EDITORIAL
Why is there no morphine concentration–response curve for acute pain?
The goal of any treatment is a desired response, known as the target effect. This effect might be pain reduction to a score T and 802C>T) were not associated with observed racial differences in morphine’s clearance, the wild type of the UGT2B7 isozyme was more prevalent in the African Americans (35). Further pharmacogenomic influences The role of pharmacogenomics continues to be investigated, and a number of excellent reviews are available (56–60). While each isolated pharmacogenomics influence may be discerned, the complex interplay of all these influences in any one individual makes clinical interpretation difficult. The extremely anxious child may require a greater induction dose of propofol than less anxious children (61). Increased circulating catecholamines may also contribute to perceived pain. Single-nucleotide polymorphisms for the enzyme responsible for metabolizing catecholamines (catechol-O-methyl transferase, COMT) have been described and distinct haplotypes categorized (low, average and high pain sensitivity). Haplotypes have also been associated with catecholamine synthesis (e.g., cofactor tetrahydrobiopterin (BH4) synthesis and metabolism) that are associated with chronic pain. BH4 blocking drugs may prove useful as a novel analgesic. In addition, haplotypes for the B2 adrenergic receptor, based on eight single-nucleotide polymorphisms, have been identified. It is not surprising that inflammatory cytokines (interleukins, tumor necrosis factor) have impact on the pain response. The inflammatory response mediated after surgery has impact on pain (62). Polymorphism in the interleukin-1 receptor antagonist gene is associated with serum interleukin-1 receptor antagonist concentrations and postoperative opioid consumption (63). Morphine works through the l-opioid receptor, a protein coded for by the OPRM1 gene on chromosome 6q24-q25. Polymorphisms of this gene (e.g., A118G) may increase this receptor’s affinity for morphine and its metabolite morphine 6-glucuronide (64) although clinical impact continues to be debated (65, 66) A number of other genetic variations may also influence the l-opioid receptor. The melanocortin-1 receptor that serves a role in skin pigmentation may influence morphine 6-glucuronide effects as well as the j-opioid receptor in females (67). Signal transmission from opioid receptors requires 235
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involvement in ion channels (K, Na, Ca), and polymorphisms of these channels have also been noted to have an influence on pain sensitivity. Mutations in voltagegated transient receptor potential channels have been identified and may modulate the effects of analgesics (68). Efflux transporters like the P-glycoproteins are also associated with polymorphisms and may affect transport into or out of the brain (69). Would knowledge of a concentration-response relationship improve current therapy? The therapeutic range 10–20 lgL1 associated with analgesia and infusion rates that achieve these concentrations are used widely (42). However, use of a therapeutic range implies that all concentrations within the range are equally ‘optimal’, and usually, it is understood that any concentration outside of that range is highly suboptimal and reflects inadequate treatment. Morphine concentrations below 10 lgL1 might be thought to give inadequate analgesia, while concentrations above 20 lgL1 result in respiratory depression. A concentration of 10 lgL1 may be considered to not give as good analgesia as 20 lgL1. Demonstration of a concentration–response curve may simply give practitioners a better understanding of the concepts related to dosing rather than improve current therapy. The use of patient characteristics with covariate models for the parameters can reduce predictable subject variability. While age and weight contribute greatly to PK variability in healthy children, these two covariates are not enough to reduce the between subject variability so that the medicine can be used safely and effectively in the wider pediatric population where this drug is used (e.g., critically ill children with organ dysfunction). There is also PD variability that contributes to dose requirements. Consequently, we still titrate dose to effect. Fortunately, within-patient variability appears
low, so observation of patient response can predict future dose needs. It would be nice to adjust dose further based on individual characteristics (70), but it remains uncertain how much an understanding of pharmacogenomics will play in dose individualization. If a single genetic variant was responsible for major PK or PD differences, then dose individualization would be easier. The drug irinotecan, used to treat cancer, has an active metabolite that is metabolized by a glucuronide (UGT1A1); a pathway similar to that involved in morphine clearance (UGT2B7). A variant allele UGT1A1*28 has been identified that is associated with severe neutropenia and diarrhea. Genetic testing in patients to identify this allele (present in 10% Caucasians) has been shown to be beneficial (71). However, there appears a multiplicity of genetic influences on both morphine PK and PD, and the impact from interaction of these variants is not fully understood. Pain response is further complicated by numerous other factors (e.g., psychosocial, race, environment, underlying pathology, age). Although this drug has been used for centuries, we still need to know more about it. Conflict of interest The authors declare no conflict of interest. Brian J Anderson1 & John van den Anker2,3,4 Department of Anaesthesiology, University of Auckland, Auckland, New Zealand Email: [email protected] 2 Division of Pediatric Clinical Pharmacology, Children’s National Medical Center, Washington, DC, USA 3 Intensive Care, Erasmus Medical Center-Sophia Children’s Hospital, Rotterdam, the Netherlands 4 Department of Paediatric Pharmacology, University Children’s Hospital Basel, Basel, Switzerland [email protected] 1
doi:10.1111/pan.12361
References 1 Anderson BJ, Holford NH. Understanding dosing: children are small adults, neonates are immature children. Arch Dis Child 2013; 98: 737–744. 2 Anderson BJ, Woollard GA, Holford NH. Acetaminophen analgesia in children: placebo effect and pain resolution after tonsillectomy. Eur J Clin Pharmacol 2001; 57: 559–569. 3 McFarlan CS, Anderson BJ, Short TG. The use of propofol infusions in paediatric anaesthesia: a practical guide. Paediatr Anaesth 1999; 9: 209–216.
