Medications Development for Drug Abuse Disorders

描述(由申请人提供)：这笔赠款资助了人类实验室研究曲马多的药理特性，曲马多是一种非典型的阿片类止痛剂。结果表明，曲马多具有精神活性作用，这些作用不同于安慰剂和典型的MU激动剂阿片类药物，但在长期给药条件下，曲马多可以产生阿片类物质依赖。这为曲马多可能具有非受控阿片类止痛剂以外的治疗效果的想法提供了证据基础。具体地说，这些研究为这种药物治疗阿片类药物戒断的潜在效用提供了基础。重要的是要承认，使用医学监督下的阿片类药物戒断(又名脱毒)对许多阿片依赖患者的疗效有限。尤其是对于阿片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，只会导致随后的药物使用复发。然而，有些人群可能倾向于或指示戒毒(例如，阿片成瘾史相对较短的人、身体依赖程度较低的患者、较年轻的患者以及早期对阿片类药物有身体依赖的人)。2000年《药物成瘾治疗法》目前仅限于丁丙诺啡的使用，没有具体提到丁丙诺啡--因此允许开发其他药物用于办公室阿片依赖治疗。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，比较曲马多缓释剂与可乐定和丁丙诺啡在阿片类药物戒断短期治疗中的有效性和安全性。阿片依赖参与者将在住宿单元接受治疗。该项目有三个主要阶段：对吗啡的初步稳定(以建立普遍的身体依赖水平，在此阶段接受纳洛酮挑战，并将该挑战的结果作为一个分层变量)；戒断期间，服用三种药物中的一种；以及在住院结束时过渡到双盲口服纳曲酮。曲马多的这种使用方式是新颖和创新的。此外，这项研究包括参与者的CYP2D6基因分型，这将被用作一个分层变量，因为曲马多在2D6之前的新陈代谢。主要的结果衡量标准是第二阶段研究中的阿片类药物戒断症状。 公共卫生相关性：阿片类药物依赖在美国是一个严重的问题，特别是滥用和对处方阿片类药物的依赖。这是一项住宅对照临床试验，将测试曲马多与可乐定和丁丙诺啡治疗阿片类药物戒断的疗效和安全性。

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.