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Clinical Pharmacokinetics
Published in: Clinical Pharmacokinetics 10/2009

01-10-2009 | Review Article

Pharmacology of Morphine in Obese Patients

Clinical Implications

Authors: Célia Lloret Linares, Xavier Decléves, Jean Michel Oppert, Arnaud Basdevant, Karine Clement, Christophe Bardin, Jean Michel Scherrmann, Jean Pierre Lepine, Jean François Bergmann, Prof. Stéphane Mouly

Published in: Clinical Pharmacokinetics | Issue 10/2009

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Abstract

Morphine is an analgesic drug used to treat acute and chronic pain. Obesity is frequently associated with pain of various origins (e.g. arthritis, fibromyalgia, cancer), which increases the need for analgesic drugs. Obesity changes drug pharmacokinetics, and for certain drugs, specific modalities of prescription have been proposed for obese patients. However, scant data are available regarding the pharmacokinetics and pharmacodynamics of morphine in obesity. Prescription of morphine depends on pain relief but the occurrence of respiratory adverse effects correlates with obesity, and is not currently taken into account. Variations in the volume of distribution, elimination half-life and oral clearance of morphine, as well as recent advances in the respective roles of drug-metabolizing enzymes, catechol-O-methyltransferase and the μ opioid receptor in morphine pharmacokinetics and pharmacodynamics, may contribute to differences between obese and non-obese patients. In addition, drug-drug interactions may alter the disposition of morphine and its glucuronide metabolites, which may either increase the risk of adverse effects or reduce drug efficacy.
Literature
1.
2.
Ogden CL, Carroll MD, Curtin LR, et al. Prevalence of overweight and obesity in the United States, 1999-2004. JAMA 2006; 295(13): 1549–55PubMedCrossRef
3.
James WP, Rigby N, Leach R. Obesity and the metabolic syndrome: the stress on society. Ann N Y Acad Sci 2006; 10831-10
4.
Charles MA, Eschwége E, Basdevant A. Monitoring the obesity epidemic in France: the Obepi surveys 1997–2006. Obesity (Silver Spring) 2008 Sep; 16(9): 2182–6CrossRef
5.
6.
Pischon T, Lahmann PH, Boeing H, et al. Body size and risk of colon and rectal cancer in the European Prospective Investigation Into Cancer and Nutrition (EPIC). J Natl Cancer Inst 2006; 98(13): 920–31PubMedCrossRef
7.
Raebel MA, Malone DC, Conner DA, et al. Health services use and health care costs of obese and nonobese individuals. Arch Intern Med 2004; 164(19): 2135–40PubMedCrossRef
8.
Lee YY, Kim KH, Yom YH. Predictive models for post-operative nausea and vomiting in patients using patient-controlled analgesia. J Int Med Res 2007; 35(4): 497–507PubMed
9.
Shapiro A, Zohar E, Zaslansky R, et al. The frequency and timing of respiratory depression in 1524 postoperative patients treated with systemic or neuraxial morphine. J Clin Anesth 2005; 17(7): 537–42PubMedCrossRef
10.
Rose DK, Cohen MM, Wigglesworth DF, et al. Critical respiratory events in the postanesthesia care unit: patient, surgical, and anesthetic factors. Anesthesiology 1994; 81(2): 410–8PubMedCrossRef
11.
Bennett R, Batenhorst R, Graves DA, et al. Variation in postoperative analgesic requirements in the morbidly obese following gastric bypass surgery. Pharmacotherapy 1982; 2(1): 50–3PubMed
12.
Streetman DS. Metabolic basis of drug interactions in the intensive care unit. Crit Care Nurs Q 2000; 22(4): 1–13PubMed
13.
Lötsch J, Weiss M, Ahne G, et al. Pharmacokinetic modeling of M6G formation after oral administration of morphine in healthy volunteers. Anesthesiology 1999; 90(4): 1026–38PubMedCrossRef
14.
Tan T, Kuramoto M, Takahashi T, et al. Characteristics of the gastrointestinal absorption of morphine in rats. Chem Pharm Bull (Tokyo) 1989; 37(1): 168–73CrossRef
15.
Kunta JR, Sinko PJ. Intestinal drug transporters: in vivo function and clinical importance. Curr Drug Metab 2004; 5(1): 109–24PubMedCrossRef
16.
Wacher VJ, Silverman JA, Zhang Y, et al. Role of P-glycoprotein and cytochrome P450 3A in limiting oral absorption of peptides and peptidomimetics. J Pharm Sci 1998; 87(11): 1322–30PubMedCrossRef
17.
Suzuki H, Sugiyama Y. Single nucleotide polymorphisms in multidrug resistance associated protein 2 (MRP2/ABCC2): its impact on drug disposition. Adv Drug Deliv Rev 2002; 54(10): 1311–31PubMedCrossRef
18.
Mouly S, Paine MF. P-glycoprotein increases from proximal to distal regions of human small intestine. Pharm Res 2003; 20(10): 1595–9PubMedCrossRef
19.
Kharasch ED, Hoffer C, Whittington D, et al. Role of P-glycoprotein in the intestinal absorption and clinical effects of morphine. Clin Pharmacol Ther 2003; 74(6): 543–54PubMedCrossRef
20.
Dietrich CG, Geier A, Oude Elferink RP. ABC of oral bioavailability: transporters as gatekeepers in the gut. Gut 2003; 52(12): 1788–95PubMedCrossRef
21.
22.
Yamada H, Ishii K, Ishii Y, et al. Formation of highly analgesic morphine-6-glucuronide following physiologic concentration of morphine in human brain. J Toxicol Sci 2003; 28(5): 395–401PubMedCrossRef
23.