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4 Mani V, Morton NS. Overview of total intravenous anesthesia in children. Pediatr Anesth 2010; 20: 211–222. 5 Lerman J, Sikich N, Kleinman S et al. The pharmacology of sevoflurane in infants and children. Anesthesiology 1994; 80: 814–824. 6 Rigouzzo A, Girault L, Louvet N et al. The relationship between bispectral index and propofol during target-controlled infusion anesthesia: a comparative study between children and young adults. Anesth Analg 2008; 106: 1109–1116.
7 Standing JF, Hammer GB, Sam WJ et al. Pharmacokinetic-pharmacodynamic modeling of the hypotensive effect of remifentanil in infants undergoing cranioplasty. Pediatr Anesth 2011; 20: 7–18. 8 Fuentes R, Cortinez LI, Struys MM et al. The dynamic relationship between end-tidal sevoflurane concentrations, bispectral index, and cerebral state index in children. Anesth Analg 2008; 107: 1573–1578. 9 Bouwmeester NJ, van den Anker JN, Hop WC et al. Age- and therapy-related effects on morphine requirements and plasma
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concentrations of morphine and its metabolites in postoperative infants. Br J Anaesth 2003; 90: 642–652. Lynn AM, Nespeca MK, Opheim KE et al. Respiratory effects of intravenous morphine infusions in neonates, infants, and children after cardiac surgery. Anesth Analg 1993; 77: 695–701. Anderson BJ, Ralph CJ, Stewart AW et al. The dose-effect relationship for morphine and vomiting after day-stay tonsillectomy in children. Anaesth Intensive Care 2000; 28: 155–160. Anderson BJ, Persson M, Anderson M. Rationalising intravenous morphine prescriptions in children. Acute Pain 1999; 2: 59–67. Aubrun F, Mazoit JX, Riou B. Postoperative intravenous morphine titration. Br J Anaesth 2012; 108: 193–201. Bernard R, Salvi N, Gall O et al. MORPHIT: an observational study on morphine titration in the postanesthetic care unit in children. Pediatr Anesth 2014; 24: 303–308. Morton NS, Errera A. APA national audit of pediatric opioid infusions. Pediatr Anesth 2010; 20: 119–125. Hill AV. The possible effects of the aggregation of the molecules of haemoglobin on its dissociation curves. J Physiol 1910; 14: iv–vii. Dershwitz M, Walsh JL, Morishige RJ et al. Pharmacokinetics and pharmacodynamics of inhaled versus intravenous morphine in healthy volunteers. Anesthesiology 2000; 93: 619–628. Staahl C, Upton R, Foster DJ et al. Pharmacokinetic-pharmacodynamic modeling of morphine and oxycodone concentrations and analgesic effect in a multimodal experimental pain model. J Clin Pharmacol 2008; 48: 619– 631. Mazoit JX, Butscher K, Samii K. Morphine in postoperative patients: pharmacokinetics and pharmacodynamics of metabolites. Anesth Analg 2007; 105: 70–78. Inturrisi CE, Colburn WA. Application of pharmacokinetic-pharmacodynamic modeling to analgesia. In: Foley KM, Inturrisi CE, eds. Advances in Pain Research and Therapy Opioid Analgesics in the Management of Clinical Pain. New York: Raven Press, 1986: 441–452. Stephenson T. How children’s responses to drugs differ from adults. Br J Clin Pharmacol 2005; 59: 670–673. Anderson BJ. My child is unique; the pharmacokinetics are universal. Pediatr Anesth 2012; 22: 530–538. Holford NH, Ma SC, Anderson BJ. Prediction of morphine dose in humans. Pediatr Anesth 2012; 22: 209–222. Osborne R, Joel S, Grebenik K et al. The pharmacokinetics of morphine and morphine
