Skip to main content Accessibility help

We use cookies to distinguish you from other users and to provide you with a better experience on our websites. Close this message to accept cookies or find out how to manage your cookie settings.

Close cookie message
×
Hostname: page-component-55f67697df-4ks9w Total loading time: 0 Render date: 2025-05-09T02:58:15.940Z Has data issue: false hasContentIssue false

10 - Pharmacogenetic considerations in the treatment of cancer pain

from SECTION IV - PHARMACOLOGICAL TREATMENT

Published online by Cambridge University Press:  06 July 2010

By
PÅL KLEPSTAD
Edited by
Eduardo D. Bruera  and
Russell K. Portenoy
PÅL KLEPSTAD
Affiliation:
St. Olavs University Hospital and Norwegian University of Science and Technology
Eduardo D. Bruera
Affiliation:
University of Texas, Houston
Russell K. Portenoy
Affiliation:
Albert Einstein College of Medicine, New York
Get access

Summary

Introduction

Pain perception shows interindividual variability. This variability is partly related to gender and ethnicity, suggesting that genetic factors cause interindividual differences in pain. Besides genetic variability related to pain perception, genetic variants are associated with painful conditions such as migraine or fibromyalgia. Finally, and the primary focus of this book chapter, the pain experience may be subject to genetic variability related to efficacy of analgesics. For cancer pain, this variability is supported by the large variations among individuals in opioid doses needed for pain control, a variation that partly remains if the observations include patients at a defined stage of cancer pain. Similar variations in need for opioid doses are observed in studies in patients receiving opioids for postoperative pain following a standardized surgical procedure, even when factors such as pain intensity or age are controlled.

The complexity of genetic variability related to drug effects is high. Most drugs effects, including those of opioids, are influenced by several gene products. These gene products are involved in both pharmacokinetics (metabolism and transport) and pharmacodynamics (receptor interaction, opioid signaling, and modulation of opioid effects). Thus, effects elicited by opioids are truly polygenic traits. In addition, genes can interact with one another. Interactions between genes – gene joint effects – may enhance, suppress, or have no effect on the outcome.

Mechanisms of genetic variation

Single nucleotide polymorphisms

A single nucleotide polymorphism (SNP) is a change in a single DNA base in the DNA sequence.

Type
Chapter
Information
Cancer Pain
Assessment and Management
 , pp. 180 - 194
Publisher: Cambridge University Press
Print publication year: 2009

