Conventional opioid receptor agonists like morphine, fentanyl, and oxycodone provide powerful analgesia, but their clinical utility is greatly complicated by several adverse events, including gastrointestinal dysfunction and potentially fatal respiratory depression. In the hospital and similar settings, injectable opioids remain necessary for many patients, but opioid-related adverse events (ORAEs) can threaten patient safety and increase hospital costs. The analgesic properties of opioids occur via G protein-dependent μ-opioid receptor (MOR) signaling; however, β-arrestins are also thought to play a prominent role in modulating MOR signaling. Morphine pharmacology in β-arrestin2 knockout mice suggested that a ligand that promotes coupling of the MOR to G proteins, but not β-arrestins, would result in higher analgesic efficacy, less gastrointestinal (GI) dysfunction, and less respiratory depression than morphine. This led to efforts to identify oliceridine (TRV130), a G protein-biased ligand with less β-arrestin2 recruitment to the MOR. Pre-clinical data indicate that oliceridine is a potent analgesic with an improved safety and tolerability profile compared to conventional opioid analgesics. Intravenous oliceridine has been compared to intravenous morphine in Phase 1, Phase 2, and Phase 3 clinical trials. Evidence from these studies, using multiple measures of efficacy, safety, and tolerability, suggest that oliceridine may offer patients who require intravenous opioids the analgesic efficacy associated with conventional opioids with potential for less post-operative nausea and vomiting, and reduced risk of opioid-induced respiratory depression. To our knowledge, oliceridine was the first pain program granted Breakthrough Therapy designation by the FDA. Oliceridine is an investigational agent not approved by the FDA or any other regulatory agency.

Discovery of oliceridine (TRV130), a novel G protein biased ligand at the µ-opioid receptor, for the management of moderate to severe acute pain

255th National Meeting (2018)

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