OBJECTIVES: Lofexidine (the first US-approved non-opioid medication for opioid withdrawal management) and novel pharmaceutical formulations, extended-release naltrexone and extended-release buprenorphine depot injection for long-term maintenance therapy, are available alongside the traditional opioid agonists to treat opioid use disorder (OUD), albeit the higher costs. This study evaluates the incremental cost-effectiveness of these newer pharmacotherapies from the US healthcare perspective. METHODS: We developed a hybrid Decision Tree/Markov model to estimate the cost and effectiveness of five treatment strategies over a one-year time horizon: A) methadone-lofexidine for detoxification and buprenorphine-naloxone for maintenance; B) methadone-lofexidine for detoxification and extended-release naltrexone for maintenance; C) buprenorphine-naloxone for detoxification and extended-release buprenorphine for maintenance; D) buprenorphine-naloxone for detoxification and maintenance (i.e., usual treatment); and, E) no treatment. The effectiveness outcomes: quality-adjusted life-years (QALYs), treatment retention, and opioid-free days gained. Also, we calculated the costs of productivity loss from OUD in each of the strategies. RESULTS: B and C cost more but yield lower effectiveness than A, thus, dominated by A. Between A and D, A costs US$2,454 more and yields 0.002 higher QALYs with an incremental cost-effectiveness ratio (ICER) of US$1,247,528/QALY relative to D. As this ICER greatly exceeds the conventional willingness-to-pay threshold of $100,000/QALY, A is not cost-effective. Comparing B and C with no treatment, the treatments provide greater effectiveness but not cost-effective. In terms of treatment retention and opioid-free days, A provides higher effectiveness relative to D, costing US$175/treatment retention day and US$1277/opioid-free day gained. Among all treatment strategies, A generated the maximum reduction in productivity loss, although the magnitude of the change is insignificant. CONCLUSIONS: While the use of methadone and lofexidine for detoxification and buprenorphine-naloxone for maintenance yields greater effectiveness, it is not cost-effective due to the high cost of lofexidine. This study suggests usual treatment with buprenorphine-naloxone for detoxification and maintenance as the cost-effective treatment strategy.