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glucuronides in kidney failure. Clin Pharmacol Ther 1993; 54: 158–167. Miners JO, Knights KM, Houston JB et al. In vitro-in vivo correlation for drugs and other compounds eliminated by glucuronidation in humans: pitfalls and promises. Biochem Pharmacol 2006; 71: 1531–1539. Wang J, Evans AM, Knights KM et al. Differential disposition of intra-renal generated and preformed glucuronides: studies with 4-methylumbelliferone and 4-methylumbelliferyl glucuronide in the filtering and nonfiltering isolated perfused rat kidney. J Pharm Pharmacol 2011; 63: 507–514. Knights KM, Rowland A, Miners JO. Renal drug metabolism in humans: the potential for drug-endobiotic interactions involving cytochrome P450 (CYP) and UDP-glucuronosyltransferase (UGT). Br J Clin Pharmacol 2013; 76: 587–602. Nahata MC, Miser AW, Miser JS et al. Variation in morphine pharmacokinetics in children with cancer. Dev Pharmacol Ther 1985; 8: 182–188. Nahata MC, Miser AW, Miser JS et al. Analgesic plasma concentrations of morphine in children with terminal malignancy receiving a continuous subcutaneous infusion of morphine sulfate to control severe pain. Pain 1984; 18: 109–114. Lynn AM, Opheim KE, Tyler DC. Morphine infusion after pediatric cardiac surgery. Crit Care Med 1984; 12: 863–866. Peters JW, Anderson BJ, Simons SH et al. Morphine pharmacokinetics during venoarterial extracorporeal membrane oxygenation in neonates. Intensive Care Med 2005; 31: 257–263. Peters JW, Anderson BJ, Simons SH et al. Morphine metabolite pharmacokinetics during venoarterial extra corporeal membrane oxygenation in neonates. Clin Pharmacokinet 2006; 45: 705–714. 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: 17–26. Sawyer MB, Innocenti F, Das S et al. A pharmacogenetic study of uridine diphosphate-glucuronosyltransferase 2B7 in patients receiving morphine. Clin Pharmacol Ther 2003; 73: 566–574. Sadhasivam S, Krekels EH, Chidambaran V et al. Morphine clearance in children: does race or genetics matter? J Opioid Manag 2012; 8: 217–226. Fujita K, Ando Y, Yamamoto W et al. Association of UGT2B7 and ABCB1 genotypes with morphine-induced adverse drug
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reactions in Japanese patients with cancer. Cancer Chemother Pharmacol 2010; 65: 251–258. Qi X, Evans AM, Wang J et al. Inhibition of morphine metabolism by ketamine. Drug Metab Dispos 2010; 38: 728–731. Lotsch J, Skarke C, Schmidt H et al. The transfer half-life of morphine-6-glucuronide from plasma to effect site assessed by pupil size measurement in healthy volunteers. Anesthesiology 2001; 95: 1329–1338. Hannam JA, Anderson BJ. Contribution of morphine and morphine-6-glucuronide to respiratory depression in a child. Anaesth Intensive Care 2012; 40: 867–870. Skarke C, Darimont J, Schmidt H et al. Analgesic effects of morphine and morphine6-glucuronide in a transcutaneous electrical pain model in healthy volunteers. Clin Pharmacol Ther 2003; 73: 107–121. Gourlay GK, Plummer JL, Cherry DA. Chronopharmacokinetic variability in plasma morphine concentrations following oral doses of morphine solution. Pain 1995; 61: 375–381. Beasley SW, Tibballs J. Efficacy and safety of continuous morphine infusion for postoperative analgesia in the paediatric surgical ward. Aust N Z J Surg 1987; 57: 233–237. Hendrickson M, Myre L, Johnson DG et al. Postoperative analgesia in children: a prospective study in intermittent intramuscular injection versus continuous