5HT3 Antagonists to Treat Opioid Withdrawal and to Prevent the Progression of Phy

描述(申请人提供)：在过去的20年里，阿片类药物的处方大幅增加。1目前，阿片类药物是美国医生开出的最常见的药物之一，维柯丁(氢可酮/对乙酰氨基酚)--仅2005年就开了1亿张处方--是所有类别中最常用的处方药物。2006年，在所有12岁及以上的美国人中，13.6%(超过3300万)报告至少一次将处方阿片类药物用于非医疗目的，前一年超过1200万，前一个月为520万。4 2001年，美国处方阿片类药物滥用的总成本估计为86亿美元。我们将使用术语“身体依赖”(PD)来指代反复或连续使用药物而导致的生理状态，在停止使用时表现为戒断症状。6这不能与DSM IV诊断的“阿片依赖”的一系列症状相混淆，DSM IV诊断的“阿片依赖”还表现为强迫服药、对药物的控制失控以及持续使用药物造成的伤害。为避免混淆DSM IV所定义的“身体依赖(PD)”和“阿片依赖”，我们将使用术语“成瘾”来指代以强迫性吸毒行为、注意力集中和危害为特征的药物使用的生物、心理和社会疾病。帕金森病在成瘾发展中的作用尚未确定。目前还没有防止身体依赖恶化的药物，因此没有办法正式测试它在从吸毒到上瘾的发展过程中可能或可能不会发挥的作用。此外，帕金森病患者在戒断(阿片类药物戒断)的背景下所经历的不适，有时甚至是长期的身体不适，可能会降低对以戒断为基础的阿片成瘾疗法的接受度。因此，需要有效的策略来治疗帕金森病患者因戒断而产生的阿片类药物戒断(OW)症状，并防止与使用和滥用处方阿片类药物相关的身体依赖的进展。来自药物遗传学单倍型计算图谱、动物研究和这位研究者实验室的几项小型试点翻译研究的最新证据表明，5HT3受体在阿片类药物戒断和身体依赖的表达中发挥着重要作用。拟议的研究将评估5HT3受体拮抗剂(5HT3-RAS)在处方阿片类药物滥用治疗中的新适应症的使用。有待评估的总体假设是，5HT3-RAS可以减少已经对阿片类药物产生身体依赖的人类的阿片类药物戒断症状，并在与阿片类药物联合使用时防止身体依赖的进展。我们建议测试5HT3-RAS的能力，以(1)减少阿片类药物戒断的表达，(2)防止慢性阿片类药物治疗的慢性疼痛患者的身体依赖的进展。为了将使用处方阿片类药物的风险降至最低，我们将只招募已经长期接触阿片类药物的患者来治疗慢性背部疼痛。此外，我们还实施了一项全面的16项患者安全行动计划，以最大限度地提高患者的安全。我们将排除被发现成瘾风险增加或出现有问题的阿片类药物使用模式的患者。在研究期间，所有参与者将由研究护士PI和一名拥有成瘾和止痛药双重认证的董事会认证医生仔细监测。在研究结束时，患者将在首席调查员和一名成瘾专家的日常监测下恢复其原来的处方阿片类药物方案。首席调查员和成瘾专家将在研究结束后无条件提供服务，以防出现任何成瘾问题。虽然使用阿片类止痛药存在固有的风险，但我们正在将这项研究的额外风险降至最低，方法是限制那些已经通过正在进行的临床治疗而产生这些风险的人进入研究。他们将从这项研究中获得的额外筛查和监测水平将远远超过他们在正常临床实践中否则会接触到的水平，这可能会将相关的阿片类药物风险降低到低于没有参与研究但仍接触慢性阿片类药物的类似患者的水平。

DESCRIPTION (provided by applicant): Over the last 20 years, opioid prescriptions have increased substantially.1 Currently, opioids are among the most common medications prescribed by physicians in the US2 and Vicodin (hydrocodone/acetaminophen) -- with 100 million prescriptions in 2005 alone -- is the most commonly prescribed medication of any category.3 However, physical dependence (PD), addiction, and withdrawal complicate the use of prescription opioids. Among all Americans 12 years and older in 2006, 13.6 percent (more than 33 million) reported having used prescription opioids for nonmedical purposes at least once, more than 12 million in the prior year, and 5.2 million in the prior month.4 In 2001, the total cost of prescription opioid abuse in the US was estimated at $8.6 billion.5 For the purposes of this grant, we will use the term "physical dependence" (PD) to refer to that physiologic state induced by repeated or continuous drug use that manifests as withdrawal symptoms upon stopping use.6 This is not to be confused with the cluster of symptoms characterizing the DSM IV diagnosis of "opioid dependence," which is additionally characterized by compulsion to take the drug, loss of control over the drug, and harm resulting from ongoing drug use. To avoid confusion between the terms "physical dependence (PD)" and "opioid dependence" as defined by the DSM IV, we will use the term "addiction" to refer to the biopsychosocial disease of drug use characterized by compulsive drug taking behaviors, preoccupation, and harm. The role of PD in the development of addiction is not established. There is currently no drug to prevent the progression of physical dependence and thus there has been no way to formally test the role it may or may not play in the progression from drug use to addiction. Furthermore, the uncomfortable and sometimes prolonged physical discomfort experienced by patients with PD in the setting of abstinence (opioid withdrawal), may reduce acceptance of abstinence-based therapies of opioid addiction. Thus, there is a need for effective strategies to treat the symptoms of opioid withdrawal (OW) created by abstinence in those with PD, and also to prevent progression of physical dependence associated with the use and abuse of prescription opioid medications. Recent evidence from pharmacogenetic haplotype-based computational mapping, animal studies, and several small pilot translational studies from this investigator's laboratory point to a significant role of the 5HT3 receptor in the expression of opioid withdrawal and physical dependence. The proposed studies will evaluate the use of 5HT3 receptor antagonists (5HT3-RAs) for new indications in the treatment of prescription opioid drug abuse. The overall HYPOTHESIS to be evaluated is that 5HT3-RAs can reduce opioid withdrawal symptoms in humans who have already developed physical dependence to opioids and prevent the progression of physical dependence when co-administered with opioid medications. We propose to test the ability of 5HT3-RAs to (1) reduce the expression of opioid withdrawal and (2) prevent the progression of physical dependence in chronic pain patients on chronic opioid therapy. To minimize the risks associated with the use of prescription opioids, we will enroll only patients who are already chronically exposed to opioids to treat chronic back pain. Furthermore, we have implemented a comprehensive 16-item Patient Safety Action Plan to maximize patient safety. We will exclude patients identified to be at elevated risk of addiction or of developing problematic opioid uses patterns. During the study, all participants will be carefully monitored by the PI, research nurse, and a board-certified physician with dual credentialing in addiction and pain medicine. At the end of the study, patients will be returned to their original prescription opioid regimen under daily monitoring from the Principal Investigator and an addiction expert. The Principal Investigator and addiction expert will be available unconditionally after the study in the unlikely event that any addiction issues arise. While there are inherent risks associated with the use of opioid pain medications, we are minimizing the additional risks of this study by restricting entry to only those people who have already adopted these risks through their ongoing clinical treatment. The additional level of screening and monitoring they will receive from the study will far exceed the level they would otherwise be exposed to in normal clinical practice, and this may reduce the associated opioid risks to below the levels experience by similar patients who do not participate in the study but are nonetheless exposed to chronic opioids.