullivan [24]	Setting: USA Population: Hypothetical 21-year-old novice US heroin users and more experienced users Intervention: Community distribution of naloxone for lay administration to those at high risk of opioid overdose Comparator: No distribution Model: Integrated Markov and decision analytic Time horizon of cost: Lifetime	Intervention prevented 6.5% of overdose deaths	ICUR: $US14,000/QALY	ICUR: 15,784/QALY	Considered: - Price of naloxone - Rate of bystander response - Justice system rates Bystander response rate made largest impact on ICER; did not change conclusion	Naloxone distribution is worthwhile; recommend funding	High	Did not report: - Study viewpoints - Rationale for comparison intervention - Justification for form of economic evaluation - Quantities of resources - Justification of discount rate
Coffin and Sullivan [25]	Setting: Russia Population: Heroin users, starting at the age of 18 years Intervention: Community distribution of naloxone for lay administration to those at high risk of opioid overdose Comparator: No distribution Model: Integrated Markov and decision analytic Time horizon of cost: Lifetime	Intervention reduced overdose deaths by 13.4% in the first 5 years and 7.6% over a lifetime	ICUR: $US94/QALY	ICUR: 112/QALY	Considered: - Price of naloxone - Rate of bystander response - Justice system rates Bystander response rate made largest impact on ICER; did not change conclusion	Naloxone distribution is worthwhile; recommend funding	High	Did not report: - Study viewpoints - Rationale for comparison intervention - Justification for form of economic evaluation - Quantities of resources
Acharya et al. [26]	Setting: USA Population: high-risk prescription opioid users Intervention: naloxone distribution to all high-risk prescription opioid users either one time or biannually Comparator: baseline naloxone distribution strategy based on existing naloxone dispensing rates Model: Markov model with monthly cycle length and attached decision tree Time horizon of cost: Lifetime	Intervention modestly reduced overdose deaths	ICUR: $US56,699–76,929/QALY	ICUR: 58,400–79,237/ QALY	Considered: - Price of naloxone - Naloxone effectiveness - Proportion of overdoses witnessed - Probability of EMS intervention - Overdose survival rates Naloxone effectiveness and proportion of overdoses witnessed had the largest impact on biannual distribution; did not change conclusion	Naloxone distribution is worthwhile, assuming a $US100,000 WTP threshold	Moderate	Did not report: - Study viewpoints - Rationale for comparison intervention - Justification for form of economic evaluation, - Quantities of resources
Bird et al. [27]	Setting: Scotland Population: Those at highest risk of opioid-related death, who might be expected to benefit the most from the national naloxone program Intervention: Community distribution of naloxone to individuals at risk of opioid overdose, following prison release Comparator: Same group, prior to intervention Model: NA Time horizon of cost: NA	Intervention prevented 42 overdose deaths (3.5% decrease)	ICUR: £560–16,900/QALY	ICUR: 769–23,209/ QALY	Considered: - Averted overdose numbers No substantive impact; did not change conclusion	Naloxone distribution is worthwhile; recommend continued funding	Moderate	Did not report: - Economic importance of the research question - Justification for form of economic evaluation - Price adjustment for inflation or currency conversion - Time horizon of costs and benefits - Justification of the discount rate - Incremental analysis - Approach to sensitivity analysis - Justification for variables chosen for sensitivity analysis
Naumann et al. [28]	Setting: North Carolina, USA Population: Counties with at least five opioid overdose deaths each year in the period immediately preceding implementation Intervention: Community distribution of naloxone for lay administration Comparator: No distribution Model: Trial based Time horizon of cost: NA	Intervention prevented 352 overdoses over 3 years	ICBR: $US2742 benefit/ dollar spent ICER: $US1605/death avoided	ICBR: 2769 benefit/ dollar spent ICER: 1621/death avoided	Considered: - Price of naloxone No substantive impact; did not change conclusion	Naloxone is cost effective; recommend funding	Low	Did not report: - Justification of comparison intervention - Justification for form of economic evaluation - Details of synthesis of estimates - Price adjustment for inflation or currency conversion - Model details - Time horizon of costs and benefits - Discount rate - Approach to sensitivity analysis

EMS emergency medical services, ICBR incremental cost-benefit ratio , ICER incremental cost-effectiveness ratio , ICUR incremental cost-utility ratio , NA not available, OUD opioid use disorder, PrEP pre-exposure prophylaxis, QALY quality-adjusted life-year, WTP willingness to pay