BackgroundState- and county-level reports suggest that the COVID-19 pandemic exacerbated the opioid crisis. We examined US national trends of nonfatal opioid overdose in 2020 in comparison to pre-COVID years 2018–2019. MethodsWe used National Emergency Medical Services Information System (NEMSIS) data to conduct a temporal analysis from 2018 to 2020. Opioid-related EMS run was defined using five scenarios of naloxone administration. To determine annual patterns and slope inflection points, we used the Prophet model of the time series analysis. Linear slopes and their 95% confidence intervals (CIs) were calculated for pre-stay-at-home (pre-SaH) and SaH periods in 2020 and compared to the slopes during the same time in 2018–2019. Three cut-points for SaH start were considered: March 19, 24, and 29. ResultsWe identified 91,065, 144,802, and 242,904 opioid-related EMS runs in 2018–2020, respectively. In 2020, opioid-related runs increased in January-June, with a pronounced acceleration in March, which coincides with the stay-at-home (SaH) orders. In both 2018 and 2019, opioid-related runs increased in January-August without the spring acceleration. In 2020, weekly increases (95% CI) during SaH for all examined cut-points were significantly greater than in pre-SaH: 18.09 (16.03–20.16) vs. 6.44 (3.42–9.47) for March 19, 17.77 (15.57–19.98) vs. 4.85 (2.07–7.64) for March 24, 18.03 (15.68–20.39) vs. 4.97(2.4–7.54) for March 29. No significant difference was found between these periods in 2018–2019. ConclusionsThe acceleration of opioid-related EMS runs during the SaH period of 2020 suggests that EMS data may serve as an early warning system for local health jurisdictions to deploy harm reduction/prevention resources.