The diversion and misuse of prescription opioids, a resurgence in heroin use, and the emergence of illicit, high potency synthetic opioids such as fentanyl, has fueled what is now described as the ?opioid epidemic?. The most visible manifestation of the opioid epidemic is a dramatic increase in the number of overdose deaths, estimated at more than 33,000 in 2015, and the more than 1.25 million hospital visits linked to opioid misuse. Heroin and synthetics like fentanyl, less expensive and often more accessible than prescription opioids, have now taken center stage as a serious public health concern. Naloxone is currently the only opioid antagonist available to treat opioid overdose. The approval of both an auto-injector (Evzio, 2014) and an intranasal spray (Narcan nasal spray, 2015) has enabled non-medically trained personnel (first responders, friends and family of overdose victims) to reliably administer naloxone in an emergency with no training. While effective in reversing opioid overdose, the half-life of naloxone is relatively short (t1/2 ~2h). This project describes the development and clinical evaluation of an intranasal formulation of nalmefene, a long acting opioid antagonist (t1/2 ~ 10.8 h). Nalmefene injection (Revex) was FDA approved to treat opioid overdose, but its marketing discontinued (2008) due to low sales. The objective of this project is to develop an intranasal formulation of nalmefene possessing the pharmacokinetic characteristics (Cmax, Tmax) of parenterally administered nalmefene. A long acting opioid antagonist would be especially useful in rural areas, where access to emergency medical services may be delayed, and in situations where exposure to an unidentified opioid is either anticipated or suspected (for example, by law enforcement and customs officials).