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Morphine clearance in children: Does race or genetics matter?

Senthilkumar Sadhasivam, MD, MPH, Elke H. J. Krekels, MSc, Vidya Chidambaran, MD, Hope R. Esslinger, MPT, Pornswan Ngamprasertwong, MD, Kejian Zhang, MD, MBA, Tsuyoshi Fukuda, PhD, Alexander A. Vinks, PharmD, PhD


Objective: Interindividual variability in analgesic response and adverse effects of opioids because of narrow therapeutic indices are major clinical problems. Morphine is an opioid commonly used in children to manage perioperative pain. Although size and age often are considered primary covariates for morphine pharmacokinetic models, the impact of other factors important in personalizing care such as race and genetic variations on morphine disposition is not well documented.

Design: Genotype blinded clinical observational pharmacokinetic study. One hundred forty-six African American and Caucasian children scheduled for elective outpatient adenotonsillectomy were enrolled in our prospective genotype blinded observational study with standard perioperative clinical care.

Setting: Tertiary care pediatric institution.

Interventions: Morphine bolus for intraoperative analgesia in children and pharmacokinetic analyses in different races.

Main outcome measures: Pharmacokinetics and pharmacogenetics of intravenous morphine in a homogeneous pediatric outpatient surgical pain population were evaluated.

Results: The authors observed that African American children have higher morphine clearance than Caucasian children. The increased clearance is directed toward the formation of morphine-3-glucuronide formation, rather than the formation of morphine-6-glucuronide. Common uridine diphosphate glucuronosyl transferase (UGT) 2B7 genetic variations (-161C>T and 802C>T) were not associated with observed racial differences in morphine’s clearance although the wild type of the UGT2B7 isozyme is more prevalent in the African Americans.

Conclusions: Race of the child is an important factor in perioperative intravenous morphine’s clearance and its potential role in personalizing analgesia with morphine needs further investigation.


morphine, pharmacokinetics, children, genetics, UGT2B7

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American Pain Society Quality of Care Committee: Quality improvement guidelines for the treatment of acute pain and cancer pain. JAMA. 1995; 274(23): 1874-1880.

Anderson BJ, Holford NHG: Tips and traps analyzing pediatric PK data. Paediatr Anaesth. 2011; 21(3): 222-237.

Edwards RR, Doleys DM, Fillingim RB, et al.: Ethnic differences in pain tolerance: Clinical implications in a chronic pain population. Psychosom Med. 2001; 63(2): 316-323.

Edwards RR, Moric M, Husfeldt B, et al.: Ethnic similarities and differences in the chronic pain experience: A comparison of African American, Hispanic, and white patients. Pain Med. 2005; 6(1): 88-98.

Rahim-Williams FB, Riley JL, Herrera D, et al.: Ethnic identity predicts experimental pain sensitivity in African Americans and Hispanics. Pain. 2007; 129(1-2): 177-184.

Ng B, Dimsdale JE, Rollnik JD, et al.: The effect of ethnicity on prescriptions for patient-controlled analgesia for post-operative pain. Pain. 1996; 66(1): 9-12.

Bernabei R, Gambassi G, Lapane K, et al.: Management of pain in elderly patients with cancer. SAGE Study Group. Systematic Assessment of Geriatric Drug Use via Epidemiology. JAMA. 1998; 279(23): 1877-1882.

Rupp T, Delaney KA: Inadequate analgesia in emergency medicine. Ann Emerg Med. 2004; 43(4): 494-503.

Pletcher MJ, Kertesz SG, Kohn MA, et al.: Trends in opioid prescribing by race/ethnicity for patients seeking care in US emergency departments. JAMA. 2008; 299(1): 70-78.

US Census Bureau: National Population Estimates. Available at Accessed April 2, 2012.

Knibbe CA, Krekels EH, Danhof M: Advances in paediatric pharmacokinetics. Expert Opin Drug Metab Toxicol. 2011; 7(1): 1-8.

Coffman BL, Rios GR, King CD, et al.: Human UGT2B7 catalyzes morphine glucuronidation. Drug Metab Dispos. 1997; 25(1): 1-4.

ASA Physical Status Classification System: Available at Accessed April 2, 2012.

Clavijo CF, Hoffman KL, Thomas JJ, et al.: A sensitive assay for the quantification of morphine and its active metabolites in human plasma and dried blood spots using high-performance liquid chromatography-tandem mass spectrometry. Anal Bioanal Chem. 2011; 400(3): 715-728.

Fisher DM: PLT Tools. Available at Accessed April 2, 2012.

Krekels EHJ, van Hasselt JGC, Tibboel D, et al.: Systematic evaluation of the descriptive and predictive performance of paediatric morphine population models. Pharm Res. 2011; 28(4): 797-811.

Karlsson MO, Savic RM: Diagnosing model diagnostics. Clin Pharmacol Ther. 2007; 82(1): 17-20.

