Cost per Opioid-Free Year: A Systematic Review and Summary Analysis

Abstract

Objective

Opioids remain a leading cause of death in the U.S., and time-free from opioid use is a common measure of effectiveness in economic evaluations of opioid use disorder (OUD) interventions. This study reviews the economic evaluation literature on OUD, identify studies that calculated incremental cost-effectiveness ratios (ICER) based on time-free from opioids, and establishes a benchmark for comparison in future research.

Methods

The review examined economic evaluations of OUD interventions published in the peer-reviewed literature from inception to September 2024. ICERs of cost per period of opioid-free time were extracted or calculated from studies meeting the inclusion criteria. Monetary values were converted to 2024 USD, and ICERs normalized to cost per opioid-free year (OfY). Articles were classified by intervention location (U.S vs. International) and economic perspective.

Results

Fourteen articles met the inclusion criteria: 8 from the U.S., 4 from Australia, 1 from Malaysia, and 1 from the United Kingdom. Among the U.S.-based studies, the average ICER per OfY for the healthcare sector, the state policymaker, and the societal perspective were $243,053/OfY, $17,674/OfY, and $32,125/OfY, respectively. For international studies, average ICERs for the healthcare sector and societal perspectives were $79,765/OfY and $195,980/OfY.

Conclusion

Cost per OfY is a widely used metric in economic evaluations due to its relative importance as a measure of clinical effectiveness. However, a universally accepted benchmark for decision-making does not yet exist. This review aggregates data from existing studies that provided this measure, offering an initial step for establishing a cost-effectiveness threshold for cost per OfY.

Precis:

This systematic review serves as an initial step toward establishing a cost-effectiveness threshold for an opioid-free year, enabling comparisons across studies using this outcome.

Introduction

Opioids contributed to more than 81,000 overdose deaths in 2023.¹ The opioid crisis led to premature mortality, increased use of high-cost healthcare services (such as inpatient and emergency care), greater reliance on criminal-legal resources, and reduced workplace productivity, which have driven the annual economic burden of opioid use disorder (OUD) in the U.S. to exceed $900 billion [2024 USD]. As a result, the estimated present value of preventing a single OUD case exceeds $2 million.² Evidence-based treatment for OUD, particularly medications like methadone, buprenorphine, and extended-release naltrexone (collectively known as medication for OUD or MOUD), are available, yet significant barriers to both treatment initiation and retention persist.^3,4 Addressing these barriers is crucial for both public health and economic well-being.

However, while effectiveness is key, it should not be the only factor considered, especially when multiple treatment alternatives compete for limited resources. Economic evaluations provide a structured approach to helping stakeholders, such as treatment providers and policymakers, make informed decisions on how to allocate limited resources in ways that maximize the well-being of their target populations.⁵ Cost-effectiveness and cost-benefit analysis (CEA and CBA, respectively) are the two primary economic evaluation methods.

CEA estimates the additional cost (Δ_c) a stakeholder would incur per unit of effectiveness gained (Δ_e), on average, by pursuing one intervention relative to the other, resulting in what is known as an incremental cost-effectiveness ratio (ICER, λ = Δ_c/Δ_e).^6,7 This ICER is then compared against stakeholder-specific value thresholds (ω) to assess the probability or likelihood that the ICER is less than or equal to the maximum cost per unit of effectiveness the stakeholder is willing to pay for the intervention (i.e., Pr(λ ≤ ω)). Alternatively, the effectiveness measure can be monetized using an established threshold value (that is, ω = w), thereby allowing for a CBA. The statistical outcome measure of interest in a CBA is known as the incremental net monetary benefit (INMB, η(w) = w Δ_e−Δ_c). A positive INMB at a given w for the intervention, relative to the alternative (η(w) ≥ 0), indicates that the stakeholders will expect to gain positive economic value by pursuing.

The most recommended and utilized effectiveness measure in economic evaluations is the quality-adjusted life-year (QALY), which is a combined measure of mortality and morbidity.^6,7 The rationale for its widespread use is largely a function of generalizability, as it can theoretically be used to assess the economic value of interventions across various diseases/disorders and populations, including MOUD.⁸ Additionally, the QALY offers established value thresholds for assessing cost-effectiveness. In the U.S., for instance, an intervention is generally considered cost-effective if the cost per additional QALY gained falls within the range of $100,000 to $200,000.⁹