intravenous infusion of morphine. J Pediatr Surg 1990; 25: 185–190; discussion 190-181. Bouwmeester NJ, Anderson BJ, Tibboel D et al. Developmental pharmacokinetics of morphine and its metabolites in neonates, infants and young children. Br J Anaesth 2004; 92: 208–217. Lynn A, Nespeca MK, Bratton SL et al. Clearance of morphine in postoperative infants during intravenous infusion: the influence of age and surgery. Anesth Analg 1998; 86: 958–963. Taylor J, Liley A, Anderson BJ. The relationship between age and morphine infusion rate in children. Paediatr Anaesth 2012; 2013: 40–44. Walker SM. Biological and neurodevelopmental implications of neonatal pain. Clin Perinatol 2013; 40: 471–491. Comer SD, Cooper ZD, Kowalczyk WJ et al. Evaluation of potential sex differences in the subjective and analgesic effects of morphine in normal, healthy volunteers. Psychopharmacology 2010; 208: 45–55. Djurendic-Brenesel M, Mimica-Dukic N, Pilija V et al. Gender-related differences in the pharmacokinetics of opiates. Forensic Sci Int 2010; 194: 28–33.
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50 Sarton E, Romberg R, Dahan A. Gender differences in morphine pharmacokinetics and dynamics. Adv Exp Med Biol 2003; 523: 71–80. 51 Schmitz AK, Vierhaus M, Lohaus A. Pain tolerance in children and adolescents: sex differences and psychosocial influences on pain threshold and endurance. Eur J Pain 2013; 17: 124–131. 52 Rabbitts JA, Groenewald CB, Dietz NM et al. Perioperative opioid requirements are decreased in hypoxic children living at altitude. Pediatr Anesth 2010; 20: 1078–1083. 53 Rabbitts JA, Groenewald CB, Rasanen J. Geographic differences in perioperative opioid administration in children. Pediatr Anesth 2012; 22: 676–681. 54 Jimenez N, Anderson GD, Shen DD et al. Is ethnicity associated with morphine’s side effects in children? Morphine pharmacokinetics, analgesic response, and side effects in children having tonsillectomy. Pediatr Anesth 2012; 22: 669–675. 55 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. 56 Sadhasivam S, Chidambaran V. Pharmacogenomics of opioids and perioperative pain management. Pharmacogenomics 2012; 13: 1719–1740.
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57 Cohen M, Sadhasivam S, Vinks AA. Pharmacogenetics in perioperative medicine. Curr Opin Anaesthesiol 2012; 25: 419–427. 58 Naguib M, Bie B, Ting AH. Fundamental concepts of epigenetics for consideration in anesthesiology. Curr Opin Anaesthesiol 2012; 25: 434–443. 59 Chidambaran V, Ngamprasertwong P, Vinks AA et al. Pharmacogenetics and anesthetic drugs. Curr Clin Pharmacol 2012; 7: 78–101. 60 Fernandez Robles CR, Degnan M, Candiotti KA. Pain and genetics. Curr Opin Anaesthesiol 2012; 25: 444–449. 61 Rigby-Jones A, Sneyd JR. Cardiovascular changes after achieving constant effect site concentration of propofol. Anaesthesia 2008; 63: 780. 62 Hutchinson MR, Coats BD, Lewis SS et al. Proinflammatory cytokines oppose opioidinduced acute and chronic analgesia. Brain Behav Immun 2008; 22: 1178–1189. 63 Candiotti KA, Yang Z, Morris R et al. Polymorphism in the interleukin-1 receptor antagonist gene is associated with serum interleukin-1 receptor antagonist concentrations and postoperative opioid consumption. Anesthesiology 2011; 114: 1162–1168. 64 Lotsch J, Geisslinger G. Relevance of frequent mu-opioid receptor polymorphisms for opioid activity in healthy volunteers. Pharmacogenomics J 2006; 6: 200–210.