Hasselström J, Eriksson S, Persson A, et al. The metabolism and bioavailability of morphine in patients with severe liver cirrhosis. Br J Clin Pharmacol 1990; 29(3): 289–97PubMedCrossRef
24.
25.
Hoskin PJ, Hanks GW, Aherne GW, et al. The bioavailability and pharmacokinetics of morphine after intravenous, oral and buccal administration in healthy volunteers. Br J Clin Pharmacol 1989; 27(4): 499–505PubMedCrossRef
26.
Säwe J, Dahlstrom B, Paalzow L, et al. Morphine kinetics in cancer patients. Clin Pharmacol Ther 1981; 30(5): 629–35PubMedCrossRef
27.
Hasselström J, Säwe J. Morphine pharmacokinetics and metabolism in humans: enterohepatic cycling and relative contribution of metabolites to active opioid concentrations. Clin Pharmacokinet 1993; 24(4): 344–54PubMedCrossRef
28.
Romberg R, Olofsen E, Sarton E, et al. Pharmacodynamic effect of morphine6-glucuronide versus morphine on hypoxic and hypercapnic breathing in healthy volunteers. Anesthesiology 2003; 99(4): 788–98PubMedCrossRef
29.
Brunk SF, Delle M, Wilson WR. Effect of propranolol on morphine metabolism. Clin Pharmacol Ther 1974; 16(6): 1039–44PubMed
30.
Dahlstrom B, Tamsen A, Paalzow L, et al. Multiple and single-dose kinetics of morphine in patients with postoperative pain. Acta Anaesthesiol Scand Suppl 1982; 7444-6
31.
32.
Stanski DR, Greenblatt DJ, Lowenstein E. Kinetics of intravenous and intramuscular morphine. Clin Pharmacol Ther 1978; 24(1): 52–9PubMed
33.
Osborne R, Joel S, Grebenik K, et al. The pharmacokinetics of morphine and morphine glucuronides in kidney failure. Clin Pharmacol Ther 1993; 54(2): 158–67PubMedCrossRef
34.
Bodd E, Jacobsen D, Lund E, et al. Morphine-6-glucuronide might mediate the prolonged opioid effect of morphine in acute renal failure. Hum Exp Toxicol 1990; 9(5): 317–21PubMedCrossRef
35.
Milne RW, McLean CF, Mather LE, et al. Influence of renal failure on the disposition of morphine, morphine-3-glucuronide and morphine-6-glucuronide in sheep during intravenous infusion with morphine. J Pharmacol Exp Ther 1997; 282(2): 779–86PubMed
36.
Zelcer N, van de Wetering K, Hillebrand M, et al. Mice lacking multidrug resistance protein 3 show altered morphine pharmacokinetics and morphine-6-glucuronide antinociception. Proc Natl Acad Sci U S A 2005; 102(20): 7274–9PubMedCrossRef
37.
Meineke I, Freudenthaler S, Hofmann U, et al. 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 2002; 54(6): 592–603PubMedCrossRef
38.
Naud J, Michaud J, Leblond FA, et al. Effects of chronic renal failure on liver drug transporters. Drug Metab Dispos 2008; 36(1): 124–8PubMedCrossRef
39.
van de Wetering K, Zelcer N, Kuil A, et al. Multidrug resistance proteins 2 and 3 provide alternative routes for hepatic excretion of morphineglucuronides. Mol Pharmacol 2007; 72(2): 387–94PubMedCrossRef
40.
Cisternino S, Rousselle C, Dagenais C, et al. Screening of multidrugresistance sensitive drugs by in situ brain perfusion in P-glycoproteindeficient mice. Pharm Res 2001; 18(2): 183–90PubMedCrossRef
41.
Zong J, Pollack GM. Morphine antinociception is enhanced in MDR1a genedeficient mice. Pharm Res 2000; 17(6): 749–53PubMedCrossRef
42.
Hamabe W, Maeda T, Kiguchi N, et al. Negative relationship between morphine analgesia and P-glycoprotein expression levels in the brain. J Pharmacol Sci 2007; 105(4): 353–60PubMedCrossRef
43.
Penson RT, Joel SP, Bakhshi K, et al. Randomized placebo-controlled trial of the activity of the morphine glucuronides. Clin Pharmacol Ther 2000; 68(6): 667–76PubMedCrossRef
44.
van Dorp EL, Romberg R, Sarton E, et al. Morphine-6-glucuronide: morphine’s successor for postoperative pain relief? Anesth Analg 2006; 102(6): 1789–97PubMedCrossRef
45.
Grace D, Fee JP. A comparison of intrathecal morphine-6-glucuronide and intrathecal morphine sulfate as analgesics for total hip replacement. Anesth Analg 1996; 83(5): 1055–9PubMed
46.
Milne RW, Nation RL, Somogyi AA. The disposition of morphine and its 3- and 6-glucuronide metabolites in humans and animals, and the importance of the metabolites to the pharmacological effects of morphine. Drug Metab Rev 1996; 28(3): 345–472PubMedCrossRef
47.
Romberg R, Olofsen E, Sarton E, et al. Pharmacokinetic-pharmacodynamic modeling of morphine-6-glucuronide-induced analgesia in healthy volunteers: absence of sex differences. Anesthesiology 2004; 100(1): 120–33PubMedCrossRef
48.
Wu D, Kang YS, Bickel U, et al. Blood-brain barrier permeability to morphine-6-glucuronide is markedly reduced compared with morphine. Drug Metab Dispos 1997; 25(6): 768–71PubMed
49.
Bickel U, Schumacher OP, Kang YS, et al. Poor permeability of morphine 3-glucuronide and morphine 6-glucuronide through the blood-brain barrier in the rat. J Pharmacol Exp Ther 1996; 278(1): 107–13PubMed
50.
