Efficacy of clonidine in reducing iatrogenic-induced opioid dependence in infants

描述（由申请人提供）：许多婴儿由于在子宫内暴露于非法药物滥用（特别是阿片类药物和苯二氮卓类药物）而发展为新生儿戒断综合征，人们对这些婴儿的识别和治疗给予了很大的关注。然而，成千上万的危重婴儿（和儿童）也暴露于阿片类药物和苯二氮卓类药物中，以实现镇静和镇痛，这是新生儿和儿科重症监护病房常规护理的一部分。虽然这些药物的使用在减轻疼痛和焦虑、改善通气、降低肺血管阻力和改善预后方面无疑是有益的；其结果往往是产生耐受性和生理依赖性——类似于子宫内暴露于这些同类药物。事实上，10-90%接受阿片类药物和/或苯二氮卓类药物治疗超过5天的婴儿和儿童在减少或停用药物以促进儿童护理时将出现戒断症状。因此，有效的解毒或“逐渐减少”是必要的，以适当地恢复反适应性细胞事件，以尽量减少有害的应激反应，并实现体内平衡。与目前对子宫内药物依赖婴儿的护理标准类似，有必要逐渐减少药物剂量或增加另一类药物。不幸的是，缓慢的减少常常延长住院时间并增加护理费用。我们最近报道了一项随机安慰剂对照试验的结果，该试验显示，在逐渐减少剂量的阿片类药物的基础上，添加可口定（12-肾上腺素能激动剂）对于治疗因子宫内接触阿片类药物而患有中度至重度新生儿戒断综合征的婴儿阿片类药物依赖是有效和安全的。目前，我们建议在约翰霍普金斯医院对需要机械通气和镇静但未在子宫内暴露于阿片类药物或苯二氮卓类药物的危重婴儿进行双盲，随机安慰剂对照试验。总的假设是，在这个已知有发生医源性身体依赖和NAS风险的队列中，早期添加可乐定将是安全有效的，可以减少完成镇静和镇痛药物解毒的时间。该假设将通过解决两个特定目标来验证：1)可乐定在危重婴儿中的有效性和安全性，以及2)在这些仅作为常规护理一部分暴露于这些药物的易感婴儿群体中使用基于人群的药代动力学和药效学。在基于证据的研究之前，许多“标准护理实践”被纳入新生儿和儿科护理。这一建议将填补一个非常需要的空白，将我们已经了解到的介导依赖和戒断的基本机制转化为针对弱势儿科人群的经证实的治疗方法。

DESCRIPTION (provided by applicant): Much attention has been given to the recognition and treatment of the many infants who develop neonatal abstinence syndrome from in utero exposure to illicit drugs of abuse: specifically opioids and benzodiazepines. However, thousands of critically ill infants (and children) are also exposed to opioids and benzodiazepines to achieve sedation and analgesia as part of routine care in neonatal and pediatric intensive care units. While the use of these agents are undisputedly beneficial in reducing pain and anxiety, improving ventilation, reducing pulmonary vascular resistance and improving outcomes; the consequence is often the development of tolerance and physiologic dependence - similar to in utero exposure from these same classes of drugs. In fact, between 10-90% of infants and children who are treated for more than 5 days with opioids and/or benzodiazepines will develop symptoms of withdrawal when the drug is reduced or discontinued to facilitate the child's care. Thus, an effective detoxification or "tapering" regime is necessary to properly restore counter adaptative cellular events, to minimize a harmful stress response, and to achieve homeostasis. Similar to the current standard of care for infants with in utero drug dependence, the slow tapering of the drug or the addition of an alternative class of drugs is necessary. Unfortunately, the slow tapering often prolongs hospitalization and increases the cost of care. We have recently reported the results of randomized placebo control trial showing that the addition of clonidine (12-adrenergic agonist) to tapering doses of opioids was efficacious and safe in treating opioid dependence in infants who had moderate to severe neonatal abstinence syndrome from in utero exposure to opioids. Currently, we propose to perform a double-blinded, randomized placebo-control trial at Johns Hopkins Hospital in a cohort of critically ill infants requiring mechanical ventilation and sedation, but who have not been exposed in utero to opioids or benzodiazepines. The overall hypothesis is that early addition of clonidine to this cohort, known to be at risk for developing iatrogenic physical dependence and NAS, will be safe and efficacious in reducing the time to complete sedative and analgesic drug detoxification. The hypothesis will be tested by addressing 2 specific aims that will determine: 1) the efficacy and safety of clonidine in critically ill infants, and 2) pharmacokinetics and pharmacodynamics using population-based pharmacokinetics in this vulnerable infant population who have only been exposed to these drugs as part of their routine care. Many "standard of care practices" are incorporated in neonatal and pediatric care prior to evidence based studies. This proposal will fill a much needed gap in translating what we have learned about basic mechanisms mediating dependence and withdrawal to proven therapies for vulnerable pediatric populations. PUBLIC HEALTH RELEVANCE: Critically ill infants who are on breathing machines with major illnesses are rountinely exposed to high concentrations of opioids and sedatives manage pain and sedation. Similar to babies who are exposed these types of drugs before birth, these critically ill babies can also develop drug withdrawal requiring treatment and extending hospitalization. We propose to do a clinical study to determine whether adding another medication (clonidine) to help with the management of pain and sedation will decrease the development of drug withdrawal in this group of babies.