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

Book purchase

Temporarily unavailable

References

Kim, H, Dionne, RA. Genetics, pain, and analgesia. Pain Clinical Updates XII:1–4, 2005.Google Scholar
Cepeda, MS, Farrar, JT, Roa, JH, et al. Ethnicity influences morphine pharmacokinetics and pharmacodynamics. Clin Pharmacol Ther 70:351–61, 2001.CrossRefGoogle ScholarPubMed
Zhou, HH, Sheller, JR, Nu, HE, et al. Ethnic differences in response to morphine. Clin Pharmacol Ther 54:507–13, 1993.CrossRefGoogle ScholarPubMed
Colson, NJ, Fernandez, F, Lea, RA, Griffiths, LR. The search for migraine genes: an overview of current literature. Cell Mol Life Sci 64:331–44, 2007.CrossRefGoogle Scholar
Ablin, JN, Cohen, H, Buskila, D. Mechanism of disease: genetics of fibromyalgia. Nat Clin Pract Rheumatol 2:671–8, 2006.CrossRefGoogle Scholar
Klepstad, P.Genetic variability and opioid efficacy. Curr Anaesth Crit Care 18:149–56, 2007.CrossRefGoogle Scholar
Lotsch, J, Geisslinger, G. Current evidence for a genetic modulation of the response to analgesics. Pain 121:1–5, 2006.CrossRefGoogle ScholarPubMed
McQuay, HJ, Carroll, D, Faura, CC, et al. Oral morphine in cancer pain: influences on morphine and metabolite concentration. Clin Pharmacol Ther 48:236–44, 1990.CrossRefGoogle ScholarPubMed
Klepstad, P, Kaasa, S, Skauge, M, Borchgrevink PC: Pain intensity and side effects during titration of morphine to cancer patients using a scheduled fixed dose escalation. Acta Anaesthesiol Scand 44:656–64, 2000.CrossRefGoogle ScholarPubMed
Aubrun, F, Langeron, O, Quesnel, C, et al. Relationships between measurement of pain using visual analog score and morphine requirements during postoperative intravenous titration. Anesthesiology 98:1415–25, 2003.CrossRefGoogle Scholar
Aubrun, F, Monsel, S, Langeron, O, et al. Postoperative titration of intravenous morphine in the elderly patient. Anesthesiology 96:17–23, 2002.CrossRefGoogle ScholarPubMed
Evans, WE, McLeod, HL. Pharmacogenetics – drug disposition, drug targets, and side effects. N Engl J Med 348:538–49, 2003.CrossRefGoogle ScholarPubMed
Reyes-Gibby, CC, Shete, S, Rakvåg, T, et al. Exploring joint effects of genes and the clinical efficacy of morphine for cancer pain: OPRM1 and COMT gene. Pain 130:25–30, 2007.CrossRefGoogle ScholarPubMed
Guttmacher, AE, Collins, FS. Genomic medicine – a primer. N Engl J Med 347:1512–20, 2002.CrossRefGoogle ScholarPubMed
Kimchi-Sarfaty, C, Oh, JM, Kim, I-W, et al. A “silent” polymorphism in the MDR1 gene changes substrate specificity. Science 315:525–8, 2007.CrossRefGoogle ScholarPubMed
Zubieta, JK, Heitzeg, MM, Smith, YR, et al. COMT val158met genotype affects mu-opioid neurotransmitter responses to a pain stressor. Science 299:1240–3, 2003.CrossRefGoogle ScholarPubMed
Rakvåg, 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 116:73–8, 2005.CrossRefGoogle ScholarPubMed
Nackley, AG, Shabalina, SA, Tchivileva, IE, et al. Human catechol-O-methyltransferase haplotyopes modulate protein expression by altering mRNA secondary structure. Science 314:1930–3, 2006.CrossRefGoogle ScholarPubMed
Ross, JR, Riley, J, Taegetmeyer, AB, et al. Genetic variation and response to morphine in cancer patients: catechol-O-methyltransferase (COMT) and multi-drug resistance (MDR-1) gene polymorphism are associated with central side effects. Cancer 112:1390–403, 2008.CrossRefGoogle Scholar
Sherry, ST, Ward, M, Sirotkin, K. dbSNP – database for single nucleotide polymorphism and other class of minor genetic variation. Genome Res 9:677–9, 1999.Google Scholar
den Dunnen, JT, Antonerakis, SE. Mutation nomenclature extensions and suggestions to describe complex mutations. Hum Mutat 15:7–12, 2000.3.0.CO;2-N>CrossRefGoogle Scholar
