Medications Development for Drug Abuse Disorders

描述（由申请人提供）：该资助用于人类实验室研究曲马多的药理学特征，曲马多是一种非典型阿片类镇痛药。结果表明，曲马多具有精神活性作用，这种作用不同于安慰剂和原型mu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的身体依赖。这提供了一个证据基础，支持曲马多可能具有治疗效果，而不仅仅是作为一种非控制的阿片类镇痛药使用。具体来说，这些研究为支持这种药物治疗阿片类药物戒断的潜在效用提供了基础。必须承认，在医学监督下戒断阿片类药物（又称解毒）对许多阿片类药物依赖患者的效果有限。特别是对于阿片类药物成瘾历史较长的患者和身体依赖程度较高的患者，解毒通常是一种短期干预，只会导致随后的吸毒复发。然而，有些人群可能更倾向于或适合解毒（例如，阿片类药物成瘾史相对较短的人、身体依赖程度较低的患者、年轻患者和早期对阿片类药物有身体依赖的患者）。2000年的《药物成瘾治疗法案》目前仅限于丁丙诺啡的使用，没有特别提到丁丙诺啡，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阿片类药物短期戒断治疗的建议。将进行一项随机双盲临床试验，比较曲马多缓释形式与克拉定和丁丙诺啡短期治疗阿片类药物戒断的疗效和安全性。阿片类药物依赖的参与者将在住宅单位接受治疗。该项目有三个主要阶段：吗啡的初步稳定（建立一个共同的身体依赖水平，在此阶段进行纳洛酮挑战，并将该挑战的结果作为一个分层变量）；三种药物之一的停药期；在住院治疗结束时改用双盲口服纳曲酮。以这种方式使用曲马多是新颖和创新的。此外，该研究还包括参与者的CYP2D6基因分型，考虑到曲马多的2D6代谢，CYP2D6基因分型将作为分层变量。主要结局指标是研究第二阶段的阿片类药物戒断症状。

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.