A review of morphine and morphine-6-glucuronide's pharmacokinetic-pharmacodynamic relationships in experimental and clinical pain

European Journal of Pharmaceutical Sciences

Volumn 74, Issue , 2015, Pages 45-62

  Sverrisdóttir, Eva ^a   Lund, Trine Meldgaard ^a   Olesen, Anne Estrup ^a,b   Drewes, Asbjørn Mohr ^b,c   Christrup, Lona Louring ^a   Kreilgaard, Mads ^a  

^a UNIVERSITY OF COPENHAGEN   (Denmark)

^b AALBORG UNIVERSITY HOSPITAL   (Denmark)

^c AALBORG UNIVERSITY   (Denmark)

Author keywords

Analgesia; Modelling; Morphine; Morphine 6 glucuronide; Pharmacokinetics pharmacodynamics; Simulations

Indexed keywords

DRUG METABOLITE; MORPHINE; MORPHINE 6 GLUCURONIDE; MU OPIATE RECEPTOR; MORPHINE DERIVATIVE; MORPHINE-6-GLUCURONIDE; NARCOTIC ANALGESIC AGENT;

ANALGESIA; ARTICLE; DRUG ABSORPTION; DRUG DISTRIBUTION; DRUG EXCRETION; DRUG HALF LIFE; DRUG METABOLISM; DRUG RESPONSE; EXPERIMENTAL PAIN; HUMAN; KIDNEY FAILURE; NONHUMAN; PAIN; PHARMACOGENETICS; POPULATION RESEARCH; PRIORITY JOURNAL; SIMULATION; STUDY DESIGN; SYSTEMATIC REVIEW (TOPIC); TREATMENT RESPONSE; ACUTE PAIN; ANIMAL; BIOAVAILABILITY; BIOLOGICAL MODEL; BIOTRANSFORMATION; COMPLICATION; HALF LIFE TIME; METABOLISM; PERSONALIZED MEDICINE; TISSUE DISTRIBUTION;

ACUTE PAIN; ANALGESICS, OPIOID; ANIMALS; BIOLOGICAL AVAILABILITY; BIOTRANSFORMATION; HALF-LIFE; HUMANS; MODELS, BIOLOGICAL; MORPHINE; MORPHINE DERIVATIVES; PRECISION MEDICINE; RENAL INSUFFICIENCY; TISSUE DISTRIBUTION;

EID: 84928139287     PISSN: 09280987     EISSN: 18790720     Source Type: Journal    
DOI: 10.1016/j.ejps.2015.03.020     Document Type: Review

References (99)