Kvam, TM, Baar, C, Rakvåg, TT, et al. Genetic analysis of the murine mu opioid receptor: increased complexity of Oprm gene splicing. J Mol Med 82:250–5, 2004.CrossRefGoogle ScholarPubMed
Pasternak, GW. Incomplete cross tolerance and multiple mu opioid peptide receptors. Trends Pharmacol Sci 22:67–70, 2001.CrossRefGoogle ScholarPubMed
Rossi, GC, Leventhal, L, Pan, YX, et al. Antisense mapping of MOR-1 in rats: distinguishing between morphine and morphine-6-glucuronide antinociception. J Pharmacol Exp Ther 281:109–14, 1997.Google ScholarPubMed
Abbadie, C, Pan, YX, Pasternak, GW. Differential distribution in rat brain of mu opioid receptor carboxy terminal splice variants MOR-1C-like and MOR-1-like immunoreactivity: evidence for region-specific processing. J Comp Neurol 419:244–56, 2000.3.0.CO;2-R>CrossRefGoogle ScholarPubMed
Pasternak, GW. Molecular biology of opioid analgesia. J Pain Symptom Manage 29:S2–9, 2005.CrossRefGoogle ScholarPubMed
de Stoutz, ND, Bruera, E, Suarez-Almazor, M. Opioid rotation for toxicity reduction in terminal cancer patients. J Pain Symptom Manage 10:378–84, 1995.CrossRefGoogle ScholarPubMed
Bolan, EA, Tallrida, RJ, Pasternak, GW. Synergy between μ opioid ligands: evidence for functional interactions among μ opioid receptor subtypes. J Pharmacol Exp Ther 303:557–62, 2002.CrossRefGoogle ScholarPubMed
Pan, YX, Xu, J, Mahurter, L, et al. Identification and characterization of two human mu opioid receptor splice variants, hMOR-1O and hMOR-1X. Biochem Biophys Res Commun 301:1057–61, 2003.CrossRefGoogle ScholarPubMed
Larivere, WR, Wiolson, SG, Laughlin, TM, et al. Heritability of nociception. III. Genetic relationship among commonly used assays of nociception and hypersensitivity. Pain 97:75–86, 2002.CrossRefGoogle Scholar
Mogil, JS. Pain genetics: pre- and post-genomic findings. Glenview, IL: International Association for the Study of Pain, 2000.Google Scholar
Nielsen, CS, Stubhaug, A, Price, DD, et al. Individual differences in pain sensitivity: Genetic and environmental contributions. Pain 136:21–9, 2008.CrossRefGoogle ScholarPubMed
Edwards, CL, Fillingim, RB, Keefe, F. Race, ethnicity and pain. Pain 94:133–7, 2001.CrossRefGoogle ScholarPubMed
Lötsch, J, Stuck, B, Hummel, T. The human μ-opioid receptor gene polymorphism 118A > G decreases cortical activation in response to specific nociceptive stimuli. Behav Neurosci 120:1218–24, 2006.CrossRefGoogle Scholar
Fillingim, RB, Kaplan, L, Staud, R, et al. The A118G single nucleotide polymorphism of the μ-opioid receptor gene (OPRM1) is associated with pressure pain sensitivity in humans. J Pain 6:159–67, 2005.CrossRefGoogle ScholarPubMed
Nacley, AG, Tan, KS, Fecho, K, et al. Catechol-O-methyltransferase inhibition increases pain sensitivity through activation of both β2- and β3-adrenergic receptors. Pain 128:199–208, 2007.CrossRefGoogle Scholar
Poulsen, L, Riishede, L, Brosen, K, et al. Codeine in post-operative pain. Study of the influence of sparteine phenotype and serum concentration of morphine and morphine-6-glucuronide. Eur J Clin Pharmacol 54:451–4, 1998.CrossRefGoogle ScholarPubMed
Osborne, R, Joel, S, Trew, D, Slevin, M. Analgesic activity of morphine-6-glucuronide. Lancet 1:828, 1988.Google ScholarPubMed
Portenoy, RK, Thaler, HT, Inturrisi, CE, et al. The metabolite morphine-6-glucuronide contributes to the analgesia produced by morphine infusion in patients with pain and normal renal function. Clin Pharmacol Ther 51:422–31, 1992.CrossRefGoogle ScholarPubMed
Sachse, C, Brockmoller, J, Bauer, S, Roots, I. Cytochrome P450 2D6 variants in a Caucasian population: allele frequencies and phenotypic consequences. Am J Hum Genet 60:284–95, 1997.Google Scholar
Sindrup, SH, Brøsen, K. The pharmacogenetics of codeine hypoanalgesia. Pharmacogenetics 5:335–46, 1995.CrossRefGoogle Scholar