Clinical effectiveness measures, although widely used in economic evaluations due to their relevance to the intervention of interest, and their relatively straightforward interpretation, are limited to narrow clinical areas and lack agreed-upon value thresholds for which to assess economic value (i.e., Pr(λ ≤ ω) or η(w) ≥ 0). Common clinical effectiveness measures for substance use disorder interventions include time free from the use of the targeted substance, measure of functioning (e.g., addiction severity indices),¹⁰ and various metrics that quantify substance use disorder treatment (e.g., treatment initiation, continuation, and retention).¹¹ Among these measures, time free of substance use offers a standardized and generalizable solution that overcomes the challenges posed by the heterogeneity of treatment modalities in comparative-effectiveness studies. Moreover, it is sensitive to reductions in the frequency of use, making it a valuable metric regardless of whether sustainment is fully achieved. This study uses “opioid-free year” (OfY) as the measure of effectiveness instead of the QALY to broaden the assessment of the relative economic value of OUD intervention by establishing a benchmark for OfY. More specifically, OfY is not proposed as a replacement for QALYs but as a complementary metric that directly reflects one of the clinical priorities in OUD treatment—namely, reductions in opioid use.

The objective of this study was to review the literature of economic evaluations conducted alongside OUD interventions to identify all studies that estimated an ICER of cost per some unit of time free from opioid use, adjust all monetary values for inflation, and annualize the ICERs to create a cost-per OfY. The outcome is a range of ICER values that allow for the comparison of economic evaluations incorporating time-free from opioids as a measure of effectiveness, thereby providing valuable information for decision-makers.

Methods

Inclusion Criteria

The inclusion criteria used in this systematic literature review reflect those from the comprehensive set of existing systematic reviews of economic evaluations of OUD interventions beginning with Doran et al.,¹² followed by two from our team,^13,14 with the additional criterion that studies reported the information needed to calculate an ICER with a denominator of time free from opioid use. Those three systematic reviews summarized the peer-reviewed literature from inception to December 2019. We then extended the search to cover the period from December 2019 through September 2024. Similar to the 3 prior systematic reviews, we searched PubMed/Medline, Embase, Cochrane Library Central, and PsycINFO using the following criteria: ((cost-effectiveness[Title]) AND (opioid[Title])) AND ((“2020/01/01”[Date - Publication]: “2024/09/01”[Date - Publication])). A similar methodology was used to search the Tuft’s Cost-effectiveness registry.¹⁵ We prioritized those databases due to their comprehensive coverage of clinical and public health research particularly in the areas of substance use and addiction.^16,17

Data Extraction

The following data were extracted from each study: stakeholder perspective; year of currency; total sample size; intervention; comparator; cost and effectiveness measures; length of intervention and follow-up periods; study conclusions; and country of study origin.

Calculation of Cost per Opioid-free Year (OfY)

OfY is the proportion of the year during which an individual is opioid-free. ICERs of cost per opioid-free time were either extracted or calculated from each study that met the inclusion criteria. Where possible, this information was gathered for both the intervention period, and the entire study observation period (i.e., intervention + follow-up). Next, all monetary values were adjusted for inflation to 2024 USD, using the Consumer Price Index.¹⁸ Non-U.S. currency was converted to U.S. dollars (USD) using historic currency exchange rates, prior to being adjusted for inflation. All ICERs were then normalized such that the value represented the additional cost required to obtain a year free from opioid use (i.e., a cost-per-OfY). ICERs that indicated a strongly-dominated strategy from an economic standpoint (i.e., a strategy that was more expensive, but less effective than the alternative were not reported, in accordance with best practices.^6,7 The concept of cost-effectiveness, and the importance of understanding willingness-to-pay for a unit improvement in an effectiveness measure, does not apply in scenarios involving an economically-dominated strategy, as such findings indicate that the dominant strategy should always be chosen since it both saves money and improves health relative to the alternative.

Analytical summary

Articles were categorized according to: location (US, international); stakeholder perspective (societal, healthcare-sector, state-policymaker); and time-period covered (intervention, intervention + follow-up). Descriptive statistics were provided based on stakeholder perspectives and observation periods. Likewise, international studies were grouped by stakeholder perspectives, and descriptive statistics were computed for the ICERs.

Results

We identified 336 peer-reviewed articles for screening, of which 314 were excluded due to insufficient reporting of cost or opioid use data, thereby preventing the calculation of an OfY ICER (Figure 1). Of the 22 remaining articles, 6 were excluded due to one of the alternative strategies exhibiting economic dominance. An additional 2 were excluded for the following reasons: (i) one article reported time free from opioids+cocaine, as opposed to opioids only; and (ii) another article used stimulants and alcohol as effectiveness measures instead of opioids. In total, 14 articles met the inclusion criteria and were included in this review. U.S. and international study characteristics are presented in Tables 1 and 2, respectively. Findings are presented in 2024 USD, except for those in Tables 1 and 2, which reflect the original monetary values.

