• determine the lowest effective naloxone infusion dose to prevent opioid induced side effects
  

• determine morphine and naloxone pharmacokinetics
  
• plasma level of naloxone required to prevent opioid induced effects and whether they are pharmacokinetic or pharmacogenetic in nature
  

In patients of all ages, opioids are the cornerstone of management of moderate to severe pain. Regardless of method of administration, all opioids produce unwanted side effects, including pruritus, nausea and vomiting, constipation, urinary retention, cognitive impairment, tolerance, dependence, and (rarely) respiratory depression. Based on the results of a previously completed randomized controlled trial, children and adolescents with moderate to severe pain, are now routinely treated in the Children’s Center of the Johns Hopkins Hospital with a low dose naloxone infusion (0.25 mcg/kg/HOUR) whenever morphine intravenous patient controlled analgesia (IVPCA) or parent/nurse controlled analgesia (IVPNCA) is initiated. Although the previous study showed a marked reduction in the incidence and severity of pruritus and nausea, approximately a third of our patients still experience these side effects. The primary purpose of this study is to reduce this failure rate by determining if there is an optimal dose of naloxone to prevent opioid induced side effects as determined by a dose finding classic up down dose escalation method. Our second aim is to detemine the pharmacokinetics of morphine and naloxone and their metabolites at each of the naloxone infusion rates attempted. We will measure morphine, naloxone, and their metabolites using a liquid chromatographic-electrospray ionization-tandem mass spectrometric method (LC/MS/MS). Our final aim is to determine the pharmacogenetics of responders and non-responders using DNA isolated from patient blood. To accomplish this we will need a single blood collection from patients currently being treated with IVPCA morphine and low dose intravenous naloxone.