title: A randomized, phase 2 study investigating TRV130, a biased ligand of the μ-opioid receptor, for the intravenous treatment of acute pain.
abstract: Efficacy of conventional opioids can be limited by adverse events (AEs). TRV130 is a structurally novel biased ligand of the μ-opioid receptor that activates G protein signaling with little β-arrestin recruitment. In this phase 2, randomized, placebo- and active-controlled study, we investigated the efficacy and tolerability of TRV130 in acute pain after bunionectomy. We used an adaptive study design in which 144 patients experiencing moderate-to-severe acute pain after bunionectomy were randomized to receive double-blind TRV130, placebo, or morphine in a pilot phase. After pilot phase analysis, 195 patients were randomized to receive double-dummy TRV130 0.5, 1, 2, or 3 mg every 3 hours (q3h); placebo; or morphine 4 mg q4h intravenously. The primary end point was the time-weighted average change in numeric rating scale pain intensity over the 48-hour treatment period. Secondary end points included stopwatch and categorical assessments of pain relief. Safety and tolerability were also assessed. TRV130 2 and 3 mg q3h, and morphine 4 mg q4h produced statistically greater mean reductions in pain intensity than placebo over 48 hours (P < 0.005). TRV130 at 2 and 3 mg produced significantly greater categorical pain relief than morphine (P < 0.005) after the first dose, with meaningful pain relief occurring in under 5 minutes. TRV130 produced no serious AEs, with tolerability similar to morphine. These results demonstrate that TRV130 rapidly produces profound analgesia in moderate-to-severe acute pain, suggesting that G-protein-biased μ-opioid receptor activation is a promising target for development of novel analgesics.
authors.affiliation: Thomas Jefferson University, Philadelphia, PA, USA PRA Health Sciences, Salt Lake City, UT, USA Premier Research Group Ltd, Austin, TX, USA Cytel Inc, Chesterbrook, PA, USA Trevena, Inc, King of Prussia, PA, USA.
authors.forename: Eugene R
authors.initials: ER
authors.lastname: Viscusi
authors.forename: Lynn
authors.initials: L
authors.lastname: Webster
authors.forename: Michael
authors.initials: M
authors.lastname: Kuss
authors.forename: Stephen
authors.initials: S
authors.lastname: Daniels
authors.forename: James A
authors.initials: JA
authors.lastname: Bolognese
authors.forename: Seth
authors.initials: S
authors.lastname: Zuckerman
authors.forename: David G
authors.initials: DG
authors.lastname: Soergel
authors.forename: Ruth Ann
authors.initials: RA
authors.lastname: Subach
authors.forename: Emily
authors.initials: E
authors.lastname: Cook
authors.forename: Franck
authors.initials: F
authors.lastname: Skobieranda
mesh_terms: D059787:Acute Pain / Q000188:drug therapy* / Q000209:etiology; D000293:Adolescent; D000328:Adult; D000368:Aged; D000701:Analgesics, Opioid / Q000627:therapeutic use*; D004311:Double-Blind Method; D005260:Female; D006215:Hallux Valgus / Q000601:surgery; D006801:Humans; D008297:Male; D008875:Middle Aged; D009020:Morphine / Q000627:therapeutic use; D019637:Orthopedic Procedures / Q000009:adverse effects; D017450:Receptors, Opioid, mu / Q000819:agonists*; D013141:Spiro Compounds / Q000627:therapeutic use*; D013876:Thiophenes / Q000627:therapeutic use*; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: C586842:((3-methoxythiophen-2-yl)methyl)((2-(9-(pyridin-2-yl)-6-oxaspiro(4.5)decan-9-yl)ethyl))amine; D000701:Analgesics, Opioid; D017450:Receptors, Opioid, mu; D013141:Spiro Compounds; D013876:Thiophenes; D009020:Morphine