Figure 1:

Article review process

Table 1:

Characteristics of Cost per Opioid-Free Time – US Studies

Characteristics of Cost per Abstinent Time
Study	Participants	Study Design	Intervention	Comparator	Perspectives	Intervention Period length (weeks)	Follow-Up Period length (weeks)	Study Outcomes	Findings
Masson et al. (2004)	179 adults with OUD	Randomized controlled study	Methadone Maintenance Treatment (MMT)	180-day methadone detoxification (M180-day)	Healthcare sector	26	26	Intervention Period Costs: MMT = $7,564, M180-day = $6,696 Days of Opioid use in prior 30 days: MMT = 6.91, M180-days = 7.17 Follow-up Period Costs: MMT = $3,311, M180-day = $2,919 Days of Opioid use in prior 30 days: MMT = 6.70, M180-days = 13.95	MMT is cost effective than M180-day detoxification
Barnett et al. (2010)	255 individuals entering opioid substitution treatment	Multi-site opiate substitution treatment programs	Programs highly concordant with clinical practice guidelines	Programs Less concordant with clinical practice guidelines	Healthcare sector	52	N/A	Effect: Highly concordant sites- 334.2 opiate-free days Less concordant sites- 304.2 opiate-free days. ICER = $126 per opiate-free day	Highly concordant programs were more expensive and effective compared to less concordant
Dunlap et al. (2018)	300 newly admitted methadone patients	Randomized clinical trial	Patient-centered methadone (PCM)	Methadone treatment-as-usual (TAU)	Healthcare sector	52	N/A	Self-reported abstinence from heroin: $242/Opioid-free day	>50% chance of PCM being cost-effective from the healthcare sector perspective assuming a WTP of $1150/opioid-free day
Polsky et al. (2010)	152 patients aged 15 to 21 years old with OUD	Multisite randomized trial	Extended buprenorphine-naloxone (BUP)	Buprenorphine-naloxone detoxification (DETOX)	Healthcare sector	12	52	Intervention period: Direct medical cost / Opioid-Free year = $12,847 Study cost / Opioid-Free year = $23,602 Follow-up period: Direct Medical Cost / Opioid-Free year = $308 Study cost / Opioid-Free year = $5,610	The ICER has an 86% chance of being accepted as cost-effective for a threshold of $100,000 per QALY.
King et al. (2016)	Hypothetical cohort of 1000 OUD patients	Markov cost-effectiveness model	Office-based buprenorphine	Clinic-based methadone	Healthcare sector	52	N/A	Effect (days free of Opioid use per year): MMT = 9.16, BMT = $9.10 Cost: MMT = $4,613; BMT = $4,155	Compared to BMT, MMT is considered the most cost-effective treatment for patients with opioid dependence
Murphy et al. (2017)	308 criminal justice-involved US adults with a history of opioid use disorder	Multi-site open-label randomized-controlled effectiveness study	Extended-release naltrexone	Treatment-as-usual (TAU)	Societal	25	78	Intervention Period Costs: XR-NTX = $5,655; TAU = $2,412 Abstinent years: XR-NTX = 0.87, TAU = 0.74 Follow-up Period Costs: XR-NTX = $8,390; TAU = $6,098 Abstinent years: XR-NTX = 0.85, TAU = 0.76	At 25 weeks, the cost effectiveness probabilities are 10% at $100,000/QALY, 62% at $200,000/QALY; 95% at $90,000/abstinent year At 78 weeks, the cost effectiveness probabilities are 59% at $100,000/QALY, 76% at $200,000/QALY; 95% at $500/abstinent year
Jalali et al. (2022)	86 incarcerated participants with a history of OUD	Randomized controlled effectiveness study	Extended-release injectable naltrexone before release	Extended-release injectable naltrexone after release	Healthcare sector, State Policymaker and Societal	24	N/A	12 weeks assessment: Healthcare sector perspective - ICER = $7,295; State policymaker perspective - ICER = $7,701; Societal perspective - ICER = $5,122 24 weeks assessment: Healthcare sector perspective - ICER = $20,293; State policymaker perspective - ICER = $21,149; Societal perspective - ICER = $23,681	Across all perspectives, there is a 95% chance of XR-NTX before release being cost-effective, assuming a WTP of >$49,000/OfY
Jackson et al. (2015)	Adult males ages 18–65 in the United States initiating pharmacotherapy for OUD	Markov model	Extended-release naltrexone (XR-NTX)	(1) MMT; or (2) BMT	Healthcare sector	26	N/A	Cost-effectiveness of XR-NTX relative to MMT is $72 per opioid-free day	XR-NTX is cost-effective at a willingness to pay of $72 per opioid-free day

