Effects of Obstructive Sleep Apnea and Obesity on Morphine Pharmacokinetics in Children

Nicholas M Dalesio, Carlton K K Lee, Craig W Hendrix, Nikole Kerns, Aaron Hsu, William Clarke, Joseph M Collaco, Sharon McGrath-Morrow, Myron Yaster, Robert H Brown, Alan R Schwartz, Nicholas M Dalesio, Carlton K K Lee, Craig W Hendrix, Nikole Kerns, Aaron Hsu, William Clarke, Joseph M Collaco, Sharon McGrath-Morrow, Myron Yaster, Robert H Brown, Alan R Schwartz

Abstract

Background: Obesity increases susceptibility to chronic pain, increases metabolism, and is associated with obstructive sleep apnea syndrome (OSAS), all which can complicate perioperative pain management of patients. In addition, obesity and OSAS can cause elevation of the adipose-derived hormone leptin, which increases metabolism. We hypothesized that obesity along with sleep apnea and leptin independently enhance morphine pharmacokinetics.

Methods: Children 5-12 years of age who were presenting for surgery were administered a morphine dose of 0.05 mg/kg. Blood was collected at baseline and at subsequent preset times for pharmacokinetic analysis of morphine and its metabolites. Three groups were studied: a nonobese group with severe OSAS, an obese group with severe OSAS, and a control group.

Results: Thirty-four patients consisting of controls (n = 16), nonobese/OSAS (n = 8), and obese/OSAS (n = 10) underwent analysis. The obese/OSAS group had a higher dose-adjusted mean maximum morphine concentration (CMAX) over 540 minutes compared to the controls (P < .001) and those with only OSAS (P = .014). The obese/OSAS group also had lower volume of distribution (Vd) when compared to OSAS-only patients (P = .007). In addition, those in the obese/OSAS group had a higher morphine 3-glucuronide (M3G) maximum concentration (P = .012) and a higher ratio of M3G to morphine than did the control group (P = .011). Time to maximum morphine 6-glucuronide (M6G) concentration was significantly lower in both nonobese/OSAS and obese/OSAS groups than in the control group (P < .005). C-reactive protein (CRP), interleukin (IL)-10, and leptin were all higher in the obese/OSAS group than in controls (P = .004, 0.026, and <0.001, respectively), and compared to OSAS-only patients, CRP (P = .013) and leptin (P = .002) levels were higher in the obese/OSAS group.

Conclusions: The combination of obesity and OSAS was associated with an increase in morphine metabolism compared with that in normal-weight controls. Our previous study in mice demonstrated that obesity from leptin deficiency decreased morphine metabolism, but that metabolism normalized after leptin replacement. Leptin may be a cause of the increased morphine metabolism observed in obese patients.

Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1.
Figure 1.
Comparison of mean serum morphine concentrations measured at preset time points after morphine injection in normal-weight patients without OSAS, patients with severe OSAS only, and obese patients with severe OSAS. OSAS indicates obstructive sleep apnea syndrome.
Figure 2.
Figure 2.
CMAX of MS. Comparison of mean (±SD) CMAX for plasma morphine during 540 minutes of blood sampling time between normal-weight, non-OSAS controls, nonobese OSAS, and obese patients with OSAS. Dose-adjusted mean CMAX in obese patients with OSAS is also presented. *P < .05 versus the nonobese/non-OSAS control group. CMAX indicates maximum concentration; MS, morphine sulfate; OSAS, obstructive sleep apnea syndrome; SD, standard deviation.
Figure 3.
Figure 3.
Comparison of biomarker concentrations between normal-weight and obese patients with and without OSAS. *P < .05 versus nonobese/non-OSAS control group. +P < .05 versus obese/OSAS group. Units of measurement are as follows: CRP (μg/mL), IL-1β (pg/mL), IL-10 (pg/mL), insulin (μU/mL), leptin (ng/mL), TNF-α (pg/mL). Concentrations of IL-1, IL-6, and IL-10 were multiplied by 10 to optimize visual comparisons on the graph. CRP indicates C-reactive protein; IL, interleukin; OSAS, obstructive sleep apnea syndrome; TNF, tumor necrosis factor.