1. T.A. Aasmundstad, J. Morland, and R.E. Paulsen Distribution of morphine 6-glucuronide and morphine across the blood-brain barrier in awake, freely moving rats investigated by in vivo microdialysis sampling J. Pharmacol. Exp. Ther. 275 1995 435 441
2. T. Andresen, R.N. Upton, D.J. Foster, L.L. Christrup, L. Arendt-Nielsen, and A.M. Drewes Pharmacokinetic/pharmacodynamic relationships of transdermal buprenorphine and fentanyl in experimental human pain models Basic Clin. Pharmacol. Toxicol. 108 2011 274 284
3. M.S. Angst, M. Buhrer, and J. Lötsch Insidious intoxication after morphine treatment in renal failure: delayed onset of morphine-6-glucuronide action Anesthesiology 92 2000 1473 1476
4. S.C. Armstrong, and K.L. Cozza Pharmacokinetic drug interactions of morphine, codeine, and their derivatives: theory and clinical reality, part I Psychosomatics 44 2003 167 171
5. U. Bickel, O.P. Schumacher, Y.S. Kang, and K. Voigt Poor permeability of morphine 3-glucuronide and morphine 6-glucuronide through the blood-brain barrier in the rat J. Pharmacol. Exp. Ther. 278 1996 107 113
6. A.R. Binning, K. Przesmycki, P. Sowinski, L.M. Morrison, T.W. Smith, P. Marcus, J.P. Lees, and A. Dahan A randomised controlled trial on the efficacy and side-effect profile (nausea/vomiting/sedation) of morphine-6-glucuronide versus morphine for post-operative pain relief after major abdominal surgery Eur. J. Pain 15 2011 402 408
7. F. Bourasset, S. Cisternino, J. Temsamani, and J.M. Scherrmann Evidence for an active transport of morphine-6-beta-d-glucuronide but not P-glycoprotein-mediated at the blood-brain barrier J. Neurochem. 86 2003 1564 1567
8. M.R. Bouw, M. Gardmark, and M. Hammarlund-Udenaes Pharmacokinetic-pharmacodynamic modelling of morphine transport across the blood-brain barrier as a cause of the antinociceptive effect delay in rats-a microdialysis study Pharm. Res. 17 2000 1220 1227
9. M.R. Bouw, R. Xie, K. Tunblad, and M. Hammarlund-Udenaes Blood-brain barrier transport and brain distribution of morphine-6-glucuronide in relation to the antinociceptive effect in rats-pharmacokinetic/pharmacodynamic modelling Br. J. Pharmacol. 134 2001 1796 1804
10. H. Breivik, B. Collett, V. Ventafridda, R. Cohen, and D. Gallacher Survey of chronic pain in Europe: prevalence, impact on daily life, and treatment Eur. J. Pain 10 2006 287 333
11. K.J. Chang, and P. Cuatrecasas Multiple opiate receptors. Enkephalins and morphine bind to receptors of different specificity J. Biol. Chem. 254 1979 2610 2618
12. L.L. Christrup Morphine metabolites Acta Anaesthesiol. Scand. 41 1997 116 122
13. B.L. Coffman, G.R. Rios, C.D. King, and T.R. Tephly Human UGT2B7 catalyzes morphine glucuronidation Drug Metab. Dispos. 25 1997 1 4
14. A. Dahan, R. Romberg, L. Teppema, E. Sarton, H. Bijl, and E. Olofsen Simultaneous measurement and integrated analysis of analgesia and respiration after an intravenous morphine infusion Anesthesiology 101 2004 1201 1209
15. B. Dahlstrom, A. Tamsen, L. Paalzow, and P. Hartvig Patient-controlled analgesic therapy, Part IV: pharmacokinetics and analgesic plasma concentrations of morphine Clin. Pharmacokinet. 7 1982 266 279
16. D.S. Darbari, R.H. van Schaik, E.V. Capparelli, S. Rana, R. McCarter, and J. van den Anker UGT2B7 promoter variant -840G>A contributes to the variability in hepatic clearance of morphine in patients with sickle cell disease Am. J. Hematol. 83 2008 200 202