Table 2:

Characteristics of Cost per Opioid-Free Time – International Studies

Characteristics of Cost per Abstinent Time
Study	Participants	Study Design	Intervention	Comparator	Perspectives	Intervention Period length (weeks)	Follow-Up Period length (weeks)	Study Outcomes	Findings
Warren et al. (2006)	Prisoners in the New South Wales prison methadone program.	Randomized controlled trial	prison-based MMT	No prison-based MMT	Healthcare sector	16	N/A	ICER = $38/Opioid-free day	Prison methadone program is no more costly than a community methadone program and provides benefits in terms of reduced heroin use in prisons.
Harris et al. (2005)	139 patients with OUD which includes patients enrolled in addiction treatment and initial treatment seekers	Randomized, open-label trial	BMT	MMT	Societal	52	N/A	ICER = $13/heroin free day (Initial therapy group excluding crime costs)	No significant differences in costs or outcomes between MMT and BMT
Doran et al. (2006)	551 participants with heroin use disorder aged 18 years or over	double-blind, placebo-controlled trial	BMT and levo-α-acetyl-methadol (LAAM)	MMT	Healthcare sector	13	N/A	ICER of BMT compared to MMT = $337.22/Opioid-free day	Potential introduction of BMT and LAAM in Australia provides patients with wider treatment choices and thus greater potential to recruit a larger proportion of regular dependent users and retain them in treatment for longer
Moore et al. (2007)	AUS citizens who have used heroin and are participating in one of three treatment programs	Econ analysis of a non-randomized prospective treatment outcome study	Pharmacotherapy maintenance (BMT or MMT)	(1) Residential rehabilitation; or (2) prison	Societal	52	26, 52, 104, 260, 416	Assuming no post intervention effect, ICER for BMT or MMT = AUD $11,188 per abstinent year; ICER for residential rehabilitation = AUD $53,827; ICER for prison = AUD $73,840	BMT/MMT produced the lowest cost-per-abstinent-year ratio
Ruger et al. (2012)	126 patients in Malaysia seeking treatment for heroin use disorder	randomized, double-blind, placebo-controlled clinical trial	BMT & Naltrexone (NTX)	Placebo	Societal	26	N/A	ICER = $15.96/day (Naltrexone vs placebo); $41.12/day (BMT vs NTX); $28.18/day (BMT vs Placebo)	BMT generated cost-effectiveness ratios below $50 (in 2004 USD) for the primary outcomes and below $350 for the secondary outcomes
Marsden et al. (2023)	314 participants in England and Scotland seeking treatment for OUD	Pragmatic, parallel-group, open-label, superiority randomized controlled trial	BUP-XR	Standard-of-care (SOC)	Societal	24	N/A	Effect: SOC = 104.37 opioid free days, BUP-XR = 123.43 opioid free days Incremental Cost: £1,033 (BUP-XR) ICER = £54.2/day	Compared to SOC, BUP-XR is considered the most cost-effective treatment for patients with OUD

Methadone

Masson et al.¹⁹ conducted a CEA within a clinical trial framework, involving 179 participants, from a healthcare-sector perspective, considering treatment, labor, and healthcare utilization costs. The study compared methadone maintenance treatment for OUD to methadone detoxification services; both were supplemented with psychosocial services. The trial included a 180-day intervention period, and a 180-day follow-up. Participants seeking treatment for OUD (n=179) were randomized 1:1 to either methadone treatment, which included 1 hour per week of psychosocial therapy, or methadone detoxification, which required 3 hours per week of psychosocial therapy, with 14 education sessions during the first 180 days. Data on participants’ opioid use over the previous 30 days were collected at both 180- and 360-days post-baseline. The reported ICERs for the intervention and follow-up periods were $3,512 and $104 per opioid-free day, respectively, or $1,281,880/OfY and $37,960/OfY (Table 3).

