New pharmacological strategies for analgesic drug development: focus on biased m opioid receptor agonists

Abstract

Chronic pain affects more than 30% of people worldwide and although mortality rates are highest for other pathologies, it is one of the main sources of human suffering and disability that profoundly impacts patients' quality of life. To date, opioids still represent the reference treatment for moderate to severe chronic pain, however their use is strongly limited by a plethora of unwanted side effects including analgesic tolerance and opioid induced hyperalgesia. In the last few years, numerous efforts have been made in order to develop new analgesic drugs characterized by reduced side effects and by a safer pharmacological profile. Molecules capable of modulating different downstream pathways, known as biased agonists, are one proposed strategy for the treatment of chronic pain due to their suggested ability to discriminate between analgesic and adverse effect. In this review, we discuss the pharmacological outcomes of opioid biased ligands by bringing together cellular results and the available data from clinical trials; in particular, we focus on biased µ-opioid receptor agonists given their therapeutic relevance. Impact statementThe concept of MOR biased agonism has been used to identify new analgesic drugs. Although some criticism has been raised toward this strategy, it represents a useful step for the development of safer opioid analgesics.