Project Summary/Abstract Chronic pain presence is overrepresented among individuals with substance use disorder (SUD), with evidence suggesting that in the United States, over two-thirds of individuals with a drug use disorder have chronic pain. To inform efforts to meliorate the burden of co-occurring chronic pain and substance use, it is critical to first clarify their underlying mechanisms. Studies often conclude that chronic pain may be causally linked to substance use. Yet, the lack of research accounting for the heterogeneity across and comorbidity among chronic pain conditions themselves, as well as plausible alternative explanations of chronic pain and substance use comorbidity related to shared familial factors (i.e., genetic and environmental confounding) pose a challenge for such conclusions. The overall objective of the proposed project is to estimate the effect of chronic pain on substance use accounting for the heterogeneity across and comorbidity among chronic pain conditions. An additional objective involves receiving training that will help foster an independent research career assessing substance use and its comorbidities. The rationale for the project is that deepening understandings of chronic pain’s effect on risk of SUD/OD is likely to further knowledge of chronic pain and substance use comorbidity, which is critical for informing research and substance use prevention and treatment initiatives for individuals with chronic pain. The central hypothesis is that a general chronic pain liability can help explain risk of SUD/OD, which could promote nuanced pain management among individuals concurrently using substances. The proposal will test this hypothesis in two specific aims: 1) Estimate general and condition-specific associations between chronic pain conditions and SUD/OD and 2) Estimate general and condition-specific effects with SUD/OD accounting for familial confounding by design. Aim 1 will implement a bifactor model capturing chronic pain condition comorbidity and heterogeneity to assess the association between general chronic pain liability and risk of SUD/OD. Aim 1 will also compare this model to alternative models to justify considering the role of general chronic pain liability in risk of SUD/OD. Aim 2 will apply a co- twin control design, comparing twins discordant on chronic pain and SUD/OD to adjust for unmeasured confounding by factors shared by siblings. The proposed research is innovative, in the applicant's opinion, because it capitalizes on a unique, prospective, population-based twin cohort to assess the relationship between condition-general and condition-specific chronic pain processes and SUD/OD. Further, the proposal will use a co-twin control approach to account for shared familial factors more effectively than prior research. This proposal is significant because it is expected to help clarify the extent to which chronic pain affects risk of SUD/OD, which will help ascertain if reducing chronic pain dec...