17. A.M. Drewes, H. Gregersen, and L. Arendt-Nielsen Experimental pain in gastroenterology: a reappraisal of human studies Scand. J. Gastroenterol. 38 2003 1115 1130
18. P. Ederoth, K. Tunblad, R. Bouw, C.J. Lundberg, U. Ungerstedt, C.H. Nordstrom, and M. Hammarlund-Udenaes Blood-brain barrier transport of morphine in patients with severe brain trauma Br. J. Clin. Pharmacol. 57 2004 427 435
19. M. Foracchia, A. Hooker, P. Vicini, and A. Ruggeri POPED, a software for optimal experiment design in population kinetics Comput. Meth. Progr. Biomed. 74 2004 29 46
20. B. Frances, R. Gout, G. Campistron, E. Panconi, and J. Cros Morphine-6-glucuronide is more mu-selective and potent in analgesic tests than morphine Prog. Clin. Biol. Res. 328 1990 477 480
21. R. Gagnon, and S. Leonov Optimal population designs for PK models with serial sampling J. Biopharm. Stat. 15 2005 143 163
22. M. Gardmark, M.O. Karlsson, F. Jonsson, and M. Hammarlund-Udenaes Morphine-3-glucuronide has a minor effect on morphine antinociception Pharmacodyn. Model. J. Pharm. Sci. 87 1998 813 820
23. Q.L. Gong, J. Hedner, R. Bjorkman, and T. Hedner Morphine-3-glucuronide may functionally antagonize morphine-6-glucuronide induced antinociception and ventilatory depression in the rat Pain 48 1992 249 255
24. M.D. Green, C.D. King, B. Mojarrabi, P.I. Mackenzie, and T.R. Tephly Glucuronidation of amines and other xenobiotics catalyzed by expressed human UDP-glucuronosyltransferase 1A3 Drug Metab. Dispos. 26 1998 507 512
25. H.B. Gutstein, and H. Akil Opioid Analgesics L.S. Goodman, A. Gilman, L.L. Brunton, J.S. Lazo, K.L. Parker, Goodman & Gilman's the Pharmacological Basis of Therapeutics 2005 McGraw-Hill New York 547 590
26. G.W. Hanks, F. Conno, N. Cherny, M. Hanna, E. Kalso, H.J. McQuay, S. Mercadante, J. Meynadier, P. Poulain, C. Ripamonti, L. Radbruch, J.R. Casas, J. Sawe, R.G. Twycross, V. Ventafridda, and Expert Working Group of the Research Network of the European Association for Palliative Care Morphine and alternative opioids in cancer pain: the EAPC recommendations Br. J. Cancer 84 2001 587 593
27. G.W. Hanks, P.J. Hoskin, G.W. Aherne, D. Chapman, P. Turner, and P. Poulain Enterohepatic circulation of morphine Lancet 1 1988 469
28. M.H. Hanna, K.M. Elliott, and M. Fung Randomized, double-blind study of the analgesic efficacy of morphine-6-glucuronide versus morphine sulfate for postoperative pain in major surgery Anesthesiology 102 2005 815 821
29. J. Hasselstrom, and J. Sawe Morphine pharmacokinetics and metabolism in humans. Enterohepatic cycling and relative contribution of metabolites to active opioid concentrations Clin. Pharmacokinet. 24 1993 344 354
30. M.R. Hoehe, K. Kopke, B. Wendel, K. Rohde, C. Flachmeier, K.K. Kidd, W.H. Berrettini, and G.M. Church Sequence variability and candidate gene analysis in complex disease: association of mu opioid receptor gene variation with substance dependence Hum. Mol. Genet. 9 2000 2895 2908
31. M. Holthe, T.N. Rakvag, P. Klepstad, J.R. Idle, S. Kaasa, H.E. Krokan, and F. Skorpen Sequence variations in the UDP-glucuronosyltransferase 2B7 (UGT2B7) gene: identification of 10 novel single nucleotide polymorphisms (SNPs) and analysis of their relevance to morphine glucuronidation in cancer patients Pharmacogen. J. 3 2003 17 26