Comets E, Brendel K, Mentre F: Computing normalised prediction distribution errors to evaluate nonlinear mixed-effect models: The NPDE add-on package for R. Comput Methods Programs Biomed. 2008; 90(2): 154-166.

Holthe M, Rakvag TN, Klepstad P, et al.: 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. Pharmacogenomics J. 2003; 3(1): 17-26.

Mehlotra RK, Bockarie MJ, Zimmerman PA: Prevalence of UGT1A9 and UGT2B7 nonsynonymous single nucleotide polymorphisms in West African, Papua New Guinean, and North American populations. Eur J Clin Pharmacol. 2007; 63(1): 1-8.

Sadhasivam S, Chidambaran V, Ngamprasertwong P, et al.: Race and unequal burden of perioperative pain and opioid related adverse effects in children. Pediatrics. 2012; 129: 832-838.

Brown KA, Laferriere A, Lakheeram I, et al.: Recurrent hypoxemia in children is associated with increased analgesic sensitivity to opiates. Anesthesiology. 2006; 105(4): 665-669.

Gross JB, Bachenberg KL, Benumof JL, et al.: Practice guidelines for the perioperative management of patients with obstructive sleep apnea: A report by the American Society of Anesthesiologists Task Force on Perioperative Management of patients with obstructive sleep apnea. Anesthesiology. 2006; 104(5): 1081-1093; quiz 1117-1088.

Redline S, Tishler PV, Hans MG, et al.: Racial differences in sleep-disordered breathing in African-Americans and Caucasians. Am J Respir Crit Care Med. 1997; 155(1): 186-192.

Jun J, Polotsky VY: Metabolic consequences of sleep-disordered breathing. ILAR J. 2009; 50(3): 289-306.

Boehmer U, Kressin NR, Berlowitz DR, et al.: Self-reported vs administrative race/ethnicity data and study results. Am J Public Health. 2002; 92(9): 1471-1472.

US Office of Management and Budget: Appendix: Directive No. 15. Race and ethnic standards for federal statistics and administrative reporting. In Office of Management and Budget (US). Available at Accessed April 2, 2012.

de Wildt SN, Kearns GL, Leeder JS, et al.: Glucuronidation in humans. Pharmacogenetic and developmental aspects. Clin Pharmacokinet. 1999; 36(6): 439-452.

Bhasker CR, McKinnon W, Stone A, et al.: Genetic polymorphism of UDP-glucuronosyltransferase 2B7 (UGT2B7) at amino acid 268: Ethnic diversity of alleles and potential clinical significance. Pharmacogenetics. 2000; 10(8): 679-685.

Court MH, Krishnaswamy S, Hao Q, et al.: Evaluation of 3´- azido-3´-deoxythymidine, morphine, and codeine as probe substrates for UDP-glucuronosyltransferase 2B7 (UGT2B7) in human liver microsomes: Specificity and influence of the UGT2B7*2 polymorphism. Drug Metab Dispos. 2003; 31(9): 1125-1133.

Takeda S, Ishii Y, Iwanaga M, et al.: Modulation of UDP-glucuronosyltransferase function by cytochrome P450: Evidence for the alteration of UGT2B7-catalyzed glucuronidation of morphine by CYP3A4. Mol Pharmacol. 2005; 67(3): 665-672.

Ohno S, Kawana K, Nakajin S; Contribution of UDP-glucuronosyltransferase 1A1 and 1A8 to morphine-6-glucuronidation and its kinetic properties. Drug Metab Dispos. 2008; 36(4): 688-694.

Kaniwa N, Kurose K, Jinno H, et al.: Racial variability in haplotype frequencies of UGT1A1 and glucuronidation activity of a novel single nucleotide polymorphism 686C> T (P229L) found in an African-American. Drug Metab Dispos. 2005; 33(3): 458-465.

Gregori SD, Gregori MD, Ranzani GN, et al.: Morphine metabolism, transport and brain disposition. Metab Brain Dis. 2012; 27(1): 1-5.

Martini C, Olofsen E, Yassen A, et al.: Pharmacokinetic-pharmacodynamic modeling in acute and chronic pain: An overview of the recent literature. Expert Rev Clin Pharmacol. 2011; 4(6): 719-728.

Lorenzini KI, Daali Y, Dayer P, et al.: Pharmacokinetic-pharmacodynamic modelling of opioids in healthy human volunteers. A minireview. Basic Clin Pharmacol Toxicol. 2012; 110(3): 219-226.

Uchaipichat V, Raungrut P, Chau N, et al.: Effects of ketamine on human UDP-glucuronosyltransferases in vitro predict potential drug-drug interactions arising from ketamine inhibition of codeine and morphine glucuronidation. Drug Metab Dispos. 2011; 39(8): 1324-1328.



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