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Look before leaping: combined opioids may not be the rave

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Abstract

The use of combinations of potent opioids is a common clinical practice. The addition of one potent opioid to another has been recommended to reduce opioid side effects, improve pain control, and limit dose escalation of the first opioid. The advantages of using combined opioids have been reported to be relative to differences in receptor activation versus endocytosis (RAVE). However, the advantages and detriment to combining opioids are related to naturally occurring opioid receptor dimers. Dimers and oligomers result in a unique opioid pharmacodynamics which influence opioid binding, G protein interactions, desensitization, receptor trafficking, and endocytosis. The pharmacodynamics of dimers may lead to positive or negative cooperativity when two opioids are combined. The use of multiple opioids in practice can lead to increased risk for dosing errors, reduced patient compliance, increased drug interactions and cost. Opioid combinations should not be used until prospective randomized trials clarify the benefits and safety.

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References

  1. Davis MP, Estfan B, Walsh D, Shaheen P, LeGrand SB, Lagman RL (2004) Errors in opioids prescribing: a prospective survey. Support Care Cancer 12(6):399

    Google Scholar 

  2. Mercandate S, Villari P, Ferrera P, Casuccio A (2004) Addition of second opioid may improve opioid response in cancer pain: preliminary data. Support Care Cancer 12(11):762–766

    Article  PubMed  Google Scholar 

  3. Morita T, Tei Y, Inoue S (2003) Agitated terminal delirium and association with partial opioid substitution and hydration. J Palliat Med 6(4):557–563

    Article  PubMed  Google Scholar 

  4. Lauretti GR, Oliveria GM, Pereira NL (2003) Comparison of sustained-release morphine with sustained-release oxycodone in advanced cancer patients. Br J Cancer 89:2027–2030

    Article  CAS  PubMed  Google Scholar 

  5. Kloke M (2004) Gaps and junctions between clinical experience and theoretical framework in the use of opioids. Support Care Cancer 12:749–751

    Article  PubMed  Google Scholar 

  6. Law PY, Loh HH (1999) Regulation of opioid receptor activities. JPET 289:607–624

    CAS  Google Scholar 

  7. Watson B, Meng F, Akil H (1996) A chimeric analysis of the opioid receptor domains critical for the binding selectivity of μ opioid ligands. Neurobiol Dis 3:87–96

    Article  CAS  PubMed  Google Scholar 

  8. Jordan BA, Cvejic S, Devi LA (2000) Opioids and their complicated receptor complexes. Neuropsychopharmacology 23(S4):S5–S18

    Article  CAS  PubMed  Google Scholar 

  9. Rios CD, Jordan BA, Gomes I, Devi LA (2001) G-protein-coupled receptor dimerization: modulation of receptor function. Pharmacol Ther 92:71–87

    Article  CAS  PubMed  Google Scholar 

  10. Nester EJ (2001) Heterotrimeric G proteins. In: Siegel GJ, Agranoff BW, Albers RW, Fisher SK, Uhler MD (eds) Basic neurochemistry. Lippincott Williams and Wilkins, Philadelphia

  11. Ferguson SSG (2001) Evolving concepts in G-protein coupled receptor endocytosis: the role in receptor desensitization and signaling. Pharmacol Rev 53:1–24

    CAS  PubMed  Google Scholar 

  12. Waldhoer M, Bartlett SE, Whistler JL (2004) Opioid receptors. Annu Rev Biochem 73:953–990

    Article  CAS  PubMed  Google Scholar 

  13. Qui Y, Law PY, Loh HH (2003) Mu-opioid receptor desensitization: role of receptor phosphorylation, internalization, and representation. J Biol Chem 278(38):36733–36739

    Article  PubMed  Google Scholar 

  14. von Zastrow M (2004) A cell biologist’s perspective on physiological adaptation to opiate drugs. Neuropharmacology 47(Suppl 1):286–292

    Article  Google Scholar 

  15. von Zastrow M, Svingos A, Haberstock-Debic H, Evans C (2003) Regulated endocytosis of opioid receptors: cellular mechanisms and proposed roles of physiological adaptation to opiate drugs. Curr Opin Neurobiol 13:348–353

    Article  PubMed  Google Scholar 

  16. Whistler JL, von Zastrow M (1998) Morphine-activated opioid receptors elude desensitization by β-arrestin. Proc Natl Acad Sci U S A 95:9914–9919

