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，超过200万人在全国药物使用和健康调查的最后三年开始滥用这些药物。鉴于已知阿片类药物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），需要对这种疾病采取更有效的治疗方案。目前批准的阿片类药物依赖维持药物虽然有效，但由于患者接受度有限（纳曲酮），可用性有限（美沙酮）以及对转移的担忧（美沙酮和丁丙诺啡）而受到阻碍。曲马多是一种具有阿片激动剂活性的非典型镇痛药，不受《管制物质法案》的控制，相对于其他全mu阿片激动剂，曲马多的滥用潜力降低，可能是治疗阿片依赖的有效方法。这项为期两周的随机、安慰剂对照的住院患者研究分为两个阶段，每个阶段都有一个主要目标。第一阶段（第1-7天）将评估缓释曲马多治疗短效处方阿片类药物戒断的抑制戒断效果。第2期（第8-14天）将评估急性停止ER曲马多给药后停药的特征和严重程度，并将提供关于阿片类激动剂作用强度和曲马多产生的依赖性的进一步信息。年龄在18-55岁之间，阿片类药物尿液标本呈阳性，自我报告在过去30天中至少有21天使用短效阿片类药物，符合处方阿片类药物依赖的诊断标准（否则健康）的人将有资格进入住院研究单位。在第一次过夜后（以确保一段时间的阿片类药物戒断），显示可观察到的阿片类药物戒断迹象的参与者将被随机分配到三种双盲治疗中的一种：安慰剂或ER曲马多（每天400或800毫克，分两次给予匹配的胶囊）。分层将根据三个级别的客观阿片类戒断严重程度（低、中、高）进行，并由训练有素的工作人员在随机化之前立即进行评估。每个治疗组需要12名受试者完成（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。辅助药物可用于所有组治疗突破戒断。主要结局指标包括参与者评价的阿片类形容词问卷戒断量表和在研究的每个阶段用于突破性阿片类药物戒断的辅助药物的数量。将收集许多次要结果测量。本研究收集的数据将为ER曲马多剂量相关的戒断抑制功效提供新颖而重要的信息，并确定曲马多急性停药后是否会产生戒断综合征。这些结果将用于确定是否有必要对曲马多用于处方阿片类药物依赖进行更大规模的评估。

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.