Poulsen, L, Brøsen, K, Arendt-Nielsen, L, et al. Codeine and morphine in extensive and poor metabolizers of sparteine: pharmacokinetics, analgesic effect and side effects. Eur J Clin Pharmacol 51:289–95, 1996.CrossRefGoogle ScholarPubMed
Williams, DG, Patel, A, Howard, RF. Pharmacogenetics of codeine metabolism in an urban population of children and its implications for analgesic reliability. Br J Anaesth 89:839–45, 2002.CrossRefGoogle Scholar
Kirkwood, LC, Nation, RL, Somogyi, A. Characterization of the human cytochrome P450 enzymes involved in the metabolism of dihydrocodeine. Br J Clin Pharmacol 44:549–55, 1997.CrossRefGoogle Scholar
Hutchinson, MR, Menelaou, A, Foster, DJ, et al. CYP2D6 and CYP3A4 involvement in the primary oxidative metabolism of hydrocodone by human liver enzymes. Br J Clin Pharmacol 57:287–97, 2004.CrossRefGoogle Scholar
Lalovic, B, Phillps, B, Risler, LL, et al. Quantitative contribution of CYP2D6 and CYP3A4 to oxycodone metabolism in human liver and intestinal microsomes. Drug Metab Dispos 32:447–54, 2004.CrossRefGoogle ScholarPubMed
Heiskanen, T, Olkkola, KT, Kalso, E. Effects of blocking CYP2D6 on the pharmacokinetics and pharmacodynamics of oxycodone. Clin Pharmacol Ther 64:603–11, 1998.CrossRefGoogle ScholarPubMed
Otton, SV, Schadel, M, Cheung, SW, et al. CYP2D6 genotype determines the metabolic conversion of hydrocodone to hydromorphone. Clin Pharmacol Ther 1993:463–72, 1993.CrossRefGoogle Scholar
Stamer, UM, Lehnen, K, Hithker, F, et al. Impact of CYP2D6 genotype on postoperative tramadol analgesia. Pain 105:231–8, 2003.CrossRefGoogle ScholarPubMed
Poulsen, L, Arendt-Nielsen, L, Brøsen, K, Sindrup, SH. The hypoalgesic effect of tramadol in relation to CYP2D6. Clin Pharmacol Ther 60:636–44, 1996.CrossRefGoogle ScholarPubMed
Crettol, S, Deglon, JJ, Besson, J, et al. ABCB1 and cytochrome P450 genotypes and phenotypes: influence on methadone plasma levels and responses to treatment. Clin Pharmacol Ther 80:668–70, 2006.CrossRefGoogle Scholar
Eap, CB, Broly, F, Mino, A, et al. Cytochrome P450 2D6 genotype and methadone steady-state concentrations. J Clin Psychopharmacol 21:229–34, 2001.CrossRefGoogle ScholarPubMed
Coller, JK, Joergensen, C, Foster, DJ, et al.: Lack of influence of CYP2D6 genotype on the clearance of (R)-, (S)- and racemic-methadone. Int J Clin Pharmacol Ther 45:410–17, 2007.CrossRefGoogle ScholarPubMed
Crettol, S, Deglon, JJ, Besson, J, et al. Methadone enantiomer plasma levels, CYP2B6, CYP2C19, and CYP2C9 genotypes, and response to treatment. Clin Pharmacol Ther 78:593–604, 2005.CrossRefGoogle ScholarPubMed
Wang, JS, DeVane, CL. Involvement of CYP3A4, CYP2C8, and CYP2D6 in the metabolism of (R)- and (R)-methadone in vivo. Drug Metab Dispos 31:742–7, 2003.CrossRefGoogle Scholar
Lötsch, J, Skarke, C, Wieting, J, et al. Modulation of the central nervous effect of levomethadone by genetic polymorphisms potentially affecting its metabolism, distribution, and drug action. Clin Pharmacol Ther 79:72–89, 2006.CrossRefGoogle ScholarPubMed
Coffman, BL, Rios, GR, King, CD, Tephly, TR. Human UGT2B7 catalyzes morphine glucuronidation. Drug Metab Dispos 25:1–4, 1997.Google ScholarPubMed
Holthe, M, Rakvåg, TN, Klepstad, P, et al. Sequence variation in the UDP-glucurosyltransferase 2B7 (UGT2B7) gene: identification of 10 novel single nucleotide polymorphisms (SNPs) and analysis of their relevance to morphine glucuronidation in cancer patients. Pharmacogenomics J 3:17–26, 2003.CrossRefGoogle Scholar
Sawyer, MB, Innoceti, F, Das, S, et al. A pharmacogenetic study of uridine diphosphate-glucuronosyltransferase 2B7 in patients receiving morphine. Clin Pharmacol Ther 73:566–74, 2003.CrossRefGoogle ScholarPubMed
