kappa-Opioid receptor agonists in pain treatment

摘要

The management of pain continues to be challenging. Whereas the commonly used opioid analgesics, exemplified by morphine and its congeners, provide considerable pain relief they are also associated with significant adverse effects including respiratory depression, and have considerable abuse liability. The discovery of subtypes of the opioid receptor led to the development of novel analgesics acting at the kappa-opioid receptor. These drugs had clinical efficacy against pain and appeared to be free of respiratory depression or significant abuse liability, but clinical trials revealed adverse psychotomimetic and dysphoric effects of this class of drugs. More recent studies led to the discovery of a kappa-opioid receptor agonist that produced analgesia but without evidence of these adverse effects. During the course of clinical trials, it was serendipitously discovered that this class of drugs is potentially efficacious against chronic pruritus, which represents a significant unmet medical need. In addition, kappa-opioid agonists that do not cross the blood-brain barrier have also shown therapeutic potential for pain and pruritus without adverse psychotomimetic effects. These discoveries may be ushering in a renewed interest in this class of opioids in the development of safer analgesics and antipruritics.