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

说明(由申请人提供)：许多婴儿因在宫内接触非法滥用药物，特别是阿片类药物和苯二氮卓类药物而患上新生儿禁欲综合症，对此给予了极大的关注。然而，作为新生儿和儿科重症监护病房常规护理的一部分，数千名危重婴儿(和儿童)也接触阿片类药物和苯二氮卓类药物，以实现镇静和止痛。虽然这些药物的使用在减轻疼痛和焦虑、改善通风、减少肺血管阻力和改善预后方面无疑是有益的；但其结果往往是形成耐受性和生理依赖性--类似于在子宫内接触这些相同类别的药物。事实上，在接受阿片类药物和/或苯二氮卓类药物治疗5天以上的婴儿和儿童中，有10%-90%的人会在减少或停药以方便儿童护理时出现戒断症状。因此，一个有效的解毒或“逐渐减少”的制度是必要的，以适当地恢复对抗适应性细胞事件，最大限度地减少有害的应激反应，并实现动态平衡。与目前对患有宫内药物依赖的婴儿的护理标准类似，缓慢减少药物或增加一类替代药物是必要的。不幸的是，缓慢的缩减往往会延长住院时间，增加护理成本。我们最近报道了一项随机安慰剂对照试验的结果，结果表明，在阿片类药物逐渐减少剂量的基础上加用可乐定(12-肾上腺素能激动剂)是有效和安全的，可以治疗从宫内阿片类药物暴露到中到重度新生儿戒断综合征的阿片类药物依赖。目前，我们建议在约翰霍普金斯医院进行一项双盲、随机的安慰剂对照试验，对一组需要机械通气和镇静但在宫内未接触阿片类药物或苯二氮卓类药物的危重婴儿进行试验。总体假设是，早期将可乐定添加到该队列中将安全有效地减少完成镇静和止痛药物戒毒的时间。已知可乐定有发生医源性身体依赖和NAS的风险。这一假设将通过解决两个具体目标来检验，这两个目标将确定：1)可乐定在危重婴儿中的有效性和安全性，以及2)在这一脆弱的婴儿群体中使用基于人群的药代动力学和药效学，这些婴儿只在他们的日常护理中接触到这些药物。在循证研究之前，许多“标准护理实践”被纳入新生儿和儿科护理中。这项提议将填补一个亟需的空白，将我们所了解的调解依赖和戒断的基本机制转化为对脆弱的儿科人群有效的治疗方法。 公共卫生相关性：患有重大疾病的呼吸机上的危重婴儿普遍暴露在高浓度的阿片类药物中，镇静剂可以控制疼痛和镇静。与出生前接触这些药物的婴儿类似，这些危重婴儿也可能出现需要治疗和延长住院时间的药物戒断。我们建议进行一项临床研究，以确定添加另一种药物(可乐定)来帮助控制疼痛和镇静是否会减少这组婴儿停药的发展。

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.