65 Walter C, Lotsch J. Meta-analysis of the relevance of the OPRM1 118A>G genetic variant for pain treatment. Pain 2009; 146: 270–275. 66 Ross JR, Rutter D, Welsh K et al. Clinical response to morphine in cancer patients and genetic variation in candidate genes. Pharmacogenomics J 2005; 5: 324–336. 67 Liem EB, Joiner TV, Tsueda K et al. Increased sensitivity to thermal pain and reduced subcutaneous lidocaine efficacy in redheads. Anesthesiology 2005; 102: 509– 514. 68 Lotsch J, Geisslinger G. Pharmacogenetics of new analgesics. Br J Pharmacol 2011; 163: 447–460. 69 Tournier N, Decleves X, Saubamea B et al. Opioid transport by ATP-binding cassette transporters at the blood-brain barrier: implications for neuropsychopharmacology. Curr Pharm Des 2011; 17: 2829–2842. 70 Holford NH, Buclin T. Safe and effective variability-a criterion for dose individualization. Ther Drug Monit 2012; 34: 565– 568. 71 Palomaki GE, Bradley LA, Douglas MP et al. Can UGT1A1 genotyping reduce morbidity and mortality in patients with metastatic colorectal cancer treated with irinotecan? An evidence-based review Genet Med 2009; 11: 21–34.
© 2014 John Wiley & Sons Ltd Pediatric Anesthesia 24 (2014) 233–238
Why is there no morphine concentration–response curve for acute pain?
The goal of any treatment is a desired response, known as the target effect. This effect might be pain reduction to a score T and 802C>T) were not associated with observed racial differences in morphine’s clearance, the wild type of the UGT2B7 isozyme was more prevalent in the African Americans (35). Further pharmacogenomic influences The role of pharmacogenomics continues to be investigated, and a number of excellent reviews are available (56–60). While each isolated pharmacogenomics influence may be discerned, the complex interplay of all these influences in any one individual makes clinical interpretation difficult. The extremely anxious child may require a greater induction dose of propofol than less anxious children (61). Increased circulating catecholamines may also contribute to perceived pain. Single-nucleotide polymorphisms for the enzyme responsible for metabolizing catecholamines (catechol-O-methyl transferase, COMT) have been described and distinct haplotypes categorized (low, average and high pain sensitivity). Haplotypes have also been associated with catecholamine synthesis (e.g., cofactor tetrahydrobiopterin (BH4) synthesis and metabolism) that are associated with chronic pain. BH4 blocking drugs may prove useful as a novel analgesic. In addition, haplotypes for the B2 adrenergic receptor, based on eight single-nucleotide polymorphisms, have been identified. It is not surprising that inflammatory cytokines (interleukins, tumor necrosis factor) have impact on the pain response. The inflammatory response mediated after surgery has impact on pain (62). Polymorphism in the interleukin-1 receptor antagonist gene is associated with serum interleukin-1 receptor antagonist concentrations and postoperative opioid consumption (63). Morphine works through the l-opioid receptor, a protein coded for by the OPRM1 gene on chromosome 6q24-q25. Polymorphisms of this gene (e.g., A118G) may increase this receptor’s affinity for morphine and its metabolite morphine 6-glucuronide (64) although clinical impact continues to be debated (65, 66) A number of other genetic variations may also influence the l-opioid receptor. The melanocortin-1 receptor that serves a role in skin pigmentation may influence morphine 6-glucuronide effects as well as the j-opioid receptor in females (67). Signal transmission from opioid receptors requires 235
Editorial
involvement in ion channels (K, Na, Ca), and polymorphisms of these channels have also been noted to have an influence on pain sensitivity. Mutations in voltagegated transient receptor potential channels have been identified and may modulate the effects of analgesics (68). Efflux transporters like the P-glycoproteins are also associated with polymorphisms and may affect transport into or out of the brain (69). Would knowledge of a concentration-response relationship improve current therapy? The therapeutic range 10–20 lgL1 associated with analgesia and infusion rates that achieve these concentrations are used widely (42). However, use of a therapeutic range implies that all concentrations within the range are equally ‘optimal’, and usually, it is understood that any concentration outside of that range is highly suboptimal