References

    1. Jimenez N, Posner KL, Cheney FW, Caplan RA, Lee LA, Domino KB. An update on pediatric anesthesia liability: a closed claims analysis. Anesth Analg. 2007;104:147–153.
    1. Statham MM, Elluru RG, Buncher R, Kalra M. Adenotonsillectomy for obstructive sleep apnea syndrome in young children: prevalence of pulmonary complications. Arch Otolaryngol Head Neck Surg. 2006;132:476–480.
    1. Cheng J, Elden L. Outcomes in children under 12 months of age undergoing adenotonsillectomy for sleep-disordered breathing. Laryngoscope. 2013;123:2281–2284.
    1. Gleich SJ, Olson MD, Sprung J, et al. Perioperative outcomes of severely obese children undergoing tonsillectomy. Paediatr Anaesth. 2012;22:1171–1178.
    1. Schwengel DA, Sterni LM, Tunkel DE, Heitmiller ES. Perioperative management of children with obstructive sleep apnea. Anesth Analg. 2009;109:60–75.
    1. Sanders JC, King MA, Mitchell RB, Kelly JP. Perioperative complications of adenotonsillectomy in children with obstructive sleep apnea syndrome. Anesth Analg. 2006;103:1115–1121.
    1. Brown KA, Laferrière A, Moss IR. Recurrent hypoxemia in young children with obstructive sleep apnea is associated with reduced opioid requirement for analgesia. Anesthesiology. 2004;100:806–810; discussion 5A.
    1. Savransky V, Reinke C, Jun J, et al. Chronic intermittent hypoxia and acetaminophen induce synergistic liver injury in mice. Exp Physiol. 2009;94:228–239.
    1. Raghavendran S, Bagry H, Detheux G, Zhang X, Brouillette RT, Brown KA. An anesthetic management protocol to decrease respiratory complications after adenotonsillectomy in children with severe sleep apnea. Anesth Analg. 2010;110:1093–1101.
    1. Wu J, Li P, Wu X, Chen W. Chronic intermittent hypoxia decreases pain sensitivity and increases the expression of HIF1α and opioid receptors in experimental rats. Sleep Breath. 2015;19:561–568.
    1. Rabbitts JA, Groenewald CB, Dietz NM, Morales C, Räsänen J. Perioperative opioid requirements are decreased in hypoxic children living at altitude. Paediatr Anaesth. 2010;20:1078–1083.
    1. Redline S, Tishler PV, Schluchter M, Aylor J, Clark K, Graham G. Risk factors for sleep-disordered breathing in children. Associations with obesity, race, and respiratory problems. Am J Respir Crit Care Med. 1999;159:1527–1532.
    1. Dalesio NM, Hendrix CW, McMichael DH, et al. Effects of obesity and leptin deficiency on morphine pharmacokinetics in a mouse model. Anesth Analg. 2016;123:1611–1617.
    1. Dalesio NM, Lee CKK, Hendrix CW. In response. Anesth Analg. 2017;125:362–363.
    1. Lloret Linares C, Declèves X, Oppert JM, et al. Pharmacology of morphine in obese patients: clinical implications. Clin Pharmacokinet. 2009;48:635–651.
    1. Nasrallah MP, Ziyadeh FN. Overview of the physiology and pathophysiology of leptin with special emphasis on its role in the kidney. Semin Nephrol. 2013;33:54–65.
    1. Gozal D. Sleep, sleep disorders and inflammation in children. Sleep Med. 2009;10(suppl 1):S12–S16.
    1. Gozal D, Capdevila OS, Kheirandish-Gozal L. Metabolic alterations and systemic inflammation in obstructive sleep apnea among nonobese and obese prepubertal children. Am J Respir Crit Care Med. 2008;177:1142–1149.
    1. Cullen A, Ferguson A. Perioperative management of the severely obese patient: a selective pathophysiological review. Can J Anaesth. 2012;59:974–996.
    1. Tauman R, Serpero LD, Capdevila OS, et al. Adipokines in children with sleep disordered breathing. Sleep. 2007;30:443–449.
    1. Ip MS, Lam KS, Ho C, Tsang KW, Lam W. Serum leptin and vascular risk factors in obstructive sleep apnea. Chest. 2000;118:580–586.
