Efficacy of Extended Release Tramadol for Treating Prescription Opioid Withdrawal

描述(由申请人提供)：2007年，美国约有170万人符合处方阿片类药物滥用或依赖的诊断标准，在全国药物使用与健康调查的最后三年，有200多万人开始滥用这些药物。鉴于已知阿片成瘾是慢性和复发性的，并导致个人和社会公共卫生问题(个人发病率和死亡率、传染病传播增加和犯罪)，需要针对这一疾病的更有效的治疗选择。目前批准的阿片依赖维持药物虽然有效，但由于患者接受度有限(纳曲酮)、可获得性有限(美沙酮)以及对转移的担忧(美沙酮和丁丙诺啡)而受到阻碍。曲马多是一种非典型的止痛药，具有阿片类激动剂活性，不受《受控物质法》的控制，与其他完全的MU阿片激动剂相比，它减少了滥用潜力，可能是治疗阿片类药物依赖的有效方法。这项为期两周的随机、安慰剂对照的住院研究分为两个阶段，每个阶段都有一个主要目标。第1阶段(第1-7天)将评估缓释(ER)曲马多治疗短效处方阿片类药物戒断的戒断抑制效果。第二阶段(第8-14天)将评估ER曲马多急性停止给药的特征和严重程度，并将提供有关曲马多产生的阿片激动剂效应和依赖潜力的进一步信息。18-55岁的人，观察到的阿片类药物尿样呈阳性，自我报告在过去30天中至少有21天使用短效阿片类药物，符合处方阿片依赖的诊断标准(否则是健康的)，将有资格住院进入住院研究单位。在第一次过夜(以确保一段时间的阿片类药物戒断)之后，表现出可观察到的阿片类药物戒断迹象的参与者将被随机分成三个双盲治疗之一：安慰剂或ER曲马多(每天400或800毫克，分两个剂量的匹配胶囊给予)。分层将根据客观阿片类药物戒断严重程度的三个水平(低、中、高)进行，这是由训练有素的工作人员在紧接随机化之前评估的。完成每个治疗臂需要12名受试者(n=36)。曲马多的剂量将在最初的24小时内逐步增加，以减少副作用的可能性。所有组均可使用辅助药物来治疗突破性戒断。主要结果指标包括参与者评定的阿片形容词问卷、戒断量表以及在研究的每个阶段为突破性阿片类药物戒断所使用的辅助药物的数量。将收集许多次要结果衡量标准。这项研究收集的数据将为曲马多剂量相关的戒断抑制效果提供新的和重要的信息，并确定曲马多在急性戒断后是否会产生戒断综合征。这些结果将被用来确定是否有理由对曲马多进行更大规模的处方阿片依赖评估。 公共卫生相关性：处方阿片成瘾是一个日益严重的公共卫生问题，需要更多的药物治疗，因为目前批准的药物患者接受度有限(纳曲酮)，可获得性有限(美沙酮)，以及对滥用和转移(美沙酮和丁丙诺啡)的担忧。曲马多是一种目前被批准用于治疗中重度疼痛的药物，初步研究表明，它可能有助于治疗阿片类药物戒断后的不适综合征，而不会产生愉悦效果。这项研究将确定两种不同剂量的缓释曲马多是否可以治疗阿片类药物戒断，以及曲马多本身在停止服用后是否会产生戒断。

DESCRIPTION (provided by applicant): Approximately 1.7 million people in the United States met diagnostic criteria for prescription opioid abuse or dependence in 2007 and more than 2 million people initiated misuse of these medications in the last three years of the National Survey of Drug Use and Health. Given that opioid addiction is known to be chronic and relapsing and cause individual and societal public health problems (individual morbidity and mortality, increased transmission of infectious diseases, and crime), more efficacious treatment options for this disorder are needed. Currently approved maintenance medications for opioid dependence, while efficacious, have been hampered by limited patient acceptance (naltrexone), limited availability (methadone), and concerns about diversion (methadone and buprenorphine). Tramadol, an atypical analgesic with opioid agonist activity that is uncontrolled by the Controlled Substances Act, has reduced abuse potential relative to other full mu- opioid agonists and may be an effective treatment for opioid dependence. This two-week randomized, placebo-controlled inpatient study has two phases, each with one primary aim. Phase 1 (Days 1-7) will evaluate the withdrawal suppression efficacy of extended release (ER) tramadol for treatment of short-acting prescription opioid withdrawal. Phase 2 (Days 8-14) will assess the characteristics and severity of withdrawal from acute cessation of ER tramadol dosing and will provide further information about the strength of opioid agonist effects and dependence potential produced by tramadol. Persons age 18-55 years old with a positive observed opioid urine specimen, self-report of use of a short-acting opioid at least 21 out of the last 30 days, meeting diagnostic criteria for prescription opioid dependence (otherwise healthy) will be eligible for inpatient admission to the residential research unit. After the first overnight stay (to ensure a period of opioid abstinence), participants showing observable signs of opioid withdrawal will be randomized to one of three double-blind treatments: placebo or ER tramadol (400 or 800 mg daily given as two divided doses of matched capsules). Stratification will occur based on three levels of objective opioid withdrawal severity (low, medium, and high) as assessed by trained staff immediately prior to randomization. Twelve subjects will be needed to complete each treatment arm (n=36). Tramadol doses will be escalated over the first 24 hours to decrease chance of side effects. Ancillary medications are available to all groups to treat breakthrough withdrawal. Primary outcome measures include the participant-rated Opioid Adjectives Questionnaire Withdrawal Scale and amount of ancillary medication used for breakthrough opioid withdrawal during each Phase of the study. Numerous secondary outcome measures will be collected. The data gathered from this study will provide novel and important information regarding the dose-related withdrawal suppression efficacy of ER tramadol and determine whether tramadol produces a withdrawal syndrome after acute cessation. These results will be used to determine if a larger-scale evaluation of tramadol for prescription opioid dependence is warranted. PUBLIC HEALTH RELEVANCE: Prescription opioid addiction is a growing public health problem and more pharmacologic treatments are needed because current approved medications have had limited patient acceptance (naltrexone), limited availability (methadone), and concerns about misuse and diversion (methadone and buprenorphine). Tramadol is a currently approved medication used to treat moderate-severe pain, and initial studies demonstrate that it may be useful for treatment of the uncomfortable syndrome of opioid withdrawal without producing euphoric effects. This study will determine whether two different doses of extended release tramadol can treat opioid withdrawal and whether tramadol itself produces withdrawal after it is no longer taken.