and reflects inadequate treatment. Morphine concentrations below 10 lgL1 might be thought to give inadequate analgesia, while concentrations above 20 lgL1 result in respiratory depression. A concentration of 10 lgL1 may be considered to not give as good analgesia as 20 lgL1. Demonstration of a concentration–response curve may simply give practitioners a better understanding of the concepts related to dosing rather than improve current therapy. The use of patient characteristics with covariate models for the parameters can reduce predictable subject variability. While age and weight contribute greatly to PK variability in healthy children, these two covariates are not enough to reduce the between subject variability so that the medicine can be used safely and effectively in the wider pediatric population where this drug is used (e.g., critically ill children with organ dysfunction). There is also PD variability that contributes to dose requirements. Consequently, we still titrate dose to effect. Fortunately, within-patient variability appears
low, so observation of patient response can predict future dose needs. It would be nice to adjust dose further based on individual characteristics (70), but it remains uncertain how much an understanding of pharmacogenomics will play in dose individualization. If a single genetic variant was responsible for major PK or PD differences, then dose individualization would be easier. The drug irinotecan, used to treat cancer, has an active metabolite that is metabolized by a glucuronide (UGT1A1); a pathway similar to that involved in morphine clearance (UGT2B7). A variant allele UGT1A1*28 has been identified that is associated with severe neutropenia and diarrhea. Genetic testing in patients to identify this allele (present in 10% Caucasians) has been shown to be beneficial (71). However, there appears a multiplicity of genetic influences on both morphine PK and PD, and the impact from interaction of these variants is not fully understood. Pain response is further complicated by numerous other factors (e.g., psychosocial, race, environment, underlying pathology, age). Although this drug has been used for centuries, we still need to know more about it. Conflict of interest The authors declare no conflict of interest. Brian J Anderson1 & John van den Anker2,3,4 Department of Anaesthesiology, University of Auckland, Auckland, New Zealand Email: [email protected] 2 Division of Pediatric Clinical Pharmacology, Children’s National Medical Center, Washington, DC, USA 3 Intensive Care, Erasmus Medical Center-Sophia Children’s Hospital, Rotterdam, the Netherlands 4 Department of Paediatric Pharmacology, University Children’s Hospital Basel, Basel, Switzerland [email protected] 1
doi:10.1111/pan.12361
References 1 Anderson BJ, Holford NH. Understanding dosing: children are small adults, neonates are immature children. Arch Dis Child 2013; 98: 737–744. 2 Anderson BJ, Woollard GA, Holford NH. Acetaminophen analgesia in children: placebo effect and pain resolution after tonsillectomy. Eur J Clin Pharmacol 2001; 57: 559–569. 3 McFarlan CS, Anderson BJ, Short TG. The use of propofol infusions in paediatric anaesthesia: a practical guide. Paediatr Anaesth 1999; 9: 209–216.
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4 Mani V, Morton NS. Overview of total intravenous anesthesia in children. Pediatr Anesth 2010; 20: 211–222. 5 Lerman J, Sikich N, Kleinman S et al. The pharmacology of sevoflurane in infants and children. Anesthesiology 1994; 80: 814–824. 6 Rigouzzo A, Girault L, Louvet N et al. The relationship between bispectral index and propofol during target-controlled infusion anesthesia: a comparative study between children and young adults. Anesth Analg 2008; 106: 1109–1116.
7 Standing JF, Hammer GB, Sam WJ et al. Pharmacokinetic-pharmacodynamic modeling of the hypotensive effect of remifentanil in infants undergoing cranioplasty. Pediatr Anesth 2011; 20: 7–18. 8 Fuentes R, Cortinez LI, Struys MM et al. The dynamic relationship between end-tidal sevoflurane concentrations, bispectral index, and cerebral state index in children. Anesth Analg 2008; 107: 1573–1578. 9 Bouwmeester NJ, van den Anker JN, Hop WC et al. Age- and therapy-related effects on morphine requirements and plasma
