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

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.

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.

C_MAX of MS. Comparison of mean (±SD) C_MAX 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 C_MAX in obese patients with OSAS is also presented. *P < .05 versus the nonobese/non-OSAS control group. C_MAX indicates maximum concentration; MS, morphine sulfate; OSAS, obstructive sleep apnea syndrome; SD, standard deviation.

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.