Persistent pain after TBI, trauma to the extremities and in the situation where both types of injury exist is highly problematic. For example, persistent pain after surgery and other forms of soft tissue injury occurs in up to 50 percent of patients, and as many as 85 percent of those with TBI experience ongoing pain. Battlefield trauma, motor vehicle accidents and sports-related injuries are particularly likely to involve TBI, peripheral trauma or both. Disability due to pain and other causes is very high amongst such patients. We have no effective approaches to reducing the likelihood of developing chronic pain after TBI or peripheral injuries, and the mechanisms supporting such pain are poorly understood. Recent advances have suggested, however, that epigenetic changes occurring in the dorsal horn of the spinal cord after either brain or peripheral trauma may support chronic pain. Our work to-date has established a rodent model of TBI in combination with injury to a limb as a model for addressing this clinical problem. We have established the severity and time course of pain-related changes after TBI and incision. Critically, we have demonstrated that histone deacetylase inhibitors greatly exacerbate the pain problems while agents that block histone acetylation reduce the pain-related changes. Additional evidence suggests that changes in the levels of genes in the spinal cord along with brain-level changes after TBI may be responsible. These observations suggest novel approaches to treatment.