Bourasset F, Cisternino S, Temsamani J, et al. Evidence for an active transport of morphine-6-beta-d-glucuronide but not P-glycoprotein-mediated at the blood-brain barrier. J Neurochem 2003; 86(6): 1564–7PubMedCrossRef
51.
Dombrowski SM, Desai SY, Marroni M, et al. Overexpression of multiple drug resistance genes in endothelial cells from patients with refractory epilepsy. Epilepsia 2001; 42(12): 1501–6PubMedCrossRef
52.
Nies AT, Jedlitschky G, Konig J, et al. Expression and immunolocalization of the multidrug resistance proteins, MRP1-MRP6 (ABCC1-ABCC6), in human brain. Neuroscience 2004; 129(2): 349–60PubMedCrossRef
53.
Kilpatrick GJ, Smith TW. Morphine-6-glucuronide: actions and mechanisms. Med Res Rev 2005; 25(5): 521–44PubMedCrossRef
54.
Easterling KW, Holtzman SG. In rats, acute morphine dependence results in antagonist-induced response suppression of intracranial self-stimulation. Psychopharmacology (Berl) 2004; 175(3): 287–95CrossRef
55.
Terman B. Spinal mechanisms and their modulation. In: Loeser JD, editor. Bonica’s management of pain. 3rd ed. Philadelphia (PA): Lippincott Williams & Wilkins, 2001: 73–152
56.
Gutstein A. Opioid analgesics. In: Hardman JG, Limbird LE. Goodman & Gilman’s: the pharmacological basis of therapeutics. 10th ed. New York: McGraw-Hill, 2001: 569–619
57.
Nackley AG, Tan KS, Fecho K, et al. Catechol-O-methyltransferase inhibition increases pain sensitivity through activation of both β2- and β3-adrenergic receptors. Pain 2007; 128(3): 199–208PubMedCrossRef
58.
Klepstad P, Dale O, Skorpen F, et al. Genetic variability and clinical efficacy of morphine. Acta Anaesthesiol Scand 2005; 49(7): 902–8PubMedCrossRef
59.
Cepeda MS, Farrar JT, Roa JH, et al. Ethnicity influences morphine pharmacokinetics and pharmacodynamics. Clin Pharmacol Ther 2001; 70(4): 351–61PubMed
60.
Hoehe MR, Kopke K, Wendel B, et al. Sequence variability and candidate gene analysis in complex disease: association of μ-opioid receptor gene variation with substance dependence. Hum Mol Genet 2000; 9(19): 2895–908PubMedCrossRef
61.
Ikeda K, Ide S, Han W, et al. How individual sensitivity to opiates can be predicted by gene analyses. Trends Pharmacol Sci 2005; 26(6): 311–7PubMedCrossRef
62.
Lötsch J, Geisslinger G. Are m-opioid receptor polymorphisms important for clinical opioid therapy? Trends Mol Med 2005; 11(2): 82–9PubMedCrossRef
63.
Oertel BG, Schneider A, Rohrbacher M, et al. The partial 5-hydroxy-tryptamine 1A receptor agonist buspirone does not antagonize morphine-induced respiratory depression in humans. Clin Pharmacol Ther 2007; 81(1): 59–68PubMedCrossRef
64.
Reyes-Gibby CC, Shete S, Rakvag T, et al. Exploring joint effects of genes and the clinical efficacy of morphine for cancer pain: OPRM1 and COMT gene. Pain 2007; 130(1–2): 25–30PubMedCrossRef
65.
Klepstad P, Rakvag TT, Kaasa S, et al. 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 2004; 48(10): 1232–9PubMedCrossRef
66.
Coulbault L, Beaussier M, Verstuyft C, et al. Environmental and genetic factors associated with morphine response in the postoperative period. Clin Pharmacol Ther 2006; 79(4): 316–24PubMedCrossRef
67.
Campa D, Gioia A, Tomei A, et al. Association of ABCB1/MDR1 and OPRM1 gene polymorphisms with morphine pain relief. Clin Pharmacol Ther 2008 Apr; 83(4): 559–66PubMedCrossRef
68.
Lötsch J, Skarke C, Grosch S, et al. 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 2002; 12(1): 3–9PubMedCrossRef
69.
Lötsch J, Zimmermann M, Darimont J, et al. Does the A118G polymorphism at the mu-opioid receptor gene protect against morphine-6-glucuronide toxicity? Anesthesiology 2002; 97(4): 814–9PubMedCrossRef
70.
Rakvag TT, Klepstad P, Baar C, et al. The Val158Met polymorphism of the human catechol-O-methyltransferase (COMT) gene may influence morphine requirements in cancer pain patients. Pain 2005; 116(1–2): 73–8PubMedCrossRef
71.
Bosia M, Bechi M, Marino E, et al. Influence of catechol-O-methyltransferase Vall 58Met polymorphism on neuropsychological and functional outcomes of classical rehabilitation and cognitive remediation in schizophrenia. Neurosci Lett 2007; 417(3): 271–4PubMedCrossRef
72.
Oertel B, Lötsch J. Genetic mutations that prevent pain: implications for future pain medication. Pharmacogenomics 2008; 9(2): 179–94PubMedCrossRef
73.
Lotta T, Vidgren J, Tilgmann C, et al. Kinetics of human soluble and membrane-bound catechol O-methyltransferase: a revised mechanism and description of the thermolabile variant of the enzyme. Biochemistry 1995; 34(13): 4202–10PubMedCrossRef
74.