32. P.J. Hoskin, and G.W. Hanks Morphine: pharmacokinetics and clinical practice Br. J. Cancer 62 1990 705 707
33. J. Huwyler, J. Drewe, C. Klusemann, and G. Fricker Evidence for P-glycoprotein-modulated penetration of morphine-6-glucuronide into brain capillary endothelium Br. J. Pharmacol. 118 1996 1879 1885
34. J.T. Jorgensen Are we approaching the post-blockbuster era? Pharmacodiagnostics and rational drug development Expert Rev. Mol. Diagn. 8 2008 689 695
35. E.D. Kharasch, C. Hoffer, D. Whittington, and P. Sheffels Role of P-glycoprotein in the intestinal absorption and clinical effects of morphine Clin. Pharmacol. Ther. 74 2003 543 554
36. G.J. Kilpatrick, and T.W. Smith Morphine-6-glucuronide: actions and mechanisms Med. Res. Rev. 25 2005 521 544
37. M. King, W. Su, A. Chang, A. Zuckerman, and G.W. Pasternak Transport of opioids from the brain to the periphery by P-glycoprotein: peripheral actions of central drugs Nat. Neurosci. 4 2001 268 274
38. P. Klepstad, T.T. Rakvag, S. Kaasa, M. Holthe, O. Dale, P.C. Borchgrevink, C. Baar, T. Vikan, H.E. Krokan, and F. Skorpen The 118 A > G polymorphism in the human mu-opioid receptor gene may increase morphine requirements in patients with pain caused by malignant disease Acta Anaesthesiol. Scand. 48 2004 1232 1239
39. K. Kristensen, C.B. Christensen, and L.L. Christrup The mu1, mu2, delta, kappa opioid receptor binding profiles of methadone stereoisomers and morphine Life Sci. 56 1995 PL45-50
40. K.S. LaForge, V. Yuferov, and M.J. Kreek Opioid receptor and peptide gene polymorphisms: potential implications for addictions Eur. J. Pharmacol. 410 2000 249 268
41. B. Lalovic, E. Kharasch, C. Hoffer, L. Risler, L.Y. Liu-Chen, and D.D. Shen Pharmacokinetics and pharmacodynamics of oral oxycodone in healthy human subjects: role of circulating active metabolites Clin. Pharmacol. Ther. 79 2006 461 479
42. K.P. Leow, A.W. Wright, T. Cramond, and M.T. Smith Determination of the serum protein binding of oxycodone and morphine using ultrafiltration Ther. Drug Monit. 15 1993 440 447
43. J. Lötsch, and G. Geisslinger Current evidence for a genetic modulation of the response to analgesics Pain 121 2006 1 5
44. J. Lötsch, and G. Geisslinger Morphine-6-glucuronide: an analgesic of the future? Clin. Pharmacokinet. 40 2001 485 499
45. J. Lötsch, G. Kobal, A. Stockmann, K. Brune, and G. Geisslinger Lack of analgesic activity of morphine-6-glucuronide after short-term intravenous administration in healthy volunteers Anesthesiology 87 1997 1348 1358
46. J. Lötsch, C. Skarke, S. Grosch, J. Darimont, H. Schmidt, and G. Geisslinger The polymorphism A118G of the human mu-opioid receptor gene decreases the pupil constrictory effect of morphine-6-glucuronide but not that of morphine Pharmacogenetics 12 2002 3 9
47. J. Lötsch, C. Skarke, H. Schmidt, S. Grosch, and G. Geisslinger The transfer half-life of morphine-6-glucuronide from plasma to effect site assessed by pupil size measurement in healthy volunteers Anesthesiology 95 2001 1329 1338
48. J. Lötsch, C. Skarke, H. Schmidt, J. Liefhold, and G. Geisslinger Pharmacokinetic modeling to predict morphine and morphine-6-glucuronide plasma concentrations in healthy young volunteers Clin. Pharmacol. Ther. 72 2002 151 162
49. J. Lötsch, A. Stockmann, G. Kobal, K. Brune, R. Waibel, N. Schmidt, and G. Geisslinger Pharmacokinetics of morphine and its glucuronides after intravenous infusion of morphine and morphine-6-glucuronide in healthy volunteers Clin. Pharmacol. Ther. 60 1996 316 325
