Table 2.

Study overview: cost-benefit and cost-effectiveness studies

Study	Country	Population	Intervention	Comparator	Study Design	Perspective and time horizon	Model and Outcomes	Findings	Rating
Methadone compared to no pharmacologic treatment
Idrisov et al 201727	Russia	adults with OUD	methadone at four different levels of treatment capacity: 3.1%, 12.5%, 25%, and 55%	no methadone	decision analytic model (decision tree)	healthcare system at 10 years	program implementation costs, DALYs averted, cost per DALY averted (2015 USD)	At increasing treatment capacities (3.1%, 12.5%, 25%, 55%), methadone resulted in 49 739, 201 234, 404 265, 898 958 DALYs averted at a cost of $17 068 524, $69 051 186, $138 707 623 and $308 382 234, respectively. methadone compared to no methadone resulted in an ICER of 343 per DALY averted.	10 Good
Vuong et al. 201628	Vietnam	heroin dependent adults in Hai Phong City, Vietnam†	community-based, voluntary methadone	center-based compulsory rehabilitation	observational (cohort analysis)	program and participant at 3 years	cost per self-reported drug-free days (2013 VND and 2013 USD)	Community-based methadone compared to center-based compulsory rehabilitation resulted in lower costs (-VND85.73 million or -$4108) and increase in drug-free days (344 drug-free days) (p<0.001). Findings were robust in sensitivity analyses.	8.5 Good
Gisev et al. 201530	Australia	16,073 recently-released criminal justice involved individuals with a history of OUD	methadone	no medication	observational (cohort analysis)	treatment provider and criminal justice system at 6 months	cost per death avoided within 6 months of first prison release (2012 AUD)	Methadone dominated no medication. The probability of methadone to be cost-effective per life-year saved is 97% at a willingness to pay of $500 per life-saved	10 Good
Krebs et al. 201831	USA	individuals initially presenting for publicly funded treatment of opioid use disorder	immediate access to methadone	observed standard of care‡	decision analytic model (semi-Markov model)	societal at lifetime horizon	QALYs and costs (2016 USD)	Immediate access to methadone dominates observed standard of care by costing less ($78 257) and being more effective (0.42) and in greater than 99% of probabilistic sensitivity analyses. Total lifetime savings estimated at $3.8 billion.	10 Good
Methadone treatment modalities
Dunlap et al. 201832	USA	300 adults initiating methadone in an outpatient treatment program in Baltimore, MD	patient-centered methadone*	methadone	randomized clinical trial	treatment program at 12 months	average treatment cost per patient, cost per self-reported day of heroin use abstinence in the past 30 days, cost per one percentage increase in patients with opioid-positive urine screen, cost per one percentage increase in participants not meeting DSM-IV opioid dependence criteria (2015 USD)	Patient-centered methadone and methadone had similar costs per patient ($2395 vs $2292; p =0.49). The ICER for patient-centered MET compared to methadone was $242 per self-reported day of heroin use abstinence in the past 30 day and $1160 per one percent point increase in participants not meeting DSM-IV opioid dependence criteria. Patient-centered methadone resulted in a decreased % of patients with positive opioid-positive urine screens at a higher cost when compared to methadone (i.e., is dominated by methadone).	10 Good
Buprenorphine-Naloxone compared to no pharmacologic treatment
Busch et al. 201734	USA	329 opioid-dependent adults presenting at an urban teaching hospital ED	brief intervention with buprenorphine-naloxone initiation in the ED and ongoing integrated primary care	brief intervention with referral to community-based treatment referral alone	randomized clinical trial	healthcare system at 30 days	cost per patient enrolled in formal addiction treatment at 30 days (2013 USD) cost per self-reported opioid-free day, in the past 7 days	ED-initiated buprenorphine-naloxone dominated both comparators and has a greater than 99% of being cost-effective at a willingness-to-pay threshold of $30 per individual engaged in buprenorphine treatment at 30 days. ED-initiated buprenorphine has a 50% cost-effective at $100 per opioid-free day threshold and increases to 80% at $500 per opioid-free day.	10 Good