Diatchenko L, Slade GD, Nackley AG, et al. Genetic basis for individual variations in pain perception and the development of a chronic pain condition. Hum Mol Genet 2005; 14(1): 135–43PubMedCrossRef
75.
Gursoy S, Erdal E, Herken H, et al. Significance of catechol-O-methyltransferase gene polymorphism in fibromyalgia syndrome. Rheumatol Int 2003; 23(3): 104–7PubMed
76.
Zubieta JK, Heitzeg MM, Smith YR, et al. COMT val158met genotype affects mu-opioid neurotransmitter responses to a pain stressor. Science 2003; 299(5610): 1240–3PubMedCrossRef
77.
Li T, Vallada H, Curtis D, et al. Catechol-O-methyltransferase Val158Met polymorphism: frequency analysis in Han Chinese subjects and allelic association of the low activity allele with bipolar affective disorder. Pharmacogenetics 1997; 7(5): 349–53PubMedCrossRef
78.
Daniels JK, Williams NM, Williams J, et al. No evidence for allelic association between schizophrenia and a polymorphism determining high or low catechol O-methyltransferase activity. Am J Psychiatry 1996; 153(2): 268–70PubMed
79.
Ohara K, Nagai M, Suzuki Y, et al. No association between anxiety disorders and catechol-O-methyltransferase polymorphism. Psychiatry Res 1998; 80(2): 145–8PubMedCrossRef
80.
Ross JR, Riley J, Taegetmeyer AB, et al. Genetic variation and response to morphine in cancer patients: catechol-O-methyltransferase and multidrug resistance-1 gene polymorphisms are associated with central side effects. Cancer 2008; 112(6): 1390–403PubMedCrossRef
81.
DiBaise JK, Zhang H, Crowell MD, et al. Gut microbiota and its possible relationship with obesity. Mayo Clin Proc 2008; 83(4): 460–9PubMedCrossRef
82.
Aasmundstad TA, Storset P. Influence of ranitidine on the morphine-3-glucuronide to morphine-6-glucuronide ratio after oral administration of morphine in humans. Hum Exp Toxicol 1998; 17(6): 347–52PubMedCrossRef
83.
Bourlert A. Diclofenac intramuscular single dose to decrease pain in post operative Caesarean section: a double blind randomized controlled trial. J Med Assoc Thai 2005; 88(1): 15–9PubMed
84.
Drewe J, Ball HA, Beglinger C, et al. Effect of P-glycoprotein modulation on the clinical pharmacokinetics and adverse effects of morphine. Br J Clin Pharmacol 2000; 50(3): 237–46PubMedCrossRef
85.
Fredman B, Zohar E, Tarabykin A, et al. Continuous intravenous diclofenac does not induce opioid-sparing or improve analgesia in geriatric patients undergoing major orthopedic surgery. J Clin Anesth 2000; 12(7): 531–6PubMedCrossRef
86.
Nagasaki G, Tanaka M, Saito A, et al. Postoperative analgesia with morphine with or without diclofenac after shoulder surgery. Masui 2002; 51(8): 846–50PubMed
87.
Tighe KE, Webb AM, Hobbs GJ. Persistently high plasma morphine-6-glucuronide levels despite decreased hourly patient-controlled analgesia morphine use after single-dose diclofenac: potential for opioid-related toxicity. Anesth Analg 1999; 88(5): 1137–42PubMed
88.
Macgregor AM, Boggs L. Drug distribution in obesity and following bariatric surgery: a literature review. Obes Surg 1996; 6(1): 17–27PubMedCrossRef
89.
Miller AD, Smith KM. Medication and nutrient administration considerations after bariatric surgery. Am J Health Syst Pharm 2006; 63(19): 1852–7PubMedCrossRef
90.
Andreasen PB, Dano P, Kirk H, et al. Drug absorption and hepatic drug metabolism in patients with different types of intestinal shunt operation for obesity: a study with phenazone. Scand J Gastroenterol 1977; 12(5): 531–5PubMedCrossRef
91.
Das SK, Roberts SB, McCrory MA, et al. Long-term changes in energy expenditure and body composition after massive weight loss induced by gastric bypass surgery. Am J Clin Nutr 2003; 78(1): 22–30PubMed
92.
Bray GA, DeLany JP, Harsha DW, et al. Evaluation of body fat in fatter and leaner 10-y-old African American and white children: the Baton Rouge Children’s Study. Am J Clin Nutr 2001; 73(4): 687–702PubMed
93.
Dorbala S, Crugnale S, Yang D, et al. Effect of body mass index on left ventricular cavity size and ejection fraction. Am J Cardiol 2006; 97(5): 725–9PubMedCrossRef
94.
95.
Martinoli R, Mohamed EI, Maiolo C, et al. Total body water estimation using bioelectrical impedance: a meta-analysis of the data available in the literature. Acta Diabetol 2003; 40 Suppl. 1: S203–6PubMedCrossRef
96.
Kyle UG, Piccoli A, Pichard C. Body composition measurements: interpretation finally made easy for clinical use. Curr Opin Clin Nutr Metab Care 2003; 6(4): 387–93PubMed
97.
Waki M, Kral JG, Mazariegos M, et al. Relative expansion of extracellular fluid in obese vs nonobese women. Am JPhysiol 1991; 261(2 Pt 1): E199–203
98.
Chumlea WC, Guo SS, Zeller CM, et al. Total body water reference values and prediction equations for adults. Kidney Int 2001; 59(6): 2250–8PubMed
99.
Chumlea WC, Guo SS, Zeller CM, et al. Total body water data for white adults 18 to 64 years of age: the Fels Longitudinal Study. Kidney Int 1999; 56(1): 244–52PubMedCrossRef
100.
