Huiping Ding and colleagues have developed a painkilling compound that both relieves pain and suppresses opioid dependency in primates. The authors say the compound's dual function and lack of dangerous side effects indicate it could serve as "a viable opioid alternative or a replacement for prescription opioids." Despite the wide prevalence of abuse and side effects like addiction and dependency, opioids such as morphine and oxycodone remain the standard of care for pain relief. These drugs, which target the mu opioid peptide receptor (MOP), are still widely used because they are the most effective painkilling medications available. With the goal of developing an equally effective and non-addicting opioid alternative, Ding's research team had previously focused on the characteristics of the nociception opioid peptide receptor (NOP), another member of the opioid receptor family that blocks the dependency-related side effects of traditional opioids. In this study, they used structural and biochemical analysis to design and optimize a bifunctional compound named AT-121 that targets both the NOP and MOP receptors. After confirming the compound's activity in plasma from monkeys, the authors conducted several experiments with primates to examine AT-121's potential in a model of mild pain avoidance. They found AT-121 provided pain relief in the monkeys that was 100-fold stronger compared to morphine. Furthermore, monkeys that could self-administer a variety of drugs such as cocaine and oxycodone were no more likely to self-administer with AT-121 than with saline, indicating the drug lacks the rewarding characteristics of other opioid drugs. Importantly, high doses of AT-121 did not cause motor impairment, respiratory depression or other abnormal physiologic changes in monkeys, and cessation of treatment after three days did not cause withdrawal symptoms in the animals. Ding's team plans to further characterize the compound's safety in additional animal studies before they move into clinical trials. A related video featuring N.T. Zaveri communicates the challenges around developing opioid alternatives more broadly, and how this work overcomes them.