ABSTRACT Opioid use is a major source of morbidity and mortality in the U.S. and represents an urgent public health crisis. In recent years, a surge of adults over the age of 50 have developed opioid use disorder (OUD), a significant and alarming trend that is increasing. Increases in OUD in mid-life and older adults is partially due to high rates of pain, surgery, and physical ailments in aging populations that necessitate opioid prescription medications, including oxycodone. Oxycodone (in Percocet™ and Oxycontin™) is consistently among the medications most widely prescribed for pain, but is also most widely abused and involved in overdose deaths. Despite its potential for abuse, oxycodone can be highly effective for reducing acute pain. There is an urgent need for interventions that preserve the analgesic properties of oxycodone while curtailing its abuse potential. A promising adjunct treatment option for pain management, that could simultaneously reduce the abuse potential of opioids, is intranasal administration of the neuropeptide oxytocin. Oxytocin has no recognized addiction potential, and simultaneously has analgesic properties. Preclinical evidence suggests that oxytocin co-administered with opioids may reduce opioid reinforcing effects. Oxytocin also decreases experimental pain in human and animal models. Further, evidence in animals and humans support the shared brain structure and function changes associated with both addiction and chronic pain, which may be modulated by oxytocin administration. Doses of oxytocin are also well-tolerated by individuals receiving medications for OUD (e.g., methadone). Based on this evidence, we propose that oxytocin will significantly reduce abuse liability of opioids and reduce experimental pain. Thirty healthy 55-75 year old volunteers with some opioid experience will self-administer 48 IUs of intranasal oxytocin (or placebo) shortly after oral oxycodone (0, 2.5, 5.0 mg) in a double-blind, randomized, placebo-controlled, within-subjects laboratory study. Subject- rated abuse liability and cardiovascular and respiratory responses will be assessed before and repeatedly for 5 hours following drug administration. Pain measures will also be collected, including a standardized experimental pain battery (i.e., quantitative sensory testing with thermal and mechanical testing). This study has tremendous potential for public health impact in examining intranasal oxytocin as a promising agent for reducing opioid addictive potential and producing opioid-sparing effects, while effectively reducing pain, which could substantially advance the field of pharmacotherapy and carve out a novel treatment option, specifically in mid-life and older adults who may be at higher risk for pain. Results from this project will also advance scientific understanding of behavioral mechanisms underlying the link between abuse potential and pain. Our multidisciplinary team is well-suited to address the proposed aims with expertise in...