Clonidine Treatment for Neonatal Abstinence Syndrome

描述(申请人提供)：在美国，每年有多达20,000名婴儿出生在阿片类药物(“麻醉剂”)成瘾的母亲身边。像他们的母亲一样，这些婴儿对阿片类药物依赖。出生后，婴儿被从阿片类药物来源中移除，导致这些婴儿出现戒断综合征。新生儿的戒断症状包括呕吐、腹泻、喂养不良、心动过速、高血压、出汗、躁动、失眠、易怒、震颤、阵挛、吞噬功能亢进、生长不良和酸中毒、可逆性神经异常，甚至癫痫。这种复杂的体征和症状被称为新生儿禁欲综合征(NAS)。重新建立阿片类药物，然后缓慢缩减方案是目前的护理标准，需要延长住院时间，从几周到几个月。可乐定是一种非麻醉性中枢α2-肾上腺素能受体激动剂，可阻断交感神经系统过度兴奋的影响，是成人阿片类药物戒断的批准治疗方法。我们目前有一位医生赞助IND(#63,781)来研究可乐定作为阿片类药物辅助治疗NAS的效果。这项提议将检验这样一种假设，即可乐定和阿片类药物的联合治疗1)安全有效，2)减少阿片类药物的使用量，3)缩短治疗和住院时间。这将在一项随机、安慰剂对照的双盲临床试验中完成，该试验比较了稀释鸦片酊剂(DTO)加安慰剂(对照组)与DTO加可乐定的临床试验。其他子研究包括1)DTO和可乐定在登记队列中的药代动力学和药效学测定，以及2)通过在6个月和12个月大时用贝利婴儿发育量表(BSID)评估发育结果进行进一步的安全性评估。药物动力学将通过测量可乐定和吗啡的血清浓度以及分析分布体积、消除半衰期和清除量来确定。 这些结果将具有重要的临床意义，并可能改变护理标准，不仅适用于患有严重NAS的婴儿，而且还适用于长期使用医源性阿片类药物后的婴儿和儿童的管理，例如，在延长机械通气或多次手术的止痛之后。

DESCRIPTION (provided by applicant): In the United States, as many as 20,000 babies a year are born to opioid ("narcotic") addicted mothers. Like their mothers, these infants are opioid dependent. Following birth, the infant is removed from its opioid source, inducing a withdrawal syndrome in these infants. Withdrawal symptoms in newborns include vomiting, diarrhea, poor feeding, tachycardia, hypertension, diaphoresis, restlessness, insomnia, irritability, tremors, clonus, hyperphagia with poor growth and acidosis, reversible neurologic abnormalities, and even seizures. This complex of signs and symptoms is referred to as neonatal abstinence syndrome (NAS). Reinstitution of opioids followed by a slow tapering protocol is currently the standard of care, necessitating prolonged hospitalization from weeks to months. Clonidine is a non-narcotic central alpha2-adrenergic receptor agonist that blocks the effects of over-excitation of the sympathetic nervous system and is an approved treatment for opioid withdrawal in adults. We currently have a physician sponsored IND (#63,781) to study the effect of clonidine as adjunct therapy to opioids for the treatment of NAS. This proposal will test the hypothesis that combination therapy of clonidine and opioids is 1) safe and efficacious, 2) allows reduced amount of opioid drug use, and 3) results in shorter time of treatment and hospitalization. This will be accomplished in a randomized, placebo controlled double blind clinical trial comparing diluted tincture of opium (DTO) combined with a placebo (control) vs. DTO combined with clonidine. Additional sub-studies include determination of 1) pharmacokinetics and pharmacodynamics of DTO and clonidine in the enrolled cohort and 2) further safety evaluation by evaluating developmental outcome on the Bayley Scale of Infant Development (BSID) at 6 and 12 months of age. Pharmacokinetics will be determined by measuring serum concentrations of clonidine and morphine and analyzing volume of distribution, elimination half-life and clearance. These results will have important clinical implications and may change the standards of care not only for management of infants with severe NAS, but also for the management of infants and children, after long-term iatrogenic opioid exposure for instance following prolonged analgesia for mechanical ventilation or multiple operations.