The opioid epidemic remains a major public health challenge in the United States, requiring a multi-pronged intervention approach to mitigate harms to communities. Given the heterogeneity of the epidemic, it is crucial for policymakers to understand localized treatment effects of different intervention components and utilize limited resources efficiently. While locally calibrated simulation models can project epidemic outcomes for any given intervention policy, collecting simulation results for all intervention combinations to estimate localized treatment effects for each community is impractical because the number of combinations grows exponentially with the number of interventions and the levels at which they are applied. To tackle this, we develop a two-stage metamodel framework with a two-step sequential design for efficient sampling. The metamodel consists of a response function linking health outcomes to each intervention component's treatment effect, and a Gaussian process regression (GPR) to learn spatial and socio-economic structures of the treatment effects based on locally-contextualized covariates. With two-step sequential sampling, we leverage spatial correlations and posterior uncertainty to sequentially sample the most informative counties and treatment conditions. We apply this framework to estimate the treatment effects of buprenorphine dispensing and naloxone distribution on overdose mortality rates using a calibrated agent-based opioid epidemic model in Pennsylvania counties. Our approach achieves less than 5% average relative error using fewer than 2% of the runs required for an exhaustive simulation. Our two-stage framework provides a computationally efficient approach to support policymakers, enabling an efficient evaluation of alternative resource-allocation strategies to mitigate the opioid epidemic in local communities.

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