Table 3:

Incremental Cost per Opioid-Free Year by Study Perspective – US Studies

Cost per OfY ICERS by Study Perspective - U.S. Studies
	Healthcare Sector		State Policymaker		Societal
Study	Intervention ICER	Follow-up ICER	Intervention ICER	Follow-up ICER	Intervention ICER	Follow-up ICER
Masson et al. (2004)	$1,281,880	$37,960
Barnett et al. (2010)	$79,935
Dunlap et al. (2018)	$116,566
Polsky et al. (2010)	$19,981	$482
Polsky et al. (2010)	$36,708	$8,779
King et al. (2016)	$583,752
Murphy et al. (2017)					$61,084	$21,585
Jalali et al. (2022)	$8,938		$9,435		$6,275
Jalali et al. (2022)	$24,864		$25,913		$29,015
Jackson et al. (2015)	$34,853
Average	$243,053	$15,740	$17,674		$32,125	$21,585
Min	$8,938	$482	$9,435		$6,275	$21,585
Max	$1,281,880	$37,960	$25,913		$61,084	$21,585

Notes: All ICERs were normalized to 2024 USD

Warren et al.²⁰ evaluated the cost-effectiveness of a prison methadone program, compared to the absence of such a program. The CEA was based on data from a randomized controlled trial of the prison methadone program involving 900 inmates. Due to limited data on criminal activity, costs were evaluated solely from the treatment provider’s perspective. The study reported an ICER of $44 per heroin-free day ($16,230/OfY) as shown in Table 4.

Table 4:

Incremental Cost per Opioid-Free Year by Study Perspective – International. Studies

Cost per OfY ICERS by Study Perspective - International Studies
	Healthcare Sector		Societal
Study	Intervention ICER	Follow-up ICER	Intervention ICER	Follow-up ICER
Warren et al. (2006)	$16,230
Harris et al. (2005)			$966,235
Doran et al. (2006)	$143,299
Moore et al. (2007)			$141,585
Ruger et al. (2007)			$9,701
Ruger et al. (2007)			$24,995
Ruger et al. (2007)			$17,129
Marsden et al. (2023)			$16,232
Average	$79,765		$195,980
Min	$16,230		$9,701
Max	$143,299		$966,235

Notes: All ICERs were normalized to 2024 USD

Barnett et al.²¹ conducted a multisite study comparing new patients in opioid treatment programs across eight sites, classified by high or low compliance with clinical guidelines for methadone treatment. Costs were assessed from a healthcare sector perspective. Opioid use was self-reported for the past 30 days and collected at 6 and 12 months following the participant’s index treatment episode. The two responses were then averaged and extrapolated to an annual value. As indicated in Table 3, ICER for highly- vs. less-compliant programs was $219 per opioid-free day ($79,935/OfY).

Dunlap et al.²² conducted a CEA from a healthcare-sector perspective, alongside a randomized clinical trial where 300 participants seeking OUD treatment were assigned to methadone treatment-as-usual (TAU) or patient-centered methadone (PCM), with PCM offering greater flexibility and involving participants more in treatment decisions, such as allowing flexibility in attending counseling sessions required by TAU. Participants were followed for 12 months, and heroin use frequency was self-reported for the 30 days prior to the 12-month visit. As shown in Table 3, The reported ICER was $319 per opioid-free day ($116,566/OfY).

Buprenorphine/Buprenorphine–Naloxone Maintenance Therapy

Harris et al.²³ conducted a CEA from a broad societal perspective that accounted for health, crime, and personal costs, comparing buprenorphine to methadone treatment in a primary-care setting. The analysis used data from a randomized, open-label study involving 139 individuals who used heroin and were either already enrolled in a methadone program or seeking treatment. Findings were presented separately for perspectives with and without crime-related costs. When excluding crime costs, buprenorphine was found to be strongly dominated. However, when crime-related costs were included, methadone became more costly but also more effective. Consequently, the ICER of methadone was $2,647 per opioid-free day ($966,235/OfY) (Table 4).

Polsky et al.²⁴ conducted a CEA from a healthcare sector perspective, comparing buprenorphine-naloxone treatment to brief detoxification among youth with an OUD. In the clinical trial, 152 participants aged 15–21 were randomized to either 12-weeks of buprenorphine-naloxone or a 14-day taper, plus a 40-week follow-up. The study separately evaluated direct medical costs, which included outpatient treatment costs, and a narrower measure focused solely on outpatient program cost. During the 12-week intervention period, the ICER for direct medical costs was $19,981/OfY, and $36,708/OfY for study outpatient treatment costs. Over the entire 52-week study period, the ICER for direct medical costs was $482/OfY, while study outpatient treatment costs were $8,779/OfY (Table 3).

King et al.²⁵ used a Markov CEA model to compare clinic-based methadone therapy with office-based buprenorphine, focusing only on direct costs incurred by patients in treatment. The model included a hypothetical cohort of 1,000 adult individuals with OUD, allowing for transition between states of active use and treatment retention. The study reported an ICER of $11,226 for each additional opioid-free week gained, equivalent to $583,752/OfY (Table 3).

