The Korean Journal of Pain

The Korean Pain Society (대한통증학회)
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Can oliceridine (TRV130), an ideal novel µ receptor G protein pathway selective (µ-GPS) modulator, provide analgesia without opioid-related adverse reactions?

  • Ok, Hwoe Gyeong (Department of Anesthesia and Pain Medicine, School of Medicine, Pusan National University) ;
  • Kim, Su Young (Department of Anesthesia and Pain Medicine, School of Medicine, Pusan National University) ;
  • Lee, Su Jung (Department of Anesthesia and Pain Medicine, School of Medicine, Pusan National University) ;
  • Kim, Tae Kyun (Department of Anesthesia and Pain Medicine, School of Medicine, Pusan National University) ;
  • Huh, Billy K (Department of Pain Medicine, The University of Texas M.D. Anderson Cancer Center) ;
  • Kim, Kyung Hoon (Department of Anesthesia and Pain Medicine, School of Medicine, Pusan National University)
  • Received : 2018.02.08
  • Accepted : 2018.03.08
  • Published : 2018.04.01
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Abstract

All drugs have both favorable therapeutic and untoward adverse effects. Conventional opioid analgesics possess both analgesia and adverse reactions, such as nausea, vomiting, and respiratory depression. The opioid ligand binds to ${\mu}$ opioid receptor and non-selectively activates two intracellular signaling pathways: the G protein pathway induce analgesia, while the ${\beta}$-arrestin pathway is responsible for the opioid-related adverse reactions. An ideal opioid should activate the G protein pathway while deactivating the ${\beta}$-arrestin pathway. Oliceridine (TRV130) has a novel characteristic mechanism on the action of the ${\mu}$ receptor G protein pathway selective (${\mu}$-GPS) modulation. Even though adverse reactions (ADRs) are significantly attenuated, while the analgesic effect is augmented, the some residual ADRs persist. Consequently, a G protein biased ${\mu}$ opioid ligand, oliceridine, improves the therapeutic index owing to increased analgesia with decreased adverse events. This review article provides a brief history, mechanism of action, pharmacokinetics, pharmacodynamics, and ADRs of oliceridine.