Dugay, Y, Baar, C, Skorpen, F, Guillemette, C. A novel functional polymorphism in the uridine diphosphate-glucuronyltransferase 2B7 promoter with significant impact on promoter activity. Clin Pharmacol Ther 75:223–33, 2004.CrossRefGoogle Scholar
Toide, K, Takahashi, Y, Yamazaki, H, et al. Hepatocyte nuclear factor-1α is a causal factor responsible for the interindividual differences in the expression of UDP-glucuronosyltransferase 2B7 mRNA in human livers. Drug Metab Dispos 30:613–15, 2002.CrossRefGoogle ScholarPubMed
Coulbault, L, Beaussier, M, Verstuyft, C, et al. Environmental and genetic factors associated with morphine responses in the postoperative period. Clin Pharmacol Ther 79:316–24, 2006.CrossRefGoogle Scholar
Ross, JR, Ruttler, D, Welsh, K, et al. Clinical response to morphine in cancer patients and genetic variation in candidate genes. Pharmacogenomics J 5:324–36, 2005.CrossRefGoogle ScholarPubMed
Holthe, M, Klepstad, P, Zahlsen, K, et al. Morphine glucuronide-to-plasma ratios are unaffected by the UGT2B7 H268Y and UGT1A1*28 in cancer patients on chronic morphine therapy. Eur J Clin Pharmacol 58:353–6, 2002.CrossRefGoogle ScholarPubMed
Skarke, C, Scmidt, H, Geisslinger, G, et al. Pharmacokinetics are not altered in subjects with Gilbert's syndrome. Br J Clin Pharmacol 56:228–31, 2003.CrossRefGoogle Scholar
Klepstad, P, Borchgrevink, PC, Dale, O, et al. Relations between serum concentrations of morphine, morphine-3-glucuronide and morphine-6-glucuronide and clinical observations: a prospective survey in 300 cancer patients. Acta Anaesthesiol Scand 47:725–31, 2003.CrossRefGoogle Scholar
Hoehe, MR, Köpke, 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 9:2895–908, 2000.CrossRefGoogle ScholarPubMed
Wang, D, Quillan, JM, Winans, K, et al. Single nucleotide polymorphisms in the human mu opioid receptor gene alter basal G protein coupling and calmodulin binding. J Biol Chem 276:34624–30, 2001.CrossRefGoogle Scholar
Befort, K, Filiol, D, Decalliot, FM, et al. A single nucleotide polymorphic mutation in the human mu-opioid receptor severely impairs receptor signaling. J Biol Chem 276:3130–7, 2001.CrossRefGoogle ScholarPubMed
Zhang, Y, Wang, D, Johnson, AD, et al. Allelic expression imbalance of human mu opioid receptor (OPRM1) caused by variant A118G. J Biol Chem 280:32618–24, 2005.CrossRefGoogle ScholarPubMed
Skarke, C, Darimont, J, Schmidt, H, et al. Analgesic effects of morphine and morphine-6-glucuronide in a transcutaneous electrical pain model in healthy volunteers. Clin Pharmacol Ther 73:107–21, 2003.CrossRefGoogle Scholar
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 12:3–9, 2002.CrossRefGoogle Scholar
Romberg, R, Olufsen, E, Sarton, E, et al. Pharmacokinetic-pharmacodynamic modeling of morphine-6-glucuronide analgesia in healthy volunteers. Anesthesiology 100:120–33, 2004.CrossRefGoogle ScholarPubMed
Romberg, R, Olufsen, E, Bijl, H, et al. Polymorphism of μ-opioid receptor gene (OPRM1:c.118A>G) does not protect against opioid-induced respiratory depression despite reduced analgesic response. Anesthesiology 102:522–30, 2005.CrossRefGoogle Scholar
Oertel, BG, Schmidt, R, Schneider, A, et al. The μ-opioid receptor gene polymorphism 118A>G depletes alfentanil-induced analgesia and protects against respiratory depression in homozygous carriers. Pharmacogenet Genomics 16:625–36, 2006.CrossRefGoogle ScholarPubMed
Klepstad, P, Rakvåg, TN, Kaasa, S, et al. The 118 A>G polymorphism in the human μ-opioid receptor gene may increase morphine requirements in patients with pain caused by malignant disease. Acta Anaesthesiol Scand 48:1232–9, 2004.CrossRefGoogle ScholarPubMed
Campa, D, Gioia, A, Tomei, A, et al. Association of ACCB1/MDR1 and OPRM1 gene polymorphism with morphine pain relief. Clin Pharm Ther 83:559–66, 2008.CrossRefGoogle Scholar
