Sleep Apnea and Obesity Affects on Morphine Pharmacokinetics

NCT02732795 | Completed DMC

• 1 other identifier: IRB00034512
• Study Type: interventional
• Target: 43
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Pediatric Sleep Apnea; Obesity; Morphine Metabolism

Outcome Measures

Primary Outcomes (10)

• 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 Outcomes (1)

• Biomarker concentrations

  Through study completion, up to 24 hours after study initiation

Study Arms (1)

Morphine dosing

EXPERIMENTAL

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

Interventions

Morphine pharmacokinetic evaluation OTHER

Each group received morphine and blood drawn to evaluate morphine PK

Morphine dosing

Eligibility Criteria

• Age: 5 Years - 12 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Child (0-17)

You may qualify if:

• 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.

You may not qualify if:

• 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.)

Sponsors & Collaborators

• Johns Hopkins University: lead

Study Sites (1)

Bloomberg Children's Hospital

Baltimore, Maryland, 21287, United States

Location

MeSH Terms

Conditions

Obesity

Condition Hierarchy (Ancestors)

Overweight; Overnutrition; Nutrition Disorders; Nutritional and Metabolic Diseases; Body Weight; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 4, 2016
• First Posted: April 11, 2016
• Study Start: July 1, 2015
• Primary Completion: September 7, 2018
• Study Completion: September 7, 2018
• Last Updated: September 9, 2019

Record last verified: 2019-09

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)