The use of alcohol and prescription opioids is common among people in pain and poses significant public health burdens. This review identifies factors associated with motivation to use alcohol and prescription opioids in the context of pain. Pain-relevant, cognitive-affective, transdiagnostic vulnerability factors-expectancies/motives, pain catastrophizing, pain-related anxiety, distress intolerance, anxiety sensitivity, and perceived interrelations-were selected from theoretical conceptualizations of pain and substance use. Searches conducted in PubMed, PsycINFO, and Embase returned 25 studies that examined associations between identified variables of interest and the use of alcohol and prescription opioids in the context of pain. Consistent with a larger literature on pain and substance use, the studies included in this review demonstrated that people with chronic pain are motivated to use alcohol and opioids in response to negative affect and hold expectancies/motives for coping with pain. Vulnerabilities that engender difficulty managing aversive internal states (distress intolerance and anxiety sensitivity) and maladaptive responses to pain (pain-related anxiety and pain catastrophizing) also were implicated in motivation for alcohol and opioid use. Although one study found that pain-related anxiety was associated with co-use of alcohol and opioids, no studies examined simultaneous use. Future research directions that can explicate causal associations, identify patterns of alcohol and opioid co-use, clarify the role of pain in cessation processes, and inform treatment development are discussed.