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To improve public health surveillance and response by using spatial optimization.We identified cases of suspected nonfatal opioid overdose events in which naloxone was administered from April 2013 through December 2016 treated by the city of Pittsburgh, Pennsylvania, Bureau of Emergency Medical Services. We used spatial modeling to identify areas hardest hit to spatially optimize naloxone distribution among pharmacies in Pittsburgh.We identified 3182 opioid overdose events with our classification approach, which generated spatial patterns of opioid overdoses within Pittsburgh. We then used overdose location to spatially optimize accessibility to naloxone via pharmacies in the city. Only 24 pharmacies offered naloxone at the time, and only 3 matched with our optimized solution.Our methodology rapidly identified communities hardest hit by the opioid epidemic with standard public health data. Naloxone accessibility can be optimized with established location-allocation approaches.Our methodology can be easily implemented by public health departments for automated surveillance of the opioid epidemic and has the flexibility to optimize a variety of intervention strategies.