The quest for more effective analgesics with reduced abuse liability and fewer adverse effects: Promises, pitfalls, and future perspectives of biased agonists at opioid receptors

Chronic pain is a relevant health condition affecting one out of five individuals that is often not adequately treated by currently available analgesics. This, together with the dramatic increase in addicted people within the dramatic “opioid epidemics,” significantly spurs the quest for innovative analgesics provided with increased efficacy, reduced abuse liability, and fewer adverse effects. Within this frame, biased agonists at opioid receptors have attracted increasing interest in the last decade as they have emerged as more effective and safer candidate analgesics. In this chapter, promises, pitfalls, and future perspective of biased agonists at mu (MOR) and kappa (KOR) opioid receptors are discussed. Moreover, methodological insights are provided with regard to the most appropriate experimental settings to be employed aiming at developing novel biased KOR agonists.