Marsden et al.²⁶ evaluated the cost-effectiveness of standard-of-care (SOC) medication for OUD versus extended-release buprenorphine (BUP-XR) from a societal perspective. In this multi-site open-label trial, adults aged 18 and older were randomly assigned to either SOC which includes daily methadone maintenance or buprenorphine treatment (n=156), or BUP-XR (n=158) for a 24-week intervention period. The study reported an ICER of $16,232/OfY (Table 4).

Extended-Release Naltrexone

Murphy et al.²⁷ conducted a CEA from a societal perspective, using data from a multi-site clinical trial to compare the effectiveness of extended-release naltrexone (XR-NTX) for OUD versus TAU (referral to community-based care) among individuals with a history of criminal-legal involvement. Participants aged 18–60 were randomized to either 6 monthly injections of XR-NTX (n=153), or TAU (n=155), with both arms receiving counseling for relapses and overdose prevention. The reported ICERs at the end of the 6-month intervention and entire 18-month study period were $61,084/OfY and $21,585/OfY, respectively (Table 3).

Jalali et al.²⁸ conducted a CEA alongside a clinical trial to evaluate the effectiveness of administering XR-NTX for OUD just before release from prison, compared to referral to community-based care following release. Eighty-six people were randomized (n=38 XR-NTX before release, n=48 XR-NTX referral after release), for a 12-week intervention, with a subsequent 12-week follow-up period. Costs were evaluated from the healthcare sector, state policymaker, and societal perspectives. The ICERs for the 12-week intervention ranged from $6,275/OfY for the societal perspective, to $9,435/OfY for the state policymaker perspective. For the entire 24-week period, the ICERs ranged from $24,865/OfY for the healthcare sector, to $29,015/OfY from the societal perspective (Table 3).

Multiple Medications

Doran et al.²⁹ conducted a pooled CEA from a healthcare sector perspective, using data from three randomized clinical trials to assess the cost-effectiveness of maintenance agonist treatments for individuals aged 18 or older who used heroin. Participants received either methadone (n=272), buprenorphine (n=238), or levo-α-acetyl-methadol (LAAM; n=41). The study reported an ICER of $143,299/OfY for buprenorphine vs. methadone, while LAAM economically dominated methadone (Table 4).

Moore et al.³⁰ conducted a non-randomized prospective treatment outcome study involving 825 participants to assess the cost and effectiveness of three policy options for addressing OUD over 12 months: pharmacotherapy (either buprenorphine or methadone), residential rehabilitation, and imprisonment. Analyses were performed from a societal cost perspective. Assuming no post-intervention effects, the study reported an ICER of $141,585/OfY for pharmacotherapy compared with prison term (Table 4). Residential rehabilitation was strongly dominated.

Ruger et al.³¹ evaluated the cost-effectiveness of buprenorphine, naltrexone, and placebo interventions using a randomized, double-blind, placebo-controlled clinical trial involving 126 patients receiving treatment for heroin use disorder in Malaysia. Costs were evaluated from a societal perspective. The results showed that compared to the placebo, the ICER was $9,701/OfY for naltrexone and $17,129/OfY for buprenorphine. Furthermore, when compared to naltrexone, the ICER for buprenorphine was $24,995/OfY gained (Table 4).

Jackson et al.³² utilized a Markov model to estimate the cost-effectiveness of XR-NTX compared to methadone, and buprenorphine treatment, analyzing costs from the perspective of state addiction treatment payers. The study focused on U.S. adult males aged 18–65, with OUD. Compared to methadone, the ICER for XR-NTX was $34,853/OfY gained, while buprenorphine economically dominated methadone.

Of the 14 articles included in this review, 8 examined OUD interventions in the U.S., 4 were based in Australia, 1 in Malaysia, and 1 in the United Kingdom. Among the U.S. studies that incorporated a healthcare-sector perspective, and for which an ICER could be calculated (n=7), values during the intervention period ranged from $8,938 to $1,281,880/OfY, with an average of $243,053/OfY (Supplemental Figure 1). Excluding the $1,281,880 outlier—since effectiveness was measured over the past 30 days rather than the entire intervention period—yields a range of $8,938 to $583,752/OfY, with an average of $113,200/OfY (Table 3).

Among the studies just discussed, 2 produced a non-dominated ICER for the entire study period (i.e., intervention + follow-up); with an average ICER of $15,740/OfY and a range of $482 to $37,960/OfY. One U.S.-based study included a state policymaker’s perspective, producing ICERs that ranged from $9,435 to $25,913/OfY, over the 12- and 24-week intervention periods, however, it did not produce viable ICERs including the follow-up period. Additionally, 2 U.S.-based studies focused on a societal cost perspective, with an average ICER of $32,125/OfY for the intervention period, and a range of $6,275 to $61,084/OfY (Supplemental Figure 1). Only 1 of these studies reported an ICER for the entire study period, with an ICER of $21,585/OfY (Table 3).

