Biased agonism of the μ-opioid receptor by TRV130 increases analgesia and reduces on-target adverse effects versus morphine: A randomized, double-blind, placebo-controlled, crossover study in healthy volunteers

• Published in: Pain (Amsterdam) Vol. 155; no. 9; pp. 1829 - 1835
• Main Authors: Soergel, David G., Subach, Ruth Ann, Burnham, Nancy, Lark, Michael W., James, Ian E., Sadler, Brian M., Skobieranda, Franck, Violin, Jonathan D., Webster, Lynn R.
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA Elsevier B.V 01.09.2014; International Association for the Study of Pain; Elsevier
• Subjects: Adolescent; Adult; Analgesia; Analgesics; Analgesics, Opioid - administration & dosage; Analgesics, Opioid - adverse effects; Analgesics, Opioid - therapeutic use; Biased ligand; Biological and medical sciences; Clinical trial; Cross-Over Studies; Dizziness - chemically induced; Dose-Response Relationship, Drug; Double-Blind Method; Fundamental and applied biological sciences. Psychology; Headache - chemically induced; Healthy Volunteers; Humans; Male; Medical sciences; Middle Aged; Morphine; Morphine - administration & dosage; Morphine - adverse effects; Morphine - therapeutic use; mu-Opioid receptor; Neuropharmacology; Pain - drug therapy; Pharmacology. Drug treatments; Postoperative pain; Somesthesis and somesthetic pathways (proprioception, exteroception, nociception); interoception; electrolocation. Sensory receptors; Spiro Compounds - administration & dosage; Spiro Compounds - adverse effects; Spiro Compounds - therapeutic use; Thiophenes - administration & dosage; Thiophenes - adverse effects; Thiophenes - therapeutic use; Vertebrates: nervous system and sense organs; Vomiting - chemically induced; Young Adult; Clinical trial; Morphine; Postoperative pain; mu-Opioid receptor; Biased ligand; Postoperative; Healthy subject; μ Opioid receptor; Opiates; Narcotic analgesic; Analgesia; Pain; Placebo; Double blind study; Comparative study
• ISSN: 0304-3959; 1872-6623; 1872-6623
• DOI: 10.1016/j.pain.2014.06.011

An experimental medicine comparison of the novel biased ligand TRV130 to morphine reveals that selective signaling at the mu opioid receptor may improve opioid therapeutic index. Opioids provide powerful analgesia but also efficacy-limiting adverse effects, including severe nausea, vomiting, and respiratory depression, by activating μ-opioid receptors. Preclinical models suggest that differential activation of signaling pathways downstream of these receptors dissociates analgesia from adverse effects; however, this has not yet translated to a treatment with an improved therapeutic index. Thirty healthy men received single intravenous injections of the biased ligand TRV130 (1.5, 3, or 4.5mg), placebo, or morphine (10mg) in a randomized, double-blind, crossover study. Primary objectives were to measure safety and tolerability (adverse events, vital signs, electrocardiography, clinical laboratory values), and analgesia (cold pain test) versus placebo. Other measures included respiratory drive (minute volume after induced hypercapnia), subjective drug effects, and pharmacokinetics. Compared to morphine, TRV130 (3, 4.5mg) elicited higher peak analgesia (105, 116seconds latency vs 75seconds for morphine, P<.02), with faster onset and similar duration of action. More subjects doubled latency or achieved maximum latency (180seconds) with TRV130 (3, 4.5mg). Respiratory drive reduction was greater after morphine than any TRV130 dose (−15.9 for morphine versus −7.3, −7.6, and −9.4 h*L/min, P<.05). More subjects experienced severe nausea after morphine (n=7) than TRV130 1.5 or 3mg (n=0, 1), but not 4.5mg (n=9). TRV130 was generally well tolerated, and exposure was dose proportional. Thus, in this study, TRV130 produced greater analgesia than morphine at doses with less reduction in respiratory drive and less severe nausea. This demonstrates early clinical translation of ligand bias as an important new concept in receptor-targeted pharmacotherapy.