Congiu M, Mashford ML, Slavin JL, et al. UDP glucuronosyltransferase mRNA levels in human liver disease. Drug Metab Dispos 2002; 30(2): 129–34PubMedCrossRef
101.
Mazoit JX, Sandouk P, Scherrmann JM, et al. Extrahepatic metabolism of morphine occurs in humans. Clin Pharmacol Ther 1990; 48(6): 613–8PubMedCrossRef
102.
Patwardhan RV, Johnson RF, Hoyumpa Jr A, et al. Normal metabolism of morphine in cirrhosis. Gastroenterology 1981; 81(6): 1006–11PubMed
103.
Liston HL, Markowitz JS, DeVane CL. Drug glucuronidation in clinical psychopharmacology. J Clin Psychopharmacol 2001; 21(5): 500–15PubMedCrossRef
104.
Richardson TA, Sherman M, Kalman D, et al. Expression of UDP-glucuronosyltransferase isoform mRNAs during inflammation and infection in mouse liver and kidney. Drug Metab Dispos 2006; 34(3): 351–3PubMed
105.
Goralski KB, Hartmann G, Piquette-Miller M, et al. Downregulation of MDR1a expression in the brain and liver during CNS inflammation alters the in vivo disposition of digoxin. Br J Pharmacol 2003; 139(1): 35–48PubMedCrossRef
106.
Hartmann G, Kim H, Piquette-Miller M. Regulation of the hepatic multidrug resistance gene expression by endotoxin and inflammatory cytokines in mice. Int Immunopharmacol 2001; 1(2): 189–99PubMedCrossRef
107.
Piquette-Miller M, Pak A, Kim H, et al. Decreased expression and activity of P-glycoprotein in rat liver during acute inflammation. Pharm Res 1998; 15(5): 706–11PubMedCrossRef
108.
Sukhai M, Yong A, Kalitsky J, et al. Inflammation and interleukin-6 mediate reductions in the hepatic expression and transcription of the MDR1a and MDR1b genes. Mol Cell Biol Res Commun 2000; 4(4): 248–56PubMedCrossRef
109.
Buyse M, Radeva G, Bado A, et al. Intestinal inflammation induces adaptation of P-glycoprotein expression and activity. Biochem Pharmacol 2005; 69(12): 1745–54PubMedCrossRef
110.
Bertilsson PM, Olsson P, Magnusson KE. Cytokines influence mRNA expression of cytochrome P450 3A4 and MDRI in intestinal cells. J Pharm Sci 2001; 90(5): 638–46PubMedCrossRef
111.
Bauer B, Hartz AM, Miller DS. Tumor necrosis factor alpha and endothelin-1 increase P-glycoprotein expression and transport activity at the blood-brain barrier. Mol Pharmacol 2007; 71(3): 667–75PubMedCrossRef
112.
Fakhoury M, Lecordier J, Medard Y, et al. Impact of inflammation on the duodenal mRNA expression of CYP3A and P-glycoprotein in children with Crohn’s disease. Inflamm Bowel Dis 2006; 12(8): 745–9PubMedCrossRef
113.
Bonkovsky HL, Kane RE, Jones DP, et al. Acute hepatic and renal toxicity from low doses of acetaminophen in the absence of alcohol abuse or malnutrition: evidence for increased susceptibility to drug toxicity due to car-diopulmonary and renal insufficiency. Hepatology 1994; 19(5): 1141–8PubMedCrossRef
114.
Rea DJ, Heimbach JK, Grande JP, et al. Glomerular volume and renal histology in obese and non-obese living kidney donors. Kidney Int 2006; 70(9): 1636–41PubMedCrossRef
115.
Henegar JR, Bigler SA, Henegar LK, et al. Functional and structural changes in the kidney in the early stages of obesity. J Am Soc Nephrol 2001; 12(6): 1211–7PubMed
116.
Kuzman MR, Medved V, Bozina N, et al. The influence of 5-HT (2C) and MDR1 genetic polymorphisms on antipsychotic-induced weight gain in female schizophrenic patients. Psychiatry Res 2008; 160(3): 308–15PubMedCrossRef
117.
Ichihara S, Yamada Y, Kato K, et al. Association of a polymorphism of ABCB1 with obesity in Japanese individuals. Genomics 2008; 91(6): 512–6PubMedCrossRef
118.
Xu L, Zhang F, Zhang DD, et al. OPRM1 gene is associated with BMI in Uyghur population. Obesity (Silver Spring) 2009; 17(1): 121–5CrossRef
119.
Annerbrink K, Westberg L, Nilsson S, et al. Catechol O-methyltransferase vall 58-met polymorphism is associated with abdominal obesity and blood pressure in men. Metabolism 2008; 57(5): 708–11PubMedCrossRef
120.
Karayiannakis AJ, Zbar A, Makri GG, et al. Serum beta-endorphin levels in morbidly obese patients: the effect of vertical banded gastroplasty. Eur Surg Res 1998; 30(6): 409–13PubMedCrossRef
121.
Lubrano-Berthelier C, Dubern B, Lacorte JM, et al. Melanocortin 4 receptor mutations in a large cohort of severely obese adults: prevalence, functional classification, genotype-phenotype relationship, and lack of association with binge eating. J Clin Endocrinol Metab 2006; 91(5): 1811–8PubMedCrossRef
122.
Vaisse C, Clement K, Durand E, et al. Melanocortin-4 receptor mutations are a frequent and heterogeneous cause of morbid obesity. J Clin Invest 2000; 106(2): 253–62PubMedCrossRef
123.
Vrinten DH, Gispen WH, Groen GJ, et al. Antagonism of the melanocortin system reduces cold and mechanical allodynia in mononeuropathic rats. J Neurosci 2000; 20(21): 8131–7PubMed
124.
