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By 2000, chronic pain was big business. Withdrawals from the market of popular nonopioid analgesics because of cardiovascular risk and acetaminophen toxicity raised concerns about nonopioid alternatives. Short lived but indelible, some pharmaceutical marketing improperly minimized addiction potential (OxyContin) and promoted off-label use (Actiq), later giving rise to physician kickback schemes (Subsys), lucrative speaking fees, and lobbying. Contradicting the singular blame on health care as the gateway to addiction, individuals entering drug treatment are now more likely to report having started opioid use with heroin, not a specific prescription analgesic. In the vector model, the blame for this trajectory of opioid analgesic to heroin to synthetic opioid use rests with the drugs themselves and those who make them available. Although increased availability of prescription opioids fueled the overdose crisis, we have not adequately explored the source of the demand for these medicines. ROOT CAUSES The vector argument must grapple with contradictory data. Prescription opioid overdose death rates have not yet dropped following declining opioid prescribing: the number of outpatient opioid analgesic prescriptions dropped 13% nationally between 2012 and 201528 (with sharper regional declines). Yet,the national overdose death rate surged 38% during those years. Overdose deaths attributable to prescription opioids have not decreased proportionally to dispensing. Although there is a strong historic linear association between dispensed volume and overdose nationally, these associations are less pronounced at the county level. Alternative explanations include misclassification of synthetic opioid deaths,evolving autopsy protocols, time lag effects, and unused medication. There are intuitive causal connections between poor health and structural factors such as poverty, lack of opportunity, and substandard living and working conditions. A comprehensive discussion of structural determinants of pain, addiction, and overdose is beyond the scope of this commentary. What is pertinent is that, although expansion of opioid availability may have catalyzed overdose rates, an exclusive focus on opioid supply hampers effective responses. One powerful line of structural analysis focuses on “diseases of despair,” referring to the interconnected trends in fatal drug overdose, alcohol-related disease, and suicide. Since 1999, age-specific mortality attributed to these conditions has seen an extraordinary rise. The trend is especially pronounced among middle-aged Whites without a college degree, who are now dying earlier on average than did their parents— which is anomalous outside of wartime. In an analysis focused on the Midwest, Appalachia, and New England (where the heroin, fentanyl, and both comingled epidemics are most pronounced), combined mortality rates for diseases of despair increased as county economic distress worsened. An alternate hypothesis suggests that an environment that increasingly promotes obesity coupled with widespread opioid use may be the underlying drivers of increasing White middle-class mortality. Complex interconnections between obesity, disability, chronic pain, depression, and substance use have not been adequately explored. Additionally, suicides may be undercounted among overdose deaths. Under both frameworks, social distress is a likely upstream explanatory factor.