Opioids are widely used in the United States to manage moderate to severe acute postoperative pain, but adverse events, including respiratory depression and gastrointestinal dysfunction, can limit the dosing required for analgesic efficacy. Oliceridine—a novel mu-receptor G protein pathway selective modulator—may provide effective, rapid analgesia and reduce typical adverse effects, according to two recent Phase II studies in patients undergoing bunionectomy and abdominoplasty.
“Intravenous opioids are highly effective therapies for the management of acute pain in the hospital and ambulatory settings, but their side effects are really limiting—we’re trying to change that paradigm with oliceridine,” said David Soergel, MD, chief medical officer at Trevena Inc., a biotechnology company based in King of Prussia, Pa., which sponsored the studies.
Dr. Soergel presented research (poster 45) at the 2016 joint meeting of the Society for Ambulatory Anesthesia and the American Society of Anesthesiologists. Co-authors were Eugene R. Viscusi, MD, professor of anesthesiology at Thomas Jefferson University, in Philadelphia, and advisory board member of Anesthesiology News; Lynn R. Webster, MD, of PRA Health Sciences; and David Burt, MD, and Franck Skobieranda, MD, both of Trevena. The research won the meeting’s top award.
Meeting a Need
Conventional opioids, such as morphine, nonselectively activate two intracellular signaling pathways: the G protein pathway associated with analgesia and the beta-arrestin pathway associated with opioid-related adverse events and inhibition of G protein–mediated analgesia.
Oliceridine, however, is a novel mu-GPS modulator that differentially activates G protein signaling while causing low beta-arrestin recruitment to the mu-opioid receptor. During a Phase II bunionectomy study, oliceridine produced rapid and predictable analgesia.
“There remain many unmet needs in acute pain management in the hospital setting,” Dr. Viscusi said. “Opioids, with their common side effects of nausea and respiratory depression, remain the most widely used analgesics. A novel opioid with an improved side-effect profile, particularly with respiratory depression and nausea, would be an important step forward in the hospital setting.”
In the randomized, double-dummy, adaptive stage of the study, 192 patients were treated with 1, 2 or 3 mg of oliceridine every three hours, or 4 mg of morphine every four hours via fixed bolus doses for 48 hours. Pain intensity was measured with the 0- to 10-point numeric pain rating scale. Rescue analgesics were available as needed.
Effective Pain Relief Demonstrated
After three hours, mean pain scores for oliceridine were significantly reduced versus the morphine scores. After 12 hours, the differences were even more prominent. Adverse events associated with oliceridine were dose related and similar in nature to conventional opioids, and no serious adverse events were reported.
At five and 15 minutes after the first bolus dose, a greater proportion of patients receiving 2 and 3 mg of oliceridine reported “a lot” to “complete” pain relief versus patients receiving 4 mg of morphine.
“These results suggest that oliceridine may produce more rapid and effective analgesia than conventional opioids with a similar adverse event profile. We believe that, at equianalgesic doses, oliceridine may have the potential for an improved safety and tolerability profile,” Dr. Soergel said. “Our goal is to provide a powerful tool with a wider therapeutic window to treat individual patients with pain.”
At the same conference, Tong Joo (T.J.) Gan, MD, professor and chairman of the Department of Anesthesiology at Stony Brook University, in New York, presented a second poster titled “Responder Rate With Oliceridine (TRV130), a Novel Mu Receptor G Protein Pathway Selective (mu-GPS) Modulator, vs. Morphine,” in which oliceridine was evaluated versus placebo and morphine for IV patient-controlled analgesia. At equianalgesic doses, oliceridine demonstrated an improved safety and tolerability profile versus morphine, supporting the hypothesis that at equianalgesic doses, oliceridine may have improved safety and tolerability versus conventional opioids.
“These results provide strong support that oliceridine may have a wider therapeutic window compared to conventional opioids,” Dr. Gan said. The FDA has granted oliceridine a breakthrough therapy designation, the first in history for an analgesic drug candidate.