2 out of the international-based studies (n=6) produced non-dominated ICERs for the intervention period only, ranging from $16,230 to $143,299/OfY from a healthcare sector perspective. The remaining 4 studies assessed costs from a societal perspective, presenting ICERs ranging from $9,701 to $966,235/OfY. None of the international-based studies included ICERs for the follow-up periods (Table 4 or Supplemental Figure 2).

Table 5 presents ICER range by intervention length for U.S. and international-based studies, respectively. For the healthcare perspective, ICERs for U.S.-based studies with a 52-week intervention period (n=3) ranged from $79,935 to $583,752. In contrast, ICERs ranged from $8,938 to $36,708/OfY for studies with interventions lasting less than 52 weeks (n=3) (Table 5 or Supplemental Figure 3). Furthermore, for international studies using a healthcare-sector perspective, ICERs for a 52-week intervention period are the same as those reported in Table 4 ($16,230 to $143,299/OfY). ICERs from the societal perspective are also the same as indicated in Table 4 ($9,701 to $966,235) for studies with interventions less than 52 weeks.

Table 5:

Cost per Opioid-Free Year by Intervention Period

Cost per OfY ICERS by Intervention Period - U.S. Studies
	52-week intervention			< 52-week intervention
Study	Healthcare Sector	State Policymaker	Societal	Healthcare Sector	State Policymaker	Societal
Masson et al. (2004)				$1,281,880
Barnett et al. (2010)	$79,935
Dunlap et al. (2018)	$116,566
Polsky et al. (2010)				$19,981
Polsky et al. (2010)				$36,708
King et al. (2016)	$583,752
Murphy et al. (2017)					$61,084
Jalali et al. (2022)				$8,938	$9,435	$6,275
Jalali et al. (2022)				$24,864	$25,913	$29,015
Jackson et al. (2015)				$34,853
Average	$260,084			$234,537	$32,144	$17,645
Min	$79,935			$8,938	$9,435	$6,275
Max	$583,752			$1,281,880	$61,084	$29,015

Notes: All ICERs were normalized to 2024 USD

Discussion

This study reveals significant variation in ICERs across studies, driven by differences in intervention type, setting, geographic location, and stakeholder perspectives. For example, ICERs varied significantly between US and international studies, highlighting the differences in healthcare financing, workforce capacity, and service delivery models which can substantially influence both cost and effectiveness. Moreover, we find that studies conducted from a healthcare perspective tended to yield higher ICERs, as this approach excludes benefits outside the clinical domain. In contrast, studies adopting a societal perspective, which accounts for intervention’s spillover effects on other sectors such as criminal-legal (e.g., crime reduction) and education (e.g., income gain), often produced lower ICERs. The smaller ICERs reflect additional cost offsets associated with societal resources.

Interventions delivered within criminal-legal settings yielded lower ICERs compared to those implemented in outpatient or community-based clinical settings. For example, the cost per OfY was relatively lower for XR-NTX administered prior to release (e.g., $6,275 to $29,015/OfY in Jalali et al.) and XR-NTX administered after release (e.g., $21,585 to $61,084/OfY in Murphy et al.) vs studies comparing methadone delivered through opioid treatment programs—OTPs (e.g., $79,935/OfY, $116,566/OfY, and $1,281,880/OfY in Barnett et al., Dunlap et al., and Masson et al., respectively). One reason for these differences is that OTP-based interventions—where methadone are commonly administered—are generally more expensive to operate due to strict regulations requiring daily in-person dosing, extensive record-keeping, and frequent drug testing, all of which increase provider burden and staffing needs. Given the heterogeneity across interventions, geographic locations, and delivery systems, along with the limited number of studies in this review, future research should use more data to further disaggregate findings to allow for more targeted comparisons within similar system contexts to guide policymakers in identifying value within specific treatment pathways.

We highlight a critical gap in the economic evaluation literature, as there are no agreed upon thresholds for OfY. Among the 14 studies included in this review, 2 made explicit use of QALY-based value range of $100,000 to $200,000 to assess economic value of interventions with OfY as the effectiveness measure, though these thresholds may not be directly applicable to OfY. One study used estimates from the cost-effectiveness acceptability curve (CEAC) to explore the probability that an intervention would be considered cost-effective across different scenarios of willingness to pay (WTP) values. They reported over 50% probability of patient centered methadone being optimal at WTP values exceeding $250 per opioid-free day,²¹ however, the study did not make overall value conclusions. This lack of a standardized benchmark hinders stakeholders from making well-informed decisions based on a clinically relevant outcome.

