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Pain and substance use are highly prevalent and co-occurring conditions that continue to garner increasing clinical and empirical interest. Although nicotine and tobacco, alcohol, and cannabis each confer acute analgesic effects, frequent or heavy use may contribute to the development and progression of chronic pain, and pain may be heightened during abstinence. Additionally, pain can be a potent motivator of substance self-administration, and it may contribute to escalating use and poorer substance-related treatment outcomes. We integrated converging lines of evidence to propose a reciprocal model in which pain and substance use are hypothesized to interact in the manner of a positive feedback loop, resulting in the exacerbation and maintenance of both conditions over time. Theoretical mechanisms in bidirectional pain–substance use relations are reviewed, including negative reinforcement, social …