Medications Development for Drug Abuse Disorders

描述（由申请人提供）：该基金资助了人类实验室研究，检查曲马多的药理学特征，一种非典型阿片类镇痛药。结果显示曲马多产生精神活性作用，这些作用不同于安慰剂和原型μ激动剂阿片类药物，但在长期给药条件下，曲马多可产生阿片类药物身体依赖。这提供了证据基础，支持曲马多可能具有超出其作为非受控阿片类镇痛剂使用的治疗功效。具体而言，这些研究提供了支持这种药物用于治疗阿片类药物戒断的潜在效用的基础。重要的是要认识到，使用医学监督下的阿片类药物戒断（又名解毒）对许多阿片类药物依赖患者的有效性有限。特别是对于阿片类药物成瘾史较长的患者和身体依赖程度较高的患者，戒毒往往是一种短期干预措施，只会导致随后复吸。然而，有些人群可能更喜欢或需要解毒（例如，阿片类药物成瘾史相对较短的人、身体依赖性水平较低的患者、年轻患者和对阿片类药物具有早期身体依赖性的患者）。2000年的《药物成瘾治疗法》目前仅适用于丁丙诺啡的使用，没有具体提到丁丙诺啡-因此允许开发其他药物用于基于办公室的阿片类药物依赖治疗。这是一项研究曲马多作为短期阿片类药物戒断治疗药物的建议。将进行一项随机、双盲临床试验，比较曲马多缓释形式与可乐定和丁丙诺啡在阿片类药物戒断短期治疗中的疗效和安全性。阿片类药物依赖参与者将在住宅单元接受治疗。该项目有三个主要阶段：对吗啡的初始稳定（以建立共同的身体依赖水平，在此阶段进行纳洛酮挑战，将该挑战的结果用作一个分层变量）;三种药物之一的停药期;以及在住宿结束时过渡到双盲口服纳洛酮。以这种方式使用曲马多是新颖和创新的。此外，该研究包括参与者的CYP 2D 6基因分型，考虑到曲马多在2D 6时的代谢，该基因分型将用作分层变量。主要结果指标是研究第二阶段的阿片类药物戒断症状。 公共卫生相关性：阿片类药物依赖是美国的一个重要问题，特别是滥用和依赖处方阿片类药物。这是一项住院对照临床试验，将测试曲马多与可乐定和丁丙诺啡相比在阿片类药物戒断治疗中的疗效和安全性。

DESCRIPTION (provided by applicant): This grant has funded human laboratory studies examining the pharmacological characteristics of tramadol, an atypical opioid analgesic. Results show tramadol exerts psychoactive effects, these effects differ from both placebo and a prototypic mu agonist opioid, but under chronic dosing conditions tramadol can produce opioid physical dependence. This provides an evidence base supporting the idea that tramadol may have therapeutic efficacy beyond its use as a non-controlled opioid analgesic. Specifically, these studies provide a foundation supporting the potential utility of this medication for the treatment of opioid withdrawal. It is important to acknowledge that the use of medically supervised withdrawal from opioids (aka detoxification) has limited effectiveness for many patients with opioid dependence. Especially for patients with longer histories of opioid addiction and those with higher levels of physical dependence, detoxification is often a short-term intervention that simply leads to subsequent relapse to drug use. However, there are populations for which detoxification may be preferred or indicated (e.g., persons with relatively short histories of opioid addiction, patients with a lower level of physical dependence, younger patients, and those with early physical dependence on opioids). The Drug Addiction Treatment Act of 2000, which is currently limited in its application to the use of buprenorphine, does not specifically mention buprenorphine - thus allowing other medications to be developed for office based opioid dependence treatment. This is a proposal to study tramadol as an agent for short-term opioid withdrawal treatment. A randomized, double blind clinical trial comparing the efficacy and safety of the extended release form of tramadol to clonidine and buprenorphine in the short-term treatment of opioid withdrawal will be conducted. Opioid dependent participants will be treated on a residential unit. There are three primary phases to the project: an initial stabilization on morphine (to establish a common level of physical dependence, with a naloxone challenge during this phase with results from that challenge used as one stratification variable); a withdrawal period with one of the three medications; and, a transition to double-blind oral naltrexone at the end of the residential stay. The use of tramadol in this way is novel and innovative. In addition, the study includes CYP2D6 genotyping of participants, which will be used as a stratification variable given tramadol's metabolism by 2D6. The primary outcome measure is opioid withdrawal symptoms during the second phase of the study. PUBLIC HEALTH RELEVANCE: Opioid dependence is a significant problem in the United States, especially misuse and dependence upon prescription opioids. This is a residential controlled clinical trial that will test the efficacy and safety of tramadol compared to clonidine and buprenorphine in the treatment of opioid withdrawal.