Caraco, Y, Maroz, Y, Davidson, E. Variability in alfentanil analgesia may be attributed to polymorphism in the μ-opioid receptor. Clin Pharmacol Ther 69:P63, 2001.Google Scholar
Chou, WY, Yang, LC, Lu, HF, et al. Association of mu opioid receptor gene polymorphism (A118G) with variations in morphine consumption for analgesia after total knee arthroplasty. Acta Anaesthesiol Scand 50:787–92, 2006.CrossRefGoogle ScholarPubMed
Chou, WY, Wang, CH, Liu, P-H, et al. Human opioid receptor A118G polymorphisms affects intravenous patient-controlled analgesia morphine consumption after total abdominal hysterectomy. Anesthesiology 105:334–7, 2006.CrossRefGoogle ScholarPubMed
Sia, AT, Lim, Y, Lim, ECP, et al. A118G single nucleotide polymorphism of human μ-opioid receptor gene influences pain perception and patient-controlled intravenous morphine consumption after intrathecal morphine for postcesarean analgesia. Anesthesiology 109:520–6, 2008.CrossRefGoogle ScholarPubMed
Janicki, PK, Shculer, G, Francis, D, et al. A genetic association study of the functional A118G polymorphism of the human μ-opioid receptor gene in patients with acute and chronic pain. Anesth Analg 103:1011–17, 2006.CrossRefGoogle ScholarPubMed
Beyer, A, Koch, T, Schroder, H, et al. Effect of the A118G polymorphism on binding affinity, potency and agonist-mediated endocytosis, desensitization, and resensitization of the human mu-opioid receptor. J Neurochem 89:553–60, 2004.CrossRefGoogle ScholarPubMed
Landau, R, Kern, C, Columb, MO, et al. Genetic variability of the μ-opioid receptor influences intrathecal fentanyl variability in labouring women. Pain 139:5–14, 2008.CrossRefGoogle Scholar
Bond, C, LaForge, KS, Tian, M, et al. Single-nucleotide polymorphism in the human mu opioid receptor gene alters endorphin binding and activity: possible implications for opiate addiction. Proc Natl Acad Sci U S A 95:9608–13, 1998.CrossRefGoogle ScholarPubMed
Bayerer, B, Stamer, U, Hoeft, A, Stuber, F. Genomic variations and transcriptional regulation of the human mu-opioid receptor gene. Eur J Pain 11:421–7, 2007.CrossRefGoogle ScholarPubMed
Law, PY, Yang, JW, Guo, X, Loh, HH. In vivo activation of a mutant μ-opioid receptor by antagonist: future direction for opiate pain treatment paradigm that lacks undesirable side effects. Proc Natl Acad Sci U S A 100:2117–21, 2003.CrossRefGoogle Scholar
Ross, FB, Smith, MB. The intrinsic antinociceptive effects of oxycodone appear to be k-opioid receptor mediated. Pain 73:151–7, 1997.CrossRefGoogle Scholar
Kim, H, Neubert, JK, Miguel, AS, et al. Genetic influence on variability in human acute experimental pain sensitivity associated with gender, ethnicity and psychological temperament. Pain 109:488–96, 2004.CrossRefGoogle ScholarPubMed
Somogyi, A, Barrat, DT, Coller, JK. Pharmacogenetics of opioids. Clin Pharmacol Ther 81:429–44, 2007.CrossRefGoogle ScholarPubMed
Wandel, C, Kim, R, Wood, M, Wood, A. Interaction of morphine, fentanyl, sufentanil, alfentanil, and loperamide with the efflux drug transporter P-glycoprotein. Anesthesiology 96:913–20, 2002.CrossRefGoogle ScholarPubMed
Thompson, SJ, Koszdin, K, Bernards, CM. Opiate-induced analgesia is increased and prolonged in mice lacking P-glycoprotein. Anesthesiology 92:1392–9, 2000.CrossRefGoogle ScholarPubMed
Daganais, C, Graff, CL, Pollack, GM. Variable modulation of brain uptake by P-glycoprotein in mice. Biochem Pharmacol 15:269–76, 2004.CrossRefGoogle Scholar
Meineke, I, Freudenthaler, S, Hofmann, U, et al. Pharmacokinetic modeling 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 54:592–603, 2002.Google Scholar
Hoffmeyer, S, Burk, O, von Richter, O, et al. Functional polymorphisms of the human multidrug resistance gene: multiple sequence variations and correlation of one allele with P-glycoprotein expression and activity in vivo. Proc Natl Acad Sci U S A 97:3473–8, 2000.CrossRefGoogle ScholarPubMed