50. J. Lötsch, M. Weiss, G. Ahne, G. Kobal, and G. Geisslinger Pharmacokinetic modeling of M6G formation after oral administration of morphine in healthy volunteers Anesthesiology 90 1999 1026 1038
51. J. Lötsch, M. Weiss, G. Kobal, and G. Geisslinger Pharmacokinetics of morphine-6-glucuronide and its formation from morphine after intravenous administration Clin. Pharmacol. Ther. 63 1998 629 639
52. J.X. Mazoit, K. Butscher, and K. Samii Morphine in postoperative patients: pharmacokinetics and pharmacodynamics of metabolites Anesth. Analg. 105 2007 70 78
53. B. Meibohm, and H. Derendorf Basic concepts of pharmacokinetic/pharmacodynamic (PK/PD) modelling Int. J. Clin. Pharmacol. Ther. 35 1997 401 413
54. I. Meineke, S. Freudenthaler, U. Hofmann, E. Schaeffeler, G. Mikus, M. Schwab, H.W. Prange, C.H. Gleiter, and J. Brockmoller Pharmacokinetic modelling of morphine, morphine-3-glucuronide and morphine-6-glucuronide in plasma and cerebrospinal fluid of neurosurgical patients after short-term infusion of morphine Br. J. Clin. Pharmacol. 54 2002 592 603
55. R. Melzack The McGill Pain Questionnaire: major properties and scoring methods Pain 1 1975 277 299
56. R.W. Milne, R.L. Nation, A.A. Somogyi, F. Bochner, and W.M. Griggs The influence of renal function on the renal clearance of morphine and its glucuronide metabolites in intensive-care patients Br. J. Clin. Pharmacol. 34 1992 53 59
57. R.W. Milne, P.A. Sloan, C.F. McLean, L.E. Mather, R.L. Nation, W.B. Runciman, A.J. Rutten, and A.A. Somogyi Disposition of morphine and its 3- and 6-glucuronide metabolites during morphine infusion in the sheep Drug Metab. Dispos. 21 1993 1151 1156
58. M. Niesters, A. Dahan, B. Kest, J. Zacny, T. Stijnen, L. Aarts, and E. Sarton Do sex differences exist in opioid analgesia? A systematic review and meta-analysis of human experimental and clinical studies Pain 151 2010 61 68
59. A.E. Olesen, T. Andresen, C. Staahl, and A.M. Drewes Human experimental pain models for assessing the therapeutic efficacy of analgesic drugs Pharmacol. Rev. 64 2012 722 779
60. R. Osborne, S. Joel, D. Trew, and M. Slevin Morphine and metabolite behavior after different routes of morphine administration: demonstration of the importance of the active metabolite morphine-6-glucuronide Clin. Pharmacol. Ther. 47 1990 12 19
61. R. Osborne, P. Thompson, S. Joel, D. Trew, N. Patel, and M. Slevin The analgesic activity of morphine-6-glucuronide Br. J. Clin. Pharmacol. 34 1992 130 138
62. R.T. Penson, S.P. Joel, K. Bakhshi, S.J. Clark, R.M. Langford, and M.L. Slevin Randomized placebo-controlled trial of the activity of the morphine glucuronides Clin. Pharmacol. Ther. 68 2000 667 676
63. R.T. Penson, S.P. Joel, S. Clark, A. Gloyne, and M.L. Slevin Limited phase I study of morphine-3-glucuronide J. Pharm. Sci. 90 2001 1810 1816
64. R.T. Penson, S.P. Joel, M. Roberts, A. Gloyne, S. Beckwith, and M.L. Slevin The bioavailability and pharmacokinetics of subcutaneous, nebulized and oral morphine-6-glucuronide Br. J. Clin. Pharmacol. 53 2002 347 354
65. A. Pfeiffer, V. Brantl, A. Herz, and H.M. Emrich Psychotomimesis mediated by kappa opiate receptors Science 233 1986 774 776
