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Published on: December 6, 2016
Effects of Obstructive Sleep Apnea and Obesity on Morphine Pharmacokinetics in Children
Nicholas M Dalesio1, Carlton K K Lee2, Craig W Hendrix3
1From the Division of Pediatric Anesthesiology and Critical Care Medicine, Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.
Insights
Obesity and obstructive sleep apnea syndrome (OSAS) significantly increase morphine metabolism in children. This suggests elevated leptin levels in obese patients with OSAS may drive these pharmacokinetic changes.
Area of Science:
- Pharmacology
- Anesthesiology
- Endocrinology
Background:
- Obesity complicates pain management and is linked to obstructive sleep apnea syndrome (OSAS).
- Both obesity and OSAS can elevate leptin, a hormone influencing metabolism.
- These factors may alter morphine pharmacokinetics.
Purpose of the Study:
- To investigate the independent and combined effects of obesity and OSAS on morphine pharmacokinetics in children.
- To explore the role of leptin in these pharmacokinetic alterations.
Main Methods:
- Pharmacokinetic analysis of morphine and its metabolites in children aged 5-12 undergoing surgery.
- Three groups were studied: controls, nonobese with OSAS, and obese with OSAS.
- Blood samples were collected at timed intervals after a 0.05 mg/kg morphine dose.
Main Results:
- The obese/OSAS group exhibited higher CMAX and M3G concentrations compared to controls and OSAS-only groups.
- The obese/OSAS group had a lower volume of distribution (Vd) than the OSAS-only group.
- Elevated CRP, IL-10, and leptin levels were observed in the obese/OSAS group.
Conclusions:
- Obesity combined with OSAS increases morphine metabolism compared to normal-weight controls.
- Leptin elevation in obese patients may contribute to the observed increase in morphine metabolism.
- Findings highlight the complex interplay of obesity, OSAS, and drug metabolism in perioperative care.
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.
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