Di Chiara G, Imperato A. Opposite effects of mu and kappa opiate agonists on dopamine release in the nucleus accumbens and in the dorsal caudate of freely moving rats. J Pharmacol Exp Ther 1988; 244(3): 1067–80PubMed
125.
Di Chiara G, Imperato A. Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats. Proc Natl Acad Sci U S A 1988; 85(14): 5274–8PubMedCrossRef
126.
Kotz CM, Billington CJ, Levine AS. Opioids in the nucleus of the solitary tract are involved in feeding in the rat. Am J Physiol 1997; 272(4 Pt 2): R1028–32PubMed
127.
128.
Pradalier A, Willer JC, Boureau F, et al. Relationship between pain and obesity: an electrophysiological study. Physiol Behav 1981; 27(6): 961–4PubMedCrossRef
129.
130.
Khimich S. Level of sensitivity of pain in patients with obesity. Acta Chir Hung 1997; 36(1–4): 166–7PubMed
131.
Zahorska-Markiewicz B, Kucio C, Pyszkowska J. Obesity and pain. Hum Nutr Clin Nutr 1983; 37(4): 307–10PubMed
132.
Raymond NC, de Zwaan M, Faris PL, et al. Pain thresholds in obese bingeeating disorder subjects. Biol Psychiatry 1995; 37(3): 202–4PubMedCrossRef
133.
Abernethy DR, Greenblatt DJ. Drug disposition in obese humans: an update. Clin Pharmacokinet 1986; 11(3): 199–213PubMedCrossRef
134.
Rost D, Mahner S, Sugiyama Y, et al. Expression and localization of the multidrug resistance-associated protein 3 in rat small and large intestine. Am J Physiol Gastrointest Liver Physiol 2002; 282(4): G720–6PubMed
135.
Van Aubel RA, Hartog A, Bindels RJ, et al. Expression and immunolocalization of multidrug resistance protein 2 in rabbit small intestine. Eur J Pharmacol 2000; 400(2–3): 195–8PubMedCrossRef
136.
Mottino AD, Hoffman T, Jennes L, et al. Expression and localization of multidrug resistant protein MRP2 in rat small intestine. J Pharmacol Exp Ther 2000; 293(3): 717–23PubMed
137.
Lacombe O, Woodley J, Solleux C, et al. Localisation of drug permeability along the rat small intestine, using markers of the paracellular, transcellular and some transporter routes. Eur J Pharm Sci 2004; 23(4–5): 385–91PubMedCrossRef
138.
139.
Bloomberg RD, Urbach DR. Laparoscopic Roux-en-Y gastric bypass for severe gastroesophageal reflux after vertical banded gastroplasty. Obes Surg 2002; 12(3): 408–11PubMedCrossRef
140.
Hogben CA, Tocco DJ, Brodie BB, et al. On the mechanism of intestinal absorption of drugs. J Pharmacol Exp Ther 1959; 125(4): 275–82PubMed
141.
Neuvonen PJ, Kivisto KT. Enhancement of drug absorption by antacids: an unrecognised drug interaction. Clin Pharmacokinet 1994; 27(2): 120–8PubMedCrossRef
142.
Robinson M, Horn J. Clinical pharmacology of proton pump inhibitors: what the practising physician needs to know. Drugs 2003; 63(24): 2739–54PubMedCrossRef
143.
Strassburg CP, Kneip S, Topp J, et al. Polymorphic gene regulation and interindividual variation of UDP-glucuronosyltransferase activity in human small intestine. J Biol Chem 2000; 275(46): 36164–71PubMedCrossRef
144.
Garrett ER, Suverkrup RS, Eberst K, et al. Surgically affected sulfisoxazole pharmacokinetics in the morbidly obese. Biopharm Drug Dispos 1981; 2(4): 329–65PubMedCrossRef
145.
Liu X, Lazenby AJ, Clements RH, et al. Resolution of nonalcoholic steatohepatits after gastric bypass surgery. Obes Surg 2007; 17(4): 486–92PubMedCrossRef
146.
Cancello R, Tordjman J, Poitou C, et al. Increased infiltration of macrophages in omental adipose tissue is associated with marked hepatic lesions in morbid human obesity. Diabetes 2006; 55(6): 1554–61PubMedCrossRef
147.
Chitturi S, Farrell GC. Etiopathogenesis of nonalcoholic steatohepatitis. Semin Liver Dis 2001; 21(1): 27–41PubMedCrossRef
148.
Shicang Y, Guijun H, Guisheng Q, et al. Efficacy of chemotherapeutic agents under hypoxic conditions in pulmonary adenocarcinoma multidrug resistant cell line. J Chemother 2007; 19(2): 203–11PubMed
149.
Moore FD, Haley HB, Bering Jr EA, et al. Further observations on total body water: II. Changes of body composition in disease. Surg Gynecol Obstet 1952; 95(2): 155–80PubMed
150.
Schwartz AE, Matteo RS, Ornstein E, et al. Pharmacokinetics of sufentanil in obese patients. Anesth Analg 1991; 73(6): 790–3PubMed
151.
Greenblatt DJ, Abernethy DR, Locniskar A, et al. Effect of age, gender, and obesity on midazolam kinetics. Anesthesiology 1984; 61(1): 27–35PubMed
152.
Schwartz AE, Matteo RS, Ornstein E, et al. Pharmacokinetics and pharmacodynamics of vecuronium in the obese surgical patient. Anesth Analg 1992; 74(4): 515–8PubMedCrossRef
153.
Dvorchik BH, Damphousse D. The pharmacokinetics of daptomycin in moderately obese, morbidly obese, and matched nonobese subjects. J Clin Pharmacol 2005; 45(1): 48–56PubMedCrossRef
154.
