Morphine PK Subgroup Analysis

A Randomized Controlled Comparison of Ketorolac Tromethamine and Morphine for Postoperative Analgesia in Critically-ill, 3-18 Year-old Children: A Subgroup Analysis of Developmental Changes in Morphine Kinetics and Efficacy

This study was originally undertaken to evaluate the analgesic efficacy of an intravenously administered dose of ketorolac compared with intravenous morphine in the relief of acute, postoperative pain in children admitted to the Intensive Care Unit. Using the urine and plasma samples originally collected from patients in the morphine treatment group and which were never analyzed, this proposal seeks to study the pharmacokinetics and metabolism of intravenous morphine in critically-ill children along with its concentration-related efficacy using prior measures of pain.

This was a randomized, double-blind, parallel, single-dose study. All children admitted to the ICU at Children's Hospital of Michigan postoperatively who required pain management were candidates. Enrollment required a Children's Hospital of Eastern Ontario Pain Scale (CHEOPS) and/or Oucher pain score meeting the protocol definition of moderate to severe pain. Each patient was randomly assigned to receive a single dose of either morphine 0.1 mg/kg or ketorolac 0.6 mg/kg IV as the first postoperative analgesic after arriving in the ICU. Two-milliliter venous blood samples were drawn from a site contralateral to the infusion site. Samples were obtained before the dose and at 15, 30, and 60 minutes, hourly from 1-6 hours, and at 8 and 12 hours timed from the beginning of the infusion. Pain scales were assessed at the time of each pharmacokinetic sample. Plasma was immediately separated and frozen at -80°C. Urine was quantitatively collected for 12-24 hours after the study drug was administered. Urine was kept on ice at 3°C throughout the collection. At completion of the collection, the urine volume was measured and recorded, and an aliquot was frozen and maintained at -80°C. The plasma and urine samples from the morphine treated group in the original study were stored at -80°C and were not analyzed. Sets of samples of urine and plasma from 6 subjects over a range of ages have been analyzed to insure that the samples have not deteriorated during storage. This subanalysis study will provide chemical analysis of the plasma and urine samples for morphine, morphine 3 glucuronide (M3G) and morphine 6 glucuronide (M6G); pharmacokinetic analysis of morphine and its metabolites with comparison to demographics; and comparison of the morphine concentrations to the measures of analgesia. The ratio of the area under the plasma concentration vs time curves (AUC)of M6G with twice the analgesic potency as morphine and M3G with theoretical anti-analgesic properties will be compared to analgesic effects measured by the age-appropriate pain scales.

Random assignment to a single dose of morphine 0.1 mg/kg infused by syringe pump over 10 minutes; urine and blood sample frozen at -80 degrees Celsius

A single dose of morphine 0.1 mg/kg infused by syringe pump over 10 minutes; urine and blood sample frozen at -80 degrees Celsius

Chemical analysis of the plasma and urine samples for morphine concentration using high performance liquid chromatography coupled to atmospheric pressure ionization mass spectrometry

Pharmacokinetic analysis of morphine, M3G, and M6G in urine to determine clearance and percent of dose excreted

Analgesic efficacy using drug concentration and area under the curve ratio correlated with the level of analgesia measured with the age-appropriate scale

Inclusion Criteria: All children 3-18 years of age admitted to the ICU at Children's Hospital of Michigan postoperatively who required pain management during the immediate postoperative period Children's Hospital of Eastern Ontario Pain Scale (CHEOPS) and/or Oucher pain score meeting the protocol definition of moderate to severe pain Exclusion Criteria: Coma (Glasgow Coma Score < 8) or significant post-operative sedation that prevented the patient from appropriate responses to questions Requirement of administration of a sedative or neuromuscular blocking agent, or intrathecal narcotics immediately after surgery Gastrointestinal hemorrhage and/or history of ulcer disease Frequent use of NSAIDs or narcotic analgesics for >2 weeks within the 1-month period before the study Asthma Known hypersensitivity to NSAIDs, aspirin or opiates Nephrotic syndrome or acute/chronic renal failure Thrombocytopenia (platelet count <100,000) Congestive heart failure Hepatic failure Treatment with methotrexate, thiazides, β-blocking agents or warfarin at the time of the study Dehydration or hypovolemia