Klepstad, P, Dale, O, Skorpen, F, et al. Genetic variability and clinical efficacy of morphine. Acta Anaesthesiol Scand 49:902–8, 2005.CrossRefGoogle ScholarPubMed
Skarke, C, Jarrar, M, Erb, K, et al. Respiratory and miotic effects of morphine in healthy volunteers when P-glycoprotein is blocked by quinidine. Clin Pharmacol Ther 74:303–11, 2003.CrossRefGoogle ScholarPubMed
Coller, JK, Barrat, DT, Dahlen, K, et al. ABCB genetic variability and methadone dosage requirements in opioid-dependent individuals. Clin Pharmacol Ther 80:682–90, 2006.CrossRefGoogle Scholar
Park, HJ, Shinn, HK, Ryu, SH, et al. Genetic polymorphisms in the ABCB gene and the effects of fentanyl in Koreans. Clin Pharmacol Ther 81:539–46, 2007.CrossRefGoogle Scholar
Ganapathy, V, Miyauchi, S. Transport systems for opioid peptides in mammalian tissue. AAPS J 29:E852–6, 2005.CrossRefGoogle Scholar
Niemi, G, Breivik, H. The minimally effective concentration of adrenaline in a low-concentration thoracic epidural analgesic infusion of bupivacaine, fentanyl and adrenaline after major surgery. Acta Anaesthesiol Scand 47:439–50, 2003.CrossRefGoogle Scholar
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 34:4202–10, 1995.CrossRefGoogle ScholarPubMed
Rakvåg, TT, Ross, JR, Sato, H, et al. Genetic variation in the Catechol-O-Methyltransferase (COMT) gene and morphine requirements in cancer pain patients. Mol Pain 4:64, 2008.CrossRefGoogle Scholar
Xia, Y, Wikberg, JES, Chajlani, V. Expression of melanocortin 1 receptor in periaqueductal gray matter. Neuroreport 6:2193–6, 1995.CrossRefGoogle ScholarPubMed
Mogil, JS, Ritchie, J, Smith, SB, et al. Melanocortin-1 receptor gene variants affect pain and μ-opioid analgesia in mice and humans. J Med Genet 42:583–7, 2005.CrossRefGoogle ScholarPubMed
Mogil, JS, Wilson, SG, Chesler, EJ, et al. The melanocortin-1 receptor gene mediates female-specific mechanisms of analgesia in mice and humans. Proc Natl Acad Sci U S A 100:4867–72, 2003.CrossRefGoogle ScholarPubMed
Wolf, G, Gabay, E, Tal, M, et al. Genetic impairment of interleukin-1 signaling attenuates neuropathic pain, autonomy, and spontaneous ectopic neuronal activity, following nerve injury in mice. Pain 120:315–24, 2006.CrossRefGoogle Scholar
Bessler, H, Shavit, Y, Mayburd, E, et al. Postoperative pain, morphine consumption, and genetic polymorphism of IL-1beta and IL-1 receptor antagonist. Neurosci Lett 404:154–8, 2006.CrossRefGoogle ScholarPubMed
Bohn, LM, Lefkowitz, RJ, Gainetdinov, RR, et al. Enhanced morphine analgesia in mice lacking beta-arrestin 2. Science 286:2495–8, 1999.CrossRefGoogle ScholarPubMed
Raehal, KM, Walker, JK, Bohn, LM. Morphine side effects in β-arrestin 2 knockout mice. J Pharmacol Exp Ther 314:1195–201, 2005.CrossRefGoogle ScholarPubMed
Bohn, LM, Galnetdinov, RR, Lin, F-L, et al. μ-Opioid receptor desensitization by β-arrestin-2 determines morphine tolerance but not dependence. Nature 408:720–3, 2000.CrossRefGoogle Scholar
Krauss, J, Borner, C, Giannini, E, et al. Regulation of mu-opioid receptor gene transcription by interleukin-4 and influence of an allelic variation within a STAT6 transcription factor binding site. J Biol Chem 276:43901–8, 2001.CrossRefGoogle Scholar
Meuser, T, Giesecke, T, Gabriel, A, et al. Mu-opioid receptor mRNA regulation during morphine tolerance in the rat peripheral nervous system. Anesthesiology 97:1458–63, 2003.Google ScholarPubMed
Liang, DY, Liao, G, Wang, J, et al. A genetic analysis of opioid-induced hyperanalgesia in mice. Anesthesiology 104:1054–62, 2006.CrossRefGoogle Scholar
