Our survey data and a review of the literature indicate that the attitudes and practices of clinicians in the areas of neonatal pain management have changed. Today, neonatal and pediatric populations are more readily treated with opioid agonists than in the past. The widespread use of opioids is still hampered by fears of tolerance and physical dependence. These fears are supported by reports of tolerance and dependence in neonates and infants continuously receiving morphine and fentanyl to provide analgesia during painful and stressful life-saving procedures. Much remains to be learned about the vulnerability of neonates and infants to become tolerant and dependent, and virtually nothing is known about the long-term consequences as these young patients become juveniles and adults.
One aim of this grant will explore the vulnerability of neonatal rats to become tolerant and dependent to opioids. Our preliminary studies reveal that neonatal rats continuously receiving fentanyl from osmotic minipumps become tolerant and dependent. However, reports conflict about whether high potency opioids, such as fentanyl, produce tolerance and dependence. Studies will be conducted to test the hypothesis that not all opioids produce the same degree of tolerance and dependence in neonatal rats. Tolerance and dependence will be characterized in neonatal rats chronically administered low (meperidine), intermediate (morphine) and high (fentanyl) potency agonists. Another aim of this grant will explore the long-term consequences of tolerance and dependence in neonatal rats. We will test the hypothesis that neonatal tolerance and dependence alters the subsequent antinociceptive sensitivity of rats to opioids as juveniles and adults. In utero opioid exposure was reported to alter opioid antinociception in adult rats. These animals appeared normal in every respect, except when tested with opioids. We will also test the hypothesis that neonates chronically treated with opioid will exhibit, on second exposure, a greater degree of tolerance and dependence as juvenile and adult rats than rats that were opioid-naive as neonates. No studies have yet examined the effects of a second opioid exposure later in life. Finally, we will test the hypothesis that neonatal tolerance and dependence increases the propensity of rats to self-administer opioids as juveniles and adults. Adult rats exposed in utero to opioid self- administer significantly more opioid than opioid-naive animals. It is hoped that information on opioid tolerance and dependence may yield better and safer treatment regimens for human neonates.
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