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The “reversal of fortunes” in life expectancy saw rapid diffusion, going from largely limited to Appalachia and the Southwest in 2000 to nationwide by 2015. The unprecedented 20-year difference in life expectancy between the healthiest and least healthy counties is largely explained by socioeconomic factors correlated with race/ ethnicity, behavioral and metabolic risk, and health care access. These indicators are the most recent evidence of a long-term process of decline: a multidecade rise in income inequality and economic shocks stemming from deindustrialization and social safety net cuts. The 2008 financial crisis along with austerity measures and other neoliberal policies have further eroded physical and mental well-being. Poverty and substance use problems operate synergistically, at the extreme reinforced by psychiatric disorders and unstable housing. The most lucrative employment in poorer communities is dominated by manufacturing and service jobs with elevated physical hazards, including military service. When sustained over years, on-the-job injuries can give rise to chronically painful conditions, potentially resulting in a downward spiral of disability and poverty. Although opioid analgesics may allow those with otherwise debilitating injuries to maintain employment, individuals in manual labor occupations appear to be at increased risk for nonmedical use. In much of the country, the counties with the lowest levels of social capital have the highest overdose rates. The interplay between social and genetic factors, too, is being elucidated. Individuals living in low socioeconomic neighborhoods were more likely to develop chronic pain after car crashes, a process mediated by stress response genes. Interactions between environment and genetic polymorphisms may in part explain substance use early in life. The interpretation of the vector model has justified mass incarceration for minor drug charges, creating further tears in the social fabric of communities already reeling from a lack of opportunity. Perversely, incarceration of people with opioid dependence leads to interrupted opioid tolerance and a drastic elevation in overdose risk. Having a public record because of a drug conviction limits one’s ability to obtain meaningful employment, reinforcing the penury that drove problematic drug use in the first place. Although those who see the crisis through the vector lens do not necessarily advocate punishment, the rhetorical dominance of this model has crowded out investment in evidence-driven demand reduction and harm reduction approaches. In recasting pain as a broader condition that includes economic and social disadvantage, we urge an alternative explanation for the rising demand for opioids. The “reversal of fortunes” in life expectancy saw rapid diffusion, going from largely limited to Appalachia and the Southwest in 2000 to nationwide by 2015. The unprecedented 20-year difference in life expectancy between the healthiest and least healthy counties is largely explained by socioeconomic factors correlated with race/ ethnicity, behavioral and metabolic risk, and health care access. These indicators are the most recent evidence of a long-term process of decline: a multidecade rise in income inequality and economic shocks stemming from deindustrialization and social safety net cuts. The 2008 financial crisis along with austerity measures and other neoliberal policies have further eroded physical and mental well-being. Poverty and substance use problems operate synergistically, at the extreme reinforced by psychiatric disorders and unstable housing. The most lucrative employment in poorer communities is dominated by manufacturing and service jobs with elevated physical hazards, including military service. When sustained over years, on-the-job injuries can give rise to chronically painful conditions, potentially resulting in a downward spiral of disability and poverty. Although opioid analgesics may allow those with otherwise debilitating injuries to maintain employment, individuals in manual labor occupations appear to be at increased risk for nonmedical use. In much of the country, the counties with the lowest levels of social capital have the highest overdose rates. The interplay between social and genetic factors, too, is being elucidated. Individuals living in low socioeconomic neighborhoods were more likely to develop chronic pain after car crashes, a process mediated by stress response genes. Interactions between environment and genetic polymorphisms may in part explain substance use early in life. The interpretation of the vector model has justified mass incarceration for minor drug charges, creating further tears in the social fabric of communities already reeling from a lack of opportunity. Perversely, incarceration of people with opioid dependence leads to interrupted opioid tolerance and a drastic elevation in overdose risk. Having a public record because of a drug conviction limits one’s ability to obtain meaningful employment, reinforcing the penury that drove problematic drug use in the first place. Although those who see the crisis through the vector lens do not necessarily advocate punishment, the rhetorical dominance of this model has crowded out investment in evidence-driven demand reduction and harm reduction approaches. In recasting pain as a broader condition that includes economic and social disadvantage, we urge an alternative explanation for the rising demand for opioids.