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somewhat more mixed results. For this variable, higher values mean higher levels of employment. An increase of 1 percentage point in this ratio corresponds with a decrease of 0.5 percent in per capita opioid sales and Medicare Part D opioid prescriptions. No significant relationship with opioidrelated hospitalization rates was identified. The relationship with drug overdose death rates is the opposite of what was expected: an increase of 1 percentage point in the employment-to-population ratio corresponds with an increase of 0.5 percent in drug overdose death rates. DISCUSSION This research demonstrates that economically disadvantaged counties tend to be affected more deeply by substance use and the opioid crisis than counties that have stronger economic conditions. Across four different measures of opioid prescribing and substance use, and using three different measures of economic opportunity, we generally find a negative correlation between the crisis and economic opportunities. Higher poverty and unemployment rates are associated with higher rates of retail opioid sales, Medicare Part D opioid prescriptions, opioid-related hospitalizations, and drug overdose deaths. The employment-to-population ratio is negatively associated with these indicators, with the exception of overdose death rates, where the relationship was positive. On average, counties with worse economic prospects are more likely to have higher prevalence of substance use and opioid prescriptions. However, our geographic analysis finds some areas with relatively high poverty and unemployment that were relatively isolated from the indicators of the opioid epidemic as of 2016. This analysis has several limitations. First, it does not identify a causal relationship between the indicators, nor does it address the direction of any possible causal link. It is possible that economic conditions both affect and are affected by substance use. It may also be that something else drives the connection between the two; for example, traumatic experiences and other behavioral health issues may affect both economic self-sufficiency and substance use. In fact, two recent studies suggest that poor economic conditions may not be major factors in the rapid rise in drug overdose deaths and opioid prescribing. 13,14 These hypotheses are not mutually exclusive, and it is possible that the causal relationships differ in different parts of the country. A second important limitation is that the measures used do not perfectly identify opioid misuse or opioid use disorder in particular, or substance use generally. We do not have a good measure of county-level opioid misuse or opioid use disorder. While this is an important limitation, the fact that we found 10 comparable results using four distinct indicators, collected through separate mechanisms, suggests that they are good proxies for the epidemic. As decision-makers at the federal, state, and local levels consider approaches to address the opioid epidemic, these results shine light on where these efforts could be targeted. The challenges facing impoverished areas coping with the opioid crisis may be exacerbated to the extent that these areas face shortages of primary care providers, substance use and mental health treatment providers, and other important support services. Over the past few years, greater attention has been paid to increasing access to treatment services, particularly among more vulnerable populations. For example, the Centers for Medicare and Medicaid Services (CMS) is encouraging states to expand the availability of medication-assisted treatment for opioid use disorder for Medicaid recipients through mechanisms such as 1115 waivers. The 21st Century Cures Act of 2017 dedicated $1 billion to fighting the opioid epidemic, with much of the funds going to treatment and recovery services. The 2018 Consolidated Appropriations Act provided over $3 billion in additional funding, including $1 billion for State Targeted Response to the Opioid Crisis Grants through the Substance Abuse and Mental Health Services Administration and over $400 million for the Health Resources and Services Administration to improve access to addiction treatment in rural and