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: 8240984
• 负责人: LAWRENCE F CHU
• 金额: $ 38.09万
• 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/8240984
• 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（申请人提供）：在过去的20年里，阿片类药物处方大幅增加。1目前，阿片类药物是美国医生处方的最常见药物之一2，（氢可酮/对乙酰氨基酚）-仅在2005年就有1亿张处方-是任何类别中最常见的处方药。3然而，身体依赖（PD），成瘾，和戒断使处方阿片类药物的使用复杂化。2006年，在所有12岁及以上的美国人中，报告至少有一次为非医疗目的使用过处方类阿片的人数超过3，300万，前一年超过1，200万，前一个月为520万。在美国，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）指的是重复或连续使用药物引起的生理状态，在停止使用时表现为戒断症状。DSM IV诊断为“阿片类药物依赖”，其特征还包括强迫服用药物，对药物失去控制以及持续使用药物造成的伤害。为了避免DSM IV定义的术语"身体依赖（PD）"和"阿片类药物依赖"之间的混淆，我们将使用术语"成瘾"来指代以强迫性吸毒行为、专注和伤害为特征的药物使用的生物心理社会疾病。PD在成瘾发展中的作用尚未确定。目前没有药物可以阻止身体依赖的发展，因此没有办法正式测试它在从药物使用到成瘾的发展中可能或可能不起作用。此外，PD患者在戒断（阿片类药物戒断）环境中经历的不适和有时延长的身体不适可能会降低阿片类药物成瘾的戒断治疗的接受程度。因此，需要有效的策略来治疗PD患者戒断引起的阿片类戒断（OW）症状，并预防与处方阿片类药物的使用和滥用相关的身体依赖性进展。最近的证据，从药物遗传学单倍型为基础的计算映射，动物研究，和几个小的试点翻译研究，从这个研究者的实验室点的阿片类药物戒断和身体依赖的表达中的重要作用的5HT 3受体。拟定的研究将评价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应用。待评价的总体假设是，5HT3-RA可以减少已经对阿片类药物产生身体依赖的人的阿片类戒断症状，并在与阿片类药物联合给药时预防身体依赖的进展。我们建议测试5HT3-RA的能力，以（1）减少阿片类药物戒断的表达和（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。为了最大限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安全。我们将排除确定为成瘾风险升高或出现阿片类药物使用模式问题的患者。在研究期间，所有参与者将由PI、研究护士和具有成瘾和疼痛医学双重认证的委员会认证医生仔细监测。在研究结束时，患者将在主要研究者和成瘾专家的每日监测下恢复其原始处方阿片类药物方案。在研究结束后，如果出现任何成瘾问题（不太可能），主要研究者和成瘾专家将无条件提供服务。虽然存在与使用阿片类止痛药相关的固有风险，但我们正在通过限制仅进入那些通过正在进行的临床治疗已经接受这些风险的人来最大限度地减少本研究的额外风险。他们将从研究中获得的额外筛选和监测水平将远远超过他们在正常临床实践中暴露的水平，这可能会将相关阿片类药物风险降低至低于未参加研究但仍暴露于慢性阿片类药物的类似患者的水平。