Background In response to increasing opioid overdoses, US prevention efforts have focused on prescriber education and supply, demand and harm reduction strategies. Limited evidence informs which interventions are effective. We evaluated Project Lazarus, a centralised statewide intervention designed to prevent opioid overdose.

Methods Observational intervention study of seven strategies. 74 of 100 North Carolina counties implemented the intervention. Dichotomous variables were constructed for each strategy by county-month. Exposure data were: process logs, surveys, addiction treatment interviews, prescription drug monitoring data. Outcomes were: unintentional and undetermined opioid overdose deaths, overdose-related emergency department (ED) visits. Interrupted time-series Poisson regression was used to estimate rates during preintervention (2009–2012) and intervention periods (2013–2014). Adjusted IRR controlled for prescriptions, county health status and time trends. Time-lagged regression models considered delayed impact (0–6 months).

Results In adjusted immediate-impact models, provider education was associated with lower overdose mortality (IRR 0.91; 95% CI 0.81 to 1.02) but little change in overdose-related ED visits. Policies to limit ED opioid dispensing were associated with lower mortality (IRR 0.97; 95% CI 0.87 to 1.07), but higher ED visits (IRR 1.06; 95% CI 1.01 to 1.12). Expansions of medication-assisted treatment (MAT) were associated with increased mortality (IRR 1.22; 95% CI 1.08 to 1.37) but lower ED visits in time-lagged models.

Conclusions Provider education related to pain management and addiction treatment, and ED policies limiting opioid dispensing showed modest immediate reductions in mortality. MAT expansions showed beneficial effects in reducing ED-related overdose visits in time-lagged models, despite an unexpected adverse association with mortality.