Blouin RA, Bauer LA, Miller DD, et al. Vancomycin pharmacokinetics in normal and morbidly obese subjects. Antimicrob Agents Chemother 1982; 21(4): 575–80PubMedCrossRef
155.
Allard S, Kinzig M, Boivin G, et al. Intravenous ciprofloxacin disposition in obesity. Clin Pharmacol Ther 1993; 54(4): 368–73PubMedCrossRef
156.
Abernethy DR, Divoll M, Greenblatt DJ, et al. Obesity, sex, and acetaminophen disposition. Clin Pharmacol Ther 1982; 31(6): 783–90PubMedCrossRef
157.
Powis G, Reece P, Ahmann DL, et al. Effect of body weight on the pharmacokinetics of cyclophosphamide in breast cancer patients. Cancer Chemother Pharmacol 1987; 20(3): 219–22PubMedCrossRef
158.
Lind MJ, Margison JM, Cerny T, et al. Prolongation of ifosfamide elimination half-life in obese patients due to altered drug distribution. Cancer Chemother Pharmacol 1989; 25(2): 139–42PubMedCrossRef
159.
Reiss RA, Haas CE, Karki SD, et al. Lithium pharmacokinetics in the obese. Clin Pharmacol Ther 1994; 55(4): 392–8PubMedCrossRef
160.
Jaber LA, Ducharme MP, Halapy H. The effects of obesity on the pharmacokinetics and pharmacodynamics of glipizide in patients with non-insulindependent diabetes mellitus. Ther Drug Monit 1996; 18(1): 6–13PubMedCrossRef
161.
Pai MP, Bearden DT. Antimicrobial dosing considerations in obese adult patients. Pharmacotherapy 2007; 27(8): 1081–91PubMedCrossRef
162.
Casati A, Putzu M. Anesthesia in the obese patient: pharmacokinetic considerations. J Clin Anesth 2005; 17(2): 134–45PubMedCrossRef
163.
Bauer LA, Edwards WA, Dellinger EP, et al. Influence of weight on aminoglycoside pharmacokinetics in normal weight and morbidly obese patients. Eur J Clin Pharmacol 1983; 24(5): 643–7PubMedCrossRef
164.
Caldwell JB, Nilsen AK. Intravenous ciprofloxacin dosing in a morbidly obese patient. Ann Pharmacother 1994; 28(6): 806PubMed
165.
Penzak SR, Gubbins PO, Rodvold KA, et al. Therapeutic drug monitoring of vancomycin in a morbidly obese patient. Ther Drug Monit 1998; 20(3): 261–5PubMedCrossRef
166.
Shibata N, Hayakawa T, Hoshino N, et al. Effect of obesity on cyclosporine trough concentrations in psoriasis patients. Am J Health Syst Pharm 1998; 55(15): 1598–602PubMed
167.
Forse RA, Karam B, MacLean LD, et al. Antibiotic prophylaxis for surgery in morbidly obese patients. Surgery 1989; 106(4): 750–6; discussion 756-7PubMed
168.
Bauer LA, Black DJ, Lill JS. Vancomycin dosing in morbidly obese patients. Eur J Clin Pharmacol 1998; 54(8): 621–5PubMedCrossRef
169.
Rosell S, Belfrage E. Blood circulation in adipose tissue. Physiol Rev 1979; 59(4): 1078–104PubMed
170.
Jung D, Mayersohn M, Perrier D, et al. Thiopental disposition in lean and obese patients undergoing surgery. Anesthesiology 1982; 56(4): 269–74PubMedCrossRef
171.
Cloyd JC, Wright BD, Perrier D. Pharmacokinetic properties of thiopental in two patients treated for uncontrollable seizures. Epilepsia 1979; 20(3): 313–8PubMedCrossRef
172.
Servin F, Farinotti R, Haberer JP, et al. Propofol infusion for maintenance of anesthesia in morbidly obese patients receiving nitrous oxide: a clinical and pharmacokinetic study. Anesthesiology 1993; 78(4): 657–65PubMedCrossRef
173.
Egan TD, Huizinga B, Gupta SK, et al. Remifentanil pharmacokinetics in obese versus lean patients. Anesthesiology 1998; 89(3): 562–73PubMedCrossRef
174.
Wada DR, Bjorkman S, Ebling WF, et al. Computer simulation of the effects of alterations in blood flows and body composition on thiopental pharmacokinetics in humans. Anesthesiology 1997; 87(4): 884–99PubMedCrossRef
175.
Bosma RJ, Krikken JA, Homan van der Heide JJ, et al. Obesity and renal hemodynamics. Contrib Nephrol 2006; 151184-202
176.
Strum EM, Szenohradszki J, Kaufman WA, et al. Emergence and recovery characteristics of desflurane versus sevoflurane in morbidly obese adult surgical patients: a prospective, randomized study. Anesth Analg 2004; 99(6): 1848–153PubMedCrossRef
177.
Cancello R, Henegar C, Viguerie N, et al. Reduction of macrophage infiltration and chemoattractant gene expression changes in white adipose tissue of morbidly obese subjects after surgery-induced weight loss. Diabetes 2005; 54(8): 2277–86PubMedCrossRef
178.
Cancello R, Tounian A, Poitou C, et al. Adiposity signals, genetic and body weight regulation in humans. Diabetes Metab 2004; 30(3): 215–27PubMedCrossRef
179.
Clement K, Viguerie N, Poitou C, et al. Weight loss regulates inflammationrelated genes in white adipose tissue of obese subjects. Faseb J 2004; 18(14): 1657–69PubMedCrossRef
180.
