Opioid overdoses, many of which are attributed to use of illicit fentanyl, are currently one of the leading causes of death in the U.S. Although fentanyl has been used safely for decades in clinical settings, the widespread use of illicit fentanyl is a recent phenomenon. Starting in 2013, illicitly manufactured fentanyl and its analogs began to appear on the streets. These substances were added to or sold as heroin, often unbeknownst to the user. Because fentanyl is so potent, only small amounts are needed to produce pharmacological effects, but the margin between safe and toxic doses is narrow. Surprisingly little is known about the exact signaling mechanisms underlying fentanyl-related respiratory depression or the effectiveness of naloxone in reversing this effect. Similarly, little is known about the ability of treatment medications such as buprenorphine, methadone, or naltrexone to reduce illicit fentanyl use. The present article reviews the receptor, preclinical and clinical pharmacology of fentanyl, and how its pharmacology may predict the effectiveness of currently approved medications for treating illicit fentanyl use.

A critical component in development of opioid analgesics is assessment of their abuse liability (AL). Standardization of approaches and measures used in assessing AL have the potential to facilitate comparisons across studies, research laboratories, and drugs. The goal of this report is to provide consensus recommendations regarding core outcome measures for assessing the abuse potential of opioid medications in humans in a controlled laboratory setting. Although many of the recommended measures are appropriate for assessing the AL of medications from other drug classes, the focus here is on opioid medications because they present unique risks from both physiological (e.g., respiratory depression, physical dependence) and public health (e.g., individuals in pain) perspectives. A brief historical perspective on AL testing is provided, and those measures that can be considered primary and secondary outcomes and possible additional outcomes in AL assessment are then discussed. These outcome measures include the following: subjective effects (some of which comprise the primary outcome measures, including drug liking; physiological responses; drug self-administration behavior; and cognitive and psychomotor performance. Before presenting recommendations for standardized approaches and measures to be used in AL assessments, the appropriateness of using these measures in clinical trials with patients in pain is discussed.