    1. Capdevila OS, Kheirandish-Gozal L, Dayyat E, Gozal D. Pediatric obstructive sleep apnea: complications, management, and long-term outcomes. Proc Am Thorac Soc. 2008;5:274–282.
    1. Iber C; Medicine AAOS. The AASM Manual for the Scoring of Sleep and Associated Events: Rules, Terminology and Technical Specifications. Winchester, IL: American Academy of Sleep Medicine; 2007.
    1. Barlow SE; Expert Committee. Expert committee recommendations regarding the prevention, assessment, and treatment of child and adolescent overweight and obesity: summary report. Pediatrics. 2007;120(suppl 4):S164–S192.
    1. 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;54:592–603.
    1. Sartori D, Lewis T, Breaud A, Clarke W. The development of a high-performance liquid chromatography-tandem mass spectrometric method for simultaneous quantification of morphine, morphine-3-β-glucuronide, morphine-6-β-glucuronide, hydromorphone, and normorphine in serum. Clin Biochem. 2015;48:1283–1290.
    1. Gabrielsson J, Weiner D. Non-compartmental analysis. Methods Mol Biol. 2012;929:377–389.
    1. Stanski DR, Greenblatt DJ, Lowenstein E. Kinetics of intravenous and intramuscular morphine. Clin Pharmacol Ther. 1978;24:52–59.
    1. Gibaldi M, Perrier D. Noncompartmental analysis based on statistical moment theory In: Pharmacokinetics, Revised and Expanded. 2nd ed. New York, NY: Marcel Dekker; 1982:409–419.
    1. de Hoogd S, Välitalo PAJ, Dahan A, et al. Influence of morbid obesity on the pharmacokinetics of morphine, morphine-3-glucuronide, and morphine-6-glucuronide. Clin Pharmacokinet. 2017;56:1577–1587.
    1. Lloret-Linares C, Hirt D, Bardin C, et al. Effect of a roux-en-y gastric bypass on the pharmacokinetics of oral morphine using a population approach. Clin Pharmacokinet. 2014;53:919–930.
    1. Lloret-Linares C, Scherrmann JM, Declèves X. The effect of morbid obesity on morphine glucuronidation. Pharmacol Res. 2016;114:299–300.
    1. Kang M, Mischel RA, Bhave S, et al. The effect of gut microbiome on tolerance to morphine mediated antinociception in mice. Sci Rep. 2017;7:42658.
    1. Brill MJ, Diepstraten J, van Rongen A, van Kralingen S, van den Anker JN, Knibbe CA. Impact of obesity on drug metabolism and elimination in adults and children. Clin Pharmacokinet. 2012;51:277–304.
    1. Mutlib AE, Goosen TC, Bauman JN, Williams JA, Kulkarni S, Kostrubsky S. Kinetics of acetaminophen glucuronidation by UDP-glucuronosyltransferases 1A1, 1A6, 1A9 and 2B15. Potential implications in acetaminophen-induced hepatotoxicity. Chem Res Toxicol. 2006;19:701–709.
    1. Court MH, Duan SX, Guillemette C, et al. Stereoselective conjugation of oxazepam by human UDP-glucuronosyltransferases (UGTs): S-oxazepam is glucuronidated by UGT2B15, while R-oxazepam is glucuronidated by UGT2B7 and UGT1A9. Drug Metab Dispos. 2002;30:1257–1265.
    1. Miyamoto L, Ebihara K, Kusakabe T, et al. Leptin activates hepatic 5′-AMP-activated protein kinase through sympathetic nervous system and α1-adrenergic receptor: a potential mechanism for improvement of fatty liver in lipodystrophy by leptin. J Biol Chem. 2012;287:40441–40447.
    1. Raebel MA, Newcomer SR, Reifler LM, et al. Chronic use of opioid medications before and after bariatric surgery. JAMA. 2013;310:1369–1376.
    1. Frink EJ Jr, Morgan SE, Coetzee A, Conzen PF, Brown BR Jr. The effects of sevoflurane, halothane, enflurane, and isoflurane on hepatic blood flow and oxygenation in chronically instrumented greyhound dogs. Anesthesiology. 1992;76:85–90.

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