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

可乐定减少婴儿医源性阿片类药物依赖的功效

基本信息

批准号：
8272767
负责人：
ESTELLE B. GAUDA
金额：
$ 1.16万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-05-01 至 2013-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8272767
关键词：
Absence of pain sensation Address Adrenergic Agonists Adult Adverse effects Analgesics Anxiety Attention Benzodiazepines Birth Breathing California Caring Child Child Care Childhood Clinical Research Clonidine Consultations Critical Illness Dependence Development Diarrhea Disinhibition Dose Double-Blind Method Drug Addiction Drug Kinetics Drug Metabolic Detoxication Enrollment Environmental air flow Event Exposure to Flushing Growth Heroin Homeostasis Hospitalization Hospitals Incidence Infant Learning Length Mechanical ventilation Mediating Medical Methadone Monitor Muscle Hypertonia Neonatal Neonatal Abstinence Syndrome Neurons Norepinephrine Opiate Addiction Opiates Opioid Outcome Outcome Measure Pain Pain management Pediatric Intensive Care Units Perinatal Exposure Pharmaceutical Preparations Pharmacodynamics Pharmacotherapy Pharmacy Schools Physical Dependence Physiologic tolerance Placebo Control Population Postpartum Women Pulmonary Vascular Resistance Randomized Reflex action Reporting Risk Safety San Francisco Science Sedation procedure Seizures Severities Substance-Related Disorders Sweat Sweating Testing Time Translating Tremor Universities Vomiting Vulnerable Populations Withdrawal Withdrawal Symptom biological adaptation to stress cohort cost critically ill newborn double-blind placebo controlled trial drug development drug of abuse drug withdrawal environmental intervention evidence base experience high risk high risk infant improved in utero neonate population based pregnant prevent public health relevance randomized placebo controlled trial response restoration routine care sedative standard of care therapy development treatment strategy trial comparing

项目摘要

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.

描述（由申请人提供）：已经非常关注识别和治疗许多因子宫内对非法滥用药物的暴露而产生新生儿戒毒综合征的婴儿：特别是阿片类药物和苯二氮卓类药物。但是，成千上万的重症婴儿（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，这是新生儿和儿科重症监护病房常规护理的一部分。尽管这些药物的使用无疑是有益于减轻疼痛和焦虑，改善通风，降低肺血管耐药性和改善预后；结果通常是耐受性和生理依赖性的发展 - 类似于从这些类别的药物中的子宫暴露中。实际上，在使用阿片类药物和/或苯二氮卓类药物治疗超过5天的婴儿和儿童中，当药物减少或停止以促进儿童的护理时，接受了5天以上的治疗。因此，为正确恢复反适应性细胞事件，最大程度地减少有害压力反应并实现稳态而有效的排毒或“逐渐变细”制度是必要的。类似于在子宫药物依赖性中针对婴儿的当前护理标准，需要缓慢的药物缩减或添加替代类药物的药物。不幸的是，缓慢的逐渐减少通常会延长住院并增加护理成本。我们最近报道了随机安慰剂对照试验的结果表明，在逐渐减少阿片类药物剂量的渐变剂量中，可乐定（12-肾上腺素能激动剂）在治疗中等至重度新生儿戒断综合征的婴儿中的阿片类药物依赖性可有效且安全。目前，我们建议在约翰·霍普金斯医院（Johns Hopkins Hospital）进行一项双盲，随机的安慰剂控制试验，其中包括需要机械通气和镇静的重症病重的婴儿，但他们尚未在子宫内暴露于阿片类药物或苯二氮卓类药物。总体假设是，在该队列中早期添加可乐定，已知有发展医源性物理依赖性和NAS的风险，将在减少完整的镇静剂和镇痛药解毒的时间方面安全有效。该假设将通过解决2个确定的特定目的来检验：1）可乐定在重症婴儿中的疗效和安全性，以及2）使用基于人群的药代动力学的药代动力学和药物动力学在这种易感婴儿中，这些药代动力学仅在这些药物中暴露于这些药物作为常规护理的一部分。在基于证据的研究之前，许多“护理标准实践”纳入了新生儿和小儿护理。该提案将填补急需的空白，以翻译我们了解的有关介导的依赖性和撤回的基本机制的知识，以对脆弱的小儿种群进行验证的疗法。公共卫生的相关性：患有重大疾病的呼吸机的重症婴儿患病的婴儿暴露于高浓度的阿片类药物和镇静剂中，管理疼痛和镇静。与在出生前暴露于这些类型的药物的婴儿类似，这些重病的婴儿也可以开发出需要治疗并延长住院治疗的药物。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）以帮助治疗疼痛和镇静剂会减少这组婴儿的药物戒断的发展。