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concentrations of morphine and its metabolites in postoperative infants. Br J Anaesth 2003; 90: 642–652. Lynn AM, Nespeca MK, Opheim KE et al. Respiratory effects of intravenous morphine infusions in neonates, infants, and children after cardiac surgery. Anesth Analg 1993; 77: 695–701. Anderson BJ, Ralph CJ, Stewart AW et al. The dose-effect relationship for morphine and vomiting after day-stay tonsillectomy in children. Anaesth Intensive Care 2000; 28: 155–160. Anderson BJ, Persson M, Anderson M. Rationalising intravenous morphine prescriptions in children. Acute Pain 1999; 2: 59–67. Aubrun F, Mazoit JX, Riou B. Postoperative intravenous morphine titration. Br J Anaesth 2012; 108: 193–201. Bernard R, Salvi N, Gall O et al. MORPHIT: an observational study on morphine titration in the postanesthetic care unit in children. Pediatr Anesth 2014; 24: 303–308. Morton NS, Errera A. APA national audit of pediatric opioid infusions. Pediatr Anesth 2010; 20: 119–125. Hill AV. The possible effects of the aggregation of the molecules of haemoglobin on its dissociation curves. J Physiol 1910; 14: iv–vii. Dershwitz M, Walsh JL, Morishige RJ et al. Pharmacokinetics and pharmacodynamics of inhaled versus intravenous morphine in healthy volunteers. Anesthesiology 2000; 93: 619–628. Staahl C, Upton R, Foster DJ et al. Pharmacokinetic-pharmacodynamic modeling of morphine and oxycodone concentrations and analgesic effect in a multimodal experimental pain model. J Clin Pharmacol 2008; 48: 619– 631. Mazoit JX, Butscher K, Samii K. Morphine in postoperative patients: pharmacokinetics and pharmacodynamics of metabolites. Anesth Analg 2007; 105: 70–78. Inturrisi CE, Colburn WA. Application of pharmacokinetic-pharmacodynamic modeling to analgesia. In: Foley KM, Inturrisi CE, eds. Advances in Pain Research and Therapy Opioid Analgesics in the Management of Clinical Pain. New York: Raven Press, 1986: 441–452. Stephenson T. How children’s responses to drugs differ from adults. Br J Clin Pharmacol 2005; 59: 670–673. Anderson BJ. My child is unique; the pharmacokinetics are universal. Pediatr Anesth 2012; 22: 530–538. Holford NH, Ma SC, Anderson BJ. Prediction of morphine dose in humans. Pediatr Anesth 2012; 22: 209–222. Osborne R, Joel S, Grebenik K et al. The pharmacokinetics of morphine and morphine
© 2014 John Wiley & Sons Ltd Pediatric Anesthesia 24 (2014) 233–238
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glucuronides in kidney failure. Clin Pharmacol Ther 1993; 54: 158–167. Miners JO, Knights KM, Houston JB et al. In vitro-in vivo correlation for drugs and other compounds eliminated by glucuronidation in humans: pitfalls and promises. Biochem Pharmacol 2006; 71: 1531–1539. Wang J, Evans AM, Knights KM et al. Differential disposition of intra-renal generated and preformed glucuronides: studies with 4-methylumbelliferone and 4-methylumbelliferyl glucuronide in the filtering and nonfiltering isolated perfused rat kidney. J Pharm Pharmacol 2011; 63: 507–514. Knights KM, Rowland A, Miners JO. Renal drug metabolism in humans: the potential for drug-endobiotic interactions involving cytochrome P450 (CYP) and UDP-glucuronosyltransferase (UGT). Br J Clin Pharmacol 2013; 76: 587–602. Nahata MC, Miser AW, Miser JS et al. Variation in morphine pharmacokinetics in children with cancer. Dev Pharmacol Ther 1985; 8: 182–188. Nahata MC, Miser AW, Miser JS et al. Analgesic plasma concentrations of morphine in children with terminal malignancy receiving a continuous subcutaneous infusion of morphine sulfate to control severe pain. Pain 1984; 18: 109–114. Lynn AM, Opheim KE, Tyler DC. Morphine infusion after pediatric cardiac surgery. Crit Care Med 1984; 12: 863–866. Peters JW, Anderson BJ, Simons SH et al. Morphine pharmacokinetics during venoarterial extracorporeal membrane oxygenation in neonates. Intensive Care Med 2005; 31: 257–263. Peters JW, Anderson BJ, Simons SH et al. Morphine metabolite pharmacokinetics during venoarterial extra corporeal membrane oxygenation in neonates. Clin Pharmacokinet 2006; 45: 705–714. 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: 17–26. Sawyer MB, Innocenti F, Das S et al. A pharmacogenetic study of uridine diphosphate-glucuronosyltransferase 2B7 in patients receiving morphine. Clin Pharmacol Ther 2003; 73: 566–574. Sadhasivam S, Krekels EH, Chidambaran V et al. Morphine clearance in children: does race or genetics matter? J Opioid Manag 2012; 8: 217–226. Fujita K, Ando Y, Yamamoto W et al. Association of UGT2B7 and ABCB1 genotypes with morphine-induced adverse drug
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