    Article  CAS  PubMed  Google Scholar 

  17. Adams JU, Paronis CA, Holtzman SG (1990) Assessment of relative intrinsic activity of mu-opioid analgesics vivo by using funaltrexamine. JPET 255(3):1027–1032

    CAS  Google Scholar 

  18. Ueda H (2004) Locus-specific involvement of anti-opioid systems in morphine tolerance and dependence. Ann NY Acad Sci 1025:376–382

    Article  CAS  PubMed  Google Scholar 

  19. Burford NT, Tolbert LM, Sadee W (1998) Specific G protein activation and mu-opioid receptor internalization caused by morphine, DAMGO and endomorphine I. Eur J Pharmacol 342(1):123–126

    Article  CAS  PubMed  Google Scholar 

  20. Koch T, Widera A, Bartzsch K, Schulz S, Brandenburg LO, Wundrack Beyer A, Grecksch G, Hollt V (2004) Receptor endocytosis counteracts the development of opioid tolerance. Mol Pharmacol (Epub)

  21. Morgan D, Picker MJ (1998) The mu opioid irreversible antagonist beta-funaltrexamine differentiates the discriminative stimulus effects of opioids with high and low efficacy at the mu receptor. Psychopharmacology (Berl) 140(1):20–28

    Article  CAS  Google Scholar 

  22. Bohn LM, Gainetdinov RR, Caron MG (2004) G protein-coupled receptor kinase/β-arrestin systems and drugs of abuse. Neuromol Med 5:41–50

    Article  CAS  Google Scholar 

  23. Liu-Chen LY (2004) Agonist-induced regulation and trafficking of kappa opioid receptors. Life Sci 75(5):511–536

    Article  CAS  PubMed  Google Scholar 

  24. Zhang J, Ferguson SSG, Barak LS, Bodduluri SR, Laporte SA, Law PY, Caron MG (1998) Role for G protein-coupled receptor kinase in agonist-specific regulation of μ-opioid receptor responsiveness. PNAS 95(12):7157–7162

    Article  CAS  PubMed  Google Scholar 

  25. Trapaidze N, Gomes I, Bansinath M, Devi LA (2000) Recycling and resensitization of delta opioid receptors. DNA Cell Biol 19(4):195–204

    Article  CAS  PubMed  Google Scholar 

  26. Trapaidze N, Gomes I, Cvejic S, Bansinath M, Devi LA (2000) Opioid receptor endocytosis and activation of MAP kinase pathway. Brain Res Mol Brain Res 76(2):220–228

    Article  CAS  PubMed  Google Scholar 

  27. Eisinger DA, Ammer H, Schulz R (2002) J Neurosci 22(23):10192–10200

    CAS  PubMed  Google Scholar 

  28. He L, Fong J, von Zastrow M, Whistler JL (2002) Regulation of opioid receptor trafficking and morphine tolerance by receptor oligomerization. Cell 108(2):271–282

    Article  CAS  PubMed  Google Scholar 

  29. von Zastrow M (2004) Opioid receptor regulation. Neuromol Med 5(1):51–58

    Article  Google Scholar 

  30. Zachariou V, Georgescu D, Sanchez N, Rahman Z, DiLeone R, Berton O, Neve RL, Sim-Selley LJ, Selley DE, Gold SJ, Nestler EJ (2003) Essential role for RGS9 in opiate action. PNAS 100(23):13656–13661

    Article  CAS  PubMed  Google Scholar 

  31. Clark MJ, Harrison C, Zhong H, Neubig RR, Traynor JR (2003) Endogenous RGS protein action modulated μ-opioid signaling through Gα. J Biol Chem 278(11):9418–9425

    Article  CAS  PubMed  Google Scholar 

  32. Xu H, Wang X, Wang J, Rothman RB (2004) Opioid peptide receptor studies. 17. attenuation of chronic morphine effects after antisense olgiodeoxynucleotide knock-down of RGS9 protein in cells expressing the cloned Mu opioid receptor. Synapse 52:209–217

    Article  CAS  PubMed  Google Scholar 

  33. Clark MJ, Traynor JR (2004) Endogenous RGS proteins reduce mu-opioid receptor desensitization and down-regulation and adenylyl cyclase tolerance in C6 cells. JPET 278(11):9418–9424