Finally, this study presents a range of ICERs for cost per OfY to aid policymakers in comparing OUD interventions. These findings provide a foundation for establishing cost-effectiveness thresholds tailored to the OfY measure and facilitate comparisons across existing studies using the same outcome. QALYs remain valuable for comparing interventions across diseases, however, incremental QALY gains in economic evaluation are often small (less than 0.1),³³ which can result in unstable ICERs. The OfY metric offers a complementary approach by capturing a condition-specific outcome that aligns more directly with one of the goals of OUD treatment. As a next step towards establishing OfY benchmark, similar to Braithwaite et al.,³⁴ we will employ two approaches. First, to inform the lower bound estimate, we will estimate the incremental cost of modern OUD treatment alongside its associated benefits in reducing the frequency of opioid use, to infer the society’s WTP for opioid-free outcomes. Second, we will evaluate the cost-effectiveness of non-employer-subsidized health insurance, using individuals’ decisions to forgo such coverage as an indicator of the upper limit of their WTP for health improvements. In addition to these efforts, future research should aim to elicit stakeholder and policymakers’ preferences regarding acceptable costs for achieving opioid-free outcomes.³⁵ Moreover, future work should continue to report CEACs estimates to help decision makers understand how confident we can be that an intervention is worth funding under different budget constraints.

Strengths and Limitations

A key strength of this systematic review and descriptive analysis is its use of data from peer-reviewed publications covering the full history for economic evaluations of OUD interventions through September 2024. Another strength is the adjustment of all monetary values for inflation to 2024 USD, offering a standardized basis for comparison in future research.

However, the review has some limitations. First, the relatively small number of articles included (n=14), and the variation in intervention types, observation periods, and stakeholder perspectives evaluated, restricted the number of meaningful subgroups from which inferences can be drawn. More studies are needed to strengthen the evidence base and enable more definitive OfY benchmarks. Second, one study produced results from decision analytic models, versus observed participant-level data. Third, methods for calculating changes in cost and effectiveness varied; thus, requiring different assumptions in the process of creating ICERs. For example, some studies may have only captured cost and effectiveness over a limited period (e.g., past 30 days), versus over the entire observation period, as required of a rigorous economic evaluation. Specifically, in one study, costs were computed for the entire study period, but effectiveness was only assessed for the 30 days prior to the end. To facilitate comparison, we applied a linear extrapolation method to normalize ICERs to a 52-week period when study durations differed or when effectiveness and/or costs were assessed over shorter windows. While this approach allows for comparability across studies, it may not accurately reflect true patterns of opioid use or cost accumulation, particularly in the presence of time trends (e.g., diminishing intervention effects). Fourth, as with any measure of opioid intervention effectiveness, caution is warranted when comparing outcomes across different follow-up periods, as studies with shorter follow-up duration may overestimate treatment effects by failing to capture relapse rate. Fifth, despite the strengths of the OfY measure, it does not account for variations in the quantity of opioids consumed on days of use. Consequently, OfY may underestimate the impact of interventions that reduce opioid quantity per use day, whether those reductions occur alongside, or instead of, reductions in the frequency of use. Lastly, excluding economically dominated strategies, although appropriate for this study, limits the use of our findings to directly inform real-world decisions.

Conclusion

Economic evaluations that incorporate clinical measures of effectiveness can provide meaningful and comprehensible results to bolster the resource allocation decisions faced by stakeholders with a specific focus. However, unlike QALYs, clinical effectiveness measures are not associated with generally accepted value thresholds that infer “cost-effectiveness”. The results of this systematic review and analysis represent an initial step to establishing a cost-effectiveness threshold for an opioid-free year (OfY) and provide a framework by which comparable measures can be derived for other clinical measures of effectiveness.

Highlights.

• Reduction in the frequency of opioid use is a key indicator of clinical effectiveness. However, previous economic evaluations have primarily relied on QALYs for resource allocation decisions due to established cost-effectiveness thresholds. This systematic review fills the gap by taking an initial step toward defining opioid-free year (OfY) thresholds specific to OUD interventions.

• U.S. studies reported higher average ICERs for OUD interventions, ranging from $17,674 per OfY to $243,053 per OfY across three stakeholder perspectives, reflecting the higher healthcare costs. In contrast, international studies showed ICERs ranging from $79,765 per OfY to $195,980 per OfY across stakeholder perspectives.

• These findings allow for comparison of economic evaluations and guide policymakers in making optimal decisions about resource allocation.