66. F. Porreca, H.I. Mosberg, R. Hurst, V.J. Hruby, and T.F. Burks Roles of mu, delta and kappa opioid receptors in spinal and supraspinal mediation of gastrointestinal transit effects and hot-plate analgesia in the mouse J. Pharmacol. Exp. Ther. 230 1984 341 348
67. R. Romberg, E. Olofsen, E. Sarton, J. den Hartigh, P.E. Taschner, and A. Dahan Pharmacokinetic-pharmacodynamic modeling of morphine-6-glucuronide-induced analgesia in healthy volunteers: absence of sex differences Anesthesiology 100 2004 120 133
68. R. Romberg, E. Olofsen, E. Sarton, L. Teppema, and A. Dahan Pharmacodynamic effect of morphine-6-glucuronide versus morphine on hypoxic and hypercapnic breathing in healthy volunteers Anesthesiology 99 2003 788 798
69. R.R. Romberg, E. Olofsen, H. Bijl, P.E. Taschner, L.J. Teppema, E.Y. Sarton, J.W. van Kleef, and A. Dahan Polymorphism of mu-opioid receptor gene (OPRM1:c.118A>G) does not protect against opioid-induced respiratory depression despite reduced analgesic response Anesthesiology 102 2005 522 530
70. E. Sarton, E. Olofsen, R. Romberg, J. den Hartigh, B. Kest, D. Nieuwenhuijs, A. Burm, L. Teppema, and A. Dahan Sex differences in morphine analgesia: an experimental study in healthy volunteers Anesthesiology 93 2000 1245 1254 discussion 6A
71. M. Sattari, P. Routledge, and S. Mashayekhi The influence of active transport systems on morphine -6-glucuronide transport in MDCKII and MDCK-PGP cells Daru 19 2011 412 416
72. R.M. Savic, D.M. Jonker, T. Kerbusch, and M.O. Karlsson Implementation of a transit compartment model for describing drug absorption in pharmacokinetic studies J. Pharmacokinet. Pharmacodyn. 34 2007 711 726
73. A.H. Schinkel, E. Wagenaar, L. van Deemter, C.A. Mol, and P. Borst Absence of the mdr1a P-Glycoprotein in mice affects tissue distribution and pharmacokinetics of dexamethasone, digoxin, and cyclosporin A J. Clin. Invest. 96 1995 1698 1705
74. K. Shimomura, O. Kamata, S. Ueki, S. Ida, and K. Oguri Analgesic effect of morphine glucuronides Tohoku J. Exp. Med. 105 1971 45 52
75. C. Skarke, J. Darimont, H. Schmidt, G. Geisslinger, and J. Lötsch Analgesic effects of morphine and morphine-6-glucuronide in a transcutaneous electrical pain model in healthy volunteers Clin. Pharmacol. Ther. 73 2003 107 121
76. M.T. Smith, J.A. Watt, and T. Cramond Morphine-3-glucuronide-a potent antagonist of morphine analgesia Life Sci. 47 1990 579 585
77. A.A. Somogyi, D.T. Barratt, and J.K. Coller Pharmacogenetics of opioids Clin. Pharmacol. Ther. 81 2007 429 444
78. S. Spector, and E.S. Vesell Disposition of morphine in man Science 174 1971 421 422
79. C. Staahl, and A.M. Drewes Experimental human pain models: a review of standardised methods for preclinical testing of analgesics Basic Clin. Pharmacol. Toxicol. 95 2004 97 111
80. C. Staahl, R. Upton, D.J. Foster, L.L. Christrup, K. Kristensen, S.H. Hansen, L. Arendt-Nielsen, and A.M. Drewes Pharmacokinetic-pharmacodynamic modeling of morphine and oxycodone concentrations and analgesic effect in a multimodal experimental pain model J. Clin. Pharmacol. 48 2008 619 631
81. F. Stain-Texier, G. Boschi, P. Sandouk, and J.M. Scherrmann Elevated concentrations of morphine 6-beta-D-glucuronide in brain extracellular fluid despite low blood-brain barrier permeability Br. J. Pharmacol. 128 1999 917 924
82. C. Stein, K. Comisel, E. Haimerl, A. Yassouridis, K. Lehrberger, A. Herz, and K. Peter Analgesic effect of intraarticular morphine after arthroscopic knee surgery N. Engl. J. Med. 325 1991 1123 1126