    Google Scholar 

  34. Garzon J, Rodriguez-Munoz, Lopez-Fando A, Garcia-Espana A, Sanchez-Biazquez P (2001) RGSZ1 and GAIP regulate μ- but not ş opioid receptors in mouse CNS: role in tachyphylaxis and acute tolerance to mu-opioid effects. Eur J Neurosci 13(4):801–811

    Article  CAS  PubMed  Google Scholar 

  35. Garzon J, Rodriguez-Diaz M, Lopez-Fando A, Sanchez-Blazquez P (2001) RGS9 proteins facilitate acute tolerance to mu-opioid effects. Eur J Neurosci 13(4):801–811

    Article  CAS  PubMed  Google Scholar 

  36. Gomes I, Jordan BA, Gupta A, Rios C, Trapaidze N, Devi LA (2001) G protein coupled receptor dimerization: implications in modulating receptor function. J Mol Med 79(5–6):226–242

    Article  CAS  PubMed  Google Scholar 

  37. McVey M, Ramsay D, Kellett E, Rees S, Wilson S, Pope AJ, Milligan G (2001) Monitoring receptor oligomerization using time-resolved fluorescence resonance energy transfer. The human delta-opioid receptor displays constitutive oligomerization at the cell surface, which is not regulated by receptor occupancy. J Biol Chem 276(17):14092–14099

    CAS  PubMed  Google Scholar 

  38. George SR, Fan T, Xie Z, Tse R, Tam V, Varghese G, O’Dowd BF (2000) Oligomerization of μ and ş-opioid receptors. J Biol Chem 275(34):26128–26135

    Article  CAS  PubMed  Google Scholar 

  39. Gomes I, Filipovska J, Jordan BA, Devi LA (2002) Oligomerization of opioid receptors. Methods 27(4):358–365

    Article  CAS  PubMed  Google Scholar 

  40. George SR, O’Dowd BF, Lee SP (2002) G-protein-coupled receptor oligomerization and its potential for drug discovery. Nature 1:808–820

    Article  CAS  Google Scholar 

  41. Gomes I, Jordan BA, Gupta A, Trapaidze N (2000) Heterodimerization of μ and μ opioid receptors: a role in opiate synergy. J Neurosci 20:15

    Google Scholar 

  42. Rios CD, Jordan BA, Gomes I, Devi LA (2001) G-protein-coupled receptor dimerization: modulation of receptor function. Pharmacol Ther 92(2–3):71–87

    Article  CAS  PubMed  Google Scholar 

  43. Gomes I, Gupta A, Filipovska J, Szeto HH, Pintar JE, Devi LA (2004) A role for heterodimerization of μ and ð opiate receptors in enhancing morphine analgesia. PNAS 101(14):5135–5139

    Article  CAS  PubMed  Google Scholar 

  44. Filizola M, Olmea O, Weinstein H (2002) Prediction of heterodimerization interfaces of G-protein coupled receptors with a new subtractive correlated mutation method. Protein Eng 15(11):881–885

    Article  CAS  PubMed  Google Scholar 

  45. Levac BA, O’Dowd BF, George SR (2002) Oligomerization of opioid receptors: generation of novel signaling units. Curr Opin Pharmacol 2(1):76–81

    Article  CAS  PubMed  Google Scholar 

  46. Bolan EA, Tallarida RJ, Pasternak GW (2002) Synergy between μ opioid ligands: evidence for functional interactions among μ opioid receptor subtypes. JPET 303:557–562

    Article  CAS  Google Scholar 

  47. Whistler JL, Chuang HH, Chu P, Jan LY, von Zastrow M (1999) Functional dissociation of mu opioid receptor signaling and endocytosis: implications for the biology of opiate tolerance and addiction. Neuron 23(4):737–746

    Article  CAS  PubMed  Google Scholar 

  48. Grach M, Massalla W, Pud D, Adler R, Eisenberg E (2004) Can Coadministration of oxycodone and morphine produce analgesic synergy in humans? An experimental cold pain study. Br J Clin Pharmacol 58(3):235–242

    Article  CAS  PubMed  Google Scholar 

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Correspondence to Mellar P. Davis.

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A World Health Organization Demonstration Project

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Davis, M.P., LeGrand, S.B. & Lagman, R. Look before leaping: combined opioids may not be the rave. Support Care Cancer 13, 769–774 (2005). https://doi.org/10.1007/s00520-005-0839-y

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  • DOI: https://doi.org/10.1007/s00520-005-0839-y

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