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References

  1. Chen XT, Pitis P, Liu G, Yuan C, Gotchev D, Cowan CL, et al. Structure-activity relationships and discovery of a G protein biased ${\mu}$ opioid receptor ligand, [(3-methoxythiophen-2-yl)methyl]({2-[(9R)-9-(pyridin-2-yl)-6- oxaspiro-[4.5]de can-9-yl]ethyl})amine (TRV130), for the treatment of acute severe pain. J Med Chem 2013; 56: 8019-31. https://doi.org/10.1021/jm4010829
  2. Williams JT, Ingram SL, Henderson G, Chavkin C, von Zastrow M, Schulz S, et al. Regulation of ${\mu}$-opioid receptors: desensitization, phosphorylation, internalization, and tolerance. Pharmacol Rev 2013; 65: 223-54. https://doi.org/10.1124/pr.112.005942
  3. Fredriksson R, Lagerstrom MC, Lundin LG, Schioth HB. The G-protein-coupled receptors in the human genome form five main families. Phylogenetic analysis, paralogon groups, and fingerprints. Mol Pharmacol 2003; 63: 1256-72. https://doi.org/10.1124/mol.63.6.1256
  4. Kochman K. Superfamily of G-protein coupled receptors (GPCRs)--extraordinary and outstanding success of evolution. Postepy Hig Med Dosw (Online) 2014; 68: 1225-37. https://doi.org/10.5604/17322693.1127326
  5. Schioth HB, Fredriksson R. The GRAFS classification system of G-protein coupled receptors in comparative perspective. Gen Comp Endocrinol 2005; 142: 94-101. https://doi.org/10.1016/j.ygcen.2004.12.018
  6. Smith HS. Peripherally-acting opioids. Pain Physician 2008; 11: S121-32.
  7. Sehgal N, Smith HS, Manchikanti L. Peripherally acting opioids and clinical implications for pain control. Pain Physician 2011; 14: 249-58.
  8. Burness CB, Keating GM. Oxycodone/naloxone prolongedrelease: a review of its use in the management of chronic pain while counteracting opioid-induced constipation. Drugs 2014; 74: 353-75. https://doi.org/10.1007/s40265-014-0177-9
  9. Morlion B, Clemens KE, Dunlop W. Quality of life and healthcare resource in patients receiving opioids for chronic pain: a review of the place of oxycodone/naloxone. Clin Drug Investig 2015; 35: 1-11.
  10. Violin JD, Crombie AL, Soergel DG, Lark MW. Biased ligands at G-protein-coupled receptors: promise and progress. Trends Pharmacol Sci 2014; 35: 308-16. https://doi.org/10.1016/j.tips.2014.04.007
  11. Bohn LM, Lefkowitz RJ, Gainetdinov RR, Peppel K, Caron MG, Lin FT. Enhanced morphine analgesia in mice lacking beta-arrestin 2. Science 1999; 286: 2495-8.
  12. Bohn LM, Gainetdinov RR, Lin FT, Lefkowitz RJ, Caron MG. Mu-opioid receptor desensitization by beta-arrestin-2 determines morphine tolerance but not dependence. Nature 2000; 408: 720-3. https://doi.org/10.1038/35047086
  13. Raehal KM, Walker JK, Bohn LM. Morphine side effects in beta-arrestin 2 knockout mice. J Pharmacol Exp Ther 2005; 314: 1195-201.
  14. Soergel DG, Subach RA, Sadler B, Connell J, Marion AS, Cowan CL, et al. First clinical experience with TRV130: pharmacokinetics and pharmacodynamics in healthy volunteers. J Clin Pharmacol 2014; 54: 351-7. https://doi.org/10.1002/jcph.207
  15. Soergel DG, Subach RA, Burnham N, Lark MW, James IE, Sadler BM, et al. Biased agonism of the ${\mu}$-opioid receptor by TRV130 increases analgesia and reduces on-target adverse effects versus morphine: a randomized, doubleblind, placebo-controlled, crossover study in healthy volunteers. Pain 2014; 155: 1829-35.
  16. Fossler M, Sadler B, Farrell C, Burt D, Pitsiu M, Skobieranda F, et al. (342) Oliceridine (TRV130), a novel ${\mu}$ receptor G protein pathway selective modulator (${\mu}$-GPS), demonstrates a predictable relationship between plasma concentrations and pain relief. I: development of a pharmacokinetic/pharmacodynamic (PK/PD) model. J Pain 2016; 17: S61.
  17. Fossler M, Sadler B, Farrell C, Burt D, Pitsiu M, Skobieranda F, et al. (343) Oliceridine (TRV130), a novel ${\mu}$ receptor G protein pathway selective modulator (${\mu}$-GPS), demonstrates a predictable relationship between plasma concentrations and pain relief. II: simulation of potential dosing regimens using a pharmacokinetic/pharmacodynamic (PK/PD) model. J Pain 2016; 17: S61.
  18. Viscusi E, Minkowitz H, Webster L, Soergel D, Burt D, Subach R, et al. (433) Rapid reduction in pain intensity with oliceridine (TRV130), a novel ${\mu}$ receptor G protein pathway selective modulator (${\mu}$-GPS), vs. morphine: an analysis of two phase 2 randomized clinical trials. J Pain 2016; 17:S82-3.
  19. Singla N, Minkowitz H, Soergel D, Burt D, Skobieranda F. (432) Respiratory safety signal with oliceridine (TRV130), a novel ${\mu}$ receptor G protein pathway selective modulator (${\mu}$-GPS), vs morphine: a safety analysis of a phase 2b randomized clinical trial. J Pain 2016; 17: S82.
  20. Minkowitz H, Singla N, Soergel D, Burt D, Skobieranda F. (435) Nausea and vomiting with oliceridine (TRV130), a novel ${\mu}$ receptor G protein pathway selective modulator (${\mu}$-GPS), vs morphine: an analysis of tolerability from a phase 2b randomized clinical trial. J Pain 2016; 17: S83.
  21. Viscusi ER, Webster L, Kuss M, Daniels S, Bolognese JA, Zuckerman S, et al. A randomized, phase 2 study investigating TRV130, a biased ligand of the ${\mu}$-opioid receptor, for the intravenous treatment of acute pain. Pain 2016; 157: 264-72.
  22. Madariaga-Mazon A, Marmolejo-Valencia AF, Li Y, Toll L, Houghten RA, Martinez-Mayorga K. Mu-Opioid receptor biased ligands: a safer and painless discovery of analgesics? Drug Discov Today 2017; 22: 1719-29. https://doi.org/10.1016/j.drudis.2017.07.002
  23. Pierce KL, Premont RT, Lefkowitz RJ. Seven-transmembrane receptors. Nat Rev Mol Cell Biol 2002; 3: 639-50. https://doi.org/10.1038/nrm908
  24. Jacoby E, Bouhelal R, Gerspacher M, Seuwen K. The 7 TM G-protein-coupled receptor target family. ChemMedChem 2006; 1: 760-82. https://doi.org/10.1002/cmdc.200600134
  25. McCudden CR, Hains MD, Kimple RJ, Siderovski DP, Willard FS. G-protein signaling: back to the future. Cell Mol Life Sci 2005; 62: 551-77. https://doi.org/10.1007/s00018-004-4462-3
  26. Patel TB. Single transmembrane spanning heterotrimeric G protein-coupled receptors and their signaling cascades. Pharmacol Rev 2004; 56: 371-85. https://doi.org/10.1124/pr.56.3.4
  27. Whalen EJ, Rajagopal S, Lefkowitz RJ. Therapeutic potential of ${\beta}$-arrestin- and G protein-biased agonists. Trends Mol Med 2011; 17: 126-39. https://doi.org/10.1016/j.molmed.2010.11.004
  28. Kliewer A, Reinscheid RK, Schulz S. Emerging paradigms of G protein-coupled receptor dephosphorylation. Trends Pharmacol Sci 2017; 38: 621-36. https://doi.org/10.1016/j.tips.2017.04.002
  29. Dang VC, Christie MJ. Mechanisms of rapid opioid receptor desensitization, resensitization and tolerance in brain neurons. Br J Pharmacol 2012; 165: 1704-16. https://doi.org/10.1111/j.1476-5381.2011.01482.x
  30. Allouche S, Noble F, Marie N. Opioid receptor desensitization: mechanisms and its link to tolerance. Front Pharmacol 2014; 5: 280.
  31. Wright JM. The double-edged sword of COX-2 selective NSAIDs. CMAJ 2002; 167: 1131-7.
  32. Del Vecchio G, Spahn V, Stein C. Novel opioid analgesics and side effects. ACS Chem Neurosci 2017; 8: 1638-40. https://doi.org/10.1021/acschemneuro.7b00195
  33. Manglik A, Lin H, Aryal DK, McCorvy JD, Dengler D, Corder G, et al. Structure-based discovery of opioid analgesics with reduced side effects. Nature 2016; 537: 185-90.
  34. Siuda ER, Carr R 3rd, Rominger DH, Violin JD. Biased mu-opioid receptor ligands: a promising new generation of pain therapeutics. Curr Opin Pharmacol 2017; 32: 77-84.

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