83. E. Sverrisdóttir, D.J.R. Foster, R.N. Upton, A.E. Olesen, T.M. Lund, C. Gabel-Jensen, A.M. Drewes, L.L. Christrup, and M. Kreilgaard Modelling concentration-analgesia relationships for morphine to evaluate experimental pain models Eur. J. Pharm. Sci. 2014
84. P.I. Thompson, S.P. Joel, L. John, J.A. Wedzicha, M. Maclean, and M.L. Slevin Respiratory depression following morphine and morphine-6-glucuronide in normal subjects Br. J. Clin. Pharmacol. 40 1995 145 152
85. S.J. Thompson, K. Koszdin, and C.M. Bernards Opiate-induced analgesia is increased and prolonged in mice lacking P-glycoprotein Anesthesiology 92 2000 1392 1399
86. A.M. Trescot, S. Datta, M. Lee, and H. Hansen Opioid pharmacology Pain Phys. 11 2008 S133 53
87. K. Tunblad, E.N. Jonsson, and M. Hammarlund-Udenaes Morphine blood-brain barrier transport is influenced by probenecid co-administration Pharm. Res. 20 2003 618 623
88. R.N. Upton, T.J. Semple, P.E. Macintyre, and D.J.R. Foster Population pharmacokinetic modelling of subcutaneous morphine in the elderly Acute Pain 8 2006 109 116
89. J.T. Van Crugten, B.C. Sallustio, R.L. Nation, and A.A. Somogyi Renal tubular transport of morphine, morphine-6-glucuronide, and morphine-3-glucuronide in the isolated perfused rat kidney Drug Metab. Dispos. 19 1991 1087 1092
90. H.H. Villesen, B. Hedal, J. Engbaek, S. Frokjaer, S.H. Hansen, N.H. Jensen, M. Rasmussen, U. Skram, L. Stevner, and L.L. Christrup Pharmacokinetics of M6G following intravenous and oral administration in healthy volunteers Acute Pain 8 2006 63 71
91. H.H. Villesen, K. Kristensen, S.H. Hansen, N.H. Jensen, U. Skram, and L.L. Christrup Pharmacokinetics of morphine-6-glucuronide following oral administration in healthy volunteers Eur. J. Clin. Pharmacol. 63 2007 761 767
92. Y.H. Wang, J.F. Sun, Y.M. Tao, Z.Q. Chi, and J.G. Liu The role of kappa-opioid receptor activation in mediating antinociception and addiction Acta Pharmacol. Sin. 31 2010 1065 1070
93. B.L. Wolozin, and G.W. Pasternak Classification of multiple morphine and enkephalin binding sites in the central nervous system Proc. Natl. Acad. Sci. USA 78 1981 6181 6185
94. World Health Organization, 2004. World Health Organization supports global effort to relieve chronic pain. 2012.
95. D. Wu, Y.S. Kang, U. Bickel, and W.M. Pardridge Blood-brain barrier permeability to morphine-6-glucuronide is markedly reduced compared with morphine Drug Metab. Dispos. 25 1997 768 771
96. H.A. Wynne, L.H. Cope, E. Mutch, M.D. Rawlins, K.W. Woodhouse, and O.F. James The effect of age upon liver volume and apparent liver blood flow in healthy man Hepatology 9 1989 297 301
97. R. Xie, M. Hammarlund-Udenaes, A.G. de Boer, and E.C. de Lange The role of P-glycoprotein in blood-brain barrier transport of morphine: transcortical microdialysis studies in mdr1a (-/-) and mdr1a (+/+) mice Br. J. Pharmacol. 128 1999 563 568
98. S.Y. Yeh, C.W. Gorodetzky, and H.A. Krebs Isolation and identification of morphine 3- and 6-glucuronides, morphine 3,6-diglucuronide, morphine 3-ethereal sulfate, normorphine, and normorphine 6-glucuronide as morphine metabolites in humans J. Pharm. Sci. 66 1977 1288 1293
99. Q. Zhang, M. Schaffer, R. Elde, and C. Stein Effects of neurotoxins and hindpaw inflammation on opioid receptor immunoreactivities in dorsal root ganglia Neuroscience 85 1998 281 291