Sleep Apnea and Obesity Affects on Morphine Pharmacokinetics

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

Adenotonsillectomy (AT) is one of the most common pediatric surgeries performed, and is estimated to comprise 530,000 procedures in children under 15 years of age. Historically, the leading cause for these procedures was recurrent infections; however, more recently surgical indications include sleep disordered breathing and obstructive sleep apnea (OSAS). Pre-operative polysomnography (PSG) is recommended for all children with suspected OSAS prior to undergoing AT, although it is unclear whether sleep disordered breathing characteristics predict post-operative outcomes or complications.

Obesity has become an epidemic in the pediatric population. More recently, an increased population of obese children are presenting for AT with upper airway obstruction with or without tonsillar hypertrophy, which is similar to the adult etiology of OSAS. Obesity is a multisystem disease, causing fatty liver and cardiac disease, defects in glucose metabolism, insulin resistance, leptin resistance, and creates a state of chronic inflammation. Markers for inflammation, including tumor necrosis factor (TNF)-α, C-reactive protein (CRP), leptin, interleukin (IL)-6 and IL-10, are abnormal in obese patients and have also been linked to more severe OSAS disease in children even after controlling for BMI.

In pediatrics, medication dosing is based on an actual body-weight calculation, however, recent reports suggest that this dosing method is over-dosing patients with obesity. Therefore, increased respiratory complications after surgery may be related to inappropriate intra-operative opioid dosing.

Specific Aim 1 (SA1): To compare morphine pharmacokinetics in normal children <=12 years of age, non-obese children with severe OSAS, and obese children with severe OSAS. The investigators hypothesize that obesity independently enhances morphine pharmacokinetics.

Specific Aim 2 (SA2): To determine whether biomarkers related to obesity, chronic inflammation, and OSAS predict changes to morphine pharmacokinetics. The investigators hypothesize that inflammatory and obesity-related biomarkers are elevated in overweight children with OSAS, more so in obese children with OSA, compared to lean children with OSAS. In addition, the investigators hypothesizes that leptin independently is linked to altered morphine pharmacokinetics.

Study Overview

• Status: Completed
• Conditions: Obesity; Pediatric Sleep Apnea; Morphine Metabolism
• Intervention / Treatment: Other: Morphine pharmacokinetic evaluation

• Study Type: Interventional
• Enrollment (Actual): 43
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Bloomberg Children's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 5 years to 12 years (Child)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Child presenting for surgery that will require opioids
• Age between 5 -12 years of age

OSAS group:

• Pre-operative polysomnography study conducted prior to day of surgery

Obese:

• Body weight >95th percentile for age.

Exclusion Criteria:

• Emergency procedures involving AT, including tonsillar bleeding
• Patients allergic to morphine
• Patients with comorbidities altering opioid metabolism (i.e. liver disease)
• Patients with chronic inflammatory, rheumatologic, or other confounding co-morbid diseases (i.e. Crohns disease, ulcerative colitis, sickle cell, Sjogren's, etc.)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Morphine dosing; Evaluating morphine pharmacokinetics (PK) in 3 groups: normal controls, children with severe OSAS, and obese children with OSAS. Morphine is dosed on ideal body weight in obese children, as recommended by manufacturer. Biomarkers were taken from patients to evaluate their relation to changes in morphine PK.	Other: Morphine pharmacokinetic evaluation; Each group received morphine and blood drawn to evaluate morphine PK

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Plasma Morphine Area Under the Curve (AUC)	To determine changes in morphine AUC due to obesity and OSAS	Through study completion, up to 24 hours after study initiation
Maximum Plasma Morphine Concentration (Cmax)	To determine changes in morphine Cmax due to obesity and OSAS	Through study completion, up to 24 hours after study initiation
Time to Maximum Plasma Morphine Concentration (Tmax)	To determine changes in morphine Tmax due to obesity and OSAS	Through study completion, up to 24 hours after study initiation
Half Life of Plasma Morphine Concentration (T1/2)	To determine changes in morphine T1/2 due to obesity and OSAS	Through study completion, up to 24 hours after study initiation
Plasma Morphine Clearance (Cl)	To determine changes in morphine Cl due to obesity and OSAS	Through study completion, up to 24 hours after study initiation
Plasma Morphine Volume of Distribution (Vd)	To determine changes in morphine Vd due to obesity and OSAS	Through study completion, up to 24 hours after study initiation
Plasma Morphine 3-glucuronide (M3G) Maximum Plasma Concentration (Cmax)	To determine changes in M3G Cmax due to obesity and OSAS	Through study completion, up to 24 hours after study initiation
Time to Maximum Morphine 3-glucuronide (M3G) Concentration (Tmax)	To determine changes in M3G Tmax due to obesity and OSAS	Through study completion, up to 24 hours after study initiation
Morphine 3-glucuronide (M3G) to Morphine ratio	To determine changes in metabolism of morphine due to obesity and OSAS	Through study completion, up to 24 hours after study initiation
Morphine 3-glucuronide (M3G) to Morphine 6-glucuronide (M6G) ratio	To determine changes in metabolism of morphine due to obesity and OSAS	Through study completion, up to 24 hours after study initiation

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Biomarker concentrations	To determine whether inflammatory biomarkers correlate to the severity of sleep apnea. Biomarkers that will be studied include IL 1,6,10, CRP, TNF-alpha, leptin, and insulin.	Through study completion, up to 24 hours after study initiation

Collaborators and Investigators

• Sponsor: Johns Hopkins University

Study record dates

Study Major Dates

• Study Start (Actual): July 1, 2015
• Primary Completion (Actual): September 7, 2018
• Study Completion (Actual): September 7, 2018

Study Registration Dates

• First Submitted: February 4, 2016
• First Submitted That Met QC Criteria: April 4, 2016
• First Posted (Estimate): April 11, 2016

Study Record Updates

• Last Update Posted (Actual): September 9, 2019
• Last Update Submitted That Met QC Criteria: September 5, 2019
• Last Verified: September 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Nervous System Diseases; Respiratory Tract Diseases; Respiration Disorders; Sleep Disorders, Intrinsic; Dyssomnias; Sleep Wake Disorders; Overnutrition; Nutrition Disorders; Overweight; Body Weight; Signs and Symptoms, Respiratory; Sleep Apnea Syndromes; Obesity; Apnea; Physiological Effects of Drugs; Central Nervous System Depressants; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Analgesics, Opioid; Narcotics; Morphine
• Other Study ID Numbers: IRB00034512

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes