The limbic system serves a number of critical functions, including regulation of behavior and memory. Perhaps no limbic structure plays a more critical role in memory processing than the hippocampus. The scientific foundation of the proposed research indicates that the hippocampus and association areas are at risk when exposed to opioids. Notably opioids often are used in large quantities, both acutely and chronically, and in many clinical contexts, leading to the current epidemic with opioid addiction, overdose, and reports of amnesia. Specific reports supporting the scientific foundations for the proposed research arise from: (1) Compelling reproducible data in animals and congruent observations in humans indicating that opioids activate the limbic system, producing hypermetabolism, acute cell injury, and memory loss with hippocampal atrophy. (2) Opioid-induced mesial hippocampal epileptiform activity with intracranial electrodes in epileptic humans. (3) Case reports of patients developing an amnestic syndrome in the setting of opioid overdose (OD) with complete diffusion-weighted hyperintensity and volume loss of both hippocampi on MRI. Notably, some reports describe OD patients without associated hypoxia, but with amnesia and MRI changes. (4) Chronic pain patients have been reported to develop cognitive deficits. It is currently unknown whether this is similar to that seen in patients presenting with opioid OD, the impetus for the proposed research. Our overall hypothesis is that patients with chronic pain who have been on long-term, high-dose opioids develop hippocampal injury and associated neurocognitive dysfunction. Therefore, we predict that these patients will have smaller hippocampal volumes and perform more poorly on neuropsychological tests of memory than matched chronic pain patients who do not use opioids. Using a combination of MRI imaging and neuropsychological testing, the specific aims of this proposal are to test the hypotheses in these patient groups that humans with chronic pain on long-term, high-dose opioids: 1. Will demonstrate smaller hippocampal volumes by MRI. 2. Will perform more poorly on neuropsychological tests of memory and associated hippocampal functions. If these high-risk but high-impact hypotheses are confirmed, thus translating ample preclinical observations, we will have revealed a previously unknown effect of opioid use on human cognitive function which could be relevant to millions of humans receiving prescription opioids, people with a history of opioid abuse, and patients who receive opioids perioperatively, peri-intensive care, or after injury. As such this would indicate a new discovery with potentially major medical, social, and economic impact.