Dunlop et al. 201735	Australia	50 patients with DSM-IV heroin dependence	outpatient buprenorphine-naloxone with weekly clinical visits	open-label waitlist§	randomized clinical trial	healthcare at 12 weeks healthcare + criminal justice at 12 weeks	Incremental cost per heroin-free day at 12 weeks (2009 AUS)	From the healthcare perspective, buprenorphine-naloxone compared to open-label waitlist resulted in an additional $18.24 per heroin-free day (95% CI: $4.50 to $28.49). Including cost of crime, buprenorphine -naloxone cost less and resulted in more heroin-free days (i.e., dominates).	10 Good
Barocas et al. 201936	USA	HIV/HCV co-infected patients who have OUD and are being considered for HCV treatment	BUP-NX in onsite care for HIV/HCV co-infected persons	referral to offsite OUD care	decision analytic model (Monte Carlo microsimulation)	healthcare at lifetime	Cost per QALY (2017 USD)	BUP-NX is cost-effective with an ICER of $57,100/QALY across a plausible range of parameter values assuming a WTP of $100,000/QALY	9.5 Good
Buprenorphine-Naloxone treatment modalities
Carter et al. 201719	USA	clinically-stable adults with OUD	subdermal implantable buprenorphine	sublingual buprenorphine	decision analytic model (Markov model)	societal at 12 months	incremental cost-per QALY incremental net monetary benefit (2016 USD)	Subdermal implantable BUP dominated sublingual BUP and is preferred in 89% of probabilistic sensitivity analyses. The incremental net monetary benefit of subdermal implantable BUP vs. sublingual BUP was $5,953 (p<.05), at a WTP of $50,000 per QALY.	10 Good
Extended-Release Naltrexone compared to no pharmacologic treatment
Murphy et al. 201723	USA	community-dwelling adults aged 18 to 60 involved with the criminal justice system with prior DSM-IV OUD	XR-NTX	counseling and offsite referral	randomized clinical trial	taxpayer at 25 weeks and 78 weeks	cost per abstinent year cost per QALY (2014 USD)	At threshold of $100,000/QALY, XR-NTX is unlikely to be cost-effective (10%) at 25 wks and likely (60%) cost-effective at 78 wks. XR-NTX is >50% cost-effective at 25 wks when WTP is >160,000/QALY. XR-NTX has >50% of being cost-effective at $50,000 /abstinent year at 25 weeks. At 78 wks, exceeds 95% at $10,000 per abstinent year.	10 Good
Unspecified medications (methadone or buprenorphine) compared to no pharmacologic treatment
Morozova et al. 201937	Ukraine	people at risk and with OUD in 3 different Ukrainian cities	Plausible OAT (Methadone or Buprenorphine) scale-up strategies	Standard of care	compartmental modeling	Payer at 10 years	Incremental cost per QALY (2016 USD)	The optimal strategy and probability of cost-effectiveness varies according to WTP threshold, as well as other inputs such as baseline OAT demand, site of PWID population, and treatment retention. Cost-effectiveness was evaluated relative to a WTP range of $0/QALY to $6,555/QALY (3 x per GDP).	9.5 Good
Multiple Medications:combinations of two or more of the following buprenorphine, methadone, injectable hydromorphone, injectable diacetylmorphine, injectable naltrexone
Bansback et al. 201838	Canada	202 persons who inject drugs with severe OUD in Vancouver	hydromorphone	diacetylmorphine or methadone	decision analytic cohort model (Markov model)	societal at 6 months and lifetime	Cost per QALY, cost per incremental costs (2015 USD)	Hydromorphone and diacetylmorphine had similar costs and benefits and dominate methadone when compared directly by providing more benefit at a lower cost. Hydromorphone and diacetylmorphine had a 67%, and 75%, respectively, of dominating methadone in probabilistic sensitivity analysis. Hydromorphone dominates diacetylmorphine and in 16% of probabilistic sensitive analyses.	9.5 Good
