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Background: Naloxone-prescription opioid co-prescribing mandates have increasingly been proposed and adopted in the U.S., at both the national and state levels, as a public health intervention for mitigating the impacts of opioid overdoses. In this study, we assess whether a hypothetical national, naloxone co-prescribing mandate has become less costly for the U.S. health system since 2018. Methods: We expand and update an existing economic model of naloxone co-prescribing to estimate annual health system spending. We refresh the model inputs through 2021 to reflect changes to the opioid and naloxone landscapes, expand the model to account for more types of market responses, and develop additional scenarios around alternate implementation strategies such as bulk purchasing. Results: We estimate annual spending increases across all retail opioid patients of $1.4–$4.0 billion with naloxone nasal sprays and auto-injectors, and $0.6–$0.9 billion with traditional injectable naloxone formulations. We also find that bulk purchasing could lead to higher spending increases in some patient populations absent volume discounts. Conclusions: Our estimates are substantially lower than prior research. Key drivers include lower prices for naloxone, higher current naloxone distribution, a longer approved shelf life for naloxone, and lower estimated sizes for some patient populations. Additional research is needed to estimate the potential benefits of naloxone co-prescribing for mitigating opioid overdoses, and whether they could outweigh spending increases. Steps that could make this policy more beneficial or less costly include targeting higher risk patient populations and promoting large-scale purchasing agreements with volume discounts to help offset potential price increases. [ABSTRACT FROM AUTHOR]