Thorn M, Finnstrom N, Lundgren S, et al. Cytochromes P450 and MDR1 mRNA expression along the human gastrointestinal tract. Br J Clin Pharmacol 2005; 60(1): 54–60PubMedCrossRef
181.
Paintaud G, Bechtel Y, Brientini MP, et al. Effects of liver diseases on drug metabolism. Therapie 1996; 51(4): 384–9PubMed
182.
Chen YL, Le Vraux V, Leneveu A, et al. Acute-phase response, interleukin-6, and alteration of cyclosporine pharmacokinetics. Clin Pharmacol Ther 1994; 55(6): 649–60PubMedCrossRef
183.
Hartz AJ, Fischer ME, Bril G, et al. The association of obesity with joint pain and osteoarthritis in the HANES data. J Chronic Dis 1986; 39(4): 311–9PubMedCrossRef
184.
Ito K, Iwatsubo T, Kanamitsu S, et al. Prediction of pharmacokinetic alterations caused by drug-drug interactions: metabolic interaction in the liver. Pharmacol Rev 1998; 50(3): 387–412PubMed
185.
Sugerman HJ, DeMaria EJ, Felton 3rd WL, et al. Increased intra-abdominal pressure and cardiac filling pressures in obesity-associated pseudotumor cerebri. Neurology 1997; 49(2): 507–11PubMedCrossRef
186.
Yeo GS, Connie Hung CC, Rochford J, et al. A de novo mutation affecting human TrkB associated with severe obesity and developmental delay. Nat Neurosci 2004; 7(11): 1187–9PubMedCrossRef
187.
Guo W, Robbins MT, Wei F, et al. Supraspinal brain-derived neurotrophic factor signaling: a novel mechanism for descending pain facilitation. J Neurosci 2006; 26(1): 126–37PubMedCrossRef
188.
Ramer LM, McPhail LT, Borisoff JF, et al. Endogenous TrkB ligands suppress functional mechanosensory plasticity in the deafferented spinal cord. J Neurosci 2007; 27(21): 5812–22PubMedCrossRef
189.
Wand GS, McCaul M, Yang X, et al. The mu-opioid receptor gene polymorphism (A118G) alters HPA axis activation induced by opioid receptor blockade. Neuropsychopharmacology 2002; 26(1): 106–14PubMedCrossRef
190.
Hernandez-Avila CA, Wand G, Luo X, et al. Association between the cortisol response to opioid blockade and the Asn40Asp polymorphism at the muopioid receptor locus (OPRM1). Am J Med Genet B Neuropsychiatr Genet 2003; 118(1): 60–5CrossRef
191.
Barnes MJ, Holmes G, Primeaux SD, et al. Increased expression of mu opioid receptors in animals susceptible to diet-induced obesity. Peptides 2006; 27(12): 3292–8PubMedCrossRef
192.
Chatoor I, Herman BH, Hartzler J. Effects of the opiate antagonist, naltrexone, on binging antecedents and plasma beta-endorphin concentrations. J Am Acad Child Adolesc Psychiatry 1994; 33(5): 748–52PubMedCrossRef
193.
Drewnowski A, Krahn DD, Demitrack MA, et al. Naloxone, an opiate blocker, reduces the consumption of sweet high-fat foods in obese and lean female binge eaters. Am J Clin Nutr 1995; 61(6): 1206–12PubMed
194.
Kotz CM, Glass MJ, Levine AS, et al. Regional effect of naltrexone in the nucleus of the solitary tract in blockade of NPY-induced feeding. Am J Physiol Regul Integr Comp Physiol 2000; 278(2): R499–503PubMed
195.
MacDonald AF, Billington CJ, Levine AS. Alterations in food intake by opioid and dopamine signaling pathways between the ventral tegmental area and the shell of the nucleus accumbens. Brain Res 2004; 1018(1): 78–85PubMedCrossRef
196.
Pijlman FT, Wolterink G, Van Ree JM. Physical and emotional stress have differential effects on preference for saccharine and open field behaviour in rats. Behav Brain Res 2003; 139(1–2): 131–8PubMedCrossRef
197.
Tabarin A, Diz-Chaves Y, Carmona MDC, et al. Resistance to diet-induced obesity in mu-opioid receptor-deficient mice: evidence for a “thrifty gene”. Diabetes 2005; 54(12): 3510–6PubMedCrossRef
198.
Zhang M, Gosnell BA, Kelley AE. Intake of high-fat food is selectively enhanced by mu opioid receptor stimulation within the nucleus accumbens. J Pharmacol Exp Ther 1998; 285(2): 908–14PubMed
199.
Bond C, LaForge KS, Tian M, et al. Single-nucleotide polymorphism in the human mu opioid receptor gene alters beta-endorphin binding and activity: possible implications for opiate addiction. Proc Natl Acad Sci U S A 1998; 95(16): 9608–13PubMedCrossRef
200.
Davis CA, Levitan RD, Reid C, et al. Dopamine for “wanting” and opioids for “liking”: a comparison of obese adults with and without binge eating. Obesity (Silver Spring) 2009; 17(6): 1220–5
Metadata
Title
Pharmacology of Morphine in Obese Patients
Clinical Implications
Authors
Célia Lloret Linares
Xavier Decléves
Jean Michel Oppert
Arnaud Basdevant
Karine Clement
Christophe Bardin
Jean Michel Scherrmann
Jean Pierre Lepine
Jean François Bergmann
Prof. Stéphane Mouly
Publication date
01-10-2009
Publisher
Springer International Publishing
Published in
Clinical Pharmacokinetics / Issue 10/2009
Print ISSN: 0312-5963
Electronic ISSN: 1179-1926
DOI
https://doi.org/10.2165/11317150-000000000-00000

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