Opioids are considered mainstay treatments for acute and terminal pain. In recent decades, however, overprescription and the increasing prevalence of illicit opioids has propelled North America into a state of “opioid crisis.” Along with the analgesic benefits, opioid use also commonly induces a number of side effects. Respiratory depression is an especially dangerous and potentially lethal example. The development of painkillers with improved safety profiles is thus a priority. Downstream to the mu-opioid receptor, which is responsible for the analgesic effects of opioids, β-arrestin-2 signaling has been suggested to be important for the manifestation of side effects, including respiratory depression. Two novel mu-opioid receptor agonists, TRV130 and PMZ21, have recently been reported to preferentially promote G protein-coupling over β-arrestin-2 signaling, thereby promoting analgesia with reduced side effects. TRV130 has been found in clinical trials to be more potent than morphine but safer in the setting of acute moderate-to-severe pain and is currently under New Drug Application review in the U.S. PMZ21 has shown promising and unique pain-relieving effects in mouse models, but further investigation is warranted to examine whether its therapeutic effects and safety profile are translatable to humans.
Role of mu opioid receptor endocytosis in the beneficial and side‐effects of prolonged opioid use