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.

描述（由申请人提供）：在过去的20年中，阿片类药物处方已大大增加。1目前，阿片类药物是US2和Vicodin和Vicodin（氢可酮/乙酰氨基酚）中医生处方的最常见药物之一 - 2005年有1亿个处方药。单独 - 是任何类别中最常见的药物。3然而，物理依赖（PD），成瘾和戒断使使用处方阿片类药物的使用复杂化。在2006年的所有12岁及以上的美国人中，有13.6％（超过3300万）报告说，在非医学目的中使用处方阿片类药物至少一次使用了一次，上一年超过1200万，在上个月中使用了520万。4。 ，美国处方阿片类药物滥用的总成本估计为86亿美元。5为此，我们将使用“物理依赖”（PD）一词来指代由重复或连续的药物使用引起的生理状态这表现为停止使用时的戒断症状。6这不应与表征“阿片类药物依赖性”的DSM IV诊断的症状群混淆，此外，它的特征是强迫服用药物，失去对药物的控制，以及持续使用毒品造成的伤害。为了避免术语“物理依赖（PD）”和DSM IV定义的“物理依赖（PD）”和“阿片类药物依赖性”，我们将使用“成瘾”一词来指代由强迫毒品服用行为，全神贯注于强迫性药物的毒品使用的生物心理社会疾病和伤害。未建立PD在成瘾发展中的作用。目前没有药物可以防止身体依赖的发展，因此没有办法正式测试它可能在吸毒到成瘾的过程中可能会或可能不会发挥作用的作用。此外，PD患者在禁欲（阿片类药物戒断）中遇到的不舒服，有时长时间的身体不适，可能会减少接受基于禁欲的阿片类药物成瘾疗法。因此，需要有效的策略来治疗由PD患者禁欲产生的阿片类药物戒断（OW）的症状，并防止与处方阿片类药物的使用和滥用相关的身体依赖的发展。来自药物遗传学单倍型的最新证据，基于药物的计算映射，动物研究以及该研究者实验室的几项小型试点翻译研究表明5HT3受体在阿片类药物戒断和物理依赖性表达中的重要作用。拟议的研究将评估5HT3受体拮抗剂（5HT3-RAS）的使用，以治疗处方阿片类药物滥用的新适应症。要评估的总体假设是，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，​​并在与阿片类药物共同服用时防止身体依赖的进展。我们建议测试5HT3-RAS（1）降低阿片类药物戒断的表达的能力，以及（2）防止慢性疼痛患者对慢性阿片类药物治疗的身体依赖性的进展。为了最大程度地减少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暴露于阿片类药物以治疗慢性背痛的患者。此外，我们已经实施了一项全面的16项患者安全行动计划，以最大程度地提高患者安全。我们将排除被确定的患者成瘾或发展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PI，研究护士和经过董事会认证的医生仔细监测，并具有成瘾和止痛药的双重证书。在研究结束时，在首席研究员和成瘾专家的日常监测下，患者将返回其原始处方阿片类药物方案。在研究后，任何成瘾问题都会在研究后无条件地提供主要研究者和成瘾专家。尽管与使用阿片类止痛药有关的固有风险，但我们通过仅通过持续的临床治疗来限制那些已经采用这些风险的人来最大程度地限制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接触到的水平，这可能会将相关的阿片类药物风险降低到不参与类似患者的水平经验以下该研究但仍暴露于慢性阿片类药物。