Diatchenko, L, Anderson, AD, Slade, GD, et al. Three major haplotypes of the beta2 adrenergic receptor define psychological profile, blood pressure, and the risk for development of a common musculoskeletal pain disorder. Am J Med Genet B Neuropsychatr Genet 141:449–62, 2006.CrossRefGoogle Scholar
Liang, DY, Liao, G, Lighthall, GK, et al. Genetic variants of the P-glycoprotein gene Abcb1b modulate opioid-induced hyperalgesia, tolerance and dependence. Pharmacogenet Genomics 16:825–35, 2006.CrossRefGoogle ScholarPubMed
Mikus, G, Trausch, B, Rodewald, C, et al. Effect of codeine on gastrointestinal motility in relation to CYP2D6 phenotype. Clin Pharmacol Ther 61:459–66, 1997.CrossRefGoogle ScholarPubMed
Hasselström, J, Yue, OY, Säwe, J. The effect of codeine on gastrointestinal transit in extensive and poor metabolisers of debrisoquine. Eur J Clin Pharmacol 53:145–8, 1997.CrossRefGoogle ScholarPubMed
Eckhardt, K, Li, S, Ammon, S, et al. Same incidence of adverse drug events after codeine administration irrespective of the genetically determined differences in morphine formation. Pain 76:27–33, 1998.CrossRefGoogle ScholarPubMed
Wang, G, Zhang, H, He, F, Fang, X: Effect of the CYP2D6*10 C188T polymorphism on postoperative tramadol analgesia in a Chinese population. Eur J Clin Pharmacol 62:927–31, 2006.CrossRefGoogle ScholarPubMed
Thirlwell, MP, Sloan, PA, Maroun, JA, et al. Pharmacokinetics and clinical efficacy of oral morphine solution and controlled-release morphine tablets in cancer patients. Cancer 63:2275–83, 1989.3.0.CO;2-4>CrossRefGoogle ScholarPubMed
Collin, E, Poulain, P, Gauvain-Piquard, A, et al. Is disease progression the major factor in morphine “tolerance” in cancer pain treatment?Pain 55:319–26, 1993.CrossRefGoogle Scholar
Klepstad, P, Borchgrevink, PC, Dale, O, et al. Routine drug monitoring of serum concentrations of morphine. Morphine-3-glucuronide and morphine-6-glucuronide do not predict clinical observations in cancer patients. Palliat Med 17:679–87, 2003.Google Scholar
Yun, CH, Wood, M, Wood, AJ, Guengerich, FP. Identification of the pharmacogenetic determinants of alfentanil metabolism: cytochrome P-450 3A4. An explanation of the variable elimination clearance. Anesthesiology 77:467–74, 1992.CrossRefGoogle ScholarPubMed
Reilly, SC, Cossins, AR, Quinn, JP, Sneddon, LU. Discovering genes: the use of microarrays and laser capture microdissection in pain research. Brain Res Rev 46:225–33, 2004.CrossRefGoogle ScholarPubMed
Max, MB. Assessing pain candidate gene studies. Pain 109:1–3, 2004.CrossRefGoogle ScholarPubMed
Belfer, I, Wu, T, Kingman, A, et al. Candidate gene studies of human pain mechanism. Anesthesiology 100:1562–72, 2004.CrossRefGoogle Scholar
Freely associating [editorial]. Nat Genet 22:1–2, 1999.CrossRef

Save book to Kindle

To save this book to your Kindle, first ensure [email protected] is added to your Approved Personal Document E-mail List under your Personal Document Settings on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part of your Kindle email address below. Find out more about saving to your Kindle.

Note you can select to save to either the @free.kindle.com or @kindle.com variations. ‘@free.kindle.com’ emails are free but can only be saved to your device when it is connected to wi-fi. ‘@kindle.com’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.

Find out more about the Kindle Personal Document Service.

Available formats
×

Save book to Dropbox

To save content items to your account, please confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your account. Find out more about saving content to Dropbox.

Available formats
×

Save book to Google Drive

To save content items to your account, please confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your account. Find out more about saving content to Google Drive.

Available formats
×