Kenworthy et al. 201720	United Kingdom	patients with OUD	buprenorphineor methadone	no medication	decision analytic model (decision tree)	societal UK National Health service & personal social service at 1 year	cost per QALY (2016 UK)	Medication compared to no medication is cost-effective at £13,923/QALY for BUP and £14,206/QALY for methadone. Medication will have a net savings £14,032 for BUP or £17,174 for methadone /year. At WTP threshold of £30,000 /QALY BUP and methadone are cost-effective in >60% of simulations when compared individually to no medication.	10 Good
King et al. 201639	USA	hypothetical cohort of 1 000 opioid-dependent adults with no history of OUD treatment in past 30 days	office-based buprenorphine	clinic-based methadone	decision analytic model (Markov model)	third party payer at 1 year	cost per additional patient in treatment gained cost per additional opioid abuse-free week gained (2014 USD)	The ICER for methadone vs buprenorphine was $10,437 per additional patient in treatment gained and $8,515 per additional opioid abuse-free week gained. Methadone is preferred in the base case at a threshold of $14,000 per patient retained in treatment at 1 year; results were sensitive to cost of methadone.	9.5 Good
Premkumar et al. 201943	USA	pregnant women with OUD	methadone or buprenorphine	detoxification w/ 14-day buprenorphine taper	decision analytical model (Markov model)	healthcare payer at 1 year	cost per QALY (2017 USD)	Buprenorphine dominated both methadone and detoxification at a WTP of $100,000 with a 70.5% of being cost-effective. Buprenorhpine no longer cost-effective if cost of MET was 8% less than base case or if overall costs for detox decreased by 79% or more.	9.5 Good
Marsden et al. 201922	London, UK	people who met DSM-IV criteria for opioid or cocaine dependence or both in the past 12 months	Methadone or buprenorphine with psychosocial intervention (PSI)	methadone or buprenorphine alone	randomized clinical trial	societal at 18 weeks	cost per QALY (2016 UK) Cost per 1% improvement in probability of treatment response	The probabilities that the PSI were cost-effective relative to treatment as usual were 60% and 67%, respectively, at the NICE willingness-to-pay thresholds of £20 000 per QALY and £30 000 per QALY but decreases to 36% and 56%, respectively, from a limited healthcare perspective at £20 000 per QALY and £30 000 per QALY. The probability the cost per 1% improvement in treatment response is high as 87% at a WTP of £1000 and low as 50% at £30.	10 Good
Murphy et al. 201945	USA	adults with DSM-V OUD presenting at community based treatment programs offering detoxification services	XR-NTX	buprenorphine-naloxone	randomized clinical trial	healthcare and societal at 24 weeks and 36 weeks	cost per QALY cost per abstinent year (2016 USD)	At a WTP of 100 000 per QALY, XR-NTX compared to buprenorphine-naloxone was unlikely to be cost-effective in the intention-to-treat (30%) and per-protocol samples (<50%) unless the time period was extended to 36 weeks; resulting in approximately 50% and 80%, respectively.	10 Good

^*defined as respectful of and responsive to individual patient preferences, needs, and values

^†defined as daily heroin use in the 3 months prior to treatment initiation

^‡observed standard of care defined as 54.3% initiate opioid use disorder treatment with medically managed withdrawal

^§no clinical intervention

USD = United States Dollars; QALY = quality-adjusted life-year; DALY = disability-adjusted life-year; VND = Vietnamese Dongs; XR-NTX = injectable naltrexone; OUD = opioid use disorder

Score rubric: poor (1–3 points); average (4–7 points); good (8–10 points). 15 Modeling & 6 RCT