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

5HT3 拮抗剂治疗阿片类药物戒断并预防 Physical 进展

• 批准号: 8041122
• 负责人: LAWRENCE F CHU
• 金额: $ 37.23万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8041122
• 关键词: 12 year old; Abstinence; Address; Adopted; Adverse effects; Affect; Agonist; American; Analgesics; Animals; Behavior; Benign; Binding; Chronic; Clinical Treatment; Clonidine; Confusion; Credentialing; Data; Detection; Development; Diagnosis; Diagnostic and Statistical Manual; Disease; Drug Metabolic Detoxication; Drug abuse; Drug usage; Enrollment; Event; Future; Goals; Grant; Haplotypes; Health; Human; Hydrocodone/Acetaminophen; Hyperactive behavior; Hypotension; Incidence; K-Series Research Career Programs; Laboratories; Link; Maps; Measures; Medical; Medicine; Methadone; Methodology; Methods; Monitor; Nursing Research; Ondansetron; Opiate Addiction; Opioid; Opioid Receptor; Pain; Pain management; Participant; Patients; Pattern; Pharmaceutical Preparations; Pharmacogenetics; Physical Dependence; Physicians; Physiological; Play; Prevention; Principal Investigator; Public Health; Qualifying; Regimen; Reporting; Research Personnel; Risk; Role; Screening procedure; Sedation procedure; Serotonin Antagonists; Symptoms; Testing; Treatment outcome; United States National Institutes of Health; Vicodin; Withdrawal; Withdrawal Symptom; addiction; base; biopsychosocial; chronic back pain; chronic pain; clinical practice; cost; drug abstinence; experience; improved; noradrenergic; opioid abuse; opioid withdrawal; patient safety; prescription opioid; prescription opioid abuse; prevent; programs; receptor; success; translational study; treatment program; treatment strategy

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.

说明（由申请人提供）：过去 20 年来，阿片类药物处方大幅增加。1 目前，阿片类药物是美国医生最常用的药物之一2，而维柯丁（氢可酮/对乙酰氨基酚）——仅 2005 年就有 1 亿张处方——是所有类别中最常用的处方药物。3 然而，身体依赖性 (PD)、成瘾和戒断使阿片类药物的使用变得复杂。 处方阿片类药物。 2006 年，在所有 12 岁及以上的美国人中，有 13.6%（超过 3,300 万）报告称曾至少一次出于非医疗目的使用过处方阿片类药物，前一年超过 1,200 万，上个月为 520 万。4 2001 年，美国滥用处方阿片类药物的总成本估计为 86 亿美元。5 在本次拨款中，我们将使用“身体依赖”(PD) 一词。指的是 重复或连续吸毒引起的生理状态，在停止吸毒时表现为戒断症状。 6 这不应与 DSM IV 诊断为“阿片类药物依赖”的一系列症状相混淆，后者的特征还包括强迫服药、对药物失去控制以及持续吸毒造成的伤害。为了避免 DSM IV 定义的“身体依赖（PD）”和“阿片类药物依赖”这两个术语之间的混淆，我们将使用“成瘾”一词来指代以强迫性吸毒行为、专注和伤害为特征的吸毒生物心理社会疾病。 PD 在成瘾发展中的作用尚未确定。目前还没有药物可以阻止身体依赖性的发展，因此无法正式测试它在吸毒到成瘾的过程中可能发挥或不发挥的作用。此外，PD 患者在戒断（阿片类药物戒断）时所经历的不舒服、有时甚至是长时间的身体不适，可能会降低对基于戒断的阿片类药物成瘾疗法的接受度。因此，需要有效的策略来治疗 PD 患者因戒断而产生的阿片类药物戒断 (OW) 症状，并防止与处方阿片类药物的使用和滥用相关的身体依赖性的进展。来自基于药物遗传学单倍型的计算图谱、动物研究和该研究人员实验室的几项小型试点转化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-RA) 在治疗处方阿片类药物滥用的新适应症中的用途。要评估的总体假设是，5HT3-RA 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，​​并在与阿片类药物共同给药时防止身体依赖性的进展。我们建议测试 5HT3-RAs 的能力：(1) 减少阿片类药物戒断的表达；(2) 防止慢性疼痛患者对长期阿片类药物治疗的身体依赖性的进展。为了最大限度地降低与使用处方阿片类药物相关的风险，我们将仅招募已经长期接触阿片类药物的患者来治疗慢性背痛。此外，我们还实施了一项包含 16 项的全面患者安全行动计划，以最大限度地提高患者安全。我们将排除被确定成瘾风险较高或出现有问题的阿片类药物使用模式的患者。在研究期间，所有参与者都将受到 PI、研究护士和具有成瘾和疼痛医学双重资格的委员会认证医生的仔细监控。研究结束时，患者将在首席研究员和成瘾专家的日常监控下恢复原来的处方阿片类药物治疗方案。万一出现任何成瘾问题，首席研究员和成瘾专家将在研究结束后无条件提供服务。虽然使用阿片类止痛药存在固有风险，但我们通过限制仅那些通过正在进行的临床治疗已经承受这些风险的人参与来最大限度地减少这项研究的额外风险。他们将从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所接触的水平，这可能会将相关的阿片类药物风险降低到低于未参加研究但仍接触慢性阿片类药物的类似患者所经历的水平。