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

描述（由申请方提供）：许多婴儿因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）而发生新生儿戒断综合征，其识别和治疗受到极大关注。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，以实现镇静和镇痛，作为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无疑有利于减轻疼痛和焦虑，改善通气，降低肺血管阻力和改善结果;其结果往往是耐受性和生理依赖性的发展-类似于子宫内暴露于这些相同类别的药物。事实上，10-90%的婴儿和儿童使用阿片类药物和/或苯二氮卓类药物治疗超过5天，当减少或停用药物以便于儿童护理时，会出现戒断症状。因此，一个有效的解毒或“逐渐减少”制度是必要的，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，并实现稳态。与目前对宫内药物依赖婴儿的护理标准类似，有必要缓慢减少药物或添加替代药物。不幸的是，缓慢的逐渐减少往往会导致住院治疗，并增加护理费用。我们最近报道了随机安慰剂对照试验的结果，结果表明，可乐定（12-肾上腺素能受体激动剂）添加到阿片类药物的剂量递减是有效的，安全的治疗阿片类药物依赖的婴儿有中度至重度新生儿戒断综合征从子宫内暴露于阿片类药物。目前，我们建议在约翰霍普金斯医院进行一项双盲、随机安慰剂对照试验，研究对象是需要机械通气和镇静但在子宫内未暴露于阿片类药物或苯二氮卓类药物的危重婴儿。总体假设是，已知该队列存在发生医源性身体依赖和NAS的风险，因此早期添加可乐定可安全有效地缩短完成镇静和镇痛药物脱毒的时间。将通过解决2个特定目的来检验该假设，这2个特定目的将确定：1）可乐定在危重婴儿中的疗效和安全性，以及2）在仅作为常规护理的一部分暴露于这些药物的脆弱婴儿人群中使用基于人群的药代动力学的药代动力学和药效学。许多“标准护理实践”被纳入新生儿和儿科护理之前，以证据为基础的研究。这项提案将填补一个急需的空白，将我们所了解到的关于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疗法。 公共卫生相关性：患有重大疾病的呼吸机上的危重婴儿经常暴露于高浓度的阿片类药物和镇静剂中，以控制疼痛和镇静。与出生前接触这些类型药物的婴儿类似，这些重症婴儿也可能出现药物戒断，需要治疗和延长住院时间。我们建议进行一项临床研究，以确定是否增加另一种药物（可乐定），以帮助管理疼痛